DRAFT Drugs for the Treatment and Prevention of Osteoporosis in Postmenopausal Women: a Technology Review

Home , Elcatonin, Menatetrenone, Minodronic acid, Risedronic acid

TECHNOLOGY REVIEW - DRAFT Drugs for the Treatment and Prevention of Osteoporosis in Postmenopausal Women: A Technology Review

PROSPERO Registration Number: CRD42019147448

Publication Date: March 4, 2020 Report Length: 311 pages

TABLE OF CONTENTS External Reviewers ...... Error! Bookmark not defined. Authorship ...... Error! Bookmark not defined. Clinical Review ...... Error! Bookmark not defined. Research Information Science ...... Error! Bookmark not defined. Acknowledgements / Contributors ...... Error! Bookmark not defined. Conflicts of Interest ...... Error! Bookmark not defined. Abbreviations ...... 16 Protocol Amendments ...... 17 EXECUTIVE SUMMARY ...... 18 CONTEXT, RATIONALE AND POLICY ISSUES ...... 23 Background / Setting in Canada ...... 23 POLICY QUESTIONS ...... 27 OBJECTIVE ...... 28 Research questions ...... 28 METHODS ...... 28 Literature Search ...... 28 Selection criteria ...... 29 Screening and Selection ...... 30 Data Extraction ...... 30 Consideration for Primary or Secondary Prevention of Fractures ...... 31 Quality Assessment of Individual Studies ...... 32 Data Analysis ...... 33 Methods for Network Meta-Analysis ...... 33 Methods for meta-analysis ...... 34 Base Case Analysis ...... 35 Subgroup Analysis ...... 35 Sensitivity Analysis ...... 35 Handling of zero events ...... 35 RESULTS: SYSTEMATIC REVIEW ...... 36 Quantity of Research Available ...... 36 Study Characteristics ...... 37 Participant Characteristics ...... 38 Primary prevention populations ...... 39 Secondary prevention populations ...... 39 Quality Assessment of Individual Studies ...... 39 Overview of Results for Primary and Secondary Prevention Populations ...... 41 RESULTS: PRIMARY PREVENTION POPULATIONS ...... 44 Summary of Analyses ...... 44 Radiographic Vertebral Fractures ...... 46 Base case ...... 46 Subgroup analyses ...... 47 Sensitivity analyses ...... 47 Clinical Vertebral Fractures ...... 47 Non-Vertebral Fractures ...... 48 Base case ...... 48 Subgroup analyses ...... 49 Sensitivity analyses ...... 50 Hip Fractures ...... 50 Base case ...... 50

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Subgroup analyses ...... 51 Sensitivity analyses ...... 52 Wrist Fractures ...... 53 Base case ...... 53 Subgroup analyses ...... 54 Sensitivity analyses ...... 55 Health related Quality of Life ...... 55 Withdrawal due to Adverse Events ...... 55 Base case ...... 55 Serious Adverse Events ...... 57 Base case ...... 57 Sensitivity analyses ...... 58 Gastrointestinal Adverse Events ...... 58 Base case ...... 59 Osteonecrosis of the Jaw ...... 59 Atypical Femoral Fracture ...... 60 Atrial Fibrillation ...... 61 RESULTS: SECONDARY PREVENTION POPULATIONS ...... 61 Summary of Analyses ...... 61 Radiographic Vertebral Fractures ...... 65 Base case ...... 65 Subgroup analyses ...... 67 Sensitivity analyses ...... 68 Clinical Vertebral Fractures ...... 68 Base case ...... 68 Subgroup analyses ...... 69 Sensitivity analyses ...... 70 Non-Vertebral Fractures ...... 71 Base case ...... 71 Subgroup analyses ...... 72 Sensitivity analyses ...... 73 Hip Fractures ...... 74 Base case ...... 74 Subgroup analyses ...... 76 Sensitivity analyses ...... 76 Wrist Fractures ...... 77 Base case ...... 77 Subgroup analyses ...... 78 Sensitivity analyses ...... 79 Health related Quality of Life (HRQoL) ...... 80 Withdrawal due to Adverse Events ...... 81 Base case ...... 81 Sensitivity analyses ...... 82 Serious Adverse Events ...... 83 Base case ...... 83 Gastrointestinal Adverse Events ...... 85 Base case ...... 85 Osteonecrosis of the Jaw ...... 86 Atypical Femoral Fracture ...... 86 Atrial Fibrillation ...... 87

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Base case ...... 87 RESULTS: POOLED PRIMARY AND SECONDARY PREVENTION POPULATIONS SENSITIVITY ANALYSIS ...... 88 DISCUSSION ...... 89 Comparisons of bisphosphonates to placebo ...... 89 Comparing bisphosphonates ...... 90 How do the bisphosphonates compare against denosumab for fracture prevention? ...... 90 Are zoledronic acid or denosumab effective alternatives in case of a contraindication to an oral bisphosphonate? ...... 91 Sensitivity with CAROC Fracture Risk ...... 91 Strengths and Limitations ...... 92 Conclusions and implications for policy-making ...... 94 REFERENCES ...... 95

APPENDIX 1: CANADIAN JURISDICTIONAL COVERAGE...... 114 APPENDIX 2: LITERATURE SEARCH STRATEGY ...... 115 APPENDIX 3: PEER REVIEW OF ELECTRONIC SEARCH STRATEGIES (PRESS) ...... 116 APPENDIX 4: APPROACHES TO HANDLING ZERO EVENTS ...... 121 Case 1: Multiple direct comparisons with 1 zero reported ...... 122 Case 2: Single direct comparisons with 1 zero reported ...... 123 Case 3: Direct comparisons with all zeros reported ...... 124 APPENDIX 5:STUDY SELECTION FLOW DIAGRAM ...... 125 APPENDIX 6: LIST OF INCLUDED STUDIES ...... 126 List of Included Studies (Primary publication), N=133 ...... 126 List of Included Studies (Companion publications), N=53 ...... 137 List of eligible studies not reporting data for outcome of interest, N=42 ...... 142 APPENDIX 7:EXCLUDED STUDY LIST (BY REASON FOR EXCLUSION) ...... 146 List of studies excluded: study design (not an RCT, N=115) ...... 146 List of studies excluded: population not of interest, N=28 (116-143) ...... 155 List of studies excluded: intervention/comparator not of interest, N=184 (144-327) ...... 158 List of studies excluded: treatment duration less than one year, N=105 (328-432) ...... 175 List of studies excluded: duplicate publications, N=4 (433-436) ...... 184 List of studies excluded: companion publications providing no further outcome data, N=220 (437- 656) ...... 185 APPENDIX 8: RISK OF BIAS ASSESSMENTS BY STUDY...... 206 APPENDIX 9: STUDY CHARACTERISTICS ...... 213 Primary ...... 213 Secondary ...... 218 APPENDIX 10: PARTICIPANT CHARACTERISTICS ...... 227 Primary ...... 227 Secondary ...... 234 APPENDIX 11: ANALYSIS RESULTS – BASE CASE, SUBGROUP AND SENSITIVITY ANALYSES FOR PRIMARY PREVENTION POPULATIONS...... 246 RADIOGRAPHIC VERTEBRAL FRACTURES...... 246 BASE CASE ANALYSIS ...... 246 SENSITIVITY ANALYSIS ...... 247 NON-VERTEBRAL FRACTURES ...... 248 BASE CASE ANALYSIS ...... 248 SUBGROUP ANALYSIS ...... 249 SENSITIVITY ANALYSIS ...... 255

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HIP FRACTURES ...... 258 BASE CASE ANALYSIS ...... 258 WRIST FRACTURES ...... 259 BASE CASE ANALYSIS ...... 259 SENSITIVITY ANALYSIS ...... 260 WITHDRAWAL DUE TO ADVERSE EVENTS ...... 261 BASE CASE ANALYSIS ...... 261 SERIOUS ADVERSE EVENTS ...... 263 BASE CASE ANALYSIS ...... 263 GASTROINTESTINAL ADVERSE EVENTS ...... 265 BASE CASE ANALYSIS ...... 265 APPENDIX 12: RESULTS – BASE CASE, SUBGROUP AND SENSITIVITY ANALYSES for SECONDARY Prevention populations ...... 266 RADIOGRAPHIC VERTEBRAL FRACTURES...... 266 BASE CASE ANALYSIS ...... 266 SUBGROUP ANALYSIS ...... 268 SENSITIVITY ANALYSIS ...... 274 CLINICAL VERTEBRAL FRACTURES ...... 275 BASE CASE ANALYSIS ...... 275 SUBGROUP ANALYSIS ...... 276 NON-VERTEBRAL FRACTURES ...... 279 BASE CASE ANALYSIS ...... 279 SUBGROUP ANALYSIS ...... 280 SENSITIVITY ANALYSIS ...... 286 HIP FRACTURES ...... 288 BASE CASE ANALYSIS ...... 288 SUBGROUP ANALYSIS ...... 289 SENSITIVITY ANALYSIS ...... 294 WRIST FRACTURES ...... 295 BASE CASE ANALYSIS ...... 295 SUBGROUP ANALYSIS ...... 296 HEALTH RELATED QUALITY OF LIFE ...... 299 BASE CASE ANALYSIS ...... 299 WITHDRAWAL DUE TO ADVERSE EVENTS ...... 300 BASE CASE ANALYSIS ...... 300 SERIOUS ADVERSE EVENTS ...... 302 BASE CASE ANALYSIS ...... 302 GASTROINTESTINAL ADVERSE EVENTS ...... 304 BASE CASE ANALYSIS ...... 304 ATRIAL FIBRILLATION ...... 306 BASE CASE ANALYSIS ...... 306 APPENDIX 13: INVESTIGATION OF NETWORK INCONSISTENCY ...... 307

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Tables

TABLE 1: ANTI-RESORPTIVE DRUGS DRUG PRODUCTS MARKETED IN CANADA ...... 25

TABLE 2: ELIGIBILITY CRITERIA FOR THE CLINICAL REVIEW ...... 29

TABLE 3: SUMMARY OF OUTCOMES AND ANALYSES ...... 42

TABLE 4: SUMMARY OF OUTCOMES REPORTED IN PRIMARY PREVENTION POPULATIONS ...... 44

TABLE 5: RADIOGRAPHIC VERTEBRAL FRACTURES, PRIMARY PREVENTION POPULATIONS, BASE CASE (RELATIVE RISK) ...... 46

TABLE 6: CLINICAL VERTEBRAL FRACTURES, PRIMARY PREVENTION POPULATIONS EXCLUDED FROM QUANTITATIVE SYNTHESIS ...... 47

TABLE 7: NON-VERTEBRAL FRACTURES, PRIMARY PREVENTION POPULATIONS, BASE CASE (RELATIVE RISK) ...... 48

TABLE 8: HIP FRACTURES, PRIMARY PREVENTION POPULATIONS EXCLUDED FROM QUANTITATIVE SYNTHESIS...... 51

TABLE 9: HIP FRACTURES, PRIMARY PREVENTION POPULATIONS EXCLUDED FROM QUANTITATIVE SYNTHESIS, BY TIME POINT ...... 51

TABLE 10: WRIST FRACTURE, PRIMARY PREVENTION POPULATIONS, BASE CASE (RELATIVE RISK) ...... 53

TABLE 11: WRIST FRACTURE, PRIMARY PREVENTION POPULATIONS EXCLUDED FROM QUANTITATIVE SYNTHESIS...... 53

TABLE 12: WITHDRAWAL DUE TO ADVERSE EVENTS, PRIMARY PREVENTION POPULATIONS, BASE CASE (RELATIVE RISK) ...... 56

TABLE 13: WITHDRAWAL DUE TO ADVERSE EVENTS, PRIMARY PREVENTION POPULATIONS EXCLUDED FROM QUANTITATIVE SYNTHESIS ...... 57

TABLE 14: SERIOUS ADVERSE EVENTS, PRIMARY PREVENTION POPULATIONS, BASE CASE (RELATIVE RISK) ...... 57

TABLE 15: GASTROINTESTINAL ADVERSE EVENTS, PRIMARY PREVENTION POPULATIONS, BASE CASE (RELATIVE RISK) ...... 59

TABLE 16: OSTEONECROSIS OF THE JAW, PRIMARY PREVENTION POPULATIONS EXCLUDED FROM QUANTITATIVE SYNTHESIS ...... 60

TABLE 17: ATYPICAL FEMORAL FRACTURE, PRIMARY PREVENTION POPULATIONS EXCLUDED FROM QUANTITATIVE SYNTHESIS ...... 60

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TABLE 18: ATRIAL FIBRILLATION, PRIMARY PREVENTION POPULATIONS EXCLUDED FROM QUANTITATIVE SYNTHESIS...... 61

TABLE 19: SUMMARY OF OUTCOMES REPORTED IN SECONDARY PREVENTION POPULATIONS ...... 62

TABLE 20: SUMMARY OF RESULTS FROM BASE CASE ANALYSES ...... 63

TABLE 21: RADIOGRAPHIC VERTEBRAL FRACTURES, SECONDARY PREVENTION POPULATIONS, BASE CASE (RELATIVE RISK) ...... 65

TABLE 22: CLINICAL VERTEBRAL FRACTURES, SECONDARY PREVENTION POPULATIONS, BASE CASE (RELATIVE RISK) ...... 68

TABLE 23: CLINICAL VERTEBRAL FRACTURES, SECONDARY PREVENTION POPULATIONS EXCLUDED FROM QUANTITATIVE SYNTHESIS ...... 69

TABLE 24: NON-VERTEBRAL FRACTURES, SECONDARY PREVENTION POPULATIONS, BASE CASE (RELATIVE RISK) ...... 71

TABLE 25: NON-VERTEBRAL FRACTURES, SECONDARY PREVENTION POPULATIONS EXCLUDED FROM QUANTITATIVE SYNTHESIS ...... 72

TABLE 26: HIP FRACTURES, SECONDARY PREVENTION POPULATIONS, BASE CASE (RELATIVE RISK) ...... 74

TABLE 27: HIP FRACTURES, SECONDARY PREVENTION POPULATIONS EXCLUDED FROM QUANTITATIVE SYNTHESIS...... 75

TABLE 28: WRIST FRACTURES, SECONDARY PREVENTION POPULATIONS, BASE CASE (RELATIVE RISK) ...... 77

TABLE 29: WRIST FRACTURES, SECONDARY PREVENTION POPULATIONS EXCLUDED FROM QUANTITATIVE SYNTHESIS...... 78

TABLE 30: HEALTH RELATED QUALITY OF LIFE, SECONDARY PREVENTION POPULATIONS, BASE CASE (RELATIVE RISK) ...... 80

TABLE 31: WITHDRAWAL DUE TO ADVERSE EVENTS, SECONDARY PREVENTION POPULATIONS, BASE CASE (RELATIVE RISK) ...... 81

TABLE 32: WITHDRAWAL DUE TO ADVERSE EVENTS, SECONDARY PREVENTION POPULATIONS EXCLUDED FROM QUANTITATIVE SYNTHESIS ...... 82

TABLE 33: SERIOUS ADVERSE EVENTS, SECONDARY PREVENTION POPULATIONS, BASE CASE (RELATIVE RISK) ...... 84

TABLE 34: SERIOUS ADVERSE EVENTS, SECONDARY PREVENTION POPULATIONS EXCLUDED FROM QUANTITATIVE SYNTHESIS ...... 84

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TABLE 35: GASTROINTESTINAL ADVERSE EVENTS, SECONDARY PREVENTION POPULATIONS, BASE CASE (RELATIVE RISK) ...... 85

TABLE 36: OSTEONECROSIS OF THE JAW, SECONDARY PREVENTION POPULATIONS EXCLUDED FROM QUANTITATIVE SYNTHESIS ...... 86

TABLE 37: ATYPICAL FEMORAL FRACTURE, SECONDARY PREVENTION POPULATIONS EXCLUDED FROM QUANTITATIVE SYNTHESIS ...... 86

TABLE 38: ATRIAL FIBRILLATION, SECONDARY PREVENTION POPULATIONS, BASE CASE (RELATIVE RISK) ...... 87

TABLE 39: ATRIAL FIBRILLATION, SECONDARY PREVENTION POPULATIONS EXCLUDED FROM QUANTITATIVE SYNTHESIS...... 88

TABLE 40. CORRESPONDING RELATIONSHIP OF CAROC FRACTURE RISK AND HIERARCHICAL CLASSIFICATION FOR PRIMARY AND SECONDARY PREVENTION TRIALS ...... 92

TABLE 41: JURISDICTIONAL COVERAGE OF DRUGS UNDER REVIEW ...... 114

TABLE 42 : RADIOGRAPHIC VERTEBRAL FRACTURES, PRIMARY PREVENTION, BASE CASE: ODDS RATIO, RELATIVE RISK, AND RISK DIFFERENCE ...... 246

TABLE 43: RADIOGRAPHIC VERTEBRAL FRACTURES, PRIMARY PREVENTION, SA2- EXCLUDING AGE-DEFINED STUDIES: ODDS RATIO, RELATIVE RISK, AND RISK DIFFERENCE ...... 247

TABLE 44: NON-VERTEBRAL FRACTURES, PRIMARY PREVENTION, BASE CASE: ODDS RATIO, RELATIVE RISK AND RISK DIFFERENCE ...... 248

TABLE 45: NON-VERTEBRAL FRACTURES, PRIMARY PREVENTION, SG1- DENOSUMAB COMPARED WITH BISPHOSPHONATES: ODDS RATIOS, RELATIVE RISKS AND RISK DIFFERENCE FOR ALL TREATMENT COMPARISONS-RANDOM EFFECTS MODEL ...... 249

TABLE 46: NON-VERTEBRAL FRACTURES, PRIMARY PREVENTION, SG2- 1YEAR: ODDS RATIOS, RELATIVE RISKS AND RISK DIFFERENCE FOR ALL TREATMENT COMPARISONS-RANDOM EFFECTS MODEL ...... 251

TABLE 47: NON-VERTEBRAL FRACTURES, PRIMARY PREVENTION, SG2- 2 YEARS: ODDS RATIOS, RELATIVE RISKS AND RISK DIFFERENCE FOR ALL TREATMENT COMPARISONS- RANDOM EFFECTS MODEL ...... 252

TABLE 48: NON-VERTEBRAL FRACTURES, PRIMARY PREVENTION, SG2- 3 YEARS: ODDS RATIOS, RELATIVE RISKS AND RISK DIFFERENCE FOR ALL TREATMENT COMPARISONS- RANDOM EFFECTS MODEL ...... 253

TABLE 49: NON-VERTEBRAL FRACTURES, PRIMARY PREVENTION, SG3- BISPHOSPHONATE- NAÏVE: ODDS RATIOS, RELATIVE RISKS AND RISK DIFFERENCE FOR ALL TREATMENT COMPARISONS-RANDOM EFFECTS MODEL ...... 254

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TABLE 50: NON-VERTEBRAL FRACTURES, PRIMARY PREVENTION, SA1- STUDIES WITH HIGH METHODOLOGICAL QUALITY: ODDS RATIOS, RELATIVE RISKS AND RISK DIFFERENCE FOR ALL TREATMENT COMPARISONS-RANDOM EFFECTS MODEL ...... 255

TABLE 51: NON-VERTEBRAL FRACTURES, PRIMARY PREVENTION SA2- EXCLUDING AGE- DEFINED STUDIES: ODDS RATIOS, RELATIVE RISKS AND RISK DIFFERENCE FOR ALL TREATMENT COMPARISONS-RANDOM EFFECTS MODEL ...... 256

TABLE 52: WRIST FRACTURE, PRIMARY PREVENTION, BASE CASE: ODDS RATIO, RELATIVE RISK AND RISK DIFFERENCE ...... 259

TABLE 53: WRIST FRACTURES, PRIMARY PREVENTION, SA2- EXCLUDING AGE-DEFINED STUDIES: ODDS RATIOS, RELATIVE RISKS AND RISK DIFFERENCE FOR ALL TREATMENT COMPARISONS-RANDOM EFFECTS MODEL ...... 260

TABLE 54: WITHDRAWAL DUE TO ADVERSE EVENTS, PRIMARY PREVENTION (BASE CASE): ODDS RATIO, RELATIVE RISK AND RISK DIFFERENCE ...... 261

TABLE 55: SERIOUS ADVERSE EVENTS, PRIMARY PREVENTION, BASE CASE: ODDS RATIO, RELATIVE RISK AND RISK DIFFERENCE ...... 263

TABLE 56: GASTROINTESTINAL ADVERSE EVENTS, PRIMARY PREVENTION, BASE CASE: ODDS RATIO, RELATIVE RISK AND RISK DIFFERENCE ...... 265

TABLE 57: RADIOGRAPHIC VERTEBRAL FRACTURES, SECONDARY PREVENTION, BASE CASE: ODDS RATIO, RELATIVE RISK, AND RISK DIFFERENCE ...... 266

TABLE 58: RADIOGRAPHIC VERTEBRAL FRACTURES, SECONDARY PREVENTION, SG1- DENOSUMAB COMPARED WITH BISPHOSPHONATES: ODDS RATIOS, RELATIVE RISKS AND RISK DIFFERENCE FOR ALL TREATMENT COMPARISONS-RANDOM EFFECTS MODEL ...... 268

TABLE 59: RADIOGRAPHIC VERTEBRAL FRACTURES, SECONDARY PREVENTION, SG2- 1 YEAR: ODDS RATIO, RELATIVE RISK, AND RISK DIFFERENCE ...... 270

TABLE 60: RADIOGRAPHIC VERTEBRAL FRACTURES, SECONDARY PREVENTION, SG2- 2 YEARS: ODDS RATIO, RELATIVE RISK, AND RISK DIFFERENCE ...... 271

TABLE 61: RADIOGRAPHIC VERTEBRAL FRACTURES, SECONDARY PREVENTION, SG2- 3 YEARS: ODDS RATIO, RELATIVE RISK, AND RISK DIFFERENCE ...... 272

TABLE 62: RADIOGRAPHIC VERTEBRAL FRACTURES, SECONDARY PREVENTION, SG3- BISPHOSPHONATE-NAÏVE: ODDS RATIO, RELATIVE RISK, AND RISK DIFFERENCE ...... 273

TABLE 63: RADIOGRAPHIC VERTEBRAL FRACTURES, SA3 CAROC- MODERATE 10-YEAR FRACTURE RISK: ODDS RATIO, RELATIVE RISK, AND RISK DIFFERENCE ...... 274

TABLE 64: CLINICAL VERTEBRAL FRACTURES, SECONDARY PREVENTION, BASE CASE: ODDS RATIO, RELATIVE RISK, AND RISK DIFFERENCE ...... 275

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TABLE 65: CLINICAL VERTEBRAL FRACTURES, SECONDARY PREVENTION, SG1- DENOSUMAB COMPARED WITH BISPHOSPHONATES: ODDS RATIO, RELATIVE RISK, AND RISK DIFFERENCE ...... 276

TABLE 66: CLINICAL VERTEBRAL FRACTURES, SG2- 3 YEARS: ODDS RATIO, RELATIVE RISK, AND RISK DIFFERENCE ...... 277

TABLE 67: NON-VERTEBRAL FRACTURES, SECONDARY PREVENTION, BASE CASE: ODDS RATIO, RELATIVE RISK AND RISK DIFFERENCE ...... 279

TABLE 68: NON-VERTEBRAL FRACTURES, SECONDARY PREVENTION, SG1- DENOSUMAB COMPARED WITH BISPHOSPHONATES: ODDS RATIOS, RELATIVE RISKS AND RISK DIFFERENCE FOR ALL TREATMENT COMPARISONS-RANDOM EFFECTS MODEL ...... 280

TABLE 69: NON-VERTEBRAL FRACTURES, SECONDARY PREVENTION, SG2- 1 YEAR: ODDS RATIOS, RELATIVE RISKS AND RISK DIFFERENCE FOR ALL TREATMENT COMPARISONS- RANDOM EFFECTS MODEL ...... 282

TABLE 70: NON-VERTEBRAL FRACTURES, SECONDARY PREVENTION, SG2- 2 YEARS: ODDS RATIOS, RELATIVE RISKS AND RISK DIFFERENCE FOR ALL TREATMENT COMPARISONS- RANDOM EFFECTS MODEL ...... 283

TABLE 71: NON-VERTEBRAL FRACTURES, SECONDARY PREVENTION, SG2- 3 YEARS: ODDS RATIOS, RELATIVE RISKS AND RISK DIFFERENCE FOR ALL TREATMENT COMPARISONS- RANDOM EFFECTS MODEL ...... 284

TABLE 72: NON-VERTEBRAL FRACTURES, SECONDARY PREVENTION, SG3- BISPHOSPHONATE- NAÏVE: ODDS RATIOS, RELATIVE RISKS AND RISK DIFFERENCE FOR ALL TREATMENT COMPARISONS-RANDOM EFFECTS MODEL ...... 285

TABLE 73: NON-VERTEBRAL FRACTURES, SECONDARY PREVENTION, SA3 CAROC- LOW 10- YEAR FRACTURE: ODDS RATIOS, RELATIVE RISKS AND RISK DIFFERENCE FOR ALL TREATMENT COMPARISONS-RANDOM EFFECTS MODEL ...... 286

TABLE 74: NON-VERTEBRAL FRACTURES, SECONDARY PREVENTION, SA3 CAROC- MODERATE 10-YEAR FRACTURE: ODDS RATIOS, RELATIVE RISKS AND RISK DIFFERENCE FOR ALL TREATMENT COMPARISONS-RANDOM EFFECTS MODEL ...... 287

TABLE 75: HIP FRACTURE, SECONDARY PREVENTION, BASE CASE: ODDS RATIO, RELATIVE RISK AND RISK DIFFERENCE ...... 288

TABLE 76: HIP FRACTURES, SECONDARY PREVENTION, SG1-DENOSUMAB COMPARED WITH BISPHOSPHONATES: ODDS RATIOS, RELATIVE RISKS AND RISK DIFFERENCE FOR ALL TREATMENT COMPARISONS-RANDOM EFFECTS MODEL ...... 289

TABLE 77: HIP FRACTURES, SECONDARY PREVENTION, SG2- 2 YEARS: ODDS RATIOS, RELATIVE RISKS AND RISK DIFFERENCE FOR ALL TREATMENT COMPARISONS-RANDOM EFFECTS MODEL ...... 291

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TABLE 78: HIP FRACTURES, SECONDARY PREVENTION, SG2- 3YEARS: ODDS RATIOS, RELATIVE RISKS AND RISK DIFFERENCE FOR ALL TREATMENT COMPARISONS-RANDOM EFFECTS MODEL ...... 292

TABLE 79: HIP FRACTURES, SECONDARY PREVENTION, SA2- EXCLUDING AGE-DEFINED STUDIES: ODDS RATIOS, RELATIVE RISKS AND RISK DIFFERENCE FOR ALL TREATMENT COMPARISONS-RANDOM EFFECTS MODEL ...... 294

TABLE 80: WRIST FRACTURE, SECONDARY PREVENTION, BASE CASE: ODDS RATIO, RELATIVE RISK AND RISK DIFFERENCE ...... 295

TABLE 81: WRIST FRACTURES, SECONDARY PREVENTION, SG1-DENOSUMAB COMPARED WITH BISPHOSPHONATES: ODDS RATIOS, RELATIVE RISKS AND RISK DIFFERENCE FOR ALL TREATMENT COMPARISONS-RANDOM EFFECTS MODE ...... 296

TABLE 82: WRIST FRACTURES, SECONDARY PREVENTION, SG2- 3 YEARS: ODDS RATIOS, RELATIVE RISKS AND RISK DIFFERENCE FOR ALL TREATMENT COMPARISONS-RANDOM EFFECTS MODE ...... 297

TABLE 83: HEALTH RELATED QUALITY OF LIFE, BASE CASE: STANDARDIZED MEAN DIFFERENCE (SMD) FOR ALL TREATMENT COMPARISONS ...... 299

TABLE 84: WITHDRAWAL DUE TO ADVERSE EVENTS, SECONDARY PREVENTION, BASE CASE: ODDS RATIO, RELATIVE RISK AND RISK ...... 300

TABLE 85: SERIOUS ADVERSE EVENTS, SECONDARY PREVENTION, BASE CASE: ODDS RATIO, RELATIVE RISK AND RISK DIFFERENCE ...... 302

TABLE 86: GASTROINTESTINAL ADVERSE EVENTS, SECONDARY PREVENTION, BASE CASE: ODDS RATIO, RELATIVE RISK AND RISK DIFFERENCE ...... 304

TABLE 87: ATRIAL FIBRILLATION, SECONDARY PREVENTION (BASE CASE): ODDS RATIO, RELATIVE RISK AND RISK DIFFERENCE ...... 306

TABLE 88: COMPARISON OF BASE CASE NMA AND BASE CASE NMA EXCLUDING QUESTIONABLE STUDY, WITHDRAWAL DUE TO ADVERSE EVENTS, SECONDARY PREVENTION ...... 307

TABLE 89: COMPARISON OF BASE CASE NMA AND BASE CASE NMA EXCLUDING QUESTIONABLE STUDY, SERIOUS ADVERSE EVENTS, PRIMARY PREVENTION ...... 308

Figures

FIGURE 1: HIERARCHICAL CLASSIFICATION FOR PRIMARY AND SECONDARY PREVENTION TRIALS ...... 32

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FIGURE 2: SUMMARY OF RISK OF BIAS ASSESSMENT RESULTS ...... 40

FIGURE 3: RADIOGRAPHIC VERTEBRAL FRACTURES, PRIMARY PREVENTION, BASE CASE .... 246

FIGURE 4: NETWORK GEOMETRY: RADIOGRAPHIC VERTEBRAL FRACTURES, PRIMARY PREVENTION, SA2- EXCLUDING AGE-DEFINED STUDIES ...... 247

FIGURE 5: NETWORK GEOMETRY: NON-VERTEBRAL FRACTURES, PRIMARY PREVENTION, BASE CASE ...... 248

FIGURE 6: NETWORK GEOMETRY: NON-VERTEBRAL FRACTURES, PRIMARY PREVENTION, SG1- DENOSUMAB COMPARED WITH BISPHOSPHONATES ...... 249

FIGURE 7: NETWORK GEOMETRY: NON-VERTEBRAL FRACTURES, PRIMARY PREVENTION, SG2- 1 YEAR ...... 251

FIGURE 8: NETWORK GEOMETRY: NON-VERTEBRAL FRACTURES, PRIMARY PREVENTION, SG2- 2 YEARS ...... 252

FIGURE 9: NETWORK GEOMETRY: NON-VERTEBRAL FRACTURES, PRIMARY PREVENTION, SG2- 3 YEARS ...... 253

FIGURE 10: NETWORK GEOMETRY: NON-VERTEBRAL FRACTURES, PRIMARY PREVENTION, SG3- BISPHOSPHONATE-NAÏVE ...... 254

FIGURE 11: NETWORK GEOMETRY: NON-VERTEBRAL FRACTURES, PRIMARY PREVENTION, SA1- STUDIES WITH HIGH METHODOLOGICAL QUALITY ...... 255

FIGURE 12: NETWORK GEOMETRY: NON-VERTEBRAL FRACTURES, PRIMARY PREVENTION, SA2- EXCLUDING AGE-DEFINED STUDIES ...... 256

FIGURE 13: HIP FRACTURES, PRIMARY PREVENTION, BASE CASE ...... 258

FIGURE 14: NETWORK GEOMETRY: WRIST FRACTURE, PRIMARY PREVENTION, BASE CASE . 259

FIGURE 15: NETWORK GEOMETRY: WRIST FRACTURES, PRIMARY PREVENTION, SA2- EXCLUDING AGE-DEFINED STUDIES ...... 260

FIGURE 16: NETWORK GEOMETRY: WITHDRAWAL DUE TO ADVERSE EVENTS, PRIMARY PREVENTION, BASE CASE ...... 261

FIGURE 17: NETWORK GEOMETRY: SERIOUS ADVERSE EVENTS, PRIMARY PREVENTION, BASE CASE ...... 263

FIGURE 18: NETWORK GEOMETRY: GASTROINTESTINAL ADVERSE EVENTS, PRIMARY PREVENTION, BASE CASE ...... 265

FIGURE 19: NETWORK GEOMETRY: RADIOGRAPHIC VERTEBRAL FRACTURES, SECONDARY PREVENTION, BASE CASE ...... 266

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FIGURE 20: NETWORK GEOMETRY: RADIOGRAPHIC VERTEBRAL FRACTURES, SECONDARY PREVENTION, SG1-DENOSUMAB COMPARED WITH BISPHOSPHONATES ...... 268

FIGURE 21: NETWORK GEOMETRY: RADIOGRAPHIC VERTEBRAL FRACTURES, SECONDARY PREVENTION, SG2-1 YEAR...... 270

FIGURE 22: NETWORK GEOMETRY: RADIOGRAPHIC VERTEBRAL FRACTURES, SECONDARY PREVENTION, SG2-2 YEARS ...... 271

FIGURE 23: NETWORK GEOMETRY: RADIOGRAPHIC VERTEBRAL FRACTURES, SECONDARY PREVENTION, SG2-3 YEARS ...... 272

FIGURE 24: NETWORK GEOMETRY: RADIOGRAPHIC VERTEBRAL FRACTURES, SECONDARY PREVENTION, SG3- BISPHOSPHONATE-NAÏVE ...... 273

SA3-STUDIES RE-DEFINED USING CAROC CALCULATOR, MODERATE LEVEL OF 10-YEAR FRACTURE RISK FIGURE 25: NETWORK GEOMETRY: RADIOGRAPHIC VERTEBRAL FRACTURES, SA3 CAROC- MODERATE 10-YEAR FRACTURE RISK ...... 274

FIGURE 26: NETWORK GEOMETRY: CLINICAL VERTEBRAL FRACTURES, SECONDARY PREVENTION, BASE CASE ...... 275

FIGURE 27: NETWORK GEOMETRY: CLINICAL VERTEBRAL FRACTURES, SECONDARY PREVENTION, SG1- DENOSUMAB COMPARED WITH BISPHOSPHONATES ...... 276

FIGURE 28: NETWORK GEOMETRY: CLINICAL VERTEBRAL FRACTURES, SECONDARY PREVENTION, SG2- 3 YEARS ...... 277

FIGURE 29: CLINICAL VERTEBRAL FRACTURES, SECONDARY PREVENTION, SG3- BISPHOSPHONATE-NAÏVE ...... 278

FIGURE 30: NETWORK GEOMETRY: NON-VERTEBRAL FRACTURES, SECONDARY PREVENTION, BASE CASE ...... 279

FIGURE 31: NETWORK GEOMETRY: NON-VERTEBRAL FRACTURES, SECONDARY PREVENTION, SG1- DENOSUMAB COMPARED WITH BISPHOSPHONATES ...... 280

FIGURE 32: NETWORK GEOMETRY: NON-VERTEBRAL FRACTURES, PRIMARY PREVENTION, SG2- 1 YEAR ...... 282

FIGURE 33: NETWORK GEOMETRY: NON-VERTEBRAL FRACTURES, PRIMARY PREVENTION, SG2- 2 YEAR ...... 283

FIGURE 34: NETWORK GEOMETRY: NON-VERTEBRAL FRACTURES, PRIMARY PREVENTION, SG2- 3 YEAR ...... 284

FIGURE 35: NETWORK GEOMETRY: NON-VERTEBRAL FRACTURES, PRIMARY PREVENTION, SG3- BISPHOSPHONATE-NAÏVE ...... 285

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FIGURE 36: NETWORK GEOMETRY: NON-VERTEBRAL FRACTURES, SA3 CAROC-LOW 10-YEAR FRACTURE RISK ...... 286

FIGURE 37: NETWORK GEOMETRY: NON-VERTEBRAL FRACTURES, SA3 CAROC-MODERATE 10- YEAR FRACTURE RISK ...... 287

FIGURE 38: NETWORK GEOMETRY: HIP FRACTURE, SECONDARY PREVENTION, BASE CASE. 288

FIGURE 39 NETWORK GEOMETRY: HIP FRACTURES, SECONDARY PREVENTION, SG1- DENOSUMAB COMPARED WITH BISPHOSPHONATES ...... 289

SG2- TREATMENT DURATIONS, 2 YEARS FIGURE 40: NETWORK GEOMETRY: HIP FRACTURES, SECONDARY PREVENTION, SG2- 2 YEARS ...... 291

FIGURE 41 NETWORK GEOMETRY: HIP FRACTURES, SECONDARY PREVENTION, SG2- 3 YEARS ...... 292

SG3- PRIOR BISPHOSPHONATE EXPERIENCE, BISPHOSPHONATE-NAÏVE FIGURE 42: HIP FRACTURES, SECONDARY PREVENTION, SG3- BISPHOSPHONATE-NAÏVE ...... 293

SA2- EXCLUDING AGE-DEFINED STUDIES FIGURE 43: NETWORK GEOMETRY: HIP FRACTURES, SECONDARY PREVENTION, SA2- EXCLUDING AGE-DEFINED STUDIES ...... 294

FIGURE 44: NETWORK GEOMETRY: WRIST FRACTURES, SECONDARY PREVENTION, BASE CASE ...... 295

SG1-DENOSUMAB COMPARED WITH BISPHOSPHONATES FIGURE 45: NETWORK GEOMETRY: WRIST FRACTURES, SECONDARY PREVENTION, SG1-DENOSUMAB COMPARED WITH BISPHOSPHONATES ...... 296

FIGURE 46: NETWORK GEOMETRY: WRIST FRACTURES, SECONDARY PREVENTION, SG2- 3 YEARS ...... 297

SG3- PRIOR BISPHOSPHONATE EXPERIENCE, BISPHOSPHONATE-NAÏVE FIGURE 47: WRIST FRACTURES, SECONDARY PREVENTION, SG3- BISPHOSPHONATE-NAÏVE ...... 298

FIGURE 48: NETWORK GEOMETRY: HEALTH RELATED QUALITY OF LIFE, SECONDARY PREVENTION, BASE CASE ...... 299

FIGURE 49: NETWORK GEOMETRY: WITHDRAWAL DUE TO ADVERSE EVENTS, SECONDARY PREVENTION, BASE CASE ...... 300

FIGURE 50: NETWORK GEOMETRY: SERIOUS ADVERSE EVENTS, SECONDARY PREVENTION, BASE CASE ...... 302

FIGURE 51: NETWORK GEOMETRY: GASTROINTESTINAL ADVERSE EVENTS, SECONDARY PREVENTION, BASE CASE ...... 304

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FIGURE 52: NETWORK GEOMETRY: ATRIAL FIBRILLATION, SECONDARY PREVENTION, BASE CASE ...... 306

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ABBREVIATIONS

BMD bone mineral density

CAROC Canadian Association of Radiologists and Osteoporosis Canada Fracture Risk Assessment Tool

DXA dual-energy x-ray absorptiometry

FDA Food and Drug Administration

FRAX Fracture Risk Assessment Tool

HRQOL health related quality of life

NMA network meta-analysis

PBM peak bone mass

PRESS Peer Review of Electronic Search Strategies

PRISMA Preferred Reporting Items for Systematic Reviews and Meta-Analyses

RCT randomized controlled trial

ROB risk of bias

SD standard deviation

WHO World Health Organization

US Unites States of America

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PROTOCOL AMENDMENTS

Additional sensitivity analyses were conducted pooling both primary and secondary prevention populations of postmenopausal women for a subset of fracture efficacy outcomes and harms. These analyses are not reported in the original study protocol.

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EXECUTIVE SUMMARY

Context and Policy Issues

Osteoporosis is a loss of bone density often associated with aging that can cause painful fractures, disability and deformity. Osteoporotic fractures are known to lead to significant morbidity and mortality, especially for postmenopausal women who have decreased production of estrogen. In Canada, bisphosphonates, including alendronate and risedronate are recommended as first-line treatments for osteoporosis in post-menopausal women for prevention of hip, non-vertebral, and vertebral fractures. They may also be used to prevent osteoporosis.

As evidence has developed, and there are newer drug options available and there is uncertainty about which bisphosphonate drug offers optimal treatment or prevention in women with varying risk levels for fracture. Possible higher risk of rare or unusual treatment effects such as jaw bone loss or thigh bone fractures associated with taking bisphosphonate drugs have been investigated in regulatory safety reviews in Canada although the benefits of bisphosphonates are considered to outweigh the risks. A comprehensive assessment and comparison of the benefits and harms for all available bisphosphonate drugs in Canada is needed to provide decision- and policy-makers with a robust overview of the available evidence.

Policy Questions

1. Within the bisphosphonates, which is the best pharmacologic treatment option?

2. How do the bisphosphonates compare against denosumab in fracture prevention?

3. Are zoledronic acid or denosumab effective alternatives in case of a contraindication to an oral bisphosphonate?

Objectives and Research Questions

The aim of this Technology Review report is to inform the policy questions by addressing the benefits and harms of the bisphosphonate drugs for the treatment or prevention of osteoporosis in postmenopausal women. The focus will be drugs available in Canada. Other comparators may include interventions used in international clinical practice for the treatment or prevention of osteoporosis.

The project will address the following research questions.

1. What are the comparative benefits and harms of bisphosphonate drugs and denosumab in the primary prevention of fractures in postmenopausal women?

2. What are the comparative benefits and harms of bisphosphonate drugs and denosumab in the secondary prevention of fractures in postmenopausal women?

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Because of the complexity of the clinical care for postmenopausal women and the diversity in osteoporosis trials, we extracted and synthesize evidence for women for different treatment purposes.

Secondary prevention populations include women at higher risk of fracture (e.g., diagnosed with osteoporosis, with low bone mineral density, prior fracture or older age) for which pharmacotherapy is recommended.

Primary prevention populations include women at lower risk of fracture (e.g., osteopenic bone mineral density, no prior fracture or younger age) who qualify for pharmacotherapy.

Included studies were categorized as primary or secondary prevention populations using a hierarchical classification scheme developed for this project in consultation with clinical experts. Application of the classification tool was carried out using study-reported eligibility criteria and participant characteristics. Where the reported information was insufficient to fully apply the classification scheme, included studies were excluded from analyses and narratively described.

Methods

We performed a systematic review and a network meta-analysis to synthesize available randomized controlled trials (RCTs) of oral and intravenous bisphosphonate drugs available in Canada and denosumab. A peer-reviewed literature search was performed on June 05, 2019 in MEDLINE, Embase, the Cochrane CENTRAL, and PubMed. Grey literature searches included regulatory documents from Canada, the United States and Europe, records of clinical trials from registry databases, and we reviewed the reference lists of relevant systematic reviews published since 2009. Two reviewers independently screened reference records, selected included studies, performed data extraction and completed a Cochrane Risk of Bias assessment.

The primary efficacy outcome is radiographic vertebral fractures. Other fracture efficacy outcomes, health related quality of life, and harms were considered secondary outcomes. Network meta- analyses were conducted when appropriate and if data were sufficient, otherwise, we synthesized data using meta-analysis or descriptive text. Synthesized results are presented for primary and secondary prevention populations of post-menopausal women separately. We conducted subgroup analyses by outcome for studies reporting bisphosphonate experienced and naïve women, women with contraindications to oral bisphosphonates, and for duration of treatment by year. Additional analyses compared bisphosphonate drugs to denosumab for select efficacy outcomes. Sensitivity analyses were conducted to examine the robustness of results with primary and secondary prevention populations combined, studies assessed to be of high methodological quality, and changes to hierarchical classification approach (removal of age-classified studies, comparison to classification by CAROC fracture risk).

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Key Findings

This review included 133 unique RCTs, among which 48 RCTs were conducted in primary prevention popultaions of post-menopausal women, and 85 RCTs conducted in secondary prevention populations classified as having a higher risk of fracture. For both primary and secondary prevention studies, a large proportion of RCTs reported zero events in one or all study arms for the outcomes of interest which required additional analysis approaches to be used and/or limited the statistical pooling of study results.

In primary prevention populations of post-menopausal women with a lower risk of fracture taking a bisphosphonate drug:

• data were available for four bisphosphonates: alendronate, risedronate, etidronate and zoledronic acid;

• there were no differences in radiographic vertebral fractures with alendronate (10 mg/day) and risedronate when compared with placebo or each other;

• there were no differences in non-vertebral or wrist fractures with alendronate (5 or 10 mg/day), risedronate, etidronate and zoledronic acid when compared with placebo or each other;

• there were no differences in hip fractures with alendronate when compared with placebo;

• there was no difference in withdrawals due to adverse events or serious adverse events with alendronate, risedronate, etidronate and zoledronic acid when compared with placebo or each other;

• there was no difference in gastrointestinal adverse events with alendronate (5 or 10 mg/day) and risedronate when compared with placebo or each other; and,

• health related quality of life was assessed in a single RCT which reported only domain- specific improvements with alendronate when compared with placebo. No overall differences in health-related quality of life were reported in the study.

No atrial fibrillation, osteonecrosis of the jaw, or atypical femoral fracture events were observed in any of the included studies reporting these outcomes. The RCTs included were not designed in size or duration to study these rare or unusual outcomes, and as such, no conclusions can be made in this review regarding increased risk of these outcomes in primary prevention populations of postmenopausal women.

In secondary prevention populations of post-menopausal women with a higher risk of fracture taking a bisphosphonate:

• data were available for four bisphosphonates: alendronate, risedronate, etidronate and zoledronic acid;

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• In the analyses conducted, we found:

o fewer radiographic vertebral fractures with alendronate (5 and 10 mg/day), risedronate and zoledronic acid (5mg/year), but not etidronate, when compared with placebo;

o fewer radiographic vertebral fractures with zoledronic acid when compared with risedronate;

o fewer radiographic vertebral fractures with denosumab in subgroup analyses when compared with both alendronate (5 mg/day) and risedronate (5 mg/day);

o fewer clinical vertebral and hip fractures with alendronate (10 mg/day) and zoledronic acid (5mg/year) when compared with placebo;

o fewer non-vertebral fractures with risedronate when compared with placebo;

o fewer withdrawals due to adverse events with zoledronic acid when compared with alendronate (10 mg/day);

o fewer gastrointestinal adverse events when zoledronic acid was compared with placebo, alendronate (10 mg/day) and risedronate;

o no differences in serious adverse events with alendronate (5 or 10 mg/day), risedronate, or zoledronic acid when compared with placebo or each other;

o no differences in health-related quality of life with alendronate (10 mg/day) and yearly zoledronic acid when compared with placebo or each other. Few studies reported this outcome.

In secondary prevention populations of post-menopausal women, there was insufficient data to detect meaningful differences between treatments for rare or unusual outcomes, including osteonecrosis of the jaw, atypical femoral fractures, and atrial fibrillation, and for many subgroups of interest. Results should be interpreted with caution given the paucity of reported outcome data for some outcomes and subgroups of interest. The RCTs included were not designed in size or duration to study these rare or unusual outcomes, and as such, evidence is insufficient to compare any reported benefits against the risk of these rare harms. Additionally, the risk of bias assessments flagged concerns in many included RCTs related to poorly reported randomization and allocation approaches, a lack of blinding and incomplete reporting of efficacy and safety outcomes resulting in unclear risk of bias for many studies.

Results from the secondary prevention populations were robust to the inclusion of data from the primary prevention studies.

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Strengths and Limitations

A strength of this review was its comprehensiveness in identifying and assessing the evidence for the oral and intravenous bisphosphonates that are currently approved in Canada for a wide range of clinically and patient important outcomes.

The systematic review was limited by the quality of the included studies. In general, for the studies included in the systematic review, overall quality was adequate; however, many studies had one or more methodological domains with an unclear risk of bias, and a large proportion failed to report important participant characteristics. The limited reporting of important study and participant characteristics also limited the optimal application of the

NMAs were not conducted for all outcomes of interest in the systematic review. Moreover, data for some outcomes were limited to reports of zero events in one or more study arms, thus limiting our ability to assess comparative efficacy and safety using standard Bayesian indirect comparison methodologies. Although we used multiple statistical approaches to incorporate zero events into the analyses, robust estimates were often not achieved when zero events were included. This additionally limited the number of trials that contributed to some of the NMAs, which may have yielded less precise estimates than if we had been able to create more robust evidence networks. Results from these analyses should therefore be interpreted with caution.

A large majority of included studies excluded subgroups of interest such as those with contraindications to oral bisphosphonates and reported outcomes in studies of relatively short duration (< 2 years). The included studies were not powered to capture rare safety outcomes and thus, we are unable contribute robust evidence to the existing assessments from regulatory agencies regarding increased risk of atrial fibrillation, osteonecrosis of the jaw, or atypical femoral fractures.

Conclusions and implications for policy-making

Based on the findings from this review, the benefits of bisphosphonate drugs, especially in populations of postmenopausal women with a higher fracture risk, outweigh any reported risks. Intravenous bisphosphonates or denosumab may provide a treatment alternative to oral bisphosphonates, although there is scarce evidence to make specific conclusions regarding post- menospausal women who are intolerant of or contraindicated to oral drugs

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CONTEXT, RATIONALE AND POLICY ISSUES

Background / Setting in Canada

Osteoporosis is a systemic skeletal disease where deterioration of the bone microarchitecture leads to increased loss of bone strength and risk of fractures. It affects two million Canadians, predominantly postmenopausal women due to decreased production of estrogen following menopause.1 Fractures associated with osteoporosis, especially fractures of the hip, lead to significant morbidity and increase risk of one-year mortality by nearly 25%.2 Health-care costs associated with osteoporotic fractures are estimated to account for more than 50% of the economic burden in acute care.3

The bone remodeling cycle is a dynamic process that consists of an osteoclast-mediated bone resorption phase and an osteoblast-mediated bone formation phase.4 The uncoupling of these processes leads to an increased rate of bone resorption without adequate bone formation. This leads to a porous, diseased state of bone susceptible to fragility fractures from falls of a standing height or less.

The diagnosis of osteoporosis is defined on the basis of an assessment of bone mineral density (BMD). The World Health Organization (WHO) criteria definition is based on femoral-neck bone mass density measured by dual-energy X-ray absorptiometry (DXA), 2.5 standard deviations (SDs) or more below the peak bone mass (PBM).5 The PBM refers to the maximum bone density attained during adulthood, typically compared to a 30-year-old adult.6 BMD can be converted into a T score, which directly expresses the number of SDs that a BMD value is below the PBM. WHO recognizes three diagnostic categories of T scores. Values of ‒1 or higher are considered normal bone density (i.e., the BMD is within 1 SD of the PBM), values of ‒1 to ‒2.5 are considered osteopenia (i.e., the BMD is 1 to 2.5 SDs lower than the PBM), and T scores lower than ‒2.5 are indicative of osteoporosis (i.e., the BMD is more than 2.5 SDs below the PBM).

However, BMD is only one determinant of bone strength and accounts for bone quantity rather than bone quality.7 It does not consider structural or material bone properties, and post-hoc studies assessing whether increases in BMD reliably predict reductions in fracture incidence are inconsistent across interventions.8,9 The FDA therefore requires fracture as the primary end point in the registration of new drug and biologic products for the treatment of osteoporosis, and guidelines indicate that fracture prevention is the most clinically important outcome.10,11 The International Osteoporosis Foundation recommends treatment failure in osteoporosis to be defined in the context of fractures that occur or are prevented in participants during the course of treatment; for example, within one year of starting treatment, as opposed to a singular decrease in BMD.12

Organizations such as the Canadian Association of Radiologists recommend using an individual’s 10-year risk of fracture as the threshold for intervention.13 The 2010 Clinical Practice Guidelines for the Diagnosis and Management of Osteoporosis in Canada recommend the Fracture Risk Assessment Tool, or FRAX, and the Canadian Association of Radiologists and Osteoporosis Canada fracture risk assessment tool (CAROC) to evaluate an individual’s absolute 10-year fracture risk, accounting for risk factors such as age, history of fracture, and glucocorticoid use.10

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The 2010 clinical practice guidelines by Osteoporosis Canada do not recommend pharmacotherapy in those assessed as having a low risk of fracture (i.e., 10-year fracture risk lower than 10%)10 However, patients with a prior spine or hip fracture, multiple fragility fractures, or with a 10-year risk of fracture greater than 10% are considered for pharmacotherapy. Drug therapy strategies are divided into the prevention and treatment of fractures based on the patient’s baseline level of fracture risk. Those who have a moderate risk of fracture (i.e., a 10-year fracture risk of 10% to 20%) and those at high risk of fracture (i.e., a 10-year fracture risk greater than 20%; a prior fragility fracture of hip or spine; and greater than 1 fragility fracture) are recommended to be considered for medications. The 2010 Canadian clinical practice guidelines recommend the bisphosphonates alendronate and risedronate as first-line treatments, with high-quality evidence supporting efficacy in the prevention of hip, non-vertebral, and vertebral fractures. Alternative first-line medications include denosumab, zoledronic acid, and raloxifene. Teriparatide is also listed; however, the high cost for therapy and the need for daily injections restrict access to the medication. Raloxifene is only recommended for the prevention of vertebral fractures. Evidence supporting the efficacy of cyclic etidronate with calcium supplementation and calcitonin is of lower quality. For patients at high risk of fractures residing in long-term care, raloxifene and cyclic etidronate with calcium supplementation are not recommended.

Recommendations in the Clinical Practice Guidelines for the Diagnosis and Treatment of Postmenopausal Osteoporosis — 2016 by the American Association of Clinical Endocrinologists and American College of Endocrinology differ for patients with moderate risk (i.e., no prior fragility fractures or 10-year major osteoporotic fracture risk of less than 20%) and high risk (i.e., prior fragility fracture, 10-year major osteoporotic fracture risk of greater than or equal to 20%, hip fracture risk of greater than or equal to 3%, or with high risk factors).14 These guidelines recommend alendronate, denosumab, risedronate and zoledronic acid for those at moderate risk. Alternatively, ibandronate (not available in Canada) and raloxifene are reserved for those intolerant to first-line medications such as oral bisphosphonates (e.g., patients with esophageal disorders, a history of bariatric surgery, chronic kidney disease, or with an inability to stay upright for at least 30 minutes). Patients at high risk of fracture are recommended to take denosumab, teriparatide, or zoledronic acid, while alendronate and risedronate are for use in those intolerant to the aforementioned drugs.

In Canada, different classes of drugs are indicated for osteoporosis, including four bisphosphonates (alendronate, risedronate, etidronate, and zoledronic acid), various dosage forms of hormone replacement therapy, a selective estrogen receptor modulator (raloxifene), calcitonin, a biologic (denosumab), and a parathyroid hormone analogue (teriparatide). Jurisdictional coverage varies widely (Appendix 1,Table 41).

Bisphosphonates are the most widely used anti-osteoporosis treatments in Canada.15 Among these, alendronate and risedronate accounted for more than 72% of all dispensed oral osteoporosis medications in 2012.16 However, bisphosphonates are associated with reduced compliance due to gastrointestinal adverse events17,18 and are investigated for potential association with rare and serious adverse events, including atrial fibrillation, osteonecrosis of the jaw, and atypical femoral fracture.19 New regimens for bisphosphonates have been developed to facilitate adherence, including weekly and monthly administrations, as well as additional routes of administration such as injectable bisphosphonates. A systematic review of women’s values and preferences indicated that the convenience of taking an osteoporosis drug treatment is important: less frequent dosing and oral

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administration is preferred, and an injectable is preferred over oral medication if given less frequently.20

New anti-osteoporosis treatments include romosozumab, a biologic approved by the US FDA in April 201921 and by Health Canada in June 2019.22 The introduction of new drugs offers patients access to additional treatment options.

Based on stakeholder feedback received on the proposed project scope, the technology review will focus on the comparative effectiveness of anti-resorptive drugs, including oral bisphosphonates, zoledronic acid, and denosumab. Raloxifene, teriparatide, and romosozumab are not included in the project scope. Teriparatide is not currently reimbursed by most jurisdictional drug plans. Similarly, romosozumab recently received market approval and is not yet considered for reimbursement. Based on clinical expert opinions, raloxifene is also excluded given its limited use and side effect profile. Consideration will be given to include the bone-forming drugs (teriparatide, romosozumab and other emerging drugs) in a subsequent technology review.

TABLE 1: ANTI-RESORPTIVE DRUGS DRUG PRODUCTS MARKETED IN CANADA

Product Drug Indication Dosage form Dose and Manufacturer Administration Anti-resorptive Drugs Bisphosphonates ALENDRONATE Fosamax Alendronate Treatment of Oral tablet Treatment: 70 mg Merck Canada sodium 70 mg osteoporosis in once weekly Inc postmenopausal women

Osteoporosis may be confirmed by the finding of low bone mass (for example, at least 2.0 standard deviations below the premenopausal mean) or by the presence or history of osteoporotic fracture

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Product Drug Indication Dosage form Dose and Manufacturer Administration Fosavance Alendronate Treatment of Oral tablet Treatment: one Merck Canada 70/2800 sodium 70 mg osteoporosis in tablet once weekly Inc with postmenopausal cholecalciferol women Fosavance (vitamin D) 70/5600 2800 IU Osteoporosis may be confirmed by the Alendronate 70 finding of low bone mg with mass (for example, cholecalciferol at least 2.5 standard (vitamin D) deviations below the 5600 IU premenopausal mean) or by the presence or history of osteoporotic fracture Generics Alendronate See individual Oral tablets Treatment: 70 mg Various sodium 5 mg, product monographs once weekly suppliers 10 mg, and 70 mg Treatment: 10 mg once daily

Prevention: 5 mg once daily ETIDRONATE ACT Etidronate Treatment of Oral tablets Treatment and Actavis Pharma Etidrocal disodium 400 established prevention: Company mg with postmenopausal Etidronate calcium osteoporosis disodium tablets to carbonate be taken once 1250 mg Prevention of daily for 14 days, osteoporosis in followed by 76 blue postmenopausal calcium carbonate women who are at tablets to be taken risk of developing once daily for the osteoporosis next 76 days RISEDRONATE Actonel Risedronate Rreatment and Oral film- Treatment: 5 mg Allergan Inc sodium 5 mg, prevention of coated tablets once daily; 35 mg 35, and 150 osteoporosis in once weekly; or mg postmenopausal 150 mg once women monthly

Prevention: 5 mg once daily or 35 mg once weekly Actonel DR Risedronate Treatment of Delayed- Treatment: 35 mg Allergan Inc sodium 35 mg osteoporosis in release tablet once weekly postmenopausal women

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Product Drug Indication Dosage form Dose and Manufacturer Administration Generics Risedronate See individual Oral tablets Treatment: 5 mg Various sodium 5 mg, product monographs once daily; 35 mg suppliers 35 and 150 mg once weekly; or 150 mg once monthly

Prevention: 5 mg once daily or 35 mg once weekly ZOLEDRONIC ACID Aclasta Zoledronic acid Treatment of Solution for Treatment: once Novartis solution 5 mg/ osteoporosis in intravenous yearly single Pharmaceuticals 100 mL postmenopausal infusion infusion Canada Inc women Prevention: single Prevention of infusion postmenopausal osteoporosis in women with osteopenia Generics Zoledronic acid See individual Solution for Treatment: once Various solution 5 mg/ product monographs intravenous yearly single suppliers 100 mL infusion infusion

Prevention: single infusion Monoclonal Antibody - RANK ligand inhibitor DENOSUMAB Prolia Denosumab Treatment of Pre-filled Treatment: 60 mg Amgen Canada solution 60 mg/ postmenopausal syringe for once every 6 Inc mL women with subcutaneous months osteoporosis at high injection risk for fracture, defined as a history of osteoporotic fracture, or multiple risk factors for fracture; or patients who have failed or are intolerant to other available osteoporosis therapy

IU: international unit; mg: milligram; mL: milliliter.

POLICY QUESTIONS

1. Within the bisphosphonates, which is the best pharmacologic treatment option?

2. How do the bisphosphonates compare against denosumab in fracture prevention?

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3. Are zoledronic acid or denosumab effective alternatives in case of a contraindication to an oral bisphosphonate?

OBJECTIVE

The aim of this Technology Review report is to inform the policy questions by addressing the benefits and harms of the bisphosphonate drugs and denosumab for the treatment or prevention of osteoporosis in postmenopausal women. The focus will be on treatments available in Canada. Other comparators may include interventions used in international clinical practice for osteoporosis.

Research questions

1. What are the comparative benefits and harms of bisphosphonate drugs and denosumab in the primary prevention of fractures in postmenopausal women?

2. What are the comparative benefits and harms of bisphosphonate drugs and denosumab in the secondary prevention of fractures in postmenopausal women?

METHODS

A systematic review (SR) of comparative clinical studies was conducted to address research questions 1 and 2. This clinical review was prepared in consideration of relevant reporting guidelines for SRs (i.e., Preferred Reporting Items for Systematic Reviews and Meta-Analyses23 [PRISMA]). A protocol was developed a priori and registered in the PROSPERO database (CRD42019147448).

Literature Search

The literature search was performed by an information specialist using a peer-reviewed search strategy. Information was identified by searching the following bibliographic databases: MEDLINE (1946- ) with in-process records & daily updates via Ovid; Embase (1974- ) via Ovid; Cochrane Central Register of Controlled Trials via Ovid; and PubMed. The search strategy consisted of both controlled vocabulary, such as the National Library of Medicine’s MeSH (Medical Subject Headings), and keywords. The main search concepts were alendronate, risedronate, etidronate, zoledronic acid, and denosumab.

Methodological filters were applied to limit retrieval to randomized controlled trials and controlled clinical trials. Where possible, retrieval was limited to the human population. Conference abstracts were included. An independent review of the search strategy using the Peer Review of Electronic Search Strategies (PRESS) guideline 24 was completed by a second information specialist. The search was completed June 5, 2019.

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Grey literature (i.e., information and reports that are not published commercially and that may be inaccessible via bibliographic databases) was located through searches of publicly available regulatory documents from Canada, United States and Europe. Additionally, Clinicaltrials.gov and the WHO International Clinical Trials Registry Platform were searched for eligible records. These searches were supplemented by reviewing reference lists of systematic reviews published since 2009. Google and other Internet search engines were used to search for additional web-based materials.

The complete search strategy and results from the PRESS guideline are presented in Appendix 2.

Selection criteria

Publications were included if they met the eligibility criteria outlined in Table 2. Studies were not excluded based on outcomes reported. Duplicate publications and multiple publications of the same study were also excluded unless they provided unique findings.

The population of interest included postmenopausal women. If a mixed-population was reported in a study (e.g., included both post-menopausal women and other ineligible study populations), the study was included if the results for post-menopausal women were reported separately. Studies reporting a mixed population were also included if post-menopausal women comprised a large proportion of the total study population (i.e., > 95%) even if results were not reported separately.

TABLE 2: ELIGIBILITY CRITERIA FOR THE CLINICAL REVIEW

Inclusion: Population • Postmenopausal women with natural or surgically induced menopause

Exclusion: • Premenopausal women • Patients with co-morbid conditions or taking medications associated with secondary osteoporosis (e.g., breast cancer, rheumatoid arthritis; tamoxifen, glucocorticoids) • Men (≥5% of study participants) • Bisphosphonates (alendronate, risedronate, etidronate, zoledronic acid) Interventionsa • Denosumab

• Any of the drugs of interest or placebo (includes no treatment or background Comparators supplementationb) • Combinations of interventions of interest

Outcomes Efficacy • Radiographic vertebral fractures • Clinical vertebral fractures • Non-vertebral fractures (including hip and wrist fractures) • Hip fractures • Wrist fractures • Health-related quality of life

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Harms • Withdrawal due to adverse events • Serious adverse events • Gastrointestinal adverse events • Osteonecrosis of the jaw • Atypical femoral fracture • Atrial fibrillation • Randomized controlled trials with at least one year of treatment Study design • Reported in peer-reviewed publications, regulatory documents, registry records, or conference abstracts

a Doses of any of the eligible drugs that are above or below the standard dose approved by Health Canada, drugs that are not currently reimbursed by most jurisdictional drug plans (i.e., teriparatide, romosozumab), or drugs with limited use and side effect profile (i.e., raloxifene) were excluded. b Supplementation of calcium (<1200 mg/day) and vitamin D (<1000 IU/day) equally administered to all participants in a trial will be considered background therapy, based on recommendations from the 2010 clinical practice guidelines by Osteoporosis Canada 10.

Screening and Selection

Two reviewers independently screened titles and abstracts of all citations retrieved from the literature search using the pre-determined eligibility criteria (Table 2). All citations were screened in DistillerSR using standardized screening forms (Evidence Partners, Ottawa, Canada). Titles and abstracts thought to be possibly eligible by either reviewer were retrieved for full-text review. The same reviewers independently reviewed all full-text reports, applying the eligibility criteria. All disagreements were resolved through discussion resulting in consensus or through consultation with a third reviewer.

Data Extraction

Data extraction for the study and participant characteristics of included studies was completed by one reviewer and verified by a second in its entirety. Outcome data were extracted independently by two reviewers. All data extraction was completed using standardized data extraction forms created for the review in DistillerSR. The data extraction forms were designed to extract relevant information from all studies, including but not limited to:

• Study characteristics, inclusion and exclusion criteria, and definitions used (as required);

• Baseline patient characteristics, including fracture history, T-score, BMD, demographics, and prior bisphosphonate experience;

• Interventions evaluated, including dose, duration, route of administration, and additional calcium and/or vitamin D supplementation;

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• Outcome definition as provided by study authors, time point(s) data were reported, type of analysis (intention-to-treat or safety population), randomized and follow-up population numbers.

Consideration for Primary or Secondary Prevention of Fractures

Studies were classified as being for primary or secondary prevention during data extraction based on available clinical information for the included women. In order to standardize this approach, we developed and used a hierarchical classification algorithm (

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Figure 1). Clinical experts assisted with the development of the classification algorithm. All studies that met the eligibility criteria were classified as a primary or secondary prevention study using the algorithm and informed by the study inclusion and exclusion criteria and/or baseline characteristics of women.

Secondary prevention populations include women at moderate or high risk of fracture: studies that recruited women with diagnosed osteoporosis, a history of vertebral fracture, a BMD T-score lower than -2.5, or mean age over 75 years were classified as secondary fracture prevention. Primary prevention populations include postmenopausal women at lower risk of fracture: studies of postmenopausal women with participants that do not meet the secondary fracture prevention criteria were classified as primary prevention (e.g., younger age, no fracture history, diagnosed osteopenia). Where information was insufficient to classify a study using the algorithm, it was not included in predefined statistical analyses; instead each study was descriptively summarized in the results.

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FIGURE 1: HIERARCHICAL CLASSIFICATION FOR PRIMARY AND SECONDARY PREVENTION TRIALS

a Study defined osteoporosis and osteopenia definitions were used regardless of criteria applied. No studies were excluded from classification based on criteria used to determine osteoporosis or osteopenia status or based on who determined this status (e.g., primary care physician, physician specialist, study physician). Osteoporosis or osteopenia status were assumed consistent across studies.

Quality Assessment of Individual Studies

Two independent reviewers applied the Cochrane Risk of Bias (ROB) tool 25 to all included studies. All disagreements were resolved through discussion resulting in consensus or through consultation with a third reviewer.

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The ROB tool was completed through assessment of the seven domains: sequence generation, allocation concealment, blinding of participants, personnel and outcome assessors, incomplete outcome data, selective outcome reporting, and other sources of bias. The domain “blinding of outcome assessors” was assessed separately for subjective and objective outcomes because subjective outcomes would be strongly influenced by a lack of proper blinding 26. Objective outcomes included all fractures, jaw osteonecrosis, atrial fibrillation and atypical femoral fracture; while subjective outcomes included health related quality of life, withdrawals due to adverse events, serious adverse events and gastrointestinal adverse events. In addition, separate considerations were made for the domain of “incomplete outcome reporting” for efficacy and safety data given that the statistical strategies and the handling of missing data of these two might vary within the study.

A ROB judgment by domain was made based on information reported in each included study. Domain assessments were then used to assign an overall ROB for the study. Included studies were assigned ‘low risk’ (i.e., unlikely to be a source of bias in the study), ‘high risk’ (i.e., likely to be a source of bias in the study), or ‘unclear risk’ (i.e., there was insufficient information to make a judgment on ROB in the study). The results from the ROB assessment were not used to further include or exclude studies, but rather to conduct sensitivity analyses based on studies assessed to have a low risk of bias. Details are provided in APPENDIX 8.

Data Analysis

A descriptive summary of study and patient characteristics was prepared that included the study design, year and country of publication, sample size, population, intervention, comparator, and outcomes of each study, where applicable.

Data analysis followed the statistical plan developed a priori 27 to detail approaches to statistical pooling. Following a thorough assessment of clinical and methodological heterogeneity, and where feasible, we conducted statistical pooling of the available effect estimates using network meta- analysis (NMA). NMA was completed by outcome for primary and secondary prevention populations separately.

Where statistical pooling was not feasible using NMA, or where the NMA estimates were not robust, we pooled the available effect estimates using meta-analyses and/or produced descriptive summaries of study results.

Methods for Network Meta-Analysis

NMAs were conducted for outcomes of interest where appropriate and feasible based on the sufficiency of the data available to derive robust and consistent network models. A Bayesian approach was used for each NMA. The software WinBUGS version 1.4.3 (MRC Biostatistics Unit, Cambridge, UK) was used to conduct all NMAs. The binomial likelihood model was used for dichotomous outcomes and the normal likelihood model for continuous outcomes, as it allows for analysis of multi-arm trials 28,29. Placebo (including no treatment or background supplementation) was considered the reference node (or main comparator). Point estimates and 95% credible intervals for odds ratios (OR) were derived using Markov Chain Monte Carlo methods. Risk ratios (RRs) and absolute risk ((1-RR) * control event rate) for an outcome of interest were estimated

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based on the ORs and the mean proportion of patients who experience the outcome in the reference group among included studies. The standard conversion of OR to relative risk is used (i.e., relative risk = OR/[1+Ic (OR1)]) where Ic is the incidence of the event in the control group. Ideally, Ic is the “real” population event rate. Often this event rate is difficult to determine and, indeed, our clinical experts were directly asked this question and could not provide this estimate. The next best choice is to base this estimate on the “control event rate” that is determined fromevent rates resulting from the NMA. A random-effects model was utilized to capture anticipated clinical and methodological heterogeneity between studies.

Posterior densities for unknown parameters were estimated using Markov Chain Monte Carlo methods. Basic parameters were assigned vague prior distributions; appropriate informative priors were considered for the between-study variance if necessary to increase the precision of parameter estimates 30. No formal sensitivity analysis were conducted to assess the potential influence of the assumed priors, however, priors were selected according to suggested best practice 30. Informative priors were deemed appropriate given that the networks had an insufficient number of studies to produce robust estimates of between-study variance and, thus, estimates would be dominated by a null prior. To ensure convergence was reached, trace plots and the Brooks–Gelman–Rubin statistic were assessed. For each analysis, three chains were fitted in WinBUGS, each including 10,000 iterations with a burn-in of at least 10,000 iterations. The findings were summarized as odds ratio (OR), relative risk (RR), and risk difference (RD) for dichotomous outcomes, and standardized mean differences for continuous outcomes (e.g., health related quality of life). NMA model assumptions of exchangeability (i.e., similarity between all included trials) and homogeneity (i.e., similarity between included trials in the same pairwise comparison) were assessed by reviewers prior to analyses. The assumption of consistency between direct and indirect evidence was quantitatively assessed using the deviance and deviance information criterion (DIC) statistics of the consistency and inconsistency models for analysed networks that included at least one ‘closed loop’ of evidence. To identify the trials and comparisons within the networks in which inconsistency may be present, the posterior mean deviances of individual data points in the inconsistency model were plotted against the posterior mean deviances of data points in the consistency model. Where substantial inconsistency was observed, studies were assessed individually to identify characteristics or features that could have contributed to inconsistency. Additional sensitivity analysis was used to assess the influence of removing inconsistent studies or comparisons.

Methods for meta-analysis

Where NMA was not feasible or when only two treatments were present for an outcome of interest, a meta-analysis was conducted using the random-effects model to statistically pool results of relevant studies (frequentist approach). Point estimates of the dichotomous outcomes were expressed in OR, RR and RD, and reported with 95% confidence intervals. For the continuous outcome health related quality of life, where multiple scales were reported by the included studies, effect estimates were expressed as standardized mean differences.

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Base Case Analysis

The base case analyses included studies that met the eligibility criteria, assessed a bisphosphonate of interest, and reported data on at least one efficacy or safety outcome. The analysis was separated for studies classified as primary prevention or secondary prevention trials.

Subgroup Analysis

Where data were available, subgroup analyses were conducted to compare the anti-fracture efficacy of denosumab with bisphosphonates in a NMA. Subgroup analyses were also conducted for trials included in the base case that 1) reported multiple yearly time points for outcomes of interest (e.g., 12 months, 24 months, 36 months); 2) enrolled women naïve to pharmacological therapy with bisphosphonates or, experienced with bisphosphonates; and 3) enrolled only women with contraindications to oral bisphosphonates. The anti-fracture efficacy of denosumab and zoledronic acid was examined in the population with contraindications to oral bisphosphonates.

Sensitivity Analysis

We conducted the following sensitivity analyses to test the robustness of the base case NMA results:

• Analysis limited to studies of high methodological quality, defined as full publication peer- reviewed randomized studies (i.e., were not abstracts or grey literature) with low risk of bias assessed in the domains of allocation concealment (i.e., reported clearly the methods that were used to conceal participant allocation) and incomplete outcome data (i.e., end-of- treatment follow-up rate of at least 80% or close to 80% with balanced attrition numbers and reasons across treatment arms).

• Analysis removing studies classified as primary or secondary prevention entirely based on the age criterion of the hierarchical classification (i.e., greater or equal to 75 years as secondary prevention).

Analysis was conducted to compare the distribution of primary and secondary prevention populations classified using the hierarchical definition in

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• Figure 1 with low, moderate, and high risk categories determined by the Canadian Association of Radiologists and Osteoporosis Canada (CAROC) tool, which was developed by CAROC based on the results of 10-year absolute fracture risk assessment conducted in 2005 (Simonoski 2005, CAROC link on osteoporosis.ca). Where a study reported average baseline femoral neck BMD T-score and age of the study women, the information was used to approximate the aggregated trial-level 10-year fracture risk according to the CAROC classification.

Handling of zero events

When modelling binary data, zero events in one or both of the treatment arms may lead to an unstable NMA model; that is, a model that fails to converge or results in effect estimates with extreme lower and/or upper bounds of the associated credible interval. We encountered three situations where zero events required an alternate analysis approach:

1. Multiple direct comparisons in the evidence network for an outcome reporting a zero event in one or more study arms;

2. Single direct comparisons in the evidence network for an outcome reporting a zero event in one or more study arms; and,

3. Direct comparisons in the evidence network for an outcome reporting zeroes in all study arms.

To make full use of all extracted binary data and to avoid unstable NMA models, we followed a systematic approach to handling zero events or sparse data in all analyses, including the base case and all subgroup or sensitivity analyses:

First, we conducted the base case analysis for each outcome including all direct comparison data in the evidence network. Where the analysis for an outcome had a stable NMA model which converged and produced robust effect estimates without extreme lower or upper credible interval bounds, no additional approaches to analyses were required.

Where statistical instability was identified in the analysis, we applied a continuity correction of 0.5 for studies in the evidence network with zero events in one or more study arms with the aim of improving model fit. Where statistical instability persisted in the NMA despite the continuity correction, we attempted a third analysis approach. Here, we identified a statistically stable subset of direct comparison data for each outcome that, when modelled using NMA, produced robust effect estimates with the most included data possible, taking into account the number of study participants, events and treatments available by outcome. This third analysis approach frequently led to studies with zero events in one or more arms to be excluded from the evidence network.

Where NMA was not feasible using any of the three approaches above, or where subsets of studies were excluded from the base case NMA, we attempted pairwise meta-analysis using the available study data for each outcome. Meta-analysis was feasible when multiple included studies reported at

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least one event in one study arm, and where more than one study reported the same bisphosphonate. In cases where the data were too sparse for quantitative analysis, results were tabulated and presented by study, listing the number of women with events and total number of women randomized by study arm, for each bisphosphonate and placebo. Important differences were summarized descriptively. Additional details are provided in APPENDIX 4.

RESULTS: SYSTEMATIC REVIEW

Quantity of Research Available

The search of bibliographic databases identified a total of 7,339 citations. Additionally, the grey literature search identified 1,493 citations from trial registries, 21 documents from regulatory agency records, and 19 systematic reviews and meta-analyses. After de-duplication, the title and abstract for 2,991 citations were screened. Following the review of titles and abstracts, 884 citations were deemed potentially relevant and retrieved for full-text review. Eight citations identified from relevant systematic reviews were found to be eligible and were included in this review. In total, 656 citations were excluded with reason, including:

• 115 citations with ineligible study designs (e.g., single-arm extension observational studies);

• 28 citations with ineligible populations (e.g., trials of women with secondary osteoporosis or men with osteoporosis);

• 184 reporting only one arm of interest;

• 105 studies with insufficient treatment duration (i.e., less than one year of treatment);

• 4 duplicate publications (exactly same contents found in more than one published source); and,

• 220 companiona publications that provided no additional data for outcomes or subgroups of interest were also excluded.

We included a total of 228 citations reporting 133 unique RCTs 31-163 and 53 companion publicationsa164-216 that provided additional outcome or subgroup data to supplement the primary study publication. An additional42 studies met the inclusion criteria but did not report any outcomes of interest and two other studies 77,94 did not report outcome data in a way that was compatible for

a Citations not considered to be the primary publication of a unique RCT were described as ‘companion’ publications. Companion publications were grouped with the primary RCT publication and may have reported additional outcomes of interest and/or subgroups of study participants.

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the proposed analyses. A total of 131 unique studies reporting data for at least one outcome of interest were included in the analyses (NMA, meta-analyses, or narrative description).

The study selection process is outlined in APPENDIX 5 using a PRISMA flow diagram. Lists of included and excluded citations (by reason for exclusion) are provided in APPENDIX 6 and APPENDIX 7, respectively.

Study Characteristics

The detailed characteristics of the 133 included primary studies 31-163 reporting at least one outcome of interest are provided in APPENDIX 9.

The 133 included primary studies were all RCTs published between 1988 and 2018, with the majority (80%) being published in 2000 or later. Eighty-one RCTs were 2-arm comparison studies (61%) and 52 (39%) had more than two treatment arms. Ninety-five were placebo-controlled and 38 had an active control which was a study intervention of interest. Randomized study populations ranged from 26 to 9,331. A total of 17 RCTs randomized 1,000 or more women. Forty RCTs randomized 100 or fewer women. Studies were conducted in more than one country in 34 RCTs and in a single country in 94 RCTs. Five studies did not report where the study was conducted 51,58,74,76,160. Studies from single countries were conducted in Australia (k=2), Canada (k=1), China, (k=20), Denmark (k=1), Finland (k=1), France (k=2), Germany (k=2), Greece (k=2), Italy (k=8), Japan (k=10), Jordan (k=1), Mexico (k=2), Netherlands (k=1), New Zealand (k=3), Romania (k=1), Taiwan (k=1), Thailand (k=1), Turkey (k=6), the United Kingdom (k=8), and the United States of America (k=19). Ninety-one studies reported their sources of funding, among which 3 were not funded, 12 were funded by not-for-profit organizations, 1 declared no funding by industry, 6 were co- funded by industry and not-for-profit organizations, and 69 were funded by industry. Forty-two RCTs did not report sources of funding or competing interests.

Of the 133 unique studies included systematic review, 48 were classified as primary prevention populations 33,34,36-38,41,47,51,55,56,59,66,68,76,79,80,82-84,86,88,89,91,93,99,106,107,112,114-116,118,120,123,124,131,132,135- 138,145,147,152-154,156,161 and 85 as secondary prevention populations 31,32,35,39,40,42-46,48-50,52-54,57,58,60- 65,67,69-75,77,78,81,85,87,90,92,94-98,100-105,108-111,113,117,119,121,122,125-130,133,134,139-144,146,148-151,155,157-160,162,217 according to the classification hierarchy described in Figure 1. Table 3 describes the characteristics of the included studies.

Alendronate (k=70) were most frequently evaluated, followed by risedronate (k=31), etidronate (k=24) and zoledronic acid (k=22). Denosumab was investigated in 7 placebo-controlled and 10 active-controlled RCTs. Studies with smaller sample sizes were mostly not designed to test for fracture efficacy and fractures were reported as adverse events. Studies reported outcomes of interest following 12 months (k=65), 24 months (k=45), 30 months (k=1), 36 months (k=15), 48 months (k=6), or 72 months (k=1) of treatment. Most studies reported calcium (range 200 to 1500 mg) and/or vitamin D (range 400 to 1200 IU) background supplementation in addition to the study interventions. Two studies supplemented with cholecalciferol. Sixteen studies reported no use of background supplementation and one study did not report this variable.

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Participant Characteristics

Detailed participant characteristics for included studies reporting at least one outcome of interest are provided in APPENDIX 10. Reporting of participant characteristics at baseline in the included studies was limited and this restricted a complete assessment of important characteristics across all studies. In studies that reported baseline characteristics, there was heterogeneity noted in the participant populations. This was investigated in detail using extracted participant data and where feasible, using sensitivity analyses and inconsistency checks in the NMA. Additional statistical approaches to investigate heterogeneity (e.g., meta-regression) based on specific participant characteristics within the study populations were not feasible.

Fifty-one studies did not report the race or ethnicity of the post-menopausal women included as study participants. Of the 82 studies that reported race, Caucasian women were most often included. A total of 28 studies were conducted in China, Japan or Taiwan entirely and a single study from the United States of America reported a 100% African-American population. Fukunaga et al. (2002)73 included 2 men in the study population.

The mean age of women for all included studies ranged from 49.5 years to 85.3 years. The reported mean BMD T-score, based on an average healthy 30-year-old female, ranged from 0.95 above to 3.7 below for the femoral neck and from 0.4 to 3.45 below for the lumbar spine.

Primary prevention populations

The mean age for primary prevention populations (k=48) ranged from 49.5 years to 71.5 years. Two studies including primary prevention populations36,116 reported women with prior use of bisphosphonates. Thirteen reported no prior use of bisphosphonates in study participants, and the remainder did not report this information. The percentage of vertebral factures was not reported in 25 studies. The reported mean BMD T-score, based on an average healthy 30-year-old female, ranged from 0.78 above to 2.14 below for the femoral neck and from 0.4 to 2.4 below for the lumbar spine. Femoral neck T-scores were not reported in 36 studies of primary prevention populations. Lumbar spine T-scores were not reported in 28 studies of primary prevention populations

Secondary prevention populations

The mean age in studies of secondary prevention populations (k=85) ranged from 50.0 years to 85.3 years. The reported mean BMD T-score, based on an average healthy 30-year-old female, ranged from 1.23 to 3.7 below for the femoral neck and from 1.76 to 3.45 below for the lumbar spine. Five studies58,100,121,122,140 reported prior use of bisphosphonates in the study population. Nineteen reported no prior use of bisphosphonates, and the remainder did not report this information. The percentage of vertebral factures ranged from 0% to 100% in studies that reported this information (k=42). Ten RCTs reported 100% of study participants having vertebral factures at baseline, and 5 RCTs reported having no women with previous vertebral fractures. Femoral neck T-scores were not reported in 58 studies of secondary prevention populations. Lumbar spine T-scores were not reported in 47 studies of secondary prevention populations.

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Quality Assessment of Individual Studies

Error! Reference source not found. provides a summary of the results of the ROB assessment for the 133 included RCTs. More detailed assessment results by study are reported in APPENDIX 8.

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FIGURE 2: SUMMARY OF RISK OF BIAS ASSESSMENT RESULTS

A large proportion of the included studies did not report methods to inform assessments for the domain of random sequence generation (61%) and allocation concealment (88%), respectively. Only 14% of included studies provided appropriate methods for both domains and were therefore judged to be at low risk of selection bias 36,37,58,59,72,80,82,83,87,91,92,99,115,118,134,138,145,162. A total of 83 studies reporting at least one objective outcome (i.e. fracture at any anatomic location) and were judged to be at low risk of bias, given that the assessment of fracture outcomes usually required radiographic evidence, morphometric methods or clinical criteria. However, for subjective outcomes, reporting practices varied and were poor in the included RCTs. The limited reporting of important details may lead to performance, attrition, or detection bias. Among 119 studies reporting at least one subjective outcome, 46 (39%) were judged to be at low risk of bias for providing sufficient details to ensure proper blinding of participants, personnel and outcome assessors; while 41 (34%) were judged to be at high risk of bias for lacking appropriate methods to secure blinding of the relevant parties along the study. About one third of included studies were judged to have an unclear risk of bias related to blinding, mostly related to insufficient reporting of study methods. While most studies appropriately reported outcome data for efficacy and safety, 20% of studies had high risk of bias each for incomplete outcome data for efficacy and safety, respectively.

For the domain of selective reporting, 86% were assessed to be at low risk of bias as the reported outcomes were consistent with those pre-specified in the protocol, other relevant publications, or stated in the methods section of the publication. Five studies were judged to be at high risk of bias because of inconsistent or illogical reporting of the results, especially safety outcomes. For example, in Watts 1990 155, 2 deaths judged to be irrelevant to the study were not reported as withdrawal due to adverse events. For this review, the domain of other risk of bias was mostly used to assess whether the study used different doses of drug in the same arm or changed doses of drugs, or whether the timeline of the reported outcomes also covered off-treatment phase. Those issues led to 10% percent of the included studies being judged to be at high risk of bias. Seventeen studies (10%) were at unclear risk of bias due to the main publication was in an abstract form or a foreign article where the extracted information and data might have been partial.

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Overview of Results for Primary and Secondary Prevention Populations

Results for analyses of included primary and secondary prevention populations are presented separately. Each results section includes results reported by outcome, from the base case, subgroup analyses and sensitivity analyses.

In total, 50 analyses (46 NMA and 4 meta-analyses) were conducted for 12 outcomes. Table 3 provides an overview of the analyses conducted for all outcomes. There were 17 analyses conducted in primary prevention populations and 30 analyses conducted in secondary prevention populations. Three analyses were conducted as sensitivity analyses using the baseline patient characteristics including study-level average age and T-score to determine a corresponding CAROC risk of fracture (i.e., low risk, moderate risk, high risk).

Results are presented in tabular format with calculated relative risk for all treatment comparisons in the random-effects models. Results for all effect estimates (OR, RR and RD) are provided in Appendix 11 and Appendix 12 alongside relevant network geometry diagrams showing the available evidence network, consistency plots and network diagnostics (e.g., deviance information criteria). Where consistency was investigated further, results are provided in Appendix 13.

Although all reported data for the outcomes of interest were extracted from all included studies, intervention/comparator arms from studies reporting products or doses not marketed in Canada (Table 1) were not included in the analyses. For example, the arms of cyclic use of alendronate139 and risedronate 124, alendronate at 1 and 2.5 mg/day45,93 , 20 and 40 mg/day55 , risedronate 2532 or 50 mg/week 49, and arm allowing interchangeable use of 2 bisphosphonates and data not separately reported 63. Studies with one eligible arm63,110,139 or those comparing equivalent therapeutic doses of the same drug32,61,62,84,119 were also excluded from the data synthesis.

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TABLE 3: SUMMARY OF OUTCOMES AND ANALYSES BASE SUBGROUP ANALYSES SENSITIVITY ANALYSES CASE SG1 SG2 Treatment durations SG3 BIS experience SG4 SA1 SA2 SA3 EFFICACY/ Oral BIS Low risk of Exclude age- Studies re-classified using CAROC SAFETY BIS BIS+DEN 1 yr 2 yrs 3 yrs 4 yrs 5 yrs Naive Experienced intolerant bias defined studies Levels of Risk OUTCOMES

E-RVF ✔ NA NA NA NA NA NA NA NA NA NA ✔ E-RVF NA

E-NVF ✔ ✔ ✔ ✔ ✔ NA NA ✔ NA NA ✔ ✔ E-NVF ✔ E-HF ✔* NA NA NA NA NA NA NA NA NA NA NA E-HF NA

E-WF ✔ NA NA NA NA NA NA NA NA NA NA ✔ Low risk E-WF NA E-CVF NA NA NA NA NA NA NA NA NA NA NA NA E-CVF NA

E-HRQoL NA E-RVF ✔ S-WDAE ✔ E-NVF ✔

S-SAE ✔ E-HF NA prevention populations prevention

S-GI AE ✔ E-WF NA Moderate risk Moderate

S-ONJ NA E-CVF NA

Primary S-AFF NA E-RVF NA

/ S-AF NA E-NVF NA

E-RVF ✔ ✔ ✔ ✔ ✔ NA NA ✔ NA NA NA NA E-HF NA

E-NVF ✔ ✔ ✔ ✔ ✔ NA NA ✔ NA NA NA NA High risk E-WF NA

E-HF ✔ ✔ NA ✔ ✔ NA NA ✔* NA NA NA ✔ Fracture Vertebral E-CVF NA Moderate Risk with with Risk Moderate E-WF ✔ ✔ NA NA ✔ NA NA ✔* NA NA NA NA E-CVF ✔ ✔ NA NA ✔ NA NA ✔* NA NA NA NA E-HRQoL ✔ S-WDAE ✔

prevention populations prevention S-SAE ✔ S-GI AE ✔ S-ONJ NA

S-AFF NA Secondary S-AF ✔

NA: Analysis was planned but not conducted, ✔: Network Meta-Analysis was conducted, ✔*: Meta-analysis was conducted. AF: atrial fibrillation; AFF: atypical femoral fracture; BIS: bisphosphonates; CAROC: Canadian Association of Radiologists and Osteoporosis Canada Risk Assessment tool; CVF: clinical vertebral fractures; DEN: denosumab; E: efficacy outcome; GI AE: gastrointestinal adverse event; HF: hip fractures; HRQoL: health related quality of life; NVF: non-vertebral fractures; ONJ: osteonecrosis of the jaw; RVF: radiographic vertebral fractures; S: safety outcome; SAE: serious adverse event; WDAE: withdrawal due to adverse event; WF: wrist fractures.

SG1: Addition of studies or study arms with denosumab to the base case. SG2: Base case subgroups based on treatment duration, by year. SG3: Base case subgroups based on study populations who are bisphosphonate-naïve, or bisphosphonate experienced. SG4: Base case subgroup based on populations who do not tolerate oral bisphosphonate drugs. SA1: Sensitivity analyses of base case involving studies assessed to be at a low risk of bias. SA2: Sensitivity analyses removing studies classified as primary or secondary using solely population age. SA3: Sensitivity analyses following reclassification of the included studies using CAROC levels of risk

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RESULTS: PRIMARY PREVENTION POPULATIONS

Summary of Analyses

A total of 48 RCTs were classified as primary prevention populations. Complete results for all base case, subgroup and sensitivity analyses are presented in APPENDIX 11.

Base case NMAs were feasible and robust for 6 outcomes (Table 4). Health related quality of life was reported in only one primary prevention study. Many base case, subgroup and sensitivity analyses were not feasible due to the large number of zero outcome events reported in one or more study arms. Descriptive summaries of results by outcome are provided where studies reported insufficient data for analyses or where select results are of interest.

TABLE 4: SUMMARY OF OUTCOMES REPORTED IN PRIMARY PREVENTION POPULATIONS

No. studies reporting No. studies included in base case Outcome outcome NMA

Total no. included studies classified as primary prevention = 48

Efficacy

Radiographic vertebral factures 8 3

Clinical vertebral fractures 10 NA

Non-vertebral fractures 13 11

Hip fractures 12 NA

Wrist fractures 10 4

Health related quality of life 1 NA

Safety

Withdrawals due to adverse events 31 27

Serious adverse events 19 19

Gastrointestinal adverse events 13 13

Osteonecrosis of the jaw 6 NA

Atypical femoral fracture 10 NA

Atrial fibrillation 3 NA NA= Not applicable, no NMA conducted

In post-menopausal women with a lower risk of fracture taking a bisphosphonate drug (from the primary prevention populations):

• data were available for four bisphosphonates: alendronate, risedronate, etidronate and zoledronic acid;

• of 12 planned analyses, only six NMAs were feasible because due to the large proportion of studies reporting zero events for the outcomes of interest.

In the analyses conducted, there were:

• no differences in radiographic vertebral fractures with alendronate (10 mg/day) and risedronate when compared with placebo or each other;

• no differences in non-vertebral or wrist fractures with alendronate (5 or 10 mg/day), risedronate, etidronate and zoledronic acid when compared with placebo or each other.

o The same results were obtained when evaluating the risk of non-vertebral fractures in bisphosphonate-naïve postmenopausal women;

• no differences in hip fractures with alendronate when compared with placebo;

• no difference in withdrawals due to adverse events or serious adverse events with alendronate, risedronate, etidronate and zoledronic acid when compared with placebo or each other;

• no difference in gastrointestinal adverse events with alendronate (5 or 10 mg/day) and risedronate when compared with placebo or each other; and,

• no atrial fibrillation, osteonecrosis of the jaw, or atypical femoral fractures were observed in any of the included studies reporting these outcomes;

• health related quality of life was assessed in a single included study which reported some domain-specific improvements with alendronate when compared with placebo.

Results from the NMA should be interpreted with caution for radiographic vertebral and wrist fractures given the limited number of studies reporting the outcome that were included in the base case analyses.

There is limited information on:

• the efficacy and safety of alendronate, risedronate, etidronate and zoledronic acid postmenopausal women at lower risk of fractures (as studied in primary prevention trials)

o who are bisphosphonate-naïve;

o with a contraindication to oral bisphosphonates.

• the effects of the bisphosphonate drugs on clinical vertebral fractures, health related quality of life and atrial fibrillation;

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• the effects of treatment duration;

• the impact of the classification approach used in this review compared with application of the 10-year CAROC fracture risk tool.

There were a small number of analyses conducted comparing bisphosphonate drugs to denosumab due to a paucity of studies reporting outcome data.

Radiographic Vertebral Fractures

Eight studies55,59,66,89,91,123,124,137 reported radiographic vertebral fractures in primary prevention populations of 4,960 postmenopausal women taking alendronate, risedronate, etidronate, zoledronic acid or placebo. Five studies reporting zero events in one or both treatment arms were excluded from NMA 55,89,123,124,137 as they caused statistical instability in the network model.

Base case

The base case analysis included three RCTs involving 4,461 women 59,66,91. There were no differences in radiographic vertebral fractures with alendronate (10mg/day) or risedronate (5 mg/day or 35 mg/week or 150 mg/month) when compared with placebo or each other in postmenopausal women (Table 5).

TABLE 5: RADIOGRAPHIC VERTEBRAL FRACTURES, PRIMARY PREVENTION POPULATIONS, BASE CASE (RELATIVE RISK)

Treatment Reference RR (95% CrI)

Alendronate (10 mg/day) Placebo 0.60 (0.34, 1.10)

Risedronate Placebo 0.96 (0.35, 2.49)

Risedronate Alendronate (10 mg/day) 1.59 (0.49, 4.80) CrI = credible intervals; RR = relative risk; Placebo (includes no treatment or background supplementation); Risedronate= 5 mg/day or 35 mg/week or 150 mg/month.

In the 5 studies excluded from the base case NMA, one study reported zero radiographic vertebral fractures in women assigned to etidronate (400 mg/day, n=40) while there were 3 fractures in women in the placebo arm (n=40) 123. A second study reported zero radiographic vertebral fracture events in 75 women taking etidronate (400 mg/day) and 77 assigned to placebo 89. When intravenous zoledronic acid (5 mg/year, n=58) was compared with alendronate (10 mg/day, n=43), 2 radiographic vertebral factures were observed in the zoledronic acid arm, and none in the alendronate arm 137. Chestnut (1995) 55 compared two doses of oral alendronate (5 or 10 mg/day) to placebo and no radiographic vertebral fractures were seen in any of the study arms (N=93). Similarly, a 1998 study by Mortensen 124 observed zero radiographic vertebral fractures in 73 postmenopausal women taking risedronate (5 mg/day or 35 mg/week or 150 mg/month, n=37) or placebo (n=36).

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Subgroup analyses

Subgroup analyses were not feasible because: No studies reporting radiographic vertebral fractures compared denosumab to a bisphosphonate or placebo, none of the studies included populations of bisphosphonate-naive postmenopausal women or those with contraindications to oral bisphosphonates.

Sensitivity analyses

Sensitivity analyses were limited or not feasible due to the limited number of studies reporting this outcome.

High methodologic quality studies

Of the 3 RCTs included in the base case analysis, only one study of alendronate was assessed to be of high methodological quality 59. The other two RCTs including alendronate and risedronate were assessed to have either an unclear risk of selection bias for conceal allocation 66, or a high risk of bias due to attrition after 24 months of treatment 91.

Removal of studies classified as primary prevention using age only

Results for the base case were robust to the removal of a single study classified as a primary prevention study using only participant age (i.e., age < 75 years)66 .

Clinical Vertebral Fractures

Ten RCTs involving 2,009 women reported clinical vertebral fractures.37,38,82,83,93,106,114,120,132,154 All studies reported zero women with events in one or both treatment arms which led to statistical instability in the analyses. No analyses were feasible and therefore, results by study arm are summarized in Table 6.

TABLE 6: CLINICAL VERTEBRAL FRACTURES, PRIMARY PREVENTION POPULATIONS EXCLUDED FROM QUANTITATIVE SYNTHESIS

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Treatment (number of women with event/number of women) Zoledronic Study Alendronate Alendronate Zoledronic acid (5 acid (5 mg Placebo Risedronate Etidronate (5 mg/day) (10 mg/day) mg/year) single dose) Aro 0/24 0/25 2018 Ascott- Evans 0/49 0/95 2003 Hosking 0/502 0/498 1998 Lewiecki 0/46 0/46 2007 Grey 0/25 0/25 2010 Grey 0/34 0/41 2012 Välimäki 0/55 0/115 2007 Etidronate= oral cyclic 400 mg/day; Placebo (includes no treatment or background supplementation; Risedronate= 5 mg/day or 35 mg/week or 150 mg/month.

No subgroup or sensitivity analyses were feasible given the limited number of studies reporting clinical vertebral fractures and the frequency of zero events.

Non-Vertebral Fractures

Thirteen studies 37,38,59,82,83,91,93,106,114,120,131,132,154 evaluated non-vertebral fractures in 8,603 postmenopausal women using bisphosphonates.

Base case

The base case analysis included 11 RCTs involving 8,410 women 59,82,83,91,93,106,114,120,131,132,154. There were no differences in non-vertebral fractures when postmenopausal women using bisphosphonates were compared with women taking placebo or a different bisphosphonate drug (or dose) (Table 7). Two RCTs could not be included in the base case analysis as they reported zero non-vertebral fractures in both study arms, which caused instability in the statistical model. One study 38 compared alendronate 10 mg/day (n=95) to placebo (n=49) and the second 37 compared zoledronic acid (5mg/year, n=25) to placebo (n=24).

TABLE 7: NON-VERTEBRAL FRACTURES, PRIMARY PREVENTION POPULATIONS, BASE CASE (RELATIVE RISK)

Treatment Reference RR (95% CrI)

Alendronate (5 mg/day) Placebo 1.24 (0.60, 2.34)

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Alendronate (10 mg/day) Placebo 0.78 (0.48, 1.12)

Etidronate Placebo 0.51 (0.14, 1.56)

Risedronate Placebo 0.67 (0.22, 1.99)

Zoledronic acid (5 mg single dose) Placebo 2.00 (0.32, 8.83)

Zoledronic acid (5 mg/year) Placebo 0.79 (0.16, 3.34)

Alendronate (10 mg/day) Alendronate (5 mg/day) 0.63 (0.29, 1.34)

Etidronate Alendronate (5 mg/day) 0.41 (0.10, 1.58)

Risedronate Alendronate (5 mg/day) 0.54 (0.15, 2.01)

Zoledronic acid (5 mg single dose) Alendronate (5 mg/day) 1.62 (0.24, 8.64)

Zoledronic acid (5 mg/year) Alendronate (5 mg/day) 0.64 (0.12, 3.32)

Etidronate Alendronate (10 mg/day) 0.66 (0.18, 2.23)

Risedronate Alendronate (10 mg/day) 0.87 (0.26, 2.87)

Zoledronic acid (5 mg single dose) Alendronate (10 mg/day) 2.61 (0.40, 12.33)

Zoledronic acid (5 mg/year) Alendronate (10 mg/day) 1.03 (0.20, 4.76)

Risedronate Etidronate 1.33 (0.26, 6.92)

Zoledronic acid (5 mg single dose) Etidronate 3.90 (0.47, 28.45)

Zoledronic acid (5 mg/year) Etidronate 1.57 (0.22, 11.03)

Zoledronic acid (5 mg single dose) Risedronate 2.99 (0.36, 20.35)

Zoledronic acid (5 mg/year) Risedronate 1.17 (0.17, 7.16)

Zoledronic acid (5 mg/year) Zoledronic acid (5 mg single dose) 0.40 (0.04, 4.18) CrI = credible intervals; RR = relative risk; Etidronate= oral cyclic 400 mg/day; Placebo (includes no treatment or background supplementation); Risedronate= 5 mg/day or 35 mg/week or 150 mg/month

Subgroup analyses

Comparisons with denosumab

One study involving denosumab47 was added to the base case NMA 59,82,83,91,93,106,114,120,131,132,154 (8,742 postmenopausal women). Results were comparable to the results from the base case analysis and there were no differences in non-vertebral fractures when postmenopausal women using denosumab were compared with women taking placebo or a bisphosphonate drug.

Effects of treatment duration

Subgroup analyses were utilized to examine the effects of treatment duration on observed outcomes. Three studies reported non-vertebral fractures at 12 months 83,106,131 (2,090 women), 7 studies at 24 months 82,83,91,93,120,132,154 (1,727 women), 2 studies at 36 months 82,114 (316 women), 1 study each at 48 months 59 (4,432 women) and 60 months 83 (75 women).

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No differences in risk of non-vertebral fractures were observed at 12, 24, or 36 months when postmenopausal women using bisphosphonates were compared with women taking placebo or a different bisphosphonate drug (or dose).

Differences in the number of women with non-vertebral fractures were observed in the placebo arm of a large RCT 59 after 48 months compared with alendronate 10 mg/day (placebo [294/2218, 13.3%]; alendronate [261/2214, 11.8%]). After 60 months, fewer non-vertebral fractures were observed in women receiving a single injection of zoledronic acid (4/41, 9.8%) compared with placebo (4/34, 11.8%).

Bisphosphonate-naïve women

In eight studies of bisphosphonate-naïve postmenopausal women 59,82,83,91,93,114,120,132 (6,240 women), there were no differences in non-vertebral fractures when women using bisphosphonates were compare with women using placebo or a different bisphosphonate.

Contraindications to oral bisphosphonates

No studies reported non-vertebral fractures in women (or subgroups of women) who had contraindications to oral bisphosphonates.

Sensitivity analyses

High methodologic quality studies

Results from the base case for alendronate, zoledronic acid and placebo were robust to sensitivity analysis involving 4 high quality RCTs included in a sensitivity analysis 59,82,83,93 (5,557 women).

Removal of studies classified as primary prevention populations using age only Results from the base case were robust to sensitivity analysis involving 8 RCTs (5,393 women) which excluded 3 studies from the base case originally classified as primary prevention populations using only participant age data (at baseline) 93,131,132.

Hip Fractures

Twelve studies evaluated hip fractures in 7,356 post-menopausal women. 37,38,59,79,82,83,106,123,131,132,137,154

Base case

A base case NMA was not feasible as eight placebo-controlled studies 37,38,82,83,106,123,132,154 reported zero hip fractures in women in both study arms and this caused the NMA model to be statistically unstable (Error! Reference source not found.). In a meta-analysis of three 3 RCTs 59,79,131 of women receiving alendronate (10 mg/day) compared with placebo (6,460 women) no differences in hip fractures were observed (RR 1.32, 95% CI, 0.75 to 2.30). An additional study 137 comparing

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zoledronic acid (5 mg/year) with alendronate (10 mg/day) observed one hip fracture in women receiving alendronate (Table 8).

TABLE 8: HIP FRACTURES, PRIMARY PREVENTION POPULATIONS EXCLUDED FROM QUANTITATIVE SYNTHESIS

Treatment (Number of women with event/number of women) Zoledronic Zoledronic Study Alendronate Alendronate acid (5 mg Placebo Risedronate Etidronate acid (5 (5 mg/day) (10 mg/day) single mg/year) dose) Robles-Carranza 1/43 0/58 2013 Ascott-Evans 2003 0/49 0/95

Lewiecki 2007 0/46 0/47

Pouilles 1997 0/55 0/54

Välimäki 2007 0/55 0/115

Aro 2018 0/24 0/25

Montessori 1997 0/40 0/40 Grey 2010 0/25 0/25 Grey 2012 0/34 0/41 Etidronate= oral cyclic 400 mg/day; Placebo (includes no treatment or background supplementation); Risedronate = 5 mg/day or 35 mg/week or 150 mg/month.

Subgroup analyses

Comparisons with denosumab

Two small RCTs involving denosumab reported zero hip fractures in both study arms: one study compared 32 postmenopausal women receiving denosumab (60 mg every 6 months) with 26 postmenopausal women taking zoledronic acid (5 mg/year) 36, and a second compared 27 postmenopausal women receiving denosumab (60 mg every 6 months) with 78 postmenopausal women taking alendronate (10 mg/day) 76. No analyses were feasible.

Effects of treatment duration

Subgroup analyses were utilized to examine the effects of treatment duration on hip fracture outcomes. Four studies reported hip fractures at 12 months 82,83,131,154, 2 studies at 24 months 82,83, 4 studies at 36 months 79,82,83,137 , and 1 study at 48 months 59. At 48 months, the Cumming et al. study observed 19 women with hip fractures in the alendronate arm (10 mg/day) compared with 24 in the placebo arm (4,432 women). Analysis was not feasible at any reported time point. Results from individual studies are reported in Table 9.

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TABLE 9: HIP FRACTURES, PRIMARY PREVENTION POPULATIONS EXCLUDED FROM QUANTITATIVE SYNTHESIS, BY TIME POINT

Treatment (Number of women with events/number of women) Zoledronic Zoledronic Months Alendronate of Placebo Risedronate Etidronate acid (5 acid (5 mg (10 mg/day) treatment Study mg/year) single dose) 12 Pols 2019 3/958 2/950 Ascott-Evans 0/49 0/95 2003 Aro 2018 0/24 0/25

Lewiecki 2007 0/46 0/47

24 Pouilles 1997 0/55 0/54

Välimäki 2007 0/55 0/115

36 Greenspan 1998 1/60 0/60 Montessori 1997 0/40 0/40 Grey 2010 0/25 0/25 Robles- 1/43 0/58 Carranza 2013 48 Cummings 1998 24/2218 19/2214 Etidronate= oral cyclic 400 mg/day; Placebo (includes no treatment or background supplementation); Risedronate = 5 mg/day or 35 mg/week or 150 mg/month.

Bisphosphonate-naïve women

One study 59 reported hip fractures in bisphosphonate-naïve postmenopausal women. The study observed hip fractures in one percent of women receiving alendronate (10 mg/day) (19/2214) and one percent of women receiving placebo (24/2218) while on treatment.

Contraindications to oral bisphosphonates

No studies reported hip fractures in postmenopausal women (or subgroups of women) who had contraindications to oral bisphosphonates.

Sensitivity analyses

Sensitivity analyses were not possible as no analyses were conducted for hip fractures. We did locate a single study of higher quality and two studies were classified based on age.

High methodologic quality studies

A single high-quality study reported hip fractures in women at 48 months 59. In the study, hip fractures were observed in one percent of women in each arm (alendronate [10 mg/day,19/2214] and placebo [24/2218]).

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Removal of studies classified as primary prevention populations using age only

Two studies, Greenspan et al. 79 and Pols et al. 131, observed hip fractures in women in primary prevention populations based on age reported at baseline. Both were included in the base-case meta-analysis of women receiving alendronate (10 mg/day) compared with placebo. No further analyses excluding these studies were feasible.

Wrist Fractures

A total of 10 RCTs 37,38,59,79,82,83,106,114,131,154 reported wrist fracture outcomes in 7,287 postmenopausal women.

Base case

The base case analysis included four placebo-controlled RCTs involving 6,630 women. There were no differences in risk of wrist fracture in any comparison involving postmenopausal women using alendronate (10 mg/day)59,79,131, risedronate154 or placebo (Table 10).

TABLE 10: WRIST FRACTURE, PRIMARY PREVENTION POPULATIONS, BASE CASE (RELATIVE RISK)

Treatment Reference RR (95% CrI)

Alendronate (5 mg/day) Placebo 1.01 (0.45, 2.39)

Risedronate Placebo 0.46 (0.02, 8.73)

Risedronate Alendronate (5 mg/day) 0.46 (0.02, 9.61) CrI = credible intervals; RR = relative risk Placebo (includes no treatment or background supplementation); Risedronate= 5 mg/day or 35 mg/week or 150 mg/month.

Six studies comparing bisphosphonates to placebo reported zero events in one 114 or both study arms 37,38,82,83,106 and could not be included in the base case analysis (Table 11).

TABLE 11: WRIST FRACTURE, PRIMARY PREVENTION POPULATIONS EXCLUDED FROM QUANTITATIVE SYNTHESIS

Treatment (number of women with event/number of women)

Study Alendronate (5 Alendronate (10 Zoledronic acid (5 Zoledronic acid (5 mg Placebo mg/day) mg/day) mg/year) single dose)

McClung,1998 0/90 0/88 1/88 Ascott-Evans 0/49 0/95 2003 Lewiecki 2007 0/46 0/47

Grey 2010 0/25 0/25

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Treatment (number of women with event/number of women)

Study Alendronate (5 Alendronate (10 Zoledronic acid (5 Zoledronic acid (5 mg Placebo mg/day) mg/day) mg/year) single dose) Grey 2012 0/34 0/41

Aro 2018 0/24 0/25 Placebo (includes no treatment or background supplementation).

Subgroup analyses

Comparisons with denosumab

Two studies of denosumab 36,76 and the denosumab arm of a study already in the base case NMA 106 (47 women added) were considered for additional analyses; however, all study arms reported zero events and no additional analyses were feasible. One added study 36 compared denosumab (32 women) to zoledronic acid 5 mg/year (26 women), while another one 76 compared denosumab (27 women) to alendronate70 mg/week (78 women).

Effects of treatment duration

Additional analyses based on duration of treatment were not feasible due to the low number of studies reporting wrist fracture outcomes.

At 12 months, a single RCT compared alendronate (10 mg/day) to placebo and reported wrist fractures (alendronate [6/950, 0.6%]; placebo [15/958, 1.6%]).

At 24 months, two studies observed zero wrist fractures when yearly injection of zoledronic acid (n=48) was compared with placebo (n=45) (84) and when a single injection of zoledronic acid (n=25) was compared with placebo (n=25) (83). Välimäki 2007 study 154 reported 1 woman incurring a wrist fracture in both the placebo (n=55) and risedronate 5 mg/day (n=115) group.

At 30 months, one study observed 0 wrist fractures in 60 women taking placebo compared with 3 wrist fractures in 60 women taking alendronate (10 mg/day)(HR 1.19, 95% CI 0.87 to 1.64, p value: 0.28).

At 48 months, Cummings 1998 observed a slightly higher frequency of wrist fractures in women taking alendronate (10 mg/day) (83/2214, 3.7%) compared with women assigned placebo (70/2218, 3.2%).

Bisphosphonate-naïve women

Only one study enrolled bisphosphonate-naïve postmenopausal women 59. In this large study of alendronate (10 mg/day) compared with placebo, 70 (3.2%) women in the placebo group and 83 (3.7%) women in the alendronate group fractured a wrist (Relative risk 1.19; 95% CI, 0.87 to 1.64).

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Contraindications to oral bisphosphonates

Among primary prevention populations reporting wrist fractures, none included only women who had contraindications to oral bisphosphonates.

Sensitivity analyses

High methodologic quality studies

Of the four studies included in base case NMA, only one trial (60) met all criteria for high methodological quality.

Removal of studies classified as primary prevention populations using age only

Results from the base case were robust to the removal of two primary prevention populations classified using only participant age at baseline 79,131.

Health related Quality of Life

A single placebo-controlled RCT 66 measured health related quality of life using the Nottingham health profile for postmenopausal women taking alendronate. Results reported show that at 12- months, women taking daily alendronate 10 mg (N=51) showed statistically significant improvements in the individual domains of pain, physical ability, energy level and social isolation when compared with placebo, with mean percentage changes of 44% with alendronate (placebo 2.8%), 36% (placebo 1.5%), 28% (placebo 3.8%), and 16% (placebo 27% worse), respectively for each domain. No differences in the domains of sleep or emotional reaction were observed and no overall health related quality of life score comparison was reported by the study authors.

Withdrawal due to Adverse Events

Thirty-one primary prevention populations reported withdrawals due to adverse events in 10,350 women.33,34,37,38,41,51,56,59,66,80,82,83,88,89,91,93,106,114-116,118,120,132,138,145,147,152-154,156,161.

Base case

The base case analysis included 27 RCTs involving 10,068 women.33,34,38,41,51,56,59,80,83,88,89,91,93,106,114-116,118,120,132,138,145,147,152,154,156,161. There were no differences in risk of withdrawal due to adverse events when bisphosphonates were compared with placebo, or another bisphosphonate. (Table 12).

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TABLE 12: WITHDRAWAL DUE TO ADVERSE EVENTS, PRIMARY PREVENTION POPULATIONS, BASE CASE (RELATIVE RISK)

Treatment Reference RR (95% CrI)

Alendronate (5 mg/day) Placebo 1.38 (0.77, 2.36)

Alendronate (10 mg/day) Placebo 0.88 (0.63,1.15)

Risedronate Placebo 0.76 (0.46,1.18)

Etidronate Placebo 1.46 (0.79,2.75)

Zoledronic acid (5 mg/year) Placebo 2.24 (0.68,7.36)

Zoledronic acid (5 mg single dose) Placebo 0.67 (0.03,7.33)

Alendronate (10 mg/day) Alendronate (5 mg/day) 0.65 (0.36,1.16)

Risedronate Alendronate (5 mg/day) 0.57 (0.28,1.12)

Etidronate Alendronate (5 mg/day) 1.08 (0.49,2.54)

Zoledronic acid (5 mg/year) Alendronate (5 mg/day) 1.67 (0.45,6.25)

Zoledronic acid (5 mg single dose) Alendronate (5 mg/day) 0.50 (0.02,5.65)

Risedronate Alendronate (10 mg/day) 0.87 (0.54,1.37)

Etidronate Alendronate (10 mg/day) 1.65 (0.85,3.37)

Zoledronic acid (5 mg/year) Alendronate (10 mg/day) 2.55 (0.78,8.44)

Zoledronic acid (5 mg single dose) Alendronate (10 mg/day) 0.77 (0.03,8.44)

Etidronate Risedronate 1.92 (0.92,4.36)

Zoledronic acid (5 mg/year) Risedronate 2.97 (0.85,10.21)

Zoledronic acid (5 mg single dose) Risedronate 0.89 (0.04,10.29)

Zoledronic acid (5 mg/year) Etidronate 1.56 (0.38,5.79)

Zoledronic acid (5 mg single dose) Etidronate 0.47 (0.02,5.12)

Zoledronic acid (5 mg single dose) Zoledronic acid (5 mg/year) 0.30 (0.01,4.42) CrI = credible intervals; RR = relative risk; Etidronate= oral cyclic 400 mg/day; Placebo (includes no treatment or background supplementation); Risedronate= 5 mg/day or 35 mg/week or 150 mg/month.

Four studies of alendronate and zoledronic acid compared with placebo did not contribute data to the base case NMA as they reported zeroes in both study arms and their inclusion led to statistical instability in the model (Table 13).37,66,82,153

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TABLE 13: WITHDRAWAL DUE TO ADVERSE EVENTS, PRIMARY PREVENTION POPULATIONS EXCLUDED FROM QUANTITATIVE SYNTHESIS

Treatment (number of women with event/number of women)

Study Alendronate Alendronate Zoledronic acid Zoledronic acid (5 Placebo (5 mg/day) (10 mg/day) (5 mg/year) mg single dose) Aro 2018 0/24 0/25

Dursun 2001 0/50 0/51

Grey 2010 0/25 0/25

Uusi-Rasi 2003 0/41 0/41 Placebo (includes no treatment or background supplementation).

Serious Adverse Events

Nineteen RCTs including 6,326 women reported serious adverse events.33,34,37,51,88,89,91,93,106,114- 116,118,120,131,132,138,145,154

Base case

The base case analysis included all 19 RCTs reporting serious adverse events.33,34,37,51,88,89,91,93,106,114-116,118,120,131,132,138,145,154. There were no differences in serious adverse events when women taking any bisphosphonate were compared with women taking placebo, or different bisphosphonate (or dose of the same bisphosphonate) (Table 14).

TABLE 14: SERIOUS ADVERSE EVENTS, PRIMARY PREVENTION POPULATIONS, BASE CASE (RELATIVE RISK)

Treatment Reference RR (95% CrI)

Alendronate (5 mg/day) Placebo 1.09 (0.67,1.69)

Alendronate (10 mg/day) Placebo 0.98 (0.72,1.31)

Risedronate Placebo 0.94 (0.60,1.45)

Etidronate Placebo 0.87 (0.48,1.58)

Zoledronic acid (5 mg/year) Placebo 0.88 (0.50,1.46)

Zoledronic acid (5 mg single dose) Placebo 0.94 (0.46,1.76)

Alendronate (10 mg/day) Alendronate (5 mg/day) 0.90 (0.54,1.54)

Risedronate Alendronate (5 mg/day) 0.86 (0.47,1.64)

Etidronate Alendronate (5 mg/day) 0.81 (0.38,1.69)

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Treatment Reference RR (95% CrI)

Zoledronic acid (5 mg/year) Alendronate (5 mg/day) 0.81 (0.41,1.60)

Zoledronic acid (5 mg single dose) Alendronate (5 mg/day) 0.86 (0.37,1.91)

Risedronate Alendronate (10 mg/day) 0.96 (0.62,1.44)

Etidronate Alendronate (10 mg/day) 0.89 (0.46,1.73)

Zoledronic acid (5 mg/year) Alendronate (10 mg/day) 0.90 (0.50,1.54)

Zoledronic acid (5 mg single dose) Alendronate (10 mg/day) 0.96 (0.46,1.87)

Etidronate Risedronate 0.93 (0.45,1.93)

Zoledronic acid (5 mg/year) Risedronate 0.94 (0.48,1.77)

Zoledronic acid (5 mg single dose) Risedronate 1.00 (0.45,2.14)

Zoledronic acid (5 mg/year) Etidronate 1.01 (0.46,2.18)

Zoledronic acid (5 mg single dose) Etidronate 1.07 (0.44,2.53)

Zoledronic acid (5 mg single dose) Zoledronic acid (5 mg/year) 1.06 (0.52,2.07) CrI = credible intervals; RR = relative risk; Etidronate= oral cyclic 400 mg/day; Placebo (includes no treatment or background supplementation); Risedronate= 5 mg/day or 35 mg/week or 150 mg/month

Sensitivity analyses

Investigating inconsistency noted in the base case analysis

When assessing results of the base case NMA, there was inconsistency in pooled estimates involving Hooper 2005 91. Further investigation highlighted a lower risk of fracture in women participating in this study. Hooper 2005 included either natural or surgical (hysterectomy without bilateral oophorectomy and aged 51–60 years) postmenopausal women. The women’s’ mean lumbar spine BMD T-score of -0.4 (SD 0.11) was higher than other studies included in the NMA. A sensitivity analysis excluding this study was conducted and no substantial differences were found in the results compared to the base case involving all studies (APPENDIX 13).

Gastrointestinal Adverse Events

Thirteen primary prevention RCTs involving 9,608 women reported gastrointestinal adverse events.34,38,59,79,89,91,93,114,131,138,147,153,154 None of the studies reporting this outcome included postmenopausal women taking zoledronic acid.

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Base case

The base case analysis included all 13 RCTs reporting gastrointestinal adverse events. There were no differences in gastrointestinal adverse events when women taking oral bisphosphonates were compared with women taking placebo or another oral bisphosphonate (Table 15).

TABLE 15: GASTROINTESTINAL ADVERSE EVENTS, PRIMARY PREVENTION POPULATIONS, BASE CASE (RELATIVE RISK)

Treatment Reference RR (95% CrI)

Alendronate (5 mg/day) Placebo 0.90 (0.68, 1.12)

Alendronate (10 mg/day) Placebo 1.04 (0.90, 1.19)

Risedronate Placebo 0.96 (0.73, 1.24)

Etidronate Placebo 0.55 (0.23, 1.13)

Alendronate (10 mg/day) Alendronate (5 mg/day) 1.15 (0.90, 1.55)

Risedronate Alendronate (5 mg/day) 1.07 (0.76, 1.55)

Etidronate Alendronate (5 mg/day) 0.61 (0.25, 1.33)

Risedronate Alendronate (10 mg/day) 0.93 (0.71, 1.19)

Etidronate Alendronate (10 mg/day) 0.53 (0.22, 1.10)

Etidronate Risedronate 0.57 (0.23, 1.23) CrI = credible intervals; RR = relative risk; Etidronate= oral cyclic 400 mg/day; Placebo (includes no treatment or background supplementation); Risedronate= 5 mg/day or 35 mg/week or 150 mg/month.

Osteonecrosis of the Jaw

Six studies including 2,327 women reported osteonecrosis of the jaw as a study outcome following use of alendronate or zoledronic acid (5 mg/year or 5 mg single dose). There were no events observed in women participating in any of the studies reporting the outcome (Table 16). Five studies had placebo comparators.37,82,83,107,115,170 One study assessed low dose of alendronate versus higher-dose alendronate (35 mg every 2 weeks versus 70 mg/week).107

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TABLE 16: OSTEONECROSIS OF THE JAW, PRIMARY PREVENTION POPULATIONS EXCLUDED FROM QUANTITATIVE SYNTHESIS

Treatment (number of women with event/number of women)

Zoledronic Zoledronic acid (5 Study Alendronate Alendronate Placebo acid (5 mg single dose) (5 mg/day) (10 mg/day) mg/year) Aro 2018 0/24 0/25

Black 2006 0/437 0/662

Grey 2010 0/25 0/25

Grey 2012 0/45 0/45

Li 2013 0/319 0/320

McClung 2009 0/202 0/198 Placebo (includes no treatment or background supplementation).

Atypical Femoral Fracture

No atypical femoral fractures were observed in 10 primary prevention populations of 2,947 postmenopausal women that reported the outcome.37,38,82,83,106,107,123,132,136,154 All but one study compared alendronate, risedronate, etidronate or zoledronic acid to placebo (Table 17). One study compared two different doses of alendronate (5 mg/day versus 10 mg/day). The longest duration of treatment was six years and involved intravenous zoledronic acid or a placebo solution given to women every 18 months for a total of four times.136

TABLE 17: ATYPICAL FEMORAL FRACTURE, PRIMARY PREVENTION POPULATIONS EXCLUDED FROM QUANTITATIVE SYNTHESIS

Treatment (number of women with event/number of women)

Zoledronic Zoledronic Study Alendronate Alendronate acid (5 mg Placebo Risedronate Etidronate acid (5 (5 mg/day) (10 mg/day) single mg/year) dose) Grey 2012 0/34 0/41

Grey 2010 0/25 0/25

Reid 2018 0/1000 0/1000

Aro 2018 0/24 0/25 Ascott-Evans 0/49 0/95 2003 Lewiecki 2007 0/46 0/47

Li 2013 0/319 0/320

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Treatment (number of women with event/number of women)

Zoledronic Zoledronic Study Alendronate Alendronate acid (5 mg Placebo Risedronate Etidronate acid (5 (5 mg/day) (10 mg/day) single mg/year) dose) Montessori 1997 0/40 0/40

Pouilles 1997 0/55 0/54

Välimäki 2007 0/55 0/115 Etidronate= oral cyclic 400 mg/day; Placebo (includes no treatment or background supplementation); Risedronate= 5 mg/day or 35 mg/week or 150 mg/month

Atrial Fibrillation

There were zero women with atrial fibrillation events in three primary prevention populations of 540 postmenopausal women using zoledronic acid (5 mg/year or 5 mg in a single dose) or placebo 82,83,115. Treatment durations of the 3 studies ranged from 12 months to 36 months (Table 18).

TABLE 18: ATRIAL FIBRILLATION, PRIMARY PREVENTION POPULATIONS EXCLUDED FROM QUANTITATIVE SYNTHESIS

Treatment (number of women with event/number of women) Study Zoledronic acid (5 Zoledronic acid (5 mg Placebo mg/year) single dose) Grey 2010 0/25 0/25 Grey 2012 0/42 0/45 Liang 2017 0/202 0/198 Placebo (includes no treatment or background supplementation).

RESULTS: SECONDARY PREVENTION POPULATIONS

Summary of Analyses

A total of 86 RCTs were classified as secondary prevention populations. Full results for all base case, sub group and sensitivity analyses are presented in APPENDIX 11. Base case NMAs were feasible and robust for 9 outcomes (Table 19). Many base case analyses excluded relevant studies, and many subgroup and sensitivity analyses were not feasible, due to the large number of studies reporting zero outcome events in one or more arms of the included studies. Descriptive summaries of results by outcome were summarized where frequencies of outcomes were reported.

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TABLE 19: SUMMARY OF OUTCOMES REPORTED IN SECONDARY PREVENTION POPULATIONS

No. studies reporting No. studies reporting included in Outcome outcome base case NMA

Total no. included studies classified as primary prevention = 85

Efficacy

Radiographic vertebral factures 15 13

Clinical vertebral fractures 16 4

Non-vertebral fractures 22 12

Hip fractures 10 9

Wrist fractures 20 5

Health related quality of life 4 2

Withdrawals due to adverse events 35 28

Serious adverse events 27 20

Gastrointestinal adverse events 21 21

Osteonecrosis of the jaw 6 NA

Atypical femoral fracture 18 NA

Atrial fibrillation 6 2

NA = Not applicable. NMA not conducted for the base case.

In post-menopausal women with a higher risk of fracture taking a bisphosphonate (from secondary prevention populations):

• data were available for four bisphosphonates: alendronate, risedronate, etidronate and zoledronic acid;

• a limited number of analyses were conducted due to the large proportion of studies reporting no events for the outcomes of interest;

In the analyses conducted, there were:

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o fewer radiographic vertebral fractures observed with alendronate (5 and 10 mg/day), risedronate and zoledronic acid (5mg/year), but not etidronate, when compared with placebo;

o fewer radiographic vertebral fractures observed with zoledronic acid when compared with risedronate;

o fewer radiographic vertebral fractures observed with denosumab in subgroup analyses when compared with both alendronate (5 mg/day) and risedronate (5 mg/day);

o fewer clinical vertebral and hip fractures observed with alendronate (10 mg/day) and zoledronic acid (5mg/year) when compared with placebo;

o fewer non-vertebral fractures observed with risedronate when compared with placebo;

o fewer withdrawals due to adverse events with zoledronic acid when compared with alendronate (10 mg/day);

o fewer gastrointestinal adverse events when zoledronic acid was compared with placebo, alendronate (10 mg/day) and risedronate;

o no differences in serious adverse events with alendronate (5 or 10 mg/day), risedronate, or zoledronic acid when compared with placebo or each other;

o no differences in health-related quality of life with alendronate (10 mg/day) and yearly zoledronic acid when compared with placebo or each other.

There was limited data available to assess atypical femoral fractures, osteonecrosis of the jaw, and atrial fibrillation.

NMA results are summarized in Table 20. Results from the NMA should be interpreted with caution for clinical and non-vertebral fractures, and wrist fractures given the limited number of studies reporting the outcome that were included in the base case analyses compared with the number of studies reporting the outcome.

TABLE 20: SUMMARY OF RESULTS FROM BASE CASE ANALYSES

No. Drugs included in secondary prevention analyses: studie Zoledronic Zoledronic Outcome Alendronate Alendronate Risedronate Etidronate s in acid 5 acid 5 mg 5 mg/day 10 mg/day 5 mg/day 400 mg/day NMA mg/year single dose Efficacy resultsa,b Radiographic Fewer Fewer Fewer Fewer Fewer women No difference vertebral 13 women with women with women with women with with fractures in any fractures fractures fractures fractures fractures compared to comparison

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No. Drugs included in secondary prevention analyses: studie Zoledronic Zoledronic Outcome Alendronate Alendronate Risedronate Etidronate s in acid 5 acid 5 mg 5 mg/day 10 mg/day 5 mg/day 400 mg/day NMA mg/year single dose compared to compared to compared to compared to placebo and placebo placebo placebo placebo risedronate Fewer Fewer women Clinical women with with fractures vertebral 4 NA fractures NA NA NA compared to fractures compared to placebo placebo Fewer No No No women with No difference Non-vertebral difference in difference in difference in 12 fractures in any NA fractures any any any compared to comparison comparison comparison comparison placebo Fewer No No Fewer women women with difference in difference in with fractures Hip fractures 9 NA fractures NA any any compared to compared to comparison comparison placebo placebo No No No difference in difference in difference in Wrist fractures 5 NA NA NA any any any comparison comparison comparison No No difference Health related difference in 2 NA NA NA in any NA quality of life any comparison comparison Safety resultsa,b No No No No Fewer women Withdrawals due difference in difference in difference in difference in with events to adverse 28 any any any any compared to NA events comparison comparison comparison comparison alendronate 10 mg/day No No No No difference No difference Serious adverse difference in difference in difference in in any in any 20 NA events any any any comparison comparison comparison comparison comparison Fewer women with events No No compared to No difference GI adverse difference in difference in placebo, 21 NA NA in any events any any alendronate comparison comparison comparison 10 mg/day and risedronate No difference No difference Atrial fibrillation 2 NA NA NA NA in any in any comparison comparison GI=gastrointestinal; NA=Not applicable (This drug was not included in the NMA for the outcome.)

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aResults showing fewer fractures/events indicate a pooled effect estimate and the associated credible interval for the drug in the column label did not include the null value. bResults showing no difference indicate a pooled effect estimate and the associated credible interval for the drug in the column label included the null value. Although results of the base case were robust to the additional subgroup and sensitivity analyses where feasible for some outcomes, limited conclusions can be made regarding:

• the efficacy and safety of alendronate, risedronate, etidronate and zoledronic acid in postmenopausal women at higher risk of fractures (in secondary prevention trials)

o compared with denosumab;

o who are bisphosphonate-naïve;

o with a contraindication to oral bisphosphonates.

• the effects of treatment duration;

• the impact of the classification approach compared with the 10-year CAROC fracture risk tool.

Radiographic Vertebral Fractures

Thirteen studies 40,43-46,60,70,87,110,113,126,150,155 reported radiographic vertebral fracture outcomes in 12,650 postmenopausal women. Two additional studies reported this outcome but were not included in analyses due to zero events in all study arms.141,143

Base case

In 13 studies reporting secondary prevention populations of postmenopausal women, alendronate (5 and 10mg/day), risedronate (5 mg/day), etidronate (400 mg/day), and zoledronic acid (5 mg/year) compared with placebo (RR range 0.32 to 0.58). The credible interval for the pooled effect estimates did not include the null value, and results indicated fewer fractures in women taking bisphosphonates compared to those taking placebo (Table 21). There were no differences in radiographic vertebral factures when zoledronic acid (5 mg single dose) was compared with placebo.

When the bisphosphonates were compared with each other, there were no differences except for zoledronic acid (5 mg/year) which had fewer fractures when compared with risedronate 5 mg/day (RR 0.55, 95% CrI 0.35 to 0.95).

TABLE 21: RADIOGRAPHIC VERTEBRAL FRACTURES, SECONDARY PREVENTION POPULATIONS, BASE CASE (RELATIVE RISK)

Treatment Reference RR (95% CrI)a

Alendronate 5 mg/day Placebo 0.56 (0.33, 0.89)

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Treatment Reference RR (95% CrI)a

Alendronate 10 mg/day Placebo 0.49 (0.33, 0.70)

Risedronate 5 mg/day Placebo 0.58 (0.42, 0.78)

Etidronate 400 mg/day Placebo 0.41 (0.16, 0.90)

Zoledronic acid (5 mg/year) Placebo 0.32 (0.22, 0.49)

Zoledronic acid (5 mg single dose) Placebo 0.73 (0.25, 1.98)

Alendronate 10 mg/day Alendronate 5 mg/day 0.88 (0.49, 1.62)

Risedronate 5 mg/day Alendronate 5 mg/day 1.04 (0.59, 1.90)

Etidronate 400 mg/day Alendronate 5 mg/day 0.73 (0.25, 1.92)

Zoledronic acid (5 mg/year) Alendronate 5 mg/day 0.57 (0.32, 1.13)

Zoledronic acid (5 mg single dose) Alendronate 5 mg/day 1.32 (0.39, 4.14)

Risedronate 5 mg/day Alendronate 10 mg/day 1.17 (0.73, 1.95)

Etidronate 400 mg/day Alendronate 10 mg/day 0.82 (0.30, 2.03)

Zoledronic acid (5 mg/year) Alendronate 10 mg/day 0.64 (0.39, 1.20)

Zoledronic acid (5 mg single dose) Alendronate 10 mg/day 1.49 (0.48, 4.47)

Etidronate 400 mg/day Risedronate 5 mg/day 0.70 (0.26, 1.65)

Zoledronic acid (5 mg/year) Risedronate 5 mg/day 0.55 (0.35, 0.95)

Zoledronic acid (5 mg single dose) Risedronate 5 mg/day 1.27 (0.41, 3.62)

Zoledronic acid (5 mg/year) Etidronate 400 mg/day 0.79 (0.33, 2.22)

Zoledronic acid (5 mg single dose) Etidronate 400 mg/day 1.81 (0.44, 7.77)

Zoledronic acid (5 mg single dose) Zoledronic acid (5 mg/year) 2.30 (0.72, 6.55) CrI = credible interval; RR = relative risk a Bolded and shaded results indicate a pooled effect estimate and associated 95% credible interval which does not include the null value.

There were zero observed radiographic vertebral fractures in the two studies not included in the base case NMA. One study141 compared alendronate (5 mg/day, n=38 women) with cyclic etidronate (400 mg/day, n=31) and the second143 compared alendronate (10 mg/day, n=25) with risedronate (5 mg/day, n=25).

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Subgroup analyses

Comparisons with denosumab

Base case analyses comparing the bisphosphonates with placebo were robust to the addition of one study comparing denosumab with placebo 60 and the denosumab arm of a study already in the network (Nakamura et al.,2014) were added to analysed with studies in the base case.

There were fewer radiographic vertebral fractures with denosumab (60 mg/6 months) when compared with placebo (RR 0.31, 95% CrI 0.21 to 0.43). There were fewer women with radiographic vertebral fracture event with denosumab compared with alendronate (5 mg/day or 35 mg/week [RR 0.53, 95% CrI 0.30 to 0.97]) and risedronate (5 mg/day or 35 mg/week or 150 mg/month [RR 0.54, 95% CrI 0.33 to 0.84]).

Effects of treatment duration

Subgroup analyses were utilized to examine the effects of treatment duration on observed outcomes. Five studies reported radiographic vertebral fractures at 12 months (44, 45, 88, 114, 134), 9 studies at 24 months (41, 44, 46, 47, 71, 114, 127, 151, 156), and 6 studies at 36 months (44, 45, 88, 111, 114, 134). There were fewer women with radiographic vertebral fractures across time points (12, 24 and 36 months) consistently observed with etidronate when compared with placebo. There were fewer women with radiographic vertebral fractures when alendronate 10 mg/day was compared with placebo at both 24 and 36 months. The risk of radiographic vertebral fractures with zoledronic acid 5 mg single injection was less compared with placebo at 12 and 36 months, but not at 24 months.

When the bisphosphates were compared with each other, there were fewer women with radiographic vertebral fractures at 36 months with zoledronic acid (5 mg/year) compared with risedronate 5 mg/day (RR 0.52, 95% CrI 0.28 to 0.96).

Interpretation of these differences is difficult given the limited number of studies reporting each bisphosphonate at each time point.

Bisphosphonate-naïve women

Six secondary prevention populations 43,45,46,110,133,155 of bisphosphonate-naïve postmenopausal women were included in a subgroup analysis. In this population, there were fewer radiographic vertebral fractures with alendronate 10 mg/day when compared with placebo (RR 0.49, 95% CrI 0.28 to 0.76). No other differences were observed when other bisphosphonates were compared to placebo or another bisphosphonate.

Contraindications to oral bisphosphonates

No studies reported radiographic vertebral fractures in postmenopausal women (or subgroups of women) who had contraindications to oral bisphosphonates.

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Sensitivity analyses

High methodologic quality studies

Of the 13 RCTs included in the base case analysis, none of the studies met the criteria for high methodological quality due to issues flagged during assessment with allocation concealment 40,44- 46,70,110,113,126,133,150,155 and incomplete outcome efficacy data.40,45 Five studies46,70,87,113,133 were judged to be at high risk of incomplete outcome data due to high attrition rates and/or the lack of appropriate methods of handling missing data.

Removal of studies classified as secondary prevention populations using age only

Among the secondary prevention base case studies, none were classified based only on age criteria.

Reclassification of studies using the CAROC levels of risk

All but 3 of the studies in postmenopausal women reporting radiographic vertebral fractures reported insufficient data on age and femoral neck BMD T-score at baseline and therefore, could not be reclassified using the CAROC 10-year fracture risk calculator.

There were differences noted in 3 studies87,126,150 that could be reclassified (all CAROC moderate risk, 2,277 women), fewer radiographic vertebral fractures were observed when risedronate was compared with placebo (RR 0.63, 95% CrI 0.45 to 0.86). No differences were observed when alendronate 5 mg/day and a single intravenous injection of zoledronic acid were compared with placebo or each other.

Clinical Vertebral Fractures

Sixteen RCTs reported clinical or symptomatic vertebral factures in secondary prevention populations (11,747 women) 35,43,44,46,54,75,104,108,109,111,130,141,151,158,159,162.

Base case

The base case analysis included four studies43,44,46,162 involving 10,006 women. Fewer clinical vertebral fractures were observed when women taking alendronate (RR 0.44, 95% CrI 0.20 to 0.98) and zoledronic acid (RR 0.21, 95% CrI 0.08 to 0.42) were compared with women taking placebo. There were no differences in clinical vertebral fractures when zoledronic acid was compared with alendronate (Table 22).

TABLE 22: CLINICAL VERTEBRAL FRACTURES, SECONDARY PREVENTION POPULATIONS, BASE CASE (RELATIVE RISK)

Treatment Reference RR (95% CrI)a

Alendronate 10 mg/day Placebo 0.44 (0.20, 0.98)

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Treatment Reference RR (95% CrI)a

Zoledronic acid 5 mg/year Placebo 0.21 (0.08, 0.42)

Zoledronic acid 5 mg/year Alendronate 10 mg/day 0.47 (0.14, 1.36) CrI = credible interval; RR = relative risk; Placebo (includes no treatment or background supplementation); a Bolded and shaded results indicate a pooled effect estimate and associated 95% credible interval which does not include the null value.

Twelve additional studies eligible for the base case reported zeroes in all study arms for clinical vertebral fractures and could not be included in the analyses (Table 23).

TABLE 23: CLINICAL VERTEBRAL FRACTURES, SECONDARY PREVENTION POPULATIONS EXCLUDED FROM QUANTITATIVE SYNTHESIS

Treatment (number of women with events/number of women) Zoledronic Study Alendronate (5 Alendronate Risedronate Etidronate 400 Placebo acid (5 mg/day) (10 mg/day) 5 mg/day mg/day mg/year) Russo 1996 0/38 0/31 Tan 2016 0/53 0/52 Chavez- Valencia 0/52 0/52 2014 Galesanu 0/132 0/132 2011 Akyol 2006 0/60 0/52 Paggiosi 0/57 0/58 2014 Qin 2007 0/25 0/22 Leung 2005 0/34 0/31 Li 2005 0/26 0/28 Liang 2017 0/95 0/155 Yan 2009 0/280 0/280 Yang 2015 0/50 0/50 Placebo (includes no treatment or background supplementation).

Subgroup analyses

Comparisons to denosumab

Two secondary prevention populations50,60 of denosumab were added to the base case NMA (18,993 women). Compared with placebo, both zoledronic acid (5 mg/year) (RR 0.21, 95% 0.09 to 0.41) and denosumab (60 mg every 60 months) (RR 0.30, 95% CrI 0.14 to 0.61) showed fewer clinical vertebral fractures. There were no differences in clinical vertebral fractures when alendronate 10 mg/day was compared with placebo, or when any of the drugs (alendronate 10 mg/day,

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denosumab 60 mg/6 months and zoledronic acid 5 mg/year) were compared with each other. One additional study involving denosumab could not be included in the NMA140 as there were zero fractures reported in one treatment arm which cause statistical instability in the NMA. This study reported zero clinical vertebral fractures in the risedronate group (5 mg/d, 429 women) and one clinical vertebral fracture in the denosumab group (60 mg/6 months, 429 women).

Effects of treatment duration

The large number of studies reporting zero events limited the subgroup analyses based on treatment duration. At 12 months on treatment, a single study reported zero clinical vertebral fractures in 50 women allocated to 5 mg/year zoledronic acid and 6 women with fractures in 51 women receiving placebo162. At 24 months, a single study reported clinical vertebral fracture in 1 woman in both of the placebo (50 women) and alendronate 10 mg/day groups (92 women) 46.

A subgroup NMA was conducted using two studies providing clinical vertebral fracture outcomes in women at 36 months43,44. When compared with placebo, there were fewer clinical vertebral fractures in women taken zoledronic acid (5 mg, yearly) when compared with women taking placebo (RR 0.23, 95% CrI 0.08 to 0.62). No differences were observed when alendronate 10 mg/day was compared with placebo or zoledronic acid.

Bisphosphonate-naïve women

Two secondary prevention populations reported clinical vertebral fracture outcomes in study population of bisphosphonate-naïve women 43,46 taking alendronate 10 mg/day or placebo. Meta- analysis pooling study results showed fewer clinical vertebral fracture in women taking alendronate when compared with women taking placebo (RR 0.48, 95% CI 0.30 to 0.77).

Contraindications to oral bisphosphonates

No secondary prevention populations reporting clinical vertebral fracture outcomes included women with contraindications to oral bisphosphonates.

Sensitivity analyses

High methodologic quality studies

Two studies reporting women with clinical vertebral fractures in secondary prevention populations were assessed to be of high methodological quality. No quantitative analysis was feasible. One study 162 reported zero clinical vertebral fractures in 50 women allocated to 5 mg/year zoledronic acid and 6 women with fractures in the 51 women taking placebo. The second RCT evaluated clinical vertebral fractures in 2,027 women allocated to alendronate 10 mg/day (2%, 23/1022) or placebo (5%, 50/1005) 43 .

Removal of studies classified as secondary prevention populations using age only

None of the studies reporting clinical vertebral fractures were classified as secondary prevention based only on participant age at baseline.

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Reclassification of studies using the CAROC levels of risk

Most studies reporting clinical vertebral fractures did not provide sufficient baseline age and T-score values to permit re-classification of fracture risk using the CAROC tool. In five studies where reclassification was feasible, four were re-classified as CAROC low risk 35,106,111,154 and one was reclassified as CAROC moderate risk.104 All five RCTs reported zero clinical vertebral fractures in all study arms and therefore, no analysis was feasible.

Non-Vertebral Fractures

Twenty-two studies 35,43,44,54,70,75,87,104,108,109,111,113,117,121,126,133,141,143,149,151,158,159 reported non- vertebral fractures in 24,787 postmenopausal women using bisphosphonates.

Base case

The base case analysis for non-vertebral fractures included 12 RCTs involving 23,451 postmenopausal women.43,44,70,87,111,113,117,121,126,133,149,158 Differences in the risk of non-vertebral fractures were observed when risedronate was compared with placebo (RR 0.75, 95% CrI 0.54 to 0.94). No other differences were observed when women using alendronate, etidronate or zoledronic acid were compared with women taking placebo or a different bisphosphonate drug (or dose) (Table 24

TABLE 24: NON-VERTEBRAL FRACTURES, SECONDARY PREVENTION POPULATIONS, BASE CASE (RELATIVE RISK)

Treatment Reference RR (95% CrI)a

Alendronate (5 mg/day) Placebo 0.58 (0.19, 1.40)

Alendronate (10 mg/day) Placebo 0.73 (0.44, 1.05)

Etidronate (400 mg/day) Placebo 0.66 (0.25, 1.64)

Risedronate Placebo 0.75 (0.54, 0.94)

Zoledronic acid (5 mg/year) Placebo 0.74 (0.49, 1.13)

Alendronate (10 mg/day) Alendronate (5 mg/day) 1.26 (0.46, 4.05)

Etidronate (400 mg/day) Alendronate (5 mg/day) 1.16 (0.30, 4.92)

Risedronate Alendronate (5 mg/day) 1.30 (0.50, 3.95)

Zoledronic acid (5 mg/year) Alendronate (5 mg/day) 1.29 (0.48, 4.12)

Etidronate (400 mg/day) Alendronate (10 mg/day) 0.92 (0.33, 2.53)

Risedronate Alendronate (10 mg/day) 1.03 (0.64, 1.75)

Zoledronic acid (5 mg/year) Alendronate (10 mg/day) 1.01 (0.60, 2.03)

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Treatment Reference RR (95% CrI)a

Risedronate Etidronate (400 mg/day) 1.12 (0.43, 3.03)

Zoledronic acid (5 mg/year) Etidronate (400 mg/day) 1.12 (0.41, 3.18)

Zoledronic acid (5 mg/year) Risedronate 0.98 (0.63, 1.73) CrI = credible interval; RR = relative risk Placebo (includes no treatment or background supplementation); Risedronate = 5 mg/day or 35 mg/week or 150 mg/month. a Bolded and shaded results indicate a pooled effect estimate and associated 95% credible interval which does not include the null value.

A total of 10 RCTs (1,336 women) were not be included in the base case analysis as they reported zero non-vertebral fractures in both study arms, which caused instability in the statistical model 35,54,75,104,108,109,141,143,151,159. Results are presented in Table 25.

TABLE 25: NON-VERTEBRAL FRACTURES, SECONDARY PREVENTION POPULATIONS EXCLUDED FROM QUANTITATIVE SYNTHESIS

Treatment (number of women with event/number of women) Zoledronic Study Alendronate Alendronate Placebo Risedronate Etidronate acid (5 (5 mg/day) (10 mg/day) mg/year) Akyol 2006 0/60 0/52 Chavez-Valencia 2014 0/52 0/52 Galesanu 2011 0/132 0/132 Leung 2005 0/34 0/31 Li 2005 0/26 0/28 Liang 2017 0/95 0/155 Russo 1996 0/38 0/31 Sarioglu 2006 0/25 0/25 Tan 2016 0/53 0/52 Yang 2015 0/50 0/50 Etidronate= oral cyclic 400 mg/day; Placebo (includes no treatment or background supplementation); Risedronate= 5 mg/day or 35 mg/week or 150 mg/month.

Subgroup analyses

Comparisons with denosumab

Three denosumab studies60,72,100 and a denosumab arm from a study already included 126 were added to the base case NMA (32,476 women). Base case results were robust to inclusion of the denosumab study data and differences were observed when alendronate (10mg/day) was compared with placebo (RR 0.71, 95% CrI 0.48 to 0.99). No differences in the risk of non-vertebral fracture were observed in women taking denosumab when compared with women taking placebo or a bisphosphonate.

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Effects of treatment duration

Subgroup analyses were utilized to examine the effects of treatment duration on observed outcomes. Six studies reported non-vertebral fractures at 12 months 43,44,87,111,133,158, 5 studies at 24 months 70,87,121,126,133, 6 studies at 36 months 43,44,87,117,133,149, and 1 study each at 48 and 60 months.

No differences in risk of non-vertebral fractures were observed at 12 or 36 months when postmenopausal women using bisphosphonates were compared with women taking placebo or a different bisphosphonate drug (or dose). Similar to the base case, differences in the risk of non- vertebral fractures were observed when risedronate was compared with placebo (RR 0.65, 95% CrI 0.42 to 0.98) at 24 months.

Although analysis was not feasible for studies reporting this outcome at 48 months, higher frequencies of non-vertebral fractures were reported in postmenopausal women in the placebo arms of three studies involving comparisons to etidronate and to risedronate. After 4 years, Lyritis et al.113 observed more non-vertebral fractures in women in the placebo arm (5/50, 10%) compared with the etidronate arm (3/50, 6%). An extension study209 of the Reginster et al RCT133 observed more women with non-vertebral fractures in the placebo arm (11/129, 9%) compared with risedronate (7/135, 5%) during the 2-year extension period (year 4 to 5) although a large proportion of the included women were lost to follow up (552/864, 68%).

Bisphosphonate-naïve women

Four secondary prevention populations 43,111,133,149 involving 2,952 bisphosphonate-naïve postmenopausal women were included in a subgroup NMA for non-vertebral fractures. In this population, no differences the risk of non-vertebral fracture were observed when bisphosphonates (alendronate 10mg/day, risedronate 5 mg/day, etidronate 400 mg) were compared with placebo or each other.

A single study of bisphosphonate-experienced women121 reported higher frequencies of non- vertebral fractures in women taking placebo (2/33, 6%) when compared with women taking alendronate 10 mg/day (1/33, 3%).

Contraindications to oral bisphosphonates

No studies reported non-vertebral fractures in women (or subgroups of women) who had contraindications to oral bisphosphonates.

Sensitivity analyses

High methodologic quality studies

Black et al. (1996) was the only study assessed to be of high methodological quality43. The study compared alendronate 10 mg/day to placebo in 2,027 women.

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Removal of studies classified as secondary prevention populations using age only

None of the studies reporting non-vertebral fractures were classified as secondary prevention based only on participant age at baseline.

Reclassification of studies using the CAROC levels of risk

Women from six studies reporting non-vertebral fractures were reclassified using the CAROC calculator. In 3 studies of 262 women reclassified as having CAROC low fracture risk106,111,154 and 2 studies of 2,349 women reclassified as having CAROC moderate fracture risk87,126 there were no differences in the risk of non-vertebral fracture observed when bisphosphonates were compared with placebo or to each other. Women in a single study117 reclassified as having CAROC high fracture risk, there was a higher frequency of non-vertebral factures observed in women receiving placebo (351/3134, 11%) compared with women receiving risedronate (583/6197, 9%).

Hip Fractures

A total of 25 RCTs reported hip fractures in 25,584 women studied in secondary prevention populations 40,43,44,53,81,110,113,117,155,35,46,54,69,75,104,108,109,111,126,130,141,143,151,158,159 were included in the base case NMA.

Base case

The base case analysis for hip fractures included 9 RCTs involving 21,903 postmenopausal women.40,43,44,53,81,110,113,117,155 Women receiving alendronate (RR 0.45, 95% CrI 0.21to 0.87) and zoledronic acid (RR 0.58, 95% CrI 0.38 to 0.88) were observed to have differences in the risk of hip fracture compared with women taking placebo (Table 26). No differences in hip fracture were observed when women taking risedronate or etidronate were compared with those taking placebo, or when women taking any bisphosphonate were compared with women taking another bisphosphonate.

TABLE 26: HIP FRACTURES, SECONDARY PREVENTION POPULATIONS, BASE CASE (RELATIVE RISK)

Treatment Reference RR (95% CrI)a

Alendronate (10 mg/day) Placebo 0.45 (0.21, 0.87)

Risedronate Placebo 0.73 (0.43, 1.21)

Etidronate Placebo 0.78 (0.10, 4.51)

Zoledronic acid (5 mg/year) Placebo 0.58 (0.38, 0.88)

Risedronate Alendronate (10 mg/day) 1.64 (0.70, 4.10)

Etidronate Alendronate (10 mg/day) 1.76 (0.19, 11.42)

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Treatment Reference RR (95% CrI)a

Zoledronic acid (5 mg/year) Alendronate (10 mg/day) 1.30 (0.60, 3.18)

Etidronate Risedronate 1.08 (0.13, 6.72)

Zoledronic acid (5 mg/year) Risedronate 0.80 (0.41, 1.52)

Zoledronic acid (5 mg/year) Etidronate (400 mg/day) 0.74 (0.12, 6.41) CrI = credible interval; RR = relative risk. Etidronate= oral cyclic 400 mg/day; Placebo (includes no treatment or background supplementation); Risedronate= 5 mg/day or 35 mg/week or 150 mg/month. a Bolded and shaded results indicate a pooled effect estimate and associated 95% credible interval which does not include the null value.

An additional 16 RCTs (2,681 women)35,46,54,69,75,104,108,109,111,126,130,141,143,151,158,159 reporting zero hip fractures in one or more study arms that could not be included in the NMA are described Table 27. In one RCT by Nakamura et al.126, two women with hip fractures were reported in the 480 women receiving placebo and in zero in the 242 women receiving alendronate (5mg/day) after 24 months.

TABLE 27: HIP FRACTURES, SECONDARY PREVENTION POPULATIONS EXCLUDED FROM QUANTITATIVE SYNTHESIS

Treatment (number of women with event/number of women) Zoledronic Study Alendronate Alendronate Placebo Risedronate Etidronate acid (5 (5 mg/day) (10 mg/day) mg/year) Nakamura 2014 2/480 0/242 Chavez-Valencia 2014 0/52 0/52 Qin 2007 0/25 0/22 Galesanu 2011 0/132 0/32 Sarioglu 2006 0/25 0/25 Bone 2000 0/50 0/92 Leung 2005 0/34 0/31 Li 2005 0/26 0/28 Liang 2017 0/95 0/155 Yan 2009 0/280 0/280 Yang 2015 0/50 0/50 Fogelman 2015 0/10 0/12 Akyol 2006 0/60 0/52 Paggiosi 2014 0/57 0/58 Russo 1996 0/38 0/31 Tan 2016 0/53 0/52 Etidronate= oral cyclic 400 mg/day; Placebo (includes no treatment or background supplementation); Risedronate= 5 mg/day or 35 mg/week or 150 mg/month.

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Subgroup analyses

Comparisons with denosumab

Results from the base case were robust to the addition of 2 denosumab RCTs into the NMA. One study compared denosumab with placebo60 and another compared denosumab with risedronate140. No differences in hip fractures were observed when postmenopausal women taking denosumab were compared with those taking placebo or any bisphosphonate drug (11 RCTs, 30,533 women).

Effects of treatment duration

Subgroup NMAs were utilized to examine the effects of treatment duration on hip fracture outcomes at 24 months40,81(2 RCTs, 810 women) and 36 months43,44,53,110,117 (5 RCTs, 20,748 women). There were no differences in risk of hip fracture when alendronate 10 mg/day and zoledronic acid 5 mg/year were compared with placebo at 24 months. At 36 months of treatment, there fewer hip fractures in women taking alendronate (10 mg/day or 70 mg/week) compared with women taking placebo (RR 0.43, 95% CrI 0.18 to 0.95). There were no differences at 36 months when zoledronic acid and risedronate were compared with placebo or with each other.

Analyses at other reported time points (12 months and 48 months) was not feasible due to the small number of studies reporting hip fractures at each time point and the high frequency of zero events on one or more study arms. At 12 months. four studies 43,75,130,151 reported hip fracture outcomes; however, only one RCT43 had non-zero events in a comparison of alendronate 5mg/d (11/3105, 0.4%) with placebo (15/3081, 0.5%]. At 48 months, Lyrtis et al. reported two woman in the placebo group with a hip fracture (2/50) compared with one women with a hip fracture in those taking etidronate ([1/50] 113.

Bisphosphonate-naïve women

Three placebo-controlled RCTs43,81,110 of alendronate were included in a subgroup meta-analysis including 3,348 bisphosphonate-naïve postmenopausal women. When pooled, fewer hip fractures were observed in women taking alendronate (10 mg/day) when compared with women assigned to placebo (RR 0.48, 95% CI 0.26 to 0.91, I2 = 0%).

Contraindications to oral bisphosphonates

None of the secondary prevention populations reporting hip fractures reported the inclusion of postmenopausal women with contraindications to oral bisphosphonates.

Sensitivity analyses

High methodologic quality studies

Sensitivity analysis was not feasible as only one RCT was assessed to be of high methodological quality 43. In that study, 2.2% (22/1005) of placebo-treated women and 1.1% (11/1022) alendronate- treatments (10 mg/day) women sustained hip fractures.

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Removal of studies classified as secondary prevention populations using age only

Base case analyses were robust to the removal of one RCT from the evidence network that was classified as a secondary prevention study using only baseline age greater or equal to 75 years81.

Reclassification of studies using the CAROC levels of risk

Seven studies were re-classified to CAROC of categories of low35,106,111,154, moderate104,126 or high117 10 year fracture risk, however, no additional analyses were feasible. All CAROC-low risk studies reported zero hip fractures in all study arms. In the 2 CAROC moderate risk studies, Nakamura et al. 126 observed 2 hip fractures in 480 women taking placebo and 0 in 242 women taking alendronate (5 mg/day), while Leung et al. observed 0 hip fractures in 34 placebo-treated and 31 risedronate- treated women104. A single RCT classified women as high risk for fracture using CAROC117 reported hip fractures among women receiving placebo (95/3134, 3%) or receiving risedronate (137/6197, 2%).

Wrist Fractures

Twenty secondary prevention populations reported wrist fracture outcomes in 6,247 women.35,43,46,54,69,75,85,87,98,104,108,109,111,113,141,143,149,151,158,159

Base case

The base case analysis for wrist fractures included 5 RCTs involving 4,456 postmenopausal women.43,46,87,113,158 When alendronate, risedronate and etidronate were compared with placebo and each other, there were no differences in risk of wrist fracture (Table 28).

TABLE 28: WRIST FRACTURES, SECONDARY PREVENTION POPULATIONS, BASE CASE (RELATIVE RISK)

Treatment Reference RR (95% CrI)

Alendronate (10 mg/day) Placebo 0.64 (0.31,2.32)

Risedronate Placebo 0.63 (0.20,1.97)

Etidronate (400 mg/day) Placebo 0.88 (0.09,7.71)

Risedronate Alendronate (10 mg/day) 0.98 (0.16,3.48)

Etidronate (400 mg/day) Alendronate (10 mg/day) 1.33 (0.10,13.16)

Etidronate (400 mg/day) Risedronate 1.39 (0.11,15.83) CrI = credible interval; RR = relative risk Placebo (includes no treatment or background supplementation); Risedronate= 5 mg/day or 35 mg/week or 150 mg/month.

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Fifteen studies 35,54,69,75,85,98,104,108,109,111,141,143,149,151,159 reporting zero wrist fractures in one or both study arms were not included in base case analysis (Table 29) as they caused statistical instability in the network model.

TABLE 29: WRIST FRACTURES, SECONDARY PREVENTION POPULATIONS EXCLUDED FROM QUANTITATIVE SYNTHESIS

Treatment (number of women with events/number of women) Zoledronic Study Alendronate Alendronate Etidronate Etidronate Placebo Risedronate acid (5 (5 mg/d) (10 mg/d) (200mg/d) (400mg/d) mg/yr) Hadji 2012 1/194 0/408 Akyol 2006 0/60 0/52 Chavez- Valencia 0/52 0/52 2014 Fogelman 0/10 0/12 2015 Galesanu 0/132 0/32 2011 Iwamoto 0/25 0/25 2005 Leung 2005 0/34 0/31 Li 2005 0/26 0/28 Liang 2017 0/95 0/155 Qin 2007 0/25 0/22 Russo 1996 0/38 0/31 0/31 Sarioglu 0/25 0/25 2006 Storm 1990 0/33 0/33 Tan 2016 0/53 0/52 Yang 2015 0/50 0/50 d=day; yr=year Placebo (includes no treatment or background supplementation); Risedronate= 5 mg/day or 35 mg/week or 150 mg/month.

Subgroup analyses

Comparisons with denosumab

Results from the base case were robust to the addition of two denosumab studies. One study compared denosumab with placebo60 and second compared denosumab with alendronate 10 mg/day50. In the subgroup analysis NMA (7 RCTs, 13,443 women), no difference in the risk of wrist fractures were observed when women taking denosumab were compared with women taking placebo or a bisphosphonate.

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Effects of treatment duration

At 12 months, 4 studies reported 3 women with wrist fractures. No analyses were feasible. The reported comparisons and events included: alendronate 10 mg/day (1/194, 0.5%) versus zoledronic acid 5 mg/year (0/408)85; alendronate 10 mg/day (2/280) versus placebo (0/280)158 ; alendronate 10 mg/day (0/132) versus risedronate 5 mg/day (0/32)75; and alendronate 10 mg/day (0/53) versus zoledronic acid 5 mg/year (0/52)151.

At 24 months, three studies observed a single wrist fracture in women treated with alendronate 10 mg/day. No analyses were feasible. The reported comparisons and events included: alendronate 10 mg/day (1/92, 1%) versus placebo (0/50)46; alendronate 10 mg/day (0/132) versus risedronate 5 mg/day (0/32)75; and alendronate 10 mg/day (0/53) versus zoledronic acid 5 mg/year (0/52)151.

At 36 months there were no differences in risk of wrist fractures with placebo, alendronate 10 mg/day or risedronate 5 mg/day when 2 studies reporting wrist fractures were compared using NMA43,87 (3,654 women).

At 48 months, Lyritis et al.113 reported the same number of women with wrist fractures in both arms of the study (etidronate 2/50 women, placebo 2/50 women).

Bisphosphonate-naïve women

In a meta-analysis of two studies of bisphosphonate-naïve postmenopausal women43,46, the pooled effect estimate showed a reduced risk of wrist fractures in women taking alendronate 10 mg/day when compared with placebo (RR 0.57, (95% CI 0.34 to 0.94, I2 0%).

Contraindications to oral bisphosphonates

None of the secondary prevention populations with wrist fracture outcomes reported the inclusion of women with contraindications to oral bisphosphonates.

Sensitivity analyses

High methodologic quality studies

Of five studies included in base case NMA43,46,87,113,158, only one RCT43 of alendronate 10 mg/day versus placebo met all criteria for high methodological quality.

Removal of studies classified as secondary prevention populations using age only

None of the secondary prevention populations included in base case NMA were defined by age. No sensitivity analysis was required.

Reclassification of studies using the CAROC levels of risk

Seven RCTs were reclassified as low35,69,106,154 or moderate85,87,104 CAROC 10-year fracture risk; Two of these studies reported fracture events in both arms. The remaining studies reported zero

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fractures in one or both groups. Välimäki et al.154, re-defined as a CAROC- low fracture risk study, reported 1 woman each in both the placebo (n=55) and risedronate (n=115) groups was observed to have a wrist fracture. Harris et al.87, re-defined as a CAROC-moderate fracture risk study, reported 22 wrist fractures in 815 (2.7%) placebo-treated women and 14 wrist fractures among 812 (1.7%) risedronate-treated women. In this 3-year study, the incidences were reported as adverse events and not tested for statistical significance. It was assessed to be at high risk of bias in the domain of incomplete outcome data due to high attrition (689/1628,42%).

Health related Quality of Life (HRQoL)

Three RCTs measured quality of life metrics using a variety of instruments, including the “quality of Life Scale”, the Mini Osteoporosis Quality of Life questionnaire, and the Qualeffo-41 questionnaire.44,85,94

Hu et al.94 assessed HRQoL in postmenopausal women taking placebo or risedronate using the “Quality of Life (QOL) Scale” which consists of 5 domains: disease, physical, social, psychologic, and satisfaction. Additional details about the instrument were not provided by study authors and the study-specific HRQoL total change scores in the 3 arms were not reported or compared. The study authors reported only that the total QOL score for the risedronate arm was higher compared with the placebo arm (P<0.001).

Sambrook et al.207 (a companion publication to HORIZONR-PFT study44 comparing zoledronic acid 5 mg/year versus placebo for three years) used the Mini-Osteoporosis Quality of Life Questionnaire in a subset (n=1,422) of the 7,765 women originally included in the study who lived in countries where English was their native language. Study-level results indicated no difference between the study arms using the overall summary score. Benefits were observed with zoledronic acid in certain subdomains, and notably in subgroups of women sustaining incident clinical fractures. Women with prevalent vertebral fractures at baseline had a lower baseline HRQoL (p<0.001).

Hadji et al.188 (a companion publication to the ROSE study 85) used the Qualeffo-41 questionnaire to assess women’s’ QoL after use of zoledronic acid (5 mg/year) or alendronate (70 mg/week). Results showed no significant differences between zoledronic acid and alendronate. Change from baseline to month 12 for zoledronic acid was -1.28.8 standard deviation (SD) and for alendronate -0.69.0 SD, with negative changes indicating improvement in HRQoL. Effect estimates were not reported. A post-hoc analysis indicated improvements in total quality of life with zoledronic acid in patients with previous fractures.

Hadji et al. and Sambrook et al. were included in the base case NMA for HRQoL. No differences in HRQoL were found in women receiving placebo, alendronate, or zoledronic acid (Table 30).

TABLE 30: HEALTH RELATED QUALITY OF LIFE, SECONDARY PREVENTION POPULATIONS, BASE CASE (RELATIVE RISK)

Treatment Reference SMD (95% CrI)

Alendronate (10 mg/day) Placebo 0.15 (-8.68,8.98)

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Treatment Reference SMD (95% CrI)

Zoledronic acid (5 mg/year) Placebo 0.06 (-6.22,6.27)

Zoledronic acid (5 mg/year) Alendronate (10 mg/day) -0.09 (-6.39,6.12) CrI = credible interval; SMD = standardized mean difference; Placebo (includes no treatment or background supplementation).

Withdrawal due to Adverse Events

Thirty-five secondary prevention populations reported the outcome of withdrawals due to adverse events.39,42,44,46,48,52,54,58,63-65,67,69-71,78,85,87,90,92,102,103,108,109,113,121,126,133,134,142,149,151,155,158,159

Base case

The base case analysis included 28 RCTs involving 16,362 women.42,44,46,48,52,54,58,63,64,67,70,71,78,85,87,90,92,102,103,108,126,133,134,142,149,155,158,159 . Women taking zoledronic acid (5 mg/year) who were less likely to withdraw from the study due to adverse events when compared with alendronate (10 mg/day; RR 0.50, 95% CrI 0.23, 0.92) (Table 31). No differences in risk of withdrawals due to adverse events were observed between any of the other treatments.

TABLE 31: WITHDRAWAL DUE TO ADVERSE EVENTS, SECONDARY PREVENTION POPULATIONS, BASE CASE (RELATIVE RISK)

Treatment Reference RR (95% CrI)a

Alendronate (5 mg/day) Placebo 1.63 (0.18,8.78)

Alendronate (10 mg/day) Placebo 1.30 (0.94,1.82)

Risedronate Placebo 1.14 (0.80,1.68)

Etidronate (400 mg/day) Placebo 0.64 (0.24,1.61)

Zoledronic acid (5 mg/year) Placebo 0.66 (0.30,1.16)

Alendronate (10 mg/day) Alendronate (5 mg/day) 0.79 (0.15,7.70)

Risedronate Alendronate (5 mg/day) 0.70 (0.13,6.89)

Etidronate (400 mg/day) Alendronate (5 mg/day) 0.39 (0.06,4.32)

Zoledronic acid (5 mg/year) Alendronate (5 mg/day) 0.39 (0.06,3.96)

Risedronate Alendronate (10 mg/day) 0.88 (0.58,1.35)

Etidronate (400 mg/day) Alendronate (10 mg/day) 0.49 (0.17,1.26)

Zoledronic acid (5 mg/year) Alendronate (10 mg/day) 0.50 (0.23,0.92)

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Treatment Reference RR (95% CrI)a

Etidronate (400 mg/day) Risedronate 0.56 (0.19,1.49)

Zoledronic acid (5 mg/year) Risedronate 0.57 (0.24,1.09)

Zoledronic acid (5 mg/year) Etidronate (400 mg/day) 1.02 (0.31,3.11) CrI = credible interval; RR = relative risk Placebo (includes no treatment or background supplementation); Risedronate = 5 mg/day or 35 mg/week or 150 mg/month. a Bolded and shaded results indicate a pooled effect estimate and associated 95% credible interval which does not include the null value.

Seven studies 39,65,69,109,113,121,151 did not contribute data to the base case analysis as they reported zero women withdrawing from the study due to adverse events in all study arms and their inclusion led to statistical instability in the model (Table 32).

TABLE 32: WITHDRAWAL DUE TO ADVERSE EVENTS, SECONDARY PREVENTION POPULATIONS EXCLUDED FROM QUANTITATIVE SYNTHESIS

Treatment (number of women with event/number of women) Zoledronic Study Alendronate (5 Alendronate Placebo Risedronate Etidronate acid (5 mg/day) (10 mg/day) mg/year) Michalska 2006 0/33 0/33 Fogelman 2015 0/12 0/14 Lyritis 1997 0/50 0/50 Dundar 2009 0/20 0/41 Liang 2017 0/110 0/175 Atmaca 2006 0/16 0/14 Tan 2016 0/53 0/52 Etidronate= oral cyclic 400 mg/day; Placebo (includes no treatment or background supplementation); Risedronate= 5 mg/day or 35 mg/week or 150 mg/month.

Sensitivity analyses

Investigating inconsistency noted in the base case analysis

When assessing results of the base case analyses, there was inconsistency in direct and indirect estimates involving Sahota 2000142. Further investigation flagged potential causes for identified inconsistency, including different drug delivery schedules (daily alendronate 10 mg compared with cyclic etidronate 400 mg), or the possibility that zero events in the study arms may have exaggerated the issue. Sensitivity analysis excluding the Sahota 2000 study did not result in any substantial differences in results (APPENDIX 13).

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Serious Adverse Events

Twenty-seven secondary prevention populations evaluated serious adverse events in 23,178 women.39,40,42,44-46,48,58,64,67,69,70,85,87,92,104,109,110,113,117,126,130,133,134,141,150,160

Base case

The base case for serious adverse events included 20 secondary prevention populations including 22,551 postmenopausal women40,42,44-46,48,58,64,67,70,85,87,92,110,117,126,130,133,134,150. None of the studies reported serious adverse events in women taking etidronate. No differences in risk of serious adverse events were observed when women taking bisphosphonates were compared with women taking placebo or a different bisphosphonate (Table 33).

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TABLE 33: SERIOUS ADVERSE EVENTS, SECONDARY PREVENTION POPULATIONS, BASE CASE (RELATIVE RISK)

Treatment Reference RR (95% CrI)

Alendronate (5 mg/day) Placebo 0.77 (0.54, 1.08)

Alendronate (10 mg/day) Placebo 0.84 (0.69, 1.01)

Risedronate Placebo 1.01 (0.89, 1.15)

Zoledronic acid (5 mg/year) Placebo 0.95 (0.77, 1.12)

Zoledronic acid (5 mg single dose) Placebo 1.32 (0.76, 2.12)

Alendronate (10 mg/day) Alendronate (5 mg/day) 1.08 (0.74, 1.59)

Risedronate Alendronate (5 mg/day) 1.31 (0.92, 1.93)

Zoledronic acid (5 mg/year) Alendronate (5 mg/day) 1.22 (0.83, 1.84)

Zoledronic acid (5 mg single dose) Alendronate (5 mg/day) 1.71 (0.88, 3.09)

Risedronate Alendronate (10 mg/day) 1.21 (0.99, 1.50)

Zoledronic acid (5 mg/year) Alendronate (10 mg/day) 1.13 (0.88, 1.44)

Zoledronic acid (5 mg single dose) Alendronate (10 mg/day) 1.58 (0.89, 2.65)

Zoledronic acid (5 mg/year) Risedronate 0.94 (0.73, 1.15)

Zoledronic acid (5 mg single dose) Risedronate 1.30 (0.74, 2.12)

Zoledronic acid (5 mg single dose) Zoledronic acid (5 mg/year) 1.40 (0.79, 2.32) CrI = credible interval; RR = relative risk; Placebo (includes no treatment or background supplementation); Risedronate= 5 mg/day or 35 mg/week or 150 mg/month.

Seven secondary prevention populations 39,69,104,109,113,141,160 reporting serious adverse events did not contribute data to the base case analysis as they reported zeroes in both study arms and their inclusion led to statistical instability in the model (Table 34).

TABLE 34: SERIOUS ADVERSE EVENTS, SECONDARY PREVENTION POPULATIONS EXCLUDED FROM QUANTITATIVE SYNTHESIS

Treatment (number of women with event/number of women) Zoledronic Study Alendronate (5 Alendronate Placebo Risedronate Etidronate acid (5 mg/day) (10 mg/day) mg/year) Atmaca 2006 0/16 0/14 Fogelman 2015 0/10 0/12 Leung 2005 0/34 0/31 Liang 2017 0/95 0/155

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Treatment (number of women with event/number of women) Zoledronic Study Alendronate (5 Alendronate Placebo Risedronate Etidronate acid (5 mg/day) (10 mg/day) mg/year) Lyritis 1997 0/50 0/50 Russo 1996 0/38 0/31 Yanik 2008 0/47 0/44 Etidronate= oral cyclic 400 mg/day; Placebo (includes no treatment or background supplementation); Risedronate= 5 mg/day or 35 mg/week or 150 mg/month.

Gastrointestinal Adverse Events

A total of 21 secondary prevention populations evaluated gastrointestinal events in 16,370 women taking bisphosphonates or placebo 42,43,45,46,48,64,67,70,71,81,85,87,92,103,104,110,117,121,133,134,158.

Base case

The base case analyses for gastrointestinal adverse events included all 21 secondary prevention populations.42,43,45,46,48,64,67,70,71,81,85,87,92,103,104,110,117,121,133,134,158. There were fewer gastrointestinal adverse events with zoledronic acid (5 mg/year) when compared with women taking placebo (RR 0.64, 95% CrI 0.42 to 0.93), alendronate (10 mg/day) (RR 0.60, 95% CrI 0.41 to 0.88), or risedronate (RR 0.64, 95% CrI 0.42, 0.94) (Table 35). No studies of etidronate reported this outcome and no other differences were observed.

TABLE 35: GASTROINTESTINAL ADVERSE EVENTS, SECONDARY PREVENTION POPULATIONS, BASE CASE (RELATIVE RISK)

Treatment Reference RR (95% CrI)a

Alendronate (5 mg/day) Placebo 0.90 (0.68, 1.15)

Alendronate (10 mg/day) Placebo 1.05 (0.94, 1.17)

Risedronate Placebo 1.00 (0.90, 1.11)

Zoledronic acid (5 mg/year) Placebo 0.64 (0.42, 0.93)

Alendronate (10 mg/day) Alendronate (5 mg/day) 1.17 (0.90, 1.57)

Risedronate Alendronate (5 mg/day) 1.11 (0.85, 1.49)

Zoledronic acid (5 mg/year) Alendronate (5 mg/day) 0.71 (0.44, 1.12)

Risedronate Alendronate (10 mg/day) 0.95 (0.83, 1.09)

Zoledronic acid (5 mg/year) Alendronate (10 mg/day) 0.60 (0.41, 0.88)

Zoledronic acid (5 mg/year) Risedronate 0.64 (0.42, 0.94) CrI = credible interval; RR = relative risk;

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Etidronate= oral cyclic 400 mg/day; Placebo (includes no treatment or background supplementation); Risedronate= 5 mg/day or 35 mg/week or 150 mg/month. a Bolded and shaded results indicate a pooled effect estimate and associated 95% credible interval which does not include the null value.

Osteonecrosis of the Jaw

Two women with osteonecrosis of the jaw were observed in the 6 RCTs (9,398 women) reporting this outcome44,54,85,109,126,159. Analysis was not feasible as five of the studies reported zero events in all study arms (Table 36). The two women with events were observed in the 36 month HORIZON study44, with one in the placebo arm ([1/3852, 2.6%] and one in the zoledronic acid arm [1/3862, 2.6%]). Authors did not test for differences between groups. This outcome was not reported in any studies of etidronate or risedronate.

TABLE 36: OSTEONECROSIS OF THE JAW, SECONDARY PREVENTION POPULATIONS EXCLUDED FROM QUANTITATIVE SYNTHESIS

Treatment (number women with event/number of women) Study Alendronate (5 Alendronate (10 Zoledronic acid (5 Placebo mg/day) mg/day) mg/year) Chavez-Valencia 0/52 0/52 2014 Hadji 2012 0/194 0/408 Liang 2017 0/95 0/155 Nakamura 2014 0/481 0/242 Yang 2015 0/50 0/50 Placebo (includes no treatment or background supplementation)

Atypical Femoral Fracture

Atypical femoral fractures were observed in both treatment arms of the Genant et al. (2010) HORIZON study (placebo [2/3852, 5.2%], zoledronic acid [3/3862, 7.8%]) 44. The outcome in this study was defined as “subtrochanteric femoral shaft fractures” which, following this, were further clarified as “..., diaphyseal fractures below the lesser trochanter and above the distal metaphysis” (Osteoporosis International. 2010; Conference: S161-S2, P407).

Seventeen additional secondary prevention populations reported this outcome in postmenopausal women, but did not observe any events 35,43,46,54,75,87,108,109,113,126,130,141,143,151,158,159 (Table 37).

TABLE 37: ATYPICAL FEMORAL FRACTURE, SECONDARY PREVENTION POPULATIONS EXCLUDED FROM QUANTITATIVE SYNTHESIS

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Treatment (number of women with event/number of women) Etidronate Zoledronic Study Alendronate Alendronate Risedronate Risedronate Placebo (400 acid (5 (5 mg/day) (10 mg/day) (2.5 mg/day) (5 mg/day) mg/day) mg/year) Akyol 2006 0/60 0/52 Black 1996 0/1005 0/1022 Bone 2000 0/50 0/92 Chavez- Valencia 2014 0/52 0/52 Galesanu 2011 0/132 0/32 Harris 1999 0/660 0/618 0/669 Li 2005 0/26 0/28 Liang 2017 0/95 0/155 Lyritis 1997 0/50 0/50 Nakamura 2014 0/481 0/242 Paggiosi 2014 0/57 0/58 Qin 2007 0/25 0/22 Russo 1996 0/38 0/31 Sarioglu 2006 0/25 0/25 Tan 2016 0/53 0/52 Yan 2009 0/280 0/280 Yang 2015 0/50 0/50 Placebo (includes no treatment or background supplementation)

Atrial Fibrillation

Six secondary prevention populations reported atrial fibrillation as an outcome of interest in 8,951 women.44,54,85,109,150,159.

Base case

Two RCTs included atrial fibrillation as an outcome of interest 44,150 and were included in the base case analysis. No differences in risk of atrial fibrillation were observed in women taking yearly or single injection of zoledronic acid (5 mg) compared with women taking placebo or the different dose of zoledronic acid (Table 38).

TABLE 38: ATRIAL FIBRILLATION, SECONDARY PREVENTION POPULATIONS, BASE CASE (RELATIVE RISK)

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Treatment Reference RR (95% CrI)

Zoledronic acid (5 mg/year) Placebo 1.28 (0.51, 3.05)

Zoledronic acid (5 mg single dose) Placebo 1.00 (0.21, 4.27)

Zoledronic acid (5 mg single dose) Zoledronic acid (5 mg/year) 0.78 (0.13, 4.22) CrI = credible interval; RR = relative risk; Placebo (includes no treatment or background supplementation)

Four additional studies were not included in the base case analyses as zero atrial fibrillation outcomes were observed in one85 or both study arms 54,109,159 (Table 39).

TABLE 39: ATRIAL FIBRILLATION, SECONDARY PREVENTION POPULATIONS EXCLUDED FROM QUANTITATIVE SYNTHESIS

Treatment number of women with events/number of women) Study Placebo Alendronate (10 mg/day) Zoledronic acid (5 mg/year) Hadji 2012 0/194 1/408 Chavez-Valencia 2014 0/52 0/52 Liang 2017 0/95 0/155 Yang 2015 0/50 0/50 Placebo (includes no treatment or background supplementation)

RESULTS: POOLED PRIMARY AND SECONDARY PREVENTION POPULATIONS SENSITIVITY ANALYSIS

Sensitivity analyses pooling the primary and secondary prevention population studies were conducted to test the robustness of the base case NMA results for four fracture outcomes (radiographic vertebral fractures, non-vertebral fractures, hip fractures, and wrist fractures) and all harms. Clinical vertebral fractures study populations were not combined as no primary prevention NMA was conducted. Results for all outcomes did not differ from those from the base case NMAs of secondary prevention populations.

For harms (withdrawal due to adverse events, serious adverse events, gastrointestinal adverse events), base case NMA results for the secondary prevention populations were robust to pooling with the primary prevention study data. For withdrawals due to adverse events, pooling of primary and secondary study populations (11 studies) resulted in a less precise credible interval including the null (RR 0.76, 95% CrI 0.44 to 1.23). No pooled analyses were feasible for osteonecrosis of the jaw, atypical femoral fractures or atrial fibrillation.

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DISCUSSION

Four bisphosphonates are available in Canada: oral alendronate, oral risedronate, oral etidronate and intravenous zoledronic acid. Various doses of these medications are marketed and reimbursed by the publicly-funded drug plans in Canada, and there are varying risk criteria used in the justifications to guide reimbursement recommendations and decisions. The 2010 Canadian clinical practice guidelines recommend for postmenopausal women requiring treatment of osteoporosis, alendronate, risedronate, zoledronic acid and denosumab can be used as first-line therapies for prevention of hip, nonvertebral and vertebral fractures with a grade of A for the certainty of evidence. High risk women should be offered pharmacologic therapy and moderate risk women should be considered for pharmacologic treatment, and additional risk factors and patient preferences should guide therapy. Integrated approaches are recommended for management of women with any risk of fracture, which includes regular weight-bearing, exercise, smoking cessation and optimization of calcium and vitamin D intake. For initiation of pharmacologic treatment for osteoporosis, the guideline suggests with a very low certainty (Grade D) that women should be assessed for absolute fracture risk using a validated fracture prediction tool. In women with a low fracture risk, pharmacologic therapy is not generally recommended (Grade C). In post-menopausal women who are intolerant of first-line therapies, etidronate (should be considered for prevention of vertebral fractures. The guidelines highlight a number of common adverse effects seen in practice with the bisphosphonates, including flu-like symptoms from initial zoledronic acid infusion, and cellulitis with denosumab. They additionally note the uncertainty around potential increased risk of osteonecrosis of the jaw, atypical femoral fractures and atrial fibrillation.

Results in this review for primary prevention populations of postmenopausal women are aimed at broadly providing evidence for the use of bisphosphonates in women with a lower fracture risk, while the results for women in the secondary prevention populations are intended to broadly provide a summary of evidence for use of bisphosphonates for postmenopausal women with a higher fracture risk, as is considered in current clinical practice and guidelines. Results in this review are generally in line with the 2010 Canadian clinical practice guidelines. Based on the findings from this review, the benefits of bisphosphonate drugs, especially in populations of postmenopausal women with a higher fracture risk, outweigh any reported risks. Intravenous bisphosphonates may provide an effective alternative to oral bisphosphonates, with fewer gastrointestinal adverse events although there is inadequate evidence to make any firm conclusions regarding post-menopausal women who are contraindicated to the oral drugs specifically.

Comparisons of bisphosphonates to placebo

When the bisphosphonates were compared to placebo in women with a lower risk of fracture (primary prevention population), there were no differences in the number of radiographic vertebral fractures, non-vertebral fractures, and wrist fractures. Analyses were not feasible for clinical vertebral fractures and for hip fractures due to the number of studies or study arms with zero events reported. We found no differences in harms and a single study reported domain-specific improvements in health-related quality of life. These findings suggest that bisphosphonate therapy may not be effective in women at lower risk of fractures. Given the limitations in the reported trial population characteristics, the limited number of trials contributing to the analyses, and unclear risk

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of bias in many included trials, these results should be interpreted with caution and both individual risk profile and potential benefits and harms should guide decision-making related to pharmacological therapy.

For postmenopausal women with a moderate to higher fracture risk (secondary prevention population), women treated with yearly intravenous zoledronic acid and oral alendronate fewer radiographic (or asymptomatic) vertebral fractures, hip fractures and clinical (or symptomatic) vertebral fractures, compared with women not taking any medications (placebo or taking only supplements such as calcium or vitamin D). Benefits from oral etidronate and risedronate varied specifically by fracture outcomes, with anti-fracture benefits in our analyses with etidronate for radiographic (or asymptomatic) and vertebral fractures, and with risedronate for radiographic vertebral fractures and non-vertebral fractures compared with placebo. No differences in harms or health related quality of life were found compared to placebo. These results support the use of bisphosphonate therapy in postmenopausal women with a higher risk of fracture.

Comparing bisphosphonates

Data were not always available in the included trials for comparisons of bisphosphonates to all other oral or intravenous bisphosphonates. When the bisphosphonates were compared to each other in women with a lower risk of fracture (primary prevention population), there were no meaningful differences found for any of the outcomes of interest (efficacy or harms).

For postmenopausal women with a moderate to higher fracture risk (secondary prevention population), we found fewer radiographic vertebral fractures in women treated with yearly intravenous zoledronic acid (5mg/year) when compared to risedronate. We also found fewer withdrawals due to adverse events in postmenopausal women taking zoledronic acid when compared with women taking 10 mg of alendronate daily. Zoledronic acid also resulted in fewer GI adverse events when compared with both alendronate (10 mg/d) and risedronate. The findings are likely associated with the intravenous administration of zoledronic acid once per year compared with the more frequent oral administration of alendronate or risedronate. No other meaningful differences were found amongst the bisphosphonates for any outcome where data were sufficient for analyses.

How do the bisphosphonates compare against denosumab for fracture prevention?

Denosumab (Prolia) has been available in Canada since 2010 and is recommended as a first-line therapy (along with alendronate, risedronate and zoledronic acid) for women requiring treatment of osteoporosis in the most recent clinical guidelines by Papaioannou et al. (2010) for prevention of hip, non-vertebral and vertebral fractures. March 2017 data from Osteoporosis Canada shows that all provincial jurisdictions restrict access to denosumab, indicating that additional criteria must be met to receive reimbursement. Some provinces require women to have a contraindication to oral bisphosphonates, different risk factors, and/or intolerance to other available osteoporosis therapies. It is unclear how federal or territorial jurisdictions in Canada.

Although limited analyses were feasible in the current review, subcutaneous denosumab showed significant reduction in the risk of radiographic vertebral fractures compared with alendronate and risedronate in postmenopausal women with a higher risk of fracture. There were insufficient data to

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determine meaningful reductions in clinical vertebral fractures, non-vertebral fractures, hip fracture and wrist fractures, and we did not assess harms for denosumab.

In women with a lower risk of fracture, no meaningful differences were seen in non-vertebral fractures when denosumab was added to the base case, and both trials of denosumab which reported wrist and hip fracture outcomes reported zero events in all study arms.

Are zoledronic acid or denosumab effective alternatives in case of a contraindication to an oral bisphosphonate?

A fulsome analysis of the efficacy and harms of zoledronic acid, or for the efficacy of denosumab, as treatment options for postmenopausal women with intolerance or inadequate response to oral bisphosphonates was not feasible due to a paucity of study data.

Of note, one 12-month, randomized, open-label trial not included in the systematic review recruited postmenopausal women who had previously been prescribed alendronate therapy and had either stopped taking alendronate or were currently taking alendronate but “demonstrated suboptimal adherence to treatment” 140. In this study, women were randomized to receive either subcutaneous denosumab every six months or monthly oral risedronate. Hip fractures outcomes in the trial registry record documented similar frequencies of hip fractures in both groups ([risedronate (1/429, 0.2%)], [denosumab (1/429, 0.2%]).

Sensitivity with CAROC Fracture Risk

CAROC fracture risk calculator has been 218 used for reimbursement criteria in some Canadian jurisdictions. However, the following issues should be considered when comparing the CAROC risk calculator, to the classification algorithm used in this review to differentiate between primary and secondary populations.

The fracture risk estimated using the CAROC calculator is intended to be applied at the individual patient level in the clinical setting as required. However, in this project, included studies did not report level of risk but rather level of prevention (primary or secondary prevention). Furthermore, the bisphosphonates were approved by Health Canada according to level of prevention and not based on risk.

There are inconsistencies across the included trials in how primary and secondary prevention is defined. In sensitivity analyses, we attempted to classify the patient populations in the included studies according to CAROC level of risk: Certain required risk factor data was extracted from trial publications, such as the baseline mean age and femoral neck BMD T-score but was often not reported which made classification of many studies using the CAROC risk not feasible. In addition, there were large variations in femoral neck BMD T-score and age at baseline across trials. Many studies did not report mean femoral neck T-score data. We therefore used mean lumbar spine T- score in CAROC algorithm (CAROC-1) when femoral neck T-score was not available.

In some jurisdictions, drugs with restrictions are reimbursed for those who have a high 10-year fracture risk or who have a moderate 10-year fracture risk and have experienced a prior fragility

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fracture. To define a study of this category, we had to use prior history of vertebral fracture instead because fragility fracture was not routinely reported or reported with rather grey definition. Further complexity is added when considering the Health Canada labelling of the available drugs, which specifies whether they are intended for prevention or treatment purposes.

All the studies calculated by CAROC and CAROC-1 as high risk and moderate risk with prior vertebral fracture were categorized by our criteria as secondary prevention trials (Table 40). Although in the low and moderate categories where our criteria have less discriminatory power, a higher percentage of secondary studies than primary prevention populations were defined in the moderate risk group, and vice versa in the low risk group. The use CAROC-1 scenario added in 21 studies which did not report women’s’ mean femoral neck BMD T-score, including 8 primary and 13 secondary studies.

TABLE 40. CORRESPONDING RELATIONSHIP OF CAROC FRACTURE RISK AND HIERARCHICAL CLASSIFICATION FOR PRIMARY AND SECONDARY PREVENTION TRIALS

Eligible 10-year fracture risk assessed by CAROC, with age and femoral neck BMD T-score studies Moderate with prior Low Moderate High Not available (N=133) vertebral fracture

Primary 7 4 0 0 36

Secondary 7 20 0 1 58

10-year fracture risk assessed by CAROC, with age and femoral neck BMD T-score

Primary 11 8 0 0 28

Secondary 8 30 2 1 45

Strengths and Limitations

This review has been developed utilizing a robust methodology. A detailed protocol was prepared, a priori; reviewed by stakeholders external to CADTH; registered with the PROSPERO database; and the final version is publicly available.

This review comprehensively summarized the available evidence on the benefits and harms for alendronate, risedronate, etidronate and zoledronic acid using a transparent and systematic approach. We have included all available randomized evidence, regardless of the outcome reported, and presented results for all outcomes of interest, where feasible, using quantitative and descriptive approaches. In addition, the list of included studies was vetted by clinical and methodological experts and posted for external stakeholder comment. Standard approaches for collecting evidence and performing data extraction, and evaluating study quality, were utilized. Heterogeneity across trials in terms of patient characteristics, trial methodologies, and treatment protocols was carefully assessed. Subgroup and sensitivity analyses were conducted, where data allowed, to explore and control for potential sources of heterogeneity.

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Despite this, we note that there are limitations in this review. As only studies of one year or longer were included, we may have overlooked important safety outcomes that occurred following initiation of treatment with a bisphosphonate. In addition, some data reported in long-term extension studies or in studies comparing different therapeutic doses of the same bisphosphonate could not be used. Inclusion of drugs and doses marketed in Canada may limit the generalizability of the results to knowledge users outside of the federal, provincial and territorial jurisdictions. There are limited statistical modelling approaches that can be utilized to handle the inclusion of a large number of zero events while also producing robust analysis results that are useful and informative. As a result, many RCTs were excluded from the analyses and this makes comparisons difficult for important outcomes.

A defining feature of this review is the broad inclusion of postmenopausal women with varying risk for fracture and the separation of analyses by primary and secondary prevention populations. Other reviews on bisphosphonates either limit included study populations to postmenopausal women with osteoporosis or additionally broadly include all postmenopausal and present the results without consideration for varying levels of fracture risk. This makes it difficult to directly compare the results of this review to previously published evidence syntheses of bisphosphonates. The vernacular used to describe the included populations in previous reviews additionally complicates these comparisons. For example, in one review which included populations of “primary osteoporotic women”, the study populations included women with osteoporosis not attributable to other disease (e.g., cancer) or who have been treated with drugs that have resulted in bone loss, like glucocorticoids or anti-tumor drugs. Despite this, the results for secondary prevention populations of postmenopausal women at a higher risk of fracture using our classification scheme are consistent with the results of previous systematic reviews. Pooled sensitivity analyses of both primary and secondary prevention populations were driven by the secondary prevention studies which outnumber the primary prevention studies.

Pooled analyses in this review included studies which evaluated doses of bisphosphonates that may not be approved for prevention and/or treatment of osteoporotic fractures in all jurisdictions (e.g., alendronate 10 mg or zoledronic acid intravenous in lower risk women and alendronate 5 mg in women with higher fracture risk). This was done to allow for a fulsome assessment and summary of all available evidence for women with varying fracture risk.

The number of trials that contributed to some of the NMAs was limited, especially in primary prevention populations, and in outcomes where trials reported zero events which caused statistical instability despite multiple approaches to analyses. This may have reduced the precision of the estimates from these analyses. In certain cases, the manner in which data were reported in the included studies limited our ability to include them in the primary NMA. Data were insufficient to conduct an NMA or MA for many subpopulations of interest, and results for single trials were summarized. Consistency was assessed whenever a closed loop was available, by comparing consistency and inconsistency models. However, in many of the analyses, there was no closed loop available. Additionally, we did not conduct direct pairwise comparisons for outcomes included in the NMA, due to the high proportion of studies reporting zero events for the outcomes of interest.

A major limitation of the trials included in the review is that the level of risk according to CAROC could not be calculated for the majority of the included trials. Some secondary prevention trials were

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conducted in women at low or moderate risk of fractures; some trials included drugs at doses that are used in the prevention of osteoporosis (for example alendronate 5 mg once daily). Furthermore, there is no consistent definition of primary prevention or secondary prevention across trials which creates uncertainty with the level of risk of the population being targeted by these research questions. Hence, the results need to be interpreted with caution.

Limited or unclear reporting of important methodological components was common in the included studies, making assessments for risk of bias challenging and potentially introducing performance, attrition, or detection bias in the studies included. In addition, many studies included in this review had unclear random sequence generation, allocation concealment and blinding. Many studies had a small sample size; lack of power calculation; and poor or insufficient reporting about study characteristics, participant demographics, and results.

In addition, the drugs included in all analyses were as-reported in the included studies, even though some doses of drugs approved for treatment in women at lower risk of fracture (e.g., alendronate ALE 10 mg and ZOL infusion) and vice versa, doses of drugs approved for prevention used in women at higher risk (ALE 5 mg).

Conclusions and implications for policy-making

Based on the findings from this review, the benefits of bisphosphonate drugs, especially in populations of postmenopausal women with a higher fracture risk, outweigh any reported risks. Intravenous bisphosphonates or denosumab may provide a treatment alternative to oral bisphosphonates, although there is scarce evidence to make specific conclusions regarding postmenopausal women who are intolerant of or contraindicated to oral drugs.

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178. E. J. P. B. Brown HGC, R. Franchimont NB, M. L. Czerwinski EK, et al. Six years of denosumab treatment in postmenopausal women with osteoporosis: Results from the first three years of the freedom. Arthritis and Rheumatism. 2011;63(12):4044-4045.

179. Eastell R, Black DM, Boonen S, et al. Effect of once-yearly zoledronic acid five milligrams on fracture risk and change in femoral neck bone mineral density. J Clin Endocrinol Metab. 2009;94:3215-3225.

180. Eastell R, Nagase S, Small M, et al. Effect of ONO-5334 on bone mineral density and biochemical markers of bone turnover in postmenopausal osteoporosis: 2-year results from the OCEAN study. Journal of Bone and Mineral Research. 2014;29:458-466.

181. Ensrud KE, Barrett-Connor EL, Schwartz A, et al. Randomized trial of effect of alendronate continuation versus discontinuation in women with low BMD: Results from the fracture intervention trial long-term extension. Journal of Bone and Mineral Research. 2004;19:1259- 1269.

182. Ensrud KE, Black DM, Palermo L, et al. Treatment with alendronate prevents fractures in women at highest risk: Results from the fracture intervention trial. Arch Intern Med. 1997;157:2617- 2624.

183. Genant HK, Bucci-Rechtweg C, Bauer DC, et al. Does zoledronic acid increase risk of atypical femoral shaft fractures? results from the HORIZON-PFT. Osteoporosis International. 2010;Conference::S161-S162.

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184. Grey A, Bolland M, Mihov B, et al. Duration of antiresorptive effects of low-dose zoledronate in osteopenic postmenopausal women: a randomized, placebo-controlled trial. Journal of Bone and Mineral Research. 2014;29:166-172.

185. Grey A, Bolland MJ, Horne A, et al. Five years of anti-resorptive activity after a single dose of zoledronate--results from a randomized double-blind placebo-controlled trial. Bone. 2012;50:1389-1393.

186. Grey A, Bolland MJ, Wattie D, Horne A, Gamble G, Reid IR. The antiresorptive effects of a single dose of zoledronate persist for two years: A randomized, placebo-controlled trial in osteopenic postmenopausal women. J Clin Endocrinol Metab. 2009;94:538-544.

187. Grey AB, M. J. Horne AM, B. Gamble GR. Duration of antiresorptive activity of zoledronate in postmenopausal women with osteopenia: a randomized, controlled multidose trial. Canadian Medical Association Journal. 2017;189(36):E1130-E1136.

188. Hadji P, Ziller V, Gamerdinger D, et al. Quality of life and health status with zoledronic acid and generic alendronate--a secondary analysis of the Rapid Onset and Sustained Efficacy (ROSE) study in postmenopausal women with low bone mass. Osteoporosis International. 2012;23:2043-2051.

189. Harris ST, Watts NB, Li Z, Chines AA, Hanley DA, Brown JP. Two-year efficacy and tolerability of risedronate once a week for the treatment of women with postmenopausal osteoporosis. Curr Med Res Opin. 2004;20:757-764.

190. Hwang JS, Chin LS, Chen JF, et al. The effects of intravenous zoledronic acid in Chinese women with postmenopausal osteoporosis. J Bone MinerMetab. 2011;29:328-333.

191. J. A. R. Simon CM, A. H JA, J. D. Franek EL, et al. Impact of denosumab on the peripheral skeleton of postmenopausal women with osteoporosis: bone density, mass, and strength of the radius, and wrist fracture. Menopause. 2013;20(2):130-137.

192. J. R. Simon CM, A. Adachi JF, E. Lewiecki EMM, et al. Effects of denosumab on radius BMD, strength, and wrist fractures: Results from the fracture reduction evaluation of denosumab in osteoporosis every 6 months (freedom) study. Journal of Bone and Mineral Research. 2011;Conference:(26 Suppl 1).

193. Jacques RM, Boonen S, Cosman F, et al. Relationship of changes in total hip bone mineral density to vertebral and nonvertebral fracture risk in women with postmenopausal osteoporosis treated with once-yearly zoledronic acid 5 mg: the HORIZON-Pivotal Fracture Trial (PFT). Journal of Bone and Mineral Research. 2012;27:1627-1634.

194. Kendler DL, McClung MR, Freemantle N, et al. Adherence, preference, and satisfaction of postmenopausal women taking denosumab or alendronate. Osteoporosis International. 2011;22:1725-1735.

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195. M. A. T. Bolognese CSZ, J. R. Lippuner KM, M. R. Brandi MLH, A. Lakatos PM, A. H. Lorenc RSW, A. Libanati C. Denosumab significantly increases DXA BMD at both trabecular and cortical sites: results from the FREEDOM study. J Clin Densitom. 2013;16(2):147-153.

196. McClung MR, Michael LE, Cohen SB, et al. Denosumab in postmenopausal women with low bone mineral density. New England Journal of Medicine. 2006;354:821-831.

197. McClung MR, Wasnich RD, Hosking DJ, et al. Prevention of postmenopausal bone loss: Six-year results from the early postmenopausal intervention cohort study. J Clin Endocrinol Metab. 2004;89:4879-4885.

198. McClung MR, Zanchetta JR, Racewicz A, et al. Efficacy and safety of risedronate 150-mg once a month in the treatment of postmenopausal osteoporosis: 2-year data. Osteoporosis International. 2013;24:293-299.

199. McClung MRB, Torring S, Roux O, et al. Effect of denosumab treatment on the risk of fractures in subgroups of women with postmenopausal osteoporosis. Journal of Bone and Mineral Research. 2012;27(1):211-218.

200. Papapoulos SC, Libanati R, Brandi C, et al. Five years of denosumab exposure in women with postmenopausal osteoporosis: results from the first two years of the FREEDOM extension. Journal of Bone and Mineral Research. 2012;27(3):694-701.

201. Popp AW, Buffat H, Cavelti A, et al. Cortical bone loss at the tibia in postmenopausal women with osteoporosis is associated with incident non-vertebral fractures: results of a randomized controlled ancillary study of HORIZON. Maturitas. 2014;77:287-293.

202. Reid DM, Hosking D, Kendler D, et al. A comparison of the effect of alendronate and risedronate on bone mineral density in postmenopausal women with osteoporosis: 24-Month results from FACTS-International. Int J Clin Pract. 2008;62:575-584.

203. Reid IR, Gamble GD, Mesenbrink P, Lakatos P, Black DM. Characterization of and risk factors for the acute-phase response after zoledronic acid. J Clin Endocrinol Metab. 2010;95:4380-4387.

204. S. L. Adami CB, S. Cummings SRH, P. R. Wang AS, et al. Denosumab treatment in postmenopausal women with osteoporosis does not interfere with fracture-healing: results from the FREEDOM trial. Journal of Bone and Joint SurgeryAmerican Volume. 2012;94(23):2113- 2119.

205. S. V. Silverman HW, A. Ragi-Eis SF, P. Gilchrist NL, et al. Evaluation of health-related quality of life in postmenopausal women with osteoporosis who participated in the freedom trial. Osteoporosis International. 2010;Conference:(22 Suppl 1):S14-S15.

206. Sambrook PN, Rodriguez JP, Wasnich RD, et al. Alendronate in the prevention of osteoporosis: 7-year follow-up. Osteoporosis International. 2004;15:483-488.

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207. Sambrook PN, Silverman SL, Cauley JA, et al. Health-related quality of life and treatment of postmenopausal osteoporosis: results from the HORIZON-PFT. Bone. 2011;48:1298-1304.

208. Seeman E, Black DM, Bucci-Rechtweg C, Eastell R, Boonen S, Mesenbrink P. Zoledronic acid substantially reduces the risk of morphometric vertebral and clinical fractures. J Clin Densitometry. 2010;Conference::132-133.

209. Sorensen OH, Crawford GM, Mulder H, et al. Long-term efficacy of risedronate: a 5-year placebo-controlled clinical experience. Bone. 2003;32:120-126.

210. Ste-Marie LG, Sod E, Johnson T, Chines A. Five years of treatment with risedronate and its effects on bone safety in women with postmenopausal osteoporosis. CalcifTissue Int. 2004;75:469-476.

211. Steven RC, Ann VS, Dennis MB. Alendronate and Atrial Fibrillation. The New England Journal of Medicine. 2007;356(18):1895.

212. Tonino RP, Meunier PJ, Emkey R, et al. Skeletal benefits of alendronate: 7-Year treatment of postmenopausal osteoporotic women. J Clin Endocrinol Metab. 2000;85:3109-3115.

213. Tucci JR, Tonino RP, Emkey RD, Peverly CA, Kher U, Santora 2nd AC. Effect of three years of oral alendronate treatment in postmenopausal women with osteoporosis. The American journal of medicine. 1996;101:488-501.

214. Warner C. NCT00247273: A Study of Monthly Risedronate for Osteoporosis. Clinicaltrialsgov. 2013.

215. Wustrack R, Seeman E, Bucci-Rechtweg C, Palermo L, Black D. Impact of zoledronic acid on severe vertebral fractures: Results from horizon-pivotal fracture trial. Bone. 2010;Conference::S194-S195.

216. Yanik B, Bavbek N, Yangk T, et al. The effect of alendronate, risedronate, and raloxifene on renal functions, based on the cockcroft and gault method, in postmenopausal women. Renal Failure. 2007;29:471-476.

217. Zhu HMT, Cheng H, He Q, et al. Efficacy and safety of denosumab in Chinese postmenopausal women with osteoporosis at increased risk of fracture: Results from a 12-month, randomized, double-blind, placebo-controlled phase III study. Journal of Bone and Mineral Research. 2017;Conference:(Supplement 1).

218. !!! INVALID CITATION !!! (13, 162).

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APPENDIX 1: CANADIAN JURISDICTIONAL COVERAGE

TABLE 41: JURISDICTIONAL COVERAGE OF DRUGS UNDER REVIEW

ALN ALN ALN Fosavance 70/2800 Fosavance 70/5600 RIS RIS RIS ETD ZOL Infusion DEN (Prolia) JURISDICTION 5 mg 10 mg 70 mg 5 mg 35 mg 150 mg 400 mg BC N SA SA N SA SA SA N N SA SA AB N SA FB N FB SA FB N N SA SA SK N EDS EDS N EDS N EDS EDS FB EDS EDS MB N EDS EDS N N EDS EDS N FB N EDS ON N FB FB FB FB FB FB FB N LU LU NS N FB FB N FB FB FB N N EDS EDS NB N FB FB N FB FB FB N N SA SA NL U FB >65* FB >65* U FB >65* SA SA SA U U SA PE N FB FB N FB FB FB N FB SA SA YK N FB FB N FB FB FB N FB EDS EDS NU FB FB FB FB FB FB FB FB FB SA SA CAF N FB FB FB FB FB FB FB FB N SA NIHB FB FB FB FB FB FB FB FB FB SA SA VAC FB FB FB N FB SA FB N FB SA SA

*full benefits for persons > 65 years; special authorization for others

Abbreviations: ? = information not found; AB = Alberta ALN = alendronate; BC = British Columbia; CAF = Canadian Armed Forces; CSC = Correctional Service Canada; DEN = denosumab; EDS = exceptional drug status; ETD = etidronate; FB = full benefit; LU = limited use; MB = Manitoba; N = not a benefit; NB = New Brunswick; NIHB = Non-Insured Health Benefits; NL = Newfoundland and Labrador; NS = Nova Scotia; NU = Nunavut; NWT = North Western Territories; RIS = risedronate; ON = Ontario; PE = Prince Edward Island; SA = special authorization; SK = Saskatchewan; SP = only for special programs; U = unknown; VAC = Veteran’s Affairs Canada; YK = Yukon; ZOL = zoledronic acid

APPENDIX 2: LITERATURE SEARCH STRATEGY

APPENDIX 3: PEER REVIEW OF ELECTRONIC SEARCH STRATEGIES (PRESS)

Reference: McGowan J, Sampson M, Salzwedel DM, Cogo E, Foerster V, Lefebvre C. PRESS Peer Review of Electronic Search Strategies: 2015 guideline statement. J Clin Epidemiol 2016;75:40-6. Available: http://www.jclinepi.com/article/S0895-4356(16)00058-5/pdf. Search submission:

Searcher: Becky Skidmore Email: redacted

Date submitted: 23 May 2019 Date requested by: 26 May 2019

Systematic Review Title

Bisphosphonates for postmenopausal osteoporosis

This search strategy is …

My PRIMARY (core) database strategy — First time submitting a strategy for search question X and database My PRIMARY (core) strategy — Follow-up review NOT the first time submitting a strategy for search question and database. If this is a response to peer review, itemize the changes made to the review suggestions SECONDARY search strategy— First time submitting a strategy for search question and

database SECONDARY search strategy — NOT the first time submitting a strategy for search question and database. If this is a response to peer review, itemize the changes made to the review suggestions

Database (e.g., MEDLINE, CINAHL) Ovid MEDLINE(R) ALL <1946 to May 22, 2019>

Interface (e.g., Ovid, EbscoHost…) [mandatory] Ovid MEDLINE(R) ALL <1946 to May 22, 2019>

Research Question (Describe the purpose of the search) [mandatory]

1. What are the comparative benefits and harms of pharmacologic therapies in the primary prevention of fractures in postmenopausal women?

TECHNOLOGY REVIEW Drugs for the Treatment and Prevention of Osteoporosis in Postmenopausal Women 118

2. What are the comparative benefits and harms of pharmacologic therapies in the secondary prevention of fractures in postmenopausal women?

PICO Format Outline the PICOs for your question — i.e., Patient, Intervention, Comparison, Outcome, and Study Design — as applicable

P Postmenopausal osteoporotic women I Bisphosphonates – Denosumab, Teriparatide C O S RCTs

Inclusion Criteria (List criteria such as age groups, study designs, etc., to be included) This search strategy is …

All years, languages

Exclusion Criteria (List criteria such as study designs, date limits, etc., to be excluded)

Was a search filter applied?

YES

If YES, which one(s) (e.g., Cochrane RCT filter, PubMed Clinical Queries filter)? Provide the source if this is a published filter.

Cochrane HSSS, slightly amended

Notes or comments you feel would be useful for the peer reviewer

This is one of several bisphosphonate-related searches. Previous searches will all be updated to a common date and will include this search with the two new drugs only. Generic vocabulary for bisphosphonates has been incorporated in 2017 search so is not covered here. All sections of this search, excluding the section containing the two new drugs, have been PRESSed earlier.

Please copy and paste your search strategy here, exactly as run, including the number of hits per line. [mandatory]

Database: Ovid MEDLINE(R) ALL <1946 to May 22, 2019> Search Strategy: ------1 Osteoporosis, Postmenopausal/ (12683) 2 (osteoporo* adj5 (postmenopaus* or post-menopaus*)).tw,kf. (8133) 3 (bone loss* adj5 (postmenopaus* or post-menopaus*)).tw,kf. (1603) 4 (osteoporo* adj5 (perimenopaus* or peri-menopaus*)).tw,kf. (67) 5 (bone loss* adj5 (perimenopaus* or peri-menopaus*)).tw,kf. (77) 6 (osteoporo* adj5 "after" adj5 menopaus*).tw,kf. (94) 7 (osteoporo* adj5 menopaus*).tw,kf. (1723)

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8 (bone loss* adj5 menopaus*).tw,kf. (628) 9 (bone loss* adj5 "after" adj5 menopaus*).tw,kf. (139) 10 (osteoporo* adj5 age-related).tw,kf. (490) 11 (bone loss* adj5 age-related).tw,kf. (701) 12 (osteoporo* adj5 senil*).tw,kf. (610) 13 (bone loss* adj5 senil*).tw,kf. (23) 14 or/1-13 (19267) 15 Osteoporosis/ (42247) 16 osteoporo*.tw,kf. (72463) 17 Bone Density/ (50606) 18 (bone? adj3 densit*).tw,kf. (51871) 19 bmd.tw,kf. (27369) 20 bone loss*.tw,kf. (27648) 21 or/15-20 (137839) 22 Menopause/ (26775) 23 Postmenopause/ (23468) 24 (postmenopaus* or post-menopaus*).tw,kf. (58478) 25 or/22-24 (79554) 26 21 and 25 (19408) 27 14 or 26 [POST-MENOPAUSAL OSTEOPOROSIS] (26301) 28 Denosumab/ (1365) 29 (denosumab or "amg 162" or amg162 or prolia or xgeva).tw,kf. (2425) 30 Teriparatide/ (1814) 31 (teriparatide or "chs 13340" or chs13340 or forsteo or forteo or "ly 333334" or ly333334 or movymia or parathar or "parathormone 1 34" or "sun e3001" or sune3001 or terrosa).tw,kf. (1662) 32 ((parathyroid hormone or pth) adj2 "1-34").tw,kf. (2047) 33 or/28-32 [BISPHOSPHONATES OF INTEREST] (6195) 34 27 and 33 [POST-MENOPAUSAL OSTEOPOROSIS - BISPHOSHONATES OF INTEREST] (1242) 35 (controlled clinical trial or randomized controlled trial or pragmatic clinical trial).pt. (571153) 36 clinical trials as topic/ (187078) 37 exp Randomized Controlled Trials as Topic/ (126308) 38 (randomi#ed or randomi#ation* or randomly or RCT? or placebo*).tw,kf. (913323) 39 ((singl* or doubl* or trebl* or tripl*) adj (mask* or blind* or dumm*)).tw,kf. (163974) 40 trial.ti. (198833) 41 or/35-40 (1324508) 42 34 and 41 [Post-menopausal Osteoporosis - Bisphosphonates of Interest - RCTs] (502) 43 Male/ not (Female/ and Male/) (2671233) 44 42 not 43 [MALE-ONLY REMOVED] (497) 45 exp Animals/ not Humans/ (4582452) 46 44 not 45 [ANIMAL-ONLY REMOVED] (495) 47 (comment or editorial or interview or news or newspaper article).pt. (1342475) 48 (letter not (letter and randomized controlled trial)).pt. (1022795) 49 46 not (47 or 48) [OPINION PIECES REMOVED] (486)

Peer review assessment:

Reviewer: redacted Email: redacted Date completed: 2019 May 26

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Do you wish to be acknowledged? Yes No

1. TRANSLATION A -No revisions X B - Revision(s) suggested

C - Revision(s) required

2. BOOLEAN AND PROXIMITY OPERATORS A -No revisions X B - Revision(s) suggested

C - Revision(s) required

3. SUBJECT HEADINGS A -No revisions X B - Revision(s) suggested

C - Revision(s) required

4. TEXT WORD SEARCHING A -No revisions X B - Revision(s) suggested

C - Revision(s) required

5. SPELLING, SYNTAX, AND LINE NUMBERS A -No revisions X B - Revision(s) suggested

C - Revision(s) required

TECHNOLOGY REVIEW Drugs for the Treatment and Prevention of Osteoporosis in Postmenopausal Women 121

6. LIMITS AND FILTERS A -No revisions X B - Revision(s) suggested

C - Revision(s) required

OVERALL EVALUATION A -No revisions X B - Revision(s) suggested

C - Revision(s) required

ADDITIONAL COMMENTS:

Solidly done. No errors or omissions detected.

TECHNOLOGY REVIEW Drugs for the Treatment and Prevention of Osteoporosis in Postmenopausal Women 122

APPENDIX 4: APPROACHES TO HANDLING ZERO EVENTS

Quantitative syntheses were run for each outcome identified a priori in the project protocol where data were sufficient and where analyses were feasible.

When modelling binary data, sparse data, or zero events in one or both of the treatment arms may lead to an unstable statistical model for NMA; that is, a model that fails to converge or results in effect estimates with either extreme lower or upper bounds of the credible interval. To make full use of all extracted data that includes zero events and to avoid unstable NMA models, we followed a systematic approach to handling zero events or sparse data in all analyses, in the base case and for all subgroup or sensitivity analyses:

First, we conducted analysis for each outcome including all direct comparison data in the evidence network. Where the analysis had a stable NMA model and/or produced robust effect estimates without extreme lower or upper bounds, no additional approaches to analyses were considered. Where there was statistical instability identified in the NMA, we applied a continuity correction of 0.5 for studies in the evidence network with zero events in one or more study arms with the aim of improving model fit. Where statistical instability persisted despite continuity correction, we attempted a third analysis approach. We identified a statistically stable subset of direct comparison data that, when modelled using NMA, produced robust effect estimates with the most included data possible, taking into account the number of study participants, events and treatments available by outcome. This third analysis approach frequently led to studies with zero events in one or more arms to be excluded from the evidence network.

Where NMA was not feasible using the approaches above, or where subsets of studies were excluded from the base case NMA, we attempted pair-wise meta-analysis using the available study data for each outcome. Meta-analysis was feasible when multiple included studies reported at least one event in one study arm, and where more than one study reported the same bisphosphonate. In cases where the data was too sparse for quantitative analysis, results by study were tabulated and presented by study, listing the number of women with events and total number of women randomized by study arm, for each bisphosphonate and placebo. Important differences were summarized descriptively.

Three cases arise with zero events:

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Case 1: Multiple direct comparisons with 1 zero reported

TECHNOLOGY REVIEW Drugs for the Treatment and Prevention of Osteoporosis in Postmenopausal Women 124

Case 2: Single direct comparisons with 1 zero reported

TECHNOLOGY REVIEW Drugs for the Treatment and Prevention of Osteoporosis in Postmenopausal Women 125

Case 3: Direct comparisons with all zeros reported

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APPENDIX 5:STUDY SELECTION FLOW DIAGRAM

Note: Two included studies reported data in such a way that it could not be included in the quantitative syntheses .

APPENDIX 6: LIST OF INCLUDED STUDIES

List of Included Studies (Primary publication), N=133

1. Adami S, Bruni V, Bianchini D, et al. Prevention of early postmenopausal bone loss with cyclical etidronate. Journal of Endocrinological Investigation. 2000;23(5):310-316.

2. Adami S, Passeri M, Ortolani S, et al. Effects of oral alendronate and intranasal salmon calcitonin on bone mass and biochemical markers of bone turnover in postmenopausal women with osteoporosis. Bone. 1995;17(4):383-390.

3. Akyol Y, Tander B, Alayli G, Durmus D, Bek Y, Canturk F. The comparison of effectiveness of alendronate and risedronate in osteoporosis treatment. Turkiye Fiziksel Tip ve Rehabilitasyon Dergisi. 2006;52(3):110-114.

4. Anastasilakis AD, Polyzos SA, Gkiomisi A, et al. Denosumab versus zoledronic acid in patients previously treated with zoledronic acid. Osteoporosis International. 2015;26:2521- 2527.

5. Aro E, Moritz N, Mattila K, Aro HT. A long-lasting bisphosphonate partially protects periprosthetic bone, but does not enhance initial stability of uncemented femoral stems: A randomized placebo-controlled trial of women undergoing total hip arthroplasty. Journal of Biomechanics. 2018;75:35-45.

6. Ascott-Evans BH, Guanabens N, Kivinen S, et al. Alendronate prevents loss of bone density associated with discontinuation of hormone replacement therapy: A randomized controlled trial. Archives of Internal Medicine. 2003;163(7):789-794.

7. Atmaca A, Gedik O. Effects of alendronate and risedronate on bone mineral density and bone turnover markers in late postmenopausal women with osteoporosis. Advances in Therapy. 2006;23(6):842-853.

8. Bai H, Jing D, Guo A, Yin S. Randomized controlled trial of zoledronic acid for treatment of osteoporosis in women. Journal of International Medical Research. 2013;41(3):697-704.

9. Bala Y, Chapurlat R, Cheung AM, et al. Risedronate slows or partly reverses cortical and trabecular microarchitectural deterioration in postmenopausal women. Journal of Bone and Mineral Research. 2014;29(2):380-388.

10. Bell NH, Bilezikian JP, Bone HG, Kaur A, Maragoto A, Santora AC. Alendronate increases bone mass and reduces bone markers in postmenopausal African-American women. Journal of Clinical Endocrinology and Metabolism. 2002;87(6):2792-2797.

11. Black DM, Cummings SR, Karpf DB, et al. Randomised trial of effect of alendronate on risk of fracture in women with existing vertebral fractures. Lancet. 1996;348(9041):1535-1541.

12. Black DM, Delmas PD, Eastell R, et al. Once-yearly zoledronic acid for treatment of postmenopausal osteoporosis. New England Journal of Medicine. 2007;356(18):1809-1822.

13. Bone HG, Downs RW, Tucci JR, et al. Dose-response relationships for alendronate treatment in osteoporotic elderly women. Alendronate Elderly Osteoporosis Study Centers. Journal of Clinical Endocrinology and Metabolism. 1997;82(1):265-274.

14. Bone HG, Greenspan SL, McKeever C, et al. Alendronate and estrogen effects in postmenopausal women with low bone mineral density. Journal of Clinical Endocrinology and Metabolism. 2000;85(2):720-726.

15. Bone HG, Bolognese M, Yuen CK, et al. Effects of denosumab on bone mineral density and bone turnover in postmenopausal women. Journal of Clinical Endocrinology and Metabolism. 2008;93(6):2149-2157.

16. Bonnick S, Broy S, Kaiser F, et al. Treatment with alendronate plus calcium, alendronate alone, or calcium alone for postmenopausal low bone mineral density. Current Medical Research and Opinion. 2007;23(6):1341-1349.

17. Brown JP, Kendler DL, McClung MR, et al. The efficacy and tolerability of risedronate once a week for the treatment of postmenopausal osteoporosis. Calcified Tissue International. 2002;71:103-111.

18. Brown JP, Prince RL, Deal C, et al. Comparison of the effect of denosumab and alendronate on BMD and biochemical markers of bone turnover in postmenopausal women with low bone mass: A randomized, blinded, phase 3 trial. Journal of Bone and Mineral Research. 2009;24(1):153-161.

19. Burghardt AJ, Kazakia GJ, Sode M, e Papp AE, Link TM, Majumdar S. A longitudinal HR- pQCT study of alendronate treatment in postmenopausal women with low bone density: Relations among density, cortical and trabecular microarchitecture, biomechanics, and bone turnover. Journal of Bone and Mineral Research. 2010;25(12):2558-2571.

20. Chailurkit LO, Jongjaroenprasert W, Rungbunnapun S, Ongphiphadhanakul B, Sae-Tung S, Rajatanavin R. Effect of alendronate on bone mineral density and bone turnover in Thai postmenopausal osteoporosis. Journal of Bone and Mineral Metabolism. 2003;21(6):421-427.

21. Chao M, Hua Q, Yingfeng Z, et al. Study on the role of zoledronic acid in treatment of postmenopausal osteoporosis women. Pakistan Journal of Medical Sciences. 2013;29(6):1381-1384.

22. Chavez-Valencia V, Arce-Salinas CA, Espinosa-Ortega F. Cost-minimization study comparing annual infusion of zoledronic acid or weekly oral alendronate in women with low bone mineral density. Journal of Clinical Densitometry. 2014;17(4):484-489.

23. Chesnut CH, McClung MR, Ensrud KE, et al. Alendronate treatment of the postmenopausal osteoporotic woman: Effect of multiple dosages on bone mass and bone remodeling. American Journal of Medicine. 1995;99(2):144-152.

TECHNOLOGY REVIEW Drugs for the Treatment and Prevention of Osteoporosis in Postmenopausal Women 129

24. Chilibeck PD, Davison KS, Whiting SJ, Suzuki Y, Janzen CL, Peloso P. The effect of strength training combined with bisphosphonate (etidronate) therapy on bone mineral, lean tissue, and fat mass in postmenopausal women. Canadian Journal of Physiology and Pharmacology. 2002;80(10):941-950.

25. Clemmesen B, Ravn P, Zegels B, Taquet AN, Christiansen C, Reginster JY. A 2-year phase II study with 1-year of follow-up of risedronate (NE-58095) in postmenopausal osteoporosis. Osteoporosis International. 1997;7(5):488-495.

26. Cosman F, Gilchrist N, McClung M, et al. A phase 2 study of MK-5442, a calcium-sensing receptor antagonist, in postmenopausal women with osteoporosis after long-term use of oral bisphosphonates. Osteoporosis International. 2016;27(1):377-386.

27. Cummings SR, Black DM, Thompson DE, et al. Effect of alendronate on risk of fracture in women with low bone density but without vertebral fractures. Results from the Fracture Intervention Trial. JAMA. 1998;280(24):2077-2082.

28. Cummings SR, San Martin J, McClung MR, et al. Denosumab for prevention of fractures in postmenopausal women with osteoporosis. New England Journal of Medicine. 2009;361(8):756-765.

29. Delmas PD, Benhamou CL, Man Z, et al. Monthly dosing of 75 mg risedronate on 2 consecutive days a month: efficacy and safety results. Osteoporosis International. 2008;19(7):1039-1045.

30. Delmas PD, McClung MR, Zanchetta JR, et al. Efficacy and safety of risedronate 150 mg once a month in the treatment of postmenopausal osteoporosis. Bone. 2008;42(1):36-42.

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35. Eastell R, Nagase S, Ohyama M, et al. Safety and efficacy of the cathepsin K inhibitor ONO- 5334 in postmenopausal osteoporosis: The OCEAN study. Journal of Bone and Mineral Research. 2011;26(6):1303-1312.

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36. Evans RA, Somers NM, Dunstan CR, Royle H, Kos S. The effect of low-dose cyclical etidronate and calcium on bone mass in early postmenopausal women. Osteoporosis International. 1993;3(2):71-75.

37. Fogelman I. EUCTR2008-001865-28-GB: The Relationship Between Osteoporosis and Aortic Calcification in Postmenopausal Women. https://www.clinicaltrialsregister.eu/ctr- search/search?query=eudract_number:2008-001865-28.

38. Fogelman I, Ribot C, Smith R, Ethgen D, Sod E, Reginster JY. Risedronate reverses bone loss in postmenopausal women with low bone mass: Results from a multinational, double- blind, placebo-controlled trial. Journal of Clinical Endocrinology and Metabolism. 2000;85(5):1895-1900.

39. Frediani B, Allegri A, Bisogno S, Marcolongo R. Effects of combined treatment with calcitriol plus alendronate on bone mass and bone turnover in postmenopausal osteoporosis: Two years of continuous treatment. Clinical Drug Investigation. 1998;15: 235-244.

40. Freemantle N, Satram-Hoang S, Tang ET, et al. Final results of the DAPS (Denosumab Adherence Preference Satisfaction) study: a 24-month, randomized, crossover comparison with alendronate in postmenopausal women. Osteoporosis International. 2012;23(1):317-326.

41. Fukunaga M, Kushida K, Kishimoto H, et al. A Comparison of the Effect of Risedronate and Etidronate on Lumbar Bone Mineral Density in Japanese Patients with Osteoporosis: A Randomized Controlled Trial. Osteoporosis International. 2002;13(12):971–979.

42. Galesanu C, Gheorghe L, Lisnic N, Zaharia V. Denosumab vs. zoledronic acid in treatment of osteoporosis in postmeno-pausal women. Osteoporosis International. 2017: S295.

43. Galesanu C, Lisnic N, Mocanu V, Florescu A, Loghin AI, Galesanu MR. Efficacy of bisphosphonates in the treatment of postmenopausal osteoporosis. Osteoporosis International. 2011:S739.

44. Galesanu C, Lisnic N, Moisii L. Denosumab significantly increases BMD compared with alendronate in postmenopausal women. Osteoporosis International. 2015: S150.

45. Gonnelli S, Cepollaro C, Pondrelli C, et al. Bone turnover and the response to alendronate treatment in postmenopausal osteoporosis. Calcified Tissue International. 1999;65(5):359-364.

46. Gonnelli S, Cepollaro C, Montagnani A, Martini S, Gennari L, Mangeri M, et al. Heel ultrasonography in monitoring alendronate therapy: a four-year longitudinal study. Osteoporosis international 2002;13:415-21.

47. Greenspan SL, Parker RA, Ferguson L, Rosen HN, Maitland-Ramsey L, Karpf DB. Early changes in biochemical markers of bone turnover predict the long- term response to alendronate therapy in representative elderly women: A randomized clinical trial. Journal of Bone and Mineral Research. 1998;13: 1431-1438.

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54. Han LW, Ma DD, Xu XJ, et al. Association Between Geranylgeranyl Pyrophosphate Synthase Gene Polymorphisms and Bone Phenotypes and Response to Alendronate Treatment in Chinese Osteoporotic Women. Chinese Medical Sciences Journal. 2016;31:8-16.

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63. Invernizzi M, Carda S, Baricich A, Cisari C. Preliminary results of a randomized head to head study between denosumab and zoledronic acid in severe osteoporotic women. Journal of Bone and Mineral Research. 2013. Conference Poster, Presentation Number: SU0383.

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70. Kung AWC, Yeung SSC, Chu LW. The efficacy and tolerability of alendronate in postmenopausal osteoporotic Chinese women: A randomized placebo-controlled study. Calcified Tissue International. 2000;67:286-290.

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71. Lau EMC, Woo J, Chan YH, Griffith J. Alendronate prevents bone loss in Chinese women with osteoporosis. Bone. 2000;27:677-680.

72. Leung JY, Ho AY, Ip TP, Lee G, Kung AW. The efficacy and tolerability of risedronate on bone mineral density and bone turnover markers in osteoporotic Chinese women: a randomized placebo-controlled study. Bone. 2005;36:358-364.

73. Leung PC, Qin L, Au SK. Prevention of osteoporotic fractures among high-risk groups of postmenopausal women. Hong Kong Medical Journal. 2006;12:36-39.

74. Lewiecki EM, Miller PD, McClung MR, et al. Two-year treatment with denosumab (AMG 162) in a randomized phase 2 study of postmenopausal women with low BMD. Journal of Bone and Mineral Research. 2007;22:1832-1841.

75. Li M, Zhang ZL, Liao EY, et al. Effect of low-dose alendronate treatment on bone mineral density and bone turnover markers in Chinese postmenopausal women with osteopenia and osteoporosis. Menopause. 2013;20(1):72-78.

76. Li Y, Zhang Z, Deng X, Chen L. Efficacy and safety of risedronate sodium in treatment of postmenopausal osteoporosis. Journal of Huazhong University of Science and Technology. 2005; 25:527-529.

77. Liang BC, Shi ZY, Wang B, et al. Intravenous Zoledronic Acid 5 mg on Bone Turnover Markers and Bone Mineral Density in East China Subjects with Newly Diagnosed Osteoporosis: A 24- month Clinical Study. Orthopaedic Surgery. 2017;9:103-109.

78. Liberman UA, Weiss SR, Broll J, et al. Effect of oral alendronate on bone mineral density and the incidence of fractures in postmenopausal osteoporosis. New England Journal of Medicine. 1995;333:1437-1443.

79. Ling Q, Wingyee C, Szeki A, Musei F, Pingchung L. Alendronate increases BMD at appendicular and axial skeletons in patients with established osteoporosis. Journal of Orthopaedic Surgery and Research. 2007;2:9.

80. Luckey MM, Gilchrist N, Bone HG, et al. Therapeutic equivalence of alendronate 35 milligrams once weekly and 5 milligrams daily in the prevention of postmenopausal osteoporosis. Obstetrics and Gynecology. 2003;101:711-721.

81. Lyritis GP, Tsakalakos N, Paspati I, Skarantavos G, Galanos A, Androulakis C. The effect of a modified etidronate cyclical regimen on postmenopausal osteoporosis: a four-year study. Clinical Rheumatology. 1997;16:354-360.

82. McClung M, Clemmesen B, Daifotis A, et al. Alendronate prevents postmenopausal bone loss in women without osteoporosis. A double-blind, randomized, controlled trial. Alendronate Osteoporosis Prevention Study Group. Annals of Internal Medicine. 1998;128:253-261.

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83. McClung M, Miller P, Recknor C, Mesenbrink P, Bucci-Rechtweg C, Benhamou CL. Zoledronic acid for the prevention of bone loss in postmenopausal women with low bone mass: A randomized controlled trial. Obstetrics and Gynecology. 2009;114:999-1007.

84. McClung M, Recker R, Miller P, et al. Intravenous zoledronic acid 5 mg in the treatment of postmenopausal women with low bone density previously treated with alendronate. Bone. 2007;41:122-128.

85. McClung MR, Geusens P, Miller PD, et al. Effect of risedronate on the risk of hip fracture in elderly women. Hip Intervention Program Study Group. The New England Journal of Medicine. 2001;344:333-340.

86. McClung MR, Grauer A, Boonen S, et al. Romosozumab in postmenopausal women with low bone mineral density. New England Journal of Medicine. 2014;370:412-420.

87. McClung MR, Miller PD, Brown JP, et al. Efficacy and safety of a novel delayed-release risedronate 35 mg once-a-week tablet. Osteoporosis International. 2012;23:267-276.

88. Meunier PJ, Confavreux E, Tupinon I, Hardouin C, Delmas PD, Balena R. Prevention of early postmenopausal bone loss with cyclical etidronate therapy (a double-blind, placebo-controlled study and 1-year follow-up). Journal of Clinical Endocrinology and Metabolism. 1997;82:2784- 2791.

89. Michalska D, Stepan JJ, Basson BR, Pavo I. The effect of raloxifene after discontinuation of long-term alendronate treatment of postmenopausal osteoporosis. Journal of Clinical Endocrinology and Metabolism. 2006;91:870-877.

90. Miller PD, Pannacciulli N, Brown JP, et al. Denosumab or zoledronic acid in postmenopausal women with osteoporosis previously treated with oral bisphosphonates. Journal of Clinical Endocrinology and Metabolism. 2016;101:3163-3170.

91. Montessori MLM, Scheele WH, Netelenbos JC, Kerkhoff JF, Bakker K. The use of etidronate and calcium versus calcium alone in the treatment of postmenopausal osteopenia: Results of three years of treatment. Osteoporosis International. 1997;7:52-58.

92. Mortensen L, Charles P, Bekker PJ, Digennaro J, Johnston CC. Risedronate increases bone mass in an early postmenopausal population: two years of treatment plus one year of follow- up. The Journal of clinical endocrinology and metabolism. 1998;83:396-402.

93. Murphy MG, Weiss S, McClung, M, et al. Effect of alendronate and MK-677 (a growth hormone secretagogue), individually and in combination, on markers of bone turnover and bone mineral density in postmenopausal osteoporotic women. Journal of Clinical Endocrinology and Metabolism. 2001; 86 (3):1116-1125.

94. Nakamura T, Matsumoto T, Sugimoto T, et al. Clinical Trials Express: fracture risk reduction with denosumab in Japanese postmenopausal women and men with osteoporosis:

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denosumab fracture intervention randomized placebo controlled trial (DIRECT). Journal of Clinical Endocrinology and Metabolism. 2014;99: 2599-2607

95. Nakamura TM, T. Sugimoto TS. Dose-response study of denosumab on bone mineral density and bone turnover markers in Japanese postmenopausal women with osteoporosis. Osteoporosis International. 2012;23(3):1131-40.

96. NCT02063854. A Phase II/III, Double-blind, Parallel Group Comparative Study of Oral Administration of NE-58095 Tablets. Clinicaltrialsgov. 2017: https://clinicaltrials.gov/ct2/show/record/NCT02063854.

97. NCT02157948. A Double-blind Study to Assess the Efficacy and Safety of Denosumab Produced by Two Different Processes in Postmenopausal Women With Osteoporosis. Clinicaltrialsgov. 2017: https://clinicaltrials.gov/ct2/show/record/NCT02157948.

98. Ohtori S, Inoue G, Orita S, Yamauchi K, Eguchi Y, Ochiai N, et al. Comparison of teriparatide and bisphosphonate treatment to reduce pedicle screw loosening after lumbar spinal fusion surgery in postmenopausal women with osteoporosis from a bone quality perspective. Spine. 2013;38:E487-E92.

99. Pacifici RM, C. Vered IR, R. Avioli LV. Coherence Therapy Does Not Prevent Axial Bone Loss in Osteoporotic Women: A Preliminary Comparative Study. Journal of Clinical Endocrinology and Metabolism. 1988;66(4):747-53.

100. Paggiosi MA, Peel N, McCloskey E, Walsh JS, Eastell R. Comparison of the effects of three oral bisphosphonate therapies on the peripheral skeleton in postmenopausal osteoporosis: the TRIO study. Osteoporosis International. 2014;25:2729-41.

101. Pols HAP, Felsenberg D, Hanley DA, Stepan J, Munoz-Torres M, Wilkin TJ, et al. Multinational, placebo-controlled, randomized trial of the effects of alendronate on bone density and fracture risk in postmenopausal women with low bone mass: Results of the FOSIT study. Osteoporosis International. 1999;9:461-8.

102. Pouilles JM, Tremollieres F, Roux C, Sebert JL, Alexandre C, Goldberg D, et al. Effects of cyclical etidronate therapy on bone loss in early postmenopausal women who are not undergoing hormonal replacement therapy. Osteoporosis International. 1997;7:213-8.

103. Reginster JY, Minne HW, Sorensen OH, Hooper M, Roux C, Brandi ML, et al. Randomized trial of the effects of risedronate on vertebral fractures in women with established postmenopausal osteoporosis. Osteoporos Int. 2000;11:83-91.

104. Reid DM, Hosking D, Kendler D, Brandi ML, Wark JD, Weryha G, et al. Alendronic acid produces greater effects than risedronic acid on bone density and turnover in postmenopausal women with osteoporosis: Results of FACTS 1 -International. Clin Drug Invest. 2006;26:63-74.

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105. Reid IR, Brown JP, Burckhardt P, Horowitz Z, Richardson P, Trechsel U, et al. Intravenous zoledronic acid in postmenopausal women with low bone mineral density. New England Journal of Medicine. 2002;346:653-61.

106. Reid IRH, A. M. Mihov BS, A. Garratt EW, S. Wiessing KRB, M. J. Bastin SG. Fracture Prevention with Zoledronate in Older Women with Osteopenia. New England Journal of Medicine. 2018;379(25):2407-16.

107. Robles-Carranza LP, Chavez-Valencia V, Arce-Salinas CA. Comparison of the efficacy of annual zoledronic acid or weekly alendronate. A 3-yr analysis of postmenopausal women with low bone mineral density. Annals of the Rheumatic Disease. 2013;Conference:.

108. Rosen CJ, Hochberg MC, Bonnick SL, McClung M, Miller P, Broy S, et al. Treatment with once-weekly alendronate 70 mg compared with once-weekly risedronate 35 mg in women with postmenopausal osteoporosis: a randomized double-blind study. Journal of Bone and Mineral Research. 2005;20:141-51.

109. Rossini M, Gatti D, Girardello S, Braga V, James G, Adami S. Effects of two intermittent alendronate regimens in the prevention or treatment of postmenopausal osteoporosis. Bone. 2000;27:119-22.

110. Roux C, Hofbauer LC, Ho PR, Wark JD, Zillikens MC, Fahrleitner-Pammer A, et al. Denosumab compared with risedronate in postmenopausal women suboptimally adherent to alendronate therapy: efficacy and safety results from a randomized open-label study. Bone. 2014;58:48-54.

111. Russo MS, Panebianco P, Di SF, Scarpinato RA, Destro G, Salamone SA, et al. The use of bisphosphonates in the treatment of osteoporosis. Arch Gerontol Geriatr. 1996;23:551-5.

112. Sahota O, Fowler I, Blackwell PJ, Lawson N, Cawte SA, San P, et al. A comparison of continuous alendronate, cyclical alendronate and cyclical etidronate with calcitriol in the treatment of postmenopausal vertebral osteoporosis: A randomized controlled trial. Osteoporosis International. 2000;11:959-66.

113. Sarioglu M, Tuzun C, Unlu Z, Tikiz C, Taneli F, Uyanik BS. Comparison of the effects of alendronate and risedronate on bone mineral density and bone turnover markers in postmenopausal osteoporosis. Rheumatology International. 2006;26:195-200.

114. Schnitzer T, Bone HG, Crepaldi G, Adami S, McClung M, Kiel D, et al. Therapeutic equivalence of alendronate 70 mg once-weekly and alendronate 10 mg daily in the treatment of osteoporosis. Aging - Clinical and Experimental Research. 2000;12:1-12.

115. Seeman E, Delmas PD, Hanley DA, Sellmeyer D, Cheung AM, Shane E, et al. Microarchitectural deterioration of cortical and trabecular bone: differing effects of denosumab and alendronate. Journal of Bone and Mineral Research. 2010;25:1886-94.

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116. Shi ZY, Zhang XG, Li CW, Liu K, Liang BC, Shi XL. Effect of Traditional Chinese Medicine Product, QiangGuYin, on Bone Mineral Density and Bone Turnover in Chinese Postmenopausal Osteoporosis. Evid Based Complement Alternat Med. 2017;2017:6062707.

117. Shilbayeh S, Zumeili A, Hilow HM. The efficacy and safety of Calidron tablets for management of osteoporosis in Jordanian women: A randomised clinical trial. Saudi Pharmaceutical Journal. 2004;12:86-95.

118. Shiota E, Tsuchiya K, Yamaoka K, Kawano O. Effect of intermittent cyclical treatment with etidronate disodium (HEBP) and calcium plus alphacalcidol in postmenopausal osteoporosis. Journal of orthopaedic science. 2001;6:133-6.

119. Storm T, Thamsborg G, Steiniche T, Genant HK, Sorensen OH. Effect of intermittent cyclical etidronate therapy on bone mass and fracture rate in women postmenopausal osteoporosis. New England Journal of Medicine. 1990;322:1265-71.

120. Susan LG, Subashan P, Mary Anne F, David AN, Neil MR. Efficacy and safety of single-dose zoledronic acid for osteoporosis in frail elderly women: a randomized clinical trial. JAMA internal medicine. 2015;175(6):913-21.

121. Tan W, Sun J, Zhou L, Li Y, Wu X. Randomized trial comparing efficacies of zoledronate and alendronate for improving bone mineral density and inhibiting bone remodelling in women with post-menopausal osteoporosis. J Clin Pharm Ther. 2016;41:519-23.

122. Tobias JH, Dalzell N, Pazianas M, Chambers TJ. Cyclical etidronate prevents spinal bone loss in early post-menopausal women. Br J Rheumatol. 1997;36:612-3.

123. Uusi-Rasi K, Kannus P, Cheng S, Sievanen H, Pasanen M, Heinonen A, et al. Effect of alendronate and exercise on bone and physical performance of postmenopausal women: A randomized controlled trial. Bone. 2003;33:132-43.

124. Valimaki MJ, Farrerons-Minguella J, Halse J, Kroger H, Maroni M, Mulder H, et al. Effects of risedronate 5 mg/d on bone mineral density and bone turnover markers in late- postmenopausal women with osteopenia: a multinational, 24-month, randomized, double- blind, placebo-controlled, parallel-group, phase III trial. Clin Ther. 2007;29:1937-49.

125. Watts NB, Harris ST, Genant HK, Wasnich RD, Miller PD, Jackson RD, et al. Intermittent cyclical etidronate treatment of postmenopausal osteoporosis. New England Journal of Medicine. 1990;323:73-9.

126. Wimalawansa SJ. Combined therapy with estrogen and etidronate has an additive effect on bone mineral density in the hip and vertebrae: Four-year randomized study. Am J Med. 1995;99:36-42.

127. Wimalawansa SJ. A four-year randomized controlled trial of hormone replacement and bisphosphonate, alone or in combination, in women with postmenopausal osteoporosis. Am J Med. 1998;104:219-26.

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128. Yan Y, Wang W, Zhu H, Li M, Liu J, Luo B, et al. The efficacy and tolerability of once-weekly alendronate 70 mg on bone mineral density and bone turnover markers in postmenopausal Chinese women with osteoporosis. J Bone MinerMetab. 2009;27:471-8.

129. Yang Y, Luo X, Yan F, Jiang Z, Li Y, Fang C, et al. Effect of zoledronic acid on vertebral marrow adiposity in postmenopausal osteoporosis assessed by MR spectroscopy. Skeletal Radiology. 2015;44:1499-505.

130. Yanik B, Kulcu DG. The effect of raloxifene, alendronate and risedronate on serum lipid profile in postmenopausal women. Turkiye Fiziksel Tip ve Rehabilitasyon Dergisi. 2008;54:4-7.

131. Yen ML, Yen BL, Jang MH, Hsu SHJ, Cheng WC, Tsai KS. Effects of alendronate on osteopenic postmenopausal Chinese women. Bone. 2000;27:681-5.

132. Zhang JZ, T. Xu XC, Q. Zhao D. Zoledronic acid combined with percutaneous kyphoplasty in the treatment of osteoporotic compression fracture in a single T12 or L1 vertebral body in postmenopausal women. Osteoporosis International. 2019;Apr 11.

133. Zhu HMT, Cheng H, He Q, Li L, Xue PQ, Chen QY, et al. Efficacy and safety of denosumab in Chinese postmenopausal women with osteoporosis at increased risk of fracture: Results from a 12-month, randomized, double-blind, placebo-controlled phase III study. Journal of Bone and Mineral Research. 2017;Conference:(Supplement 1).

List of Included Studies (Companion publications), N=53

1. Bauer DC, Black DM, Garnero P, Hochberg M, Ott S, Orloff J, et al. Change in bone turnover and hip, non-spine, and vertebral fracture in alendronate-treated women: the fracture intervention trial. Journal of Bone and Mineral Research. 2004;19:1250-8.

2. Black DM, Eastell R, Cosman F, Man Z, Bucci-Rechtweg C, Mesenbrink P. Effect of once- yearly zoledronic acid = MG on a sub-set of six non-vertebral fractures. J Clin Densitometry. 2010;Conference: 132-March.

3. Black DM, Eastell R, Cosman F, McLellan A, Man Z, Bucci-Rechtweg C, et al. Effect of once- yearly zoledronic acid 5 mg on 'Super Six' non-vertebral fractures. Osteoporosis International. 2009;Conference: S281.

4. Black DM, Reid IR, Boonen S, Bucci-Rechtweg C, Cauley JA, Cosman F, et al. The effect of 3 versus 6 years of zoledronic acid treatment of osteoporosis: a randomized extension to the HORIZON-Pivotal Fracture Trial (PFT). Journal of Bone and Mineral Research. 2012;27:243- 54.

5. Black DM, Reid IR, Cauley JA, Cosman F, Leung PC, Lakatos P, et al. The effect of 6 versus 9 years of zoledronic acid treatment in osteoporosis: A randomized second extension to the HORIZON-pivotal fracture trial (PFT). Journal of Bone and Mineral Research. 2015;30:934-44.

TECHNOLOGY REVIEW Drugs for the Treatment and Prevention of Osteoporosis in Postmenopausal Women 139

6. Black DM, Schwartz AV, Ensrud KE, Cauley JA, Levis S, Quandt SA, et al. Effects of continuing or stopping alendronate after 5 years of treatment: The Fracture Intervention Trial long-term extension (FLEX): A randomized trial. JAMA. 2006;296(24):2927-38.

7. Bone HG, Hosking D, Devogelaer JP, Tucci JR, Emkey RD, Tonino RP, et al. Ten Years' Experience with Alendronate for Osteoporosis in Postmenopausal Women. New England Journal of Medicine. 2004;350:1189-99.

8. Bonnick S, Saag KG, Kiel DP, McClung M, Hochberg M, Burnett SA, et al. Comparison of weekly treatment of postmenopausal osteoporosis with alendronate versus risedronate over two years. Journal of Clinical Endocrinology and Metabolism. 2006;91:2631-7.

9. Cauley JA, Black D, Boonen S, Cummings SR, Mesenbrink P, Palermo L, et al. Once-yearly zoledronic acid and days of disability, bed rest, and back pain: randomized, controlled HORIZON Pivotal Fracture Trial. Journal of Bone and Mineral Research. 2011;26:984-92.

10. Cosman F, Cauley JA, Eastell R, Boonen S, Palermo L, Reid IR, et al. Reassessment of fracture risk in women after 3 years of treatment with zoledronic acid: when is it reasonable to discontinue treatment? Journal of Clinical Endocrinology and Metabolism. 2014;99:4546-54.

11. Devogelaer JP, Broll H, Correa-Rotter R, Cumming DC, De Deuxchaisnes CN, Geusens P, et al. Oral alendronate induces progressive increases in bone mass of the spine, hip, and total body over 3 years in postmenopausal women with osteoporosis. Bone. 1996;18:141-50.

12. Devogelaer JP, Brown JP, Burckhardt P, Meunier PJ, Goemaere S, Lippuner K, et al. Zoledronic acid efficacy and safety over five years in postmenopausal osteoporosis. Osteoporosis International. 2007;18:1211-8.

13. Downs, Jr., Bone HG, McIlwain H, Baker MZ, Yates AJ, Lombardi A, et al. An open-label extension study of alendronate treatment in elderly women with osteoporosis. Calcified Tissue International. 1999;64:463-9.

14. E. J. P. B. Brown HGC, R. Franchimont NB, M. L. Czerwinski EK, M. A. Man ZM, D. Radominski SCR, J. Y. Resch HRI, et al. Six years of denosumab treatment in postmenopausal women with osteoporosis: Results from the first three years of the freedom. Arthritis and Rheumatism. 2011;63(12):4044-5.

15. Eastell R, Black DM, Boonen S, Adami S, Felsenberg D, Lippuner K, et al. Effect of once- yearly zoledronic acid five milligrams on fracture risk and change in femoral neck bone mineral density. Journal of Clinical Endocrinology and Metabolism. 2009;94:3215-25.

16. Eastell R, Nagase S, Small M, Boonen S, Spector T, Ohyama M, et al. Effect of ONO-5334 on bone mineral density and biochemical markers of bone turnover in postmenopausal osteoporosis: 2-year results from the OCEAN study. Journal of Bone and Mineral Research. 2014;29:458-66.

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17. Ensrud KE, Barrett-Connor EL, Schwartz A, Santora AC, Bauer DC, Suryawanshi S, et al. Randomized trial of effect of alendronate continuation versus discontinuation in women with low BMD: Results from the fracture intervention trial long-term extension. Journal of Bone and Mineral Research. 2004;19:1259-69.

18. Ensrud KE, Black DM, Palermo L, Bauer DC, Barrett-Connor E, Quandt SA, et al. Treatment with alendronate prevents fractures in women at highest risk: Results from the fracture intervention trial. Arch Intern Med. 1997;157:2617-24.

19. Genant HK, Bucci-Rechtweg C, Bauer DC, Mesenbrink PG, Palermo L, Nusgarten L, et al. Does zoledronic acid increase risk of atypical femoral shaft fractures? results from the HORIZON-PFT. Osteoporosis International. 2010;Conference: S161-S2.

20. Grey A, Bolland M, Mihov B, Wong S, Horne A, Gamble G, et al. Duration of antiresorptive effects of low-dose zoledronate in osteopenic postmenopausal women: a randomized, placebo-controlled trial. Journal of Bone and Mineral Research. 2014;29:166-72.

21. Grey A, Bolland MJ, Horne A, Wattie D, House M, Gamble G, et al. Five years of antiresorptive activity after a single dose of zoledronate--results from a randomized double-blind placebo-controlled trial. Bone. 2012;50:1389-93.

22. Grey A, Bolland MJ, Wattie D, Horne A, Gamble G, Reid IR. The antiresorptive effects of a single dose of zoledronate persist for two years: A randomized, placebo-controlled trial in osteopenic postmenopausal women. Journal of Clinical Endocrinology and Metabolism. 2009;94:538-44.

23. Grey AB, M. J. Horne AM, B. Gamble GR. Duration of antiresorptive activity of zoledronate in postmenopausal women with osteopenia: a randomized, controlled multidose trial. Canadian Medical Association Journal. 2017;189(36):E1130-E6.

24. Hadji P, Ziller V, Gamerdinger D, Spieler W, Articus K, Baier M, et al. Quality of life and health status with zoledronic acid and generic alendronate--a secondary analysis of the Rapid Onset and Sustained Efficacy (ROSE) study in postmenopausal women with low bone mass. OsteoporosInt. 2012;23:2043-51.

25. Harris ST, Watts NB, Li Z, Chines AA, Hanley DA, Brown JP. Two-year efficacy and tolerability of risedronate once a week for the treatment of women with postmenopausal osteoporosis. Curr Med Res Opin. 2004;20:757-64.

26. Hwang JS, Chin LS, Chen JF, Yang TS, Chen PQ, Tsai KS, et al. The effects of intravenous zoledronic acid in Chinese women with postmenopausal osteoporosis. J Bone Miner Metab. 2011;29:328-33.

27. J. A. R. Simon CM, A. H JA, J. D. Franek EL, E. M. McClung MRM, C. A. Ragi-Eis SN, G. C. Muschitz CN, et al. Impact of denosumab on the peripheral skeleton of postmenopausal women with osteoporosis: bone density, mass, and strength of the radius, and wrist fracture. Menopause. 2013;20(2):130-7.

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28. J. R. Simon CM, A. Adachi JF, E. Lewiecki EMM, C. A. Ragi ESN, G. C. Muschitz CN, R. Torring OW, et al. Effects of denosumab on radius BMD, strength, and wrist fractures: Results from the fracture reduction evaluation of denosumab in osteoporosis every 6 months (freedom) study. Journal of Bone and Mineral Research. 2011;Conference:(26 Suppl 1).

29. Jacques RM, Boonen S, Cosman F, Reid IR, Bauer DC, Black DM, et al. Relationship of changes in total hip bone mineral density to vertebral and nonvertebral fracture risk in women with postmenopausal osteoporosis treated with once-yearly zoledronic acid 5 mg: the HORIZON-Pivotal Fracture Trial (PFT). Journal of Bone and Mineral Research. 2012;27:1627- 34.

30. Kendler DL, McClung MR, Freemantle N, Lillestol M, Moffett AH, Borenstein J, et al. Adherence, preference, and satisfaction of postmenopausal women taking denosumab or alendronate. Osteoporosis International. 2011;22:1725-35.

31. M. A. T. Bolognese CSZ, J. R. Lippuner KM, M. R. Brandi MLH, A. Lakatos PM, A. H. Lorenc RSW, A. Libanati C. Denosumab significantly increases DXA BMD at both trabecular and cortical sites: results from the FREEDOM study. J Clin Densitom. 2013;16(2):147-53.

32. McClung MR, Michael LE, Cohen SB, Bolognese MA, Woodson GC, Moffett AH, et al. Denosumab in postmenopausal women with low bone mineral density. New England Journal of Medicine. 2006;354:821-31.

33. McClung MR, Wasnich RD, Hosking DJ, Christiansen C, Ravn P, Wu M, et al. Prevention of postmenopausal bone loss: Six-year results from the early postmenopausal intervention cohort study. Journal of Clinical Endocrinology and Metabolism. 2004;89:4879-85.

34. McClung MR, Zanchetta JR, Racewicz A, Roux C, Benhamou CL, Man Z, et al. Efficacy and safety of risedronate 150-mg once a month in the treatment of postmenopausal osteoporosis: 2-year data. Osteoporosis International. 2013;24:293-9.

35. McClung MRB, Torring S, Roux O, Rizzoli C, Bone R, Benhamou HG, et al. Effect of denosumab treatment on the risk of fractures in subgroups of women with postmenopausal osteoporosis. Journal of Bone and Mineral Research. 2012;27(1):211-8.

36. NCT00404820. Safety/Efficacy of Zoledronic Acid and Alendronate on Bone Metabolism in Postmenopausal Women With Osteoporosis (ROSE). Clinicaltrialsgov. 2011. https://clinicaltrials.gov/ct2/show/NCT00404820

37. Papapoulos SC, Libanati R, Brandi C, Brown ML, Czerwinski JP, Krieg E, et al. Five years of denosumab exposure in women with postmenopausal osteoporosis: results from the first two years of the FREEDOM extension. Journal of Bone and Mineral Research. 2012;27(3):694- 701.

38. Popp AW, Buffat H, Cavelti A, Windolf M, Perrelet R, Senn C, et al. Cortical bone loss at the tibia in postmenopausal women with osteoporosis is associated with incident non-vertebral

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fractures: results of a randomized controlled ancillary study of HORIZON. Maturitas. 2014;77:287-93.

39. Reid DM, Hosking D, Kendler D, Brandi ML, Wark JD, Marques-Neto JF, et al. A comparison of the effect of alendronate and risedronate on bone mineral density in postmenopausal women with osteoporosis: 24-Month results from FACTS-International. Int J Clin Pract. 2008;62:575-84.

40. Reid IR, Gamble GD, Mesenbrink P, Lakatos P, Black DM. Characterization of and risk factors for the acute-phase response after zoledronic acid. Journal of Clinical Endocrinology and Metabolism. 2010;95:4380-7.

41. S. L. Adami CB, S. Cummings SRH, P. R. Wang AS, E. Lane JFF-HWGA, J. D. Bhandari Md, Gregorio L. Gilchrist NL, et al. Denosumab treatment in postmenopausal women with osteoporosis does not interfere with fracture-healing: results from the FREEDOM trial. J Bone Joint Surg Am. 2012;94(23):2113-9.

42. S. V. Silverman HW, A. Ragi-Eis SF, P. Gilchrist NL, P. Nevitt MP, S. Pavelka KR, D. Simon JM, et al. Evaluation of health-related quality of life in postmenopausal women with osteoporosis who participated in the freedom trial. Osteoporosis International. 2010;Conference:(22 Suppl 1):S14-S5.

43. Sambrook PN, Rodriguez JP, Wasnich RD, Luckey MM, Kaur A, Meng L, et al. Alendronate in the prevention of osteoporosis: 7-year follow-up. OsteoporosInt. 2004;15:483-8.

44. Sambrook PN, Silverman SL, Cauley JA, Recknor C, Olson M, Su G, et al. Health-related quality of life and treatment of postmenopausal osteoporosis: results from the HORIZON-PFT. Bone. 2011;48:1298-304.

45. Seeman E, Black DM, Bucci-Rechtweg C, Eastell R, Boonen S, Mesenbrink P. Zoledronic acid substantially reduces the risk of morphometric vertebral and clinical fractures. J Clin Densitometry. 2010;Conference: 132-3.

46. Sorensen OH, Crawford GM, Mulder H, Hosking DJ, Gennari C, Mellstrom D, et al. Long-term efficacy of risedronate: a 5-year placebo-controlled clinical experience. Bone. 2003;32:120-6.

47. Ste-Marie LG, Sod E, Johnson T, Chines A. Five years of treatment with risedronate and its effects on bone safety in women with postmenopausal osteoporosis. Calcified Tissue International. 2004;75:469-76.

48. Steven RC, Ann VS, Dennis MB. Alendronate and Atrial Fibrillation. The New England Journal of Medicine. 2007;356(18):1895.

49. Tonino RP, Meunier PJ, Emkey R, Rodriguez-Portales JA, Menkes CJ, Wasnich RD, et al. Skeletal benefits of alendronate: 7-Year treatment of postmenopausal osteoporotic women. Journal of Clinical Endocrinology and Metabolism. 2000;85:3109-15.

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50. Tucci JR, Tonino RP, Emkey RD, Peverly CA, Kher U, Santora 2nd AC. Effect of three years of oral alendronate treatment in postmenopausal women with osteoporosis. The American journal of medicine. 1996;101:488-501.

51. NCT00247273. A Study of Monthly Risedronate for Osteoporosis. Clinicaltrialsgov. 2013. https://clinicaltrials.gov/ct2/show/NCT00247273

52. Wustrack R, Seeman E, Bucci-Rechtweg C, Palermo L, Black D. Impact of zoledronic acid on severe vertebral fractures: Results from horizon-pivotal fracture trial. Bone. 2010;Conference: S194-S5.

53. Yanik B, Bavbek N, Yangk T, Inegol I, Kanbay M, Turgut FH, et al. The effect of alendronate, risedronate, and raloxifene on renal functions, based on the cockcroft and gault method, in postmenopausal women. Renal Failure. 2007;29:471-6.

List of eligible studies not reporting data for outcome of interest, N=42

1. Aki S, Gulbaba RG, Eskiyurt N. Effect of alendronate on bone density and bone markers in postmenopausal osteoporosis. J Back Musculoskeletal Rehabil. 2004;17(1):27-31.

2. Aktas S, Alparslan N. A comparison of the effects of etidronate and calcitonin on postmenopausal osteoporosis. Osteoporos-Int. 1996;6 Suppl 1:265.

3. Anastasilakis AD, Polyzos SA, Gkiomisi A, Bisbinas I, Gerou S, Makras P. Comparative effect of zoledronic acid versus denosumab on serum sclerostin and dickkopf-1 levels of naive postmenopausal women with low bone mass: a randomized, head-to-head clinical trial. Journal of Clinical Endocrinology and Metabolism. 2013;98(8):3206-12.

4. Aro HT. Denosumab in prevention of periprosthetic bone loss in cementless hip replacement of postmenopausal women. Osteoporosis International. 2018(Supplement 1):S131.

5. Bilek LD, Waltman NL, Lappe JM, Kupzyk KA, Mack LR, Cullen DM, et al. Protocol for a randomized controlled trial to compare bone-loading exercises with risedronate for preventing bone loss in osteopenic postmenopausal women. BMC Womens Health. 2016;16(1):59, 2016.

6. Boutsen Y, Jamart J, Vynckier C, Borght TV, Devogelaer JP. Prevention of postmenopausal osteoporosis with two intermittent alendronate regimens: Bone mineral density and bone markers changes after 24 months. Journal of Bone and Mineral Research. 2012;Conference

7. Boyd SK, Nishiyama KK, Zebaze RM, Hanley DA, Zanchetta JR, Thomas T, et al. Denosumab decreases cortical porosity in postmenopausal women with low bmd. EndocrRev. 2011;32(3):S182.

8. Catalano A, Morabito N, Basile G, Brancatelli S, Cucinotta D, Lasco A. Zoledronic acid acutely increases sclerostin serum levels in women with postmenopausal osteoporosis. Journal of Clinical Endocrinology and Metabolism. 2013;98:1911-5.

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9. Cecelja M, Edwards S, Moore A, Fogelman I, Chowienczyk P, Frost M. A pilot study to assess effects of alendronic acid on aortic calcification and stiffness in postmenopausal women. J Hypertens. 2015;Conference:e347.

10. Cheng ZQ, Yin W, Fan JY, Ma TJ. [The efficacy of alendronate in the prevention and treatment of postmenopausal osteoporosis]. Zhongguo Yi Xue Ke Xue Yuan Xue BaoActa Academiae Medicinae Sinicae. 2002;Acta Academiae Medicinae Sinicae. 24:306-9.

11. Clemente PA, Cardama F, Armengol R, Goma MT. [ Effect of therapeutical association between hormone replacement therapy and cyclic intermittent therapy with etidronate about bone mineral content in women with postmenopausal osteoporosis. ]. ProgrObstet Ginecol. 1996;39:593-7.

12. D'Amelio P, Grimaldi A, Cristofaro MA, Ravazzoli M, Molinatti PA, Pescarmona GP, et al. Alendronate reduces osteoclast precursors in osteoporosis. Osteoporosis International. 2010;21:1741-50.

13. Dominguez LJ, Galioto A, Ferlisi A, Alessi MA, Belvedere M, Putignano E, et al. Intermittent intramuscular clodronate therapy: a valuable option for older osteoporotic women. Age and Ageing. 2005;34:633-6.

14. e Villiers T, Benhamou C, Conrad JC, Langdahl B, Saag K, Denker A, et al. Resolution of effects on bone turnover markers and BMD after discontinuation of long-term bisphosphonate use. Osteoporosis International. 2013;24(Suppl 1):S138.

15. Felsenberg D, Charpulat R, Cheung AM, LaRoche M, Morris E, Seeman E, et al. Longitudinal in vivo micro-CT assessment in osteopenic women demonstrated that risedronate reduced the deterioration of cortical bone. Bone. 2010;Conference:S35.

16. Folkesson J, Goldenstein J, Carballido-Gamio J, Kazakia G, Burghardt AJ, Rodriguez A, et al. Longitudinal evaluation of the effects of alendronate on MRI bone microarchitecture in postmenopausal osteopenic women. Bone. 2011;48:611-21.

17. Godinne UCLM. EUCTR2006-005862-38-BE: Prevention of Postmenopausal Bone Loss in Osteopenic Women with Alendronate given on a 70 mg Once-every two week Regimen : a 2- year, Double-blind, Placebo-controlled Clinical Trial. WHO ICTRP. 2012.

18. Hyuk JL. Combination therapy with raloxifene and alendronate for treatment of osteoporosis in elderly women. Maturitas. 2017:155.

19. Kendler DL, Gold DT, Horne R, Borenstein J, Varon SF, Man HS, et al. Assessment of preference and satisfaction with a weekly oral tablet versus a 6-month subcutaneous injection for the treatment of osteoporosis. Value in Health. 2009;12:A16.

20. Khanizadeh FRR, A. Asadollahi KA, M. R H. Combination therapy of curcumin and alendronate modulates bone turnover markers and enhances bone mineral density in

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postmenopausal women with osteoporosis. Archives of Endocrinology and Metabolism. 2018;62(4):438-45.

21. Kocjan T, Jensterle M, Pfeifer M, Sabati RA, Bajuk SK, Prezelj J. Evaluation of three regimens of cholecalciferol dosing in osteoporotic postmenopausal women treated with alendronate. Osteoporosis International. 2013;Conference:S286-S7.

22. Kume K, Amano K, Yamada S, Nagata H. Change in bone mineral density of osteoporosis with postmenopausal woman older than 85 years of age treated with bisphophonates. A prospective open label study. Intern MedJ. 2009;Conference:A67.

23. Lin H, Xu T, Fan L, Yang H, Chen X. Effect ofa once-yearly zoledronic acid on BMD and the risk of falling in postmenopausalwomenwithosteoporosis. Osteoporosis International. 2011;Conference:S649-S50.

24. Liu Y, Liu H, Li M, Zhou P, Xing X, Xia W, et al. Association of farnesyl diphosphate synthase polymorphisms and response to alendronate treatment in Chinese postmenopausal women with osteoporosis. Chin Med J. 2014;127:662-8.

25. Matsuzaki K, Ito M, Kaneko H, Kato M, Hikata T, Nango N, et al. Efficacy of osteoporotic agents in trabecular microstructure. Journal of Bone and Mineral Research. 2012;Conference

26. Miller PD, Pannacciulli N, Brown JP, Czerwinski E, Nedergaard BS, Bolognese MA, et al. Denosumab treatment is associated with greater transient increases in serum intact parathyroid hormone concentrations compared with zoledronic acid: Results from a study in postmenopausal women with osteoporosis previously treated with oral bisphosphonates. EndocrRev. 2016;Conference

27. Nenonen A, Cheng S, Ivaska KK, Alatalo SL, Lehtimaki T, Schmidt-Gayk H, et al. Serum TRACP 5b is a useful marker for monitoring alendronate treatment: Comparison with other markers of bone turnover. Journal of Bone and Mineral Research. 2005;20:1804-12.

28. Okamoto K, Inaba M, Furumitsu Y, Ban A, Mori N, Yukioka K, et al. Beneficial effect of risedronate on arterial thickening and stiffening with a reciprocal relationship to its effect on bone mass in female osteoporosis patients: a longitudinal study. Life Sciences. 2010;87:686- 91.

29. Pastore R, Bultrini A, Di GP, Cannuccia A, Frontoni S. Sequentialtherapy in severe osteoporosis. Osteoporosis International. 2014;Conference:S254.

30. Reid IR, Bolland M, Wong S, Horne A, Gamble G, Grey A. A randomized controlled trial ofannual low dose zoledronate in postmenopausal women. Osteoporosis International. 2011;Conference:S526.

31. Saag KG, Benhamou CL, Villiers TD, Johnston, Jr., Langdahl B, Denker A, et al. Resolution of effects on bone turnover markers and bone mineral density after discontinuation of long-term bisphosphonate use. Arthritis and Rheumatism. 2012;Conference:S835-S6.

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32. Seeman E, Borah B, Chapurlat R, Felsenberg D, Darbie L, Rizzoli R. Risedronate reduces deterioration of cortical bone microarchitecture accompanying menopause. Journal of Bone and Mineral Research. 2010;Conference:S32.

33. Tutuncu L, Arslanhan N, Mungen E, Yilmaz S, Yergok YZ. Combined usage of raloxifene and alendronate: Effects on biochemical markers. Nobel Medicus. 2005;1:12-9.

34. Vilariño SIAV, C. Schwartz ACO, O. Dotto J. Comparison of different treatments on postmenopausal patients (POSTM). Maturitas. 2009;63(Suppl 1):S95.

35. Yamaguchi K, Masuhara K, Yamasaki S, Fuji T. Efficacy of different dosing schedules of etidronate for stress shielding after cementless total hip arthroplasty. Journal of orthopaedic science : official journal of the Japanese Orthopaedic Association. 2005;10:32-6.

36. Yeter A, Kavuncu V, Evcik FD, Demirdal US, Subasi V, Cakir T. Evalution the effects of raloxifene and risedronate on serum biochemical markers. Turk Osteoporoz Dergisi. 2014;20:110-6.

37. Yildirim K, Gureser G, Karatay S, Melikoglu MA, Ugur M, Erdal A, et al. Comparison of the effects of alendronate, risedronate and calcitonin treatment in postmenopausal osteoporosis. J Back Musculoskeletal Rehabil. 2005;18:85-9.

38. Zebaze R, Libanati C, Austin M, Bilezikian J, Seeman E. Antiresorptive action is dependent on access to remodeling upon cortical and trabecular surfaces: Comparison of denosumab and alendronate. Journal of Bone and Mineral Research. 2012;Conference

39. Zebaze RM, Boyd SK, Nishiyama KK, Hanley DA, Zanchetta JR, Thomas T, et al. Denosumab decreases cortical porosity in postmenopausal women with low bone mineral density. Osteoporosis International. 2011;Conference:S527.

40. Zebaze RM, Libanati C, Austin M, Bilezikian JP, Seeman E. Denosumab reduces intracortical porosity more than alendronate in the compact-appearing cortex and outer transitional zone. Osteoporosis International. 2012;Conference:S291.

41. Zhang XZ, Song LG, Li H, Han JF, Qian GF, He M, et al. [Effects of alendronate on bone mineral density, cytokines and indices of bone metabolism in postmenopausal osteoporotic patients]. Zhonghua nei ke za zhi. 2006;45:565-8.

42. Zhou WL, Y. Guo XY, H. Xu YG. Effects of zoledronic acid on bone mineral density around prostheses and bone metabolism markers after primary total hip arthroplasty in females with postmenopausal osteoporosis. Osteoporosis International. 2019;30(8):1581–9.

TECHNOLOGY REVIEW Drugs for the Treatment and Prevention of Osteoporosis in Postmenopausal Women 147

APPENDIX 7:EXCLUDED STUDY LIST (BY REASON FOR EXCLUSION)

List of studies excluded: study design (not an RCT, N=115)

1. Effect of oral alendronate on postmenopausal osteoporosis. Am FamPhysician. 1996;53:1848.

2. Parthyroid hormone and oestrogen for treating osteoporosis. New Zealand Medical Journal. 1998;111(1069):245.

3. Risedronate in the treatment and prevention of postmenopausal osteoporosis. Geneesmiddelenbulletin. 2001;35:102-3.

4. Correction to Changes in bone mineral density at 3 years in postmenopausal women receiving anastrozole and risedronate in the IBIS-II bone substudy: an international, doubleblind, randomised, placebo-controlled trial. Lancet Oncology. 2014;15(13):e587, 2014.

5. Ackerman KE. Is denosumab a safe and effective treatment for postmenopausal osteoporosis? Nature Clinical Practice Endocrinology and Metabolism. 2008;4:376-7.

6. Anderson C, Cape RD, Crilly RG, Hodsman AB, Wolfe BM. Preliminary observations of a form of coherence therapy for osteoporosis. Calcif Tissue Int. 1984;36(3):341-3.

7. Barreira JC, Messina OD, Maldonado-Cocco JA, Roldan EJ. Site-dependent bone mineral density response to oral pamidronate and calcium in postmenopausal osteoporosis: a preliminary report. Clin Rheumatol. 1997;16:346-52.

8. Bauer D, Schwartz A, Palermo L, Cauley J, Ensrud K, Hochberg M, et al. Utility of serial bmd for fracture prediction after discontinuation of prolonged alendronate therapy: The flex trial. Journal of Bone and Mineral Research. 2010;Conference:S30-S1.

9. Bauer DC, Black D, Ensrud K, Thompson D, Hochberg M, Nevitt M, et al. Upper gastrointestinal tract safety profile of alendronate: the fracture intervention trial. Arch Intern Med. 2000;160:517-25.

10. Bauer DC, Schwartz A, Palermo L, Cauley J, Hochberg M, Santora A, et al. Fracture prediction after discontinuation of 4 to 5 years of alendronate therapy: the FLEX study. JAMA Intern Med. 2014;174:1126-34.

11. Bayram M, Soyer C, Kadioglu E, Sardas S. Assessment of DNA damage in postmenopausal women under osteoporosis therapy. European Journal of Obstetrics Gynecology and Reproductive Biology. 2006;127:227-30.

12. Bolanca S, Korsic M, Dekanic D, Cvijetic S. Effects of combined treatment with etidronate, nandrolone-decanoate and calcium on bone mineral density in postmenopausal women. Acta Med Croatica. 1998;52(3):159-63.

13. Borst H, Bock O, Beller G, Kratzsch M, Degner C, Profittlich H, et al. Monthly oral ibandronate 150 mg improves significantly bone density and structure measured in Vivo by Micro-CT at distal tibia in postmenopausal women with mild osteoporosis. Bone. 2010;Conference:S195.

14. Brandi ML. Is yearly intravenous zoledronic acid comparable to weekly oral alendronate for postmenopausal osteoporosis? Nature Clinical Practice Endocrinology and Metabolism. 2008;4:20-1.

15. Brown JP, Roux C, Ho PR, Bolognese MA, Hall J, Bone HG, et al. Denosumab significantly increases bone mineral density and reduces bone turnover compared with monthly oral ibandronate and risedronate in postmenopausal women who remained at higher risk for fracture despite previous suboptimal treatment with an oral bisphosphonate. OsteoporosInt. 2014;25:1953-61.

16. Bussy C, Dondelinger R, Belmin J. Annual biphosphonate injection to prevent osteoporotic fractures. Rev Geriatr. 2007;32:785-6.

17. Cauley J, Cummings S, Palermo L, Cosman F, Eastell R, Boonen S, et al. Fracture risk reduction with zoledronic acid by predicted fracture risk score. Journal of Bone and Mineral Research. 2010;Conference:S32.

18. Cauley JA, Cummings S, Palermo L, Cosman F, Eastell R, Boonen S, et al. Fracture risk reduction with zoledronic acid by predicted fracture risk score. Bone. 2011;Conference:S93.

19. Cauza E, Etemad M, Winkler F, Hanusch-Enserer U, Partsch G, Noske H, et al. Pamidronate increases bone mineral density in women with postmenopausal or steroid-induced osteoporosis. J Clin Pharm Ther. 2004;29:431-6.

20. Cesareo R, Di SE, Vescini F, Campagna G, Cianni R, Pasqualini V, et al. Effects of alendronate and vitamin D in patients with normocalcemic primary hyperparathyroidism. OsteoporosInt. 2014;(no.

21. Chailurkit LO, Aunphongpuwanart S, Ongphiphadhanakul B, Jongjaroenprasert W, Sae-tung S, Rajatanavin R. Efficacy of intermittent low dose alendronate in Thai postmenopausal osteoporosis. Endocrine Research. 2004;30(1):29–36.

22. Clemmesen B. A 2-Year Phase II Study with 1-Year of Follow-up of Risedronate (NE-58095) in Postmenopausal Osteoporosis. Osteoporosis international : a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA. 1997;7:488-95.

23. Cortet B, Bera-Louville A, Gauthier P, Gauthier A, Marchandise X, Delcambre B. Comparative efficacy and safety study of etidronate and alendronate in postmenopausal osteoporosis. effect of adding hormone replacement therapy. Joint, bone, spine : revue du rhumatisme. 2001;68:410-5.

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24. Cummings SR, Martin JS, McClung MR, Siris ES, Eastell R, Reid IR, et al. Denosumab for prevention of fractures in postmenopausal women with osteoporosis. Obstet Gynecol Surv. 2009;64:805-7.

25. Dempster D, Zhou H, Recker R, Brown JP, Bolognese M, Recknor C, et al. A longitudinal study of skeletal histomorphometry in subjects on teriparatide (TPTD) or zoledronic acid (ZOL), the SHOTZ study. Journal of Bone and Mineral Research. 2013;Conference

26. Duque G, Li W, Adams M, Xu S, Phipps R. Effects of risedronate on bone marrow adipocytes in postmenopausal women. Bone. 2009;Conference:S53.

27. Eastell R, Vrijens B, Cahall D, Roux C, Ringe J, Garnero P, et al. Relationships between osteoporosis medication adherence, surrogate marker outcomes and non-vertebral fracture incidence. Bone. 2010;Conference:S200-S1.

28. Engelke K, Nagase S, Fuerst T, Eastell R, Genant HK, Samll M, et al. Effects of the cathepsin K inhibitor, ONO-5334, on BMD as measured by 3D QCT in the hip and the spine after 2 years of treatment. OsteoporosInt. 2012;Conference:S62-S3.

29. Ensrud KE, Black DM, Palermo L. Alendronate reduced new fractures in postmenopausal women who had low bone-mineral density and existing vertebral fractures. Evid Based Med. 1998;3:119.

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36. Geusens PPMM, Lems WF. Fractures in postmenopausal women with osteoporosis are prevented by an annual infusion of zoledronic acid. Nederlands Tijdschrift voor Geneeskunde. 2007;151:1445-8.

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48. Harris ST, Watts NB, Jackson RD, Genant HK, Wasnick RD, Ross P, et al. Four-year study of intermittent cyclic etidronate treatment of postmenopausal osteoporosis: Three years of blinded therapy followed by one year of open therapy. Endocrinologist. 1994;4:225-6.

49. Hassler N, Gamsjaeger S, Hofstetter B, Brozek W, Klaushofer K, Paschalis EP. Effects of long-term alendronate treatment on postmenopausal osteoporosis bone material properties. OsteoporosInt. 2015;26:339-52.

50. Heijckmann AC, Juttmann JR, Wolffenbuttel BH. Intravenous pamidronate compared with oral alendronate for the treatment of postmenopausal osteoporosis. Neth J Med. 2002;60(8):315-9.

51. Hirsch C. In postmenopausal women with osteoporosis, romosozumab followed by alendronate reduced fractures vs alendronate alone. Annals of Internal Medicine. 2018;168(2):JC3, 2018.

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55. Hyldstrup L, Jorgensen JT, Sorensen TK, Baeksgaard L. Response of cortical bone to antiresorptive treatment. Calcified Tissue International. 2001;68:135-9.

56. Iwamoto J, Takeda T, Sato Y, Uzawa M. Determinants of one-year response of lumbar bone mineral density to alendronate treatment in elderly Japanese women with osteoporosis. Yonsei Med J. 2004;45(4):676-82.

57. Jacques R, Boonen S, Cosman F, Reid I, Bauer D, Black D, et al. Relationship of changes in total hip bone mineral density to vertebral and non-vertebral fracture risk in women with postmenopausal osteoporosis treated with once-yearly zoledronic acid 5 mg (ZOL): The horizon-PFT study. Journal of Bone and Mineral Research. 2011;Conference

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65. McClung MR, Bolognese MA, Brown JP, Reginster JY, Langdahl BL, Maddox J, et al. Transition to zoledronic acid after romosozumab treatment maintains bone mineral density gains. EndocrRev. 2017;Conference

66. McClung MR, Grauer A, Boonen S, Brown JP, Diez-Perez A, Langdahl B, et al. Inhibition of sclerostin with AMG 785 in postmenopausal women with low bone mineral density: Phase 2 trial results. Journal of Bone and Mineral Research. 2012;Conference

67. McClung MR, Grauer A, Boonen S, Brown JP, Diez-Perez A, Langdahl BL, et al. Inhibition of sclerostin with romosozumab in postmenopausal women with low bone mineral density: Phase 2 trial results. Ann Rheum Dis. 2011;72, CONFERENCE START: 2013 Jun 12 CONFERENCE END: 2013 Jun 15, Annual European Congress of Rheumatology of the European League Against Rheumatism, EULAR 2013 Madrid Spain.

68. McClung MR, Grauer A, Boonen S, Brown JP, Diez-Perez A, Langdahl BL, et al. Inhibition of sclerostin with romosozumab in postmenopausal women with low bone mineral density: Phase 2 trial results. Ann Rheum Dis. 2013;Conference

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71. Miller PD, Neal BJ, McIntyre DO, Yanover MJ, Anger MS, Kowalski L. Effect of cyclical therapy with phosphorus and etidronate on axial bone mineral density in postmenopausal osteoporotic women. Osteoporos Int. 1991;1(3):171-6.

72. Miller PD, Pannacciulli N, Brown JP, Czerwinski E, Nedergaard BS, Bolognese MA, et al. A randomized double-blind study of denosumab compared with zoledronic acid in postmenopausal women with osteoporosis previously treated with oral bisphosphonate. Arthritis and Rheumatology. 2015;Conference

73. Miller PD, Recker RR, Reginster JY, Riis BJ, Czerwinski E, Masanauskaite D, et al. Efficacy of monthly oral ibandronate is sustained over 5 years: the MOBILE long-term extension study. OsteoporosInt. 2012;23:1747-56.

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76. Nakamura T, Matsumoto T, Sugimoto T, Hosoi T, Miki T, Gorai I, et al. Effects of denosumab on fracture risk in japanese patients with osteoporosis-results of 2-year data from the denosumab fracture intervention randomized placebo controlled trial (DIRECT). Journal of Bone and Mineral Research. 2012;Conference

77. Orme SM, Simpson M, Stewart SP, Oldroyd B, Westmacott CF, Smith MA, et al. Comparison of changes in bone mineral in idiopathic and secondary osteoporosis following therapy with cyclical disodium etidronate and high dose calcium supplementation. Clin Endocrinol (Oxf). 1994;41(2):245-50.

78. Orr-Walker B, Wattie DJ, Evans MC, Reid IR. Effects of prolonged bisphosphonate therapy and its discontinuation on bone mineral density in post-menopausal osteoporosis. Clinical Endocrinology. 1997;46:87-92.

79. Ott SM, Woodson GC, Huffer WE, Miller PD, Watts NB. Bone histomorphometric changes after cyclic therapy with phosphate and etidronate disodium in women with postmenopausal osteoporosis. Journal of Clinical Endocrinology and Metabolism. 1994;78:968-72.

80. P. D. B. Miller JPD-C, M. Chen PM, F. Krege JHW, M. Marcus R. Occurrence of hypercalciuria in patients with osteoporosis treated with teriparatide. Journal of Clinical Endocrinology and Metabolism. 2007;92(9):3535-41.

81. Patel DV, Bolland M, Nisa Z, Al-Abuwsi F, Singh M, Horne A, et al. Incidence of ocular side effects with intravenous zoledronate: secondary analysis of a randomized controlled trial. OsteoporosInt. 2015;26:499-503.

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82. Patel DV, Horne A, House M, Reid IR, McGhee CN. The incidence of acute anterior uveitis after intravenous zoledronate. Ophthalmology. 2013;120:773-6.

83. Pelayo M, Agra Y. Biphosphonates for the prevention of osteoporosis in postmenopausal women with a low bone mass. Med Clin (Barc). 2004;122:304-10.

84. Pilipovic N, Brankovic S, Vujasinovic-Stupar N. Effects of Alendronate on bone mass in women with osteoporosis. Medicinski pregled. 2006;59:427-35.

85. Ravn P, Bidstrup M, Wasnich RD, Davis JW, McClung MR, Balske A, et al. Alendronate and estrogen-progestin in the long-term prevention of bone loss: Four-year results from the early postmenopausal intervention cohort study: A randomized, controlled trial. Annals of Internal Medicine. 1999;131:935-42.

86. Ravn P, Weiss SR, Rodriguez-Portales JA, McClung MR, Wasnich RD, Gilchrist NL, et al. Alendronate in early postmenopausal women: Effects on bone mass during long-term treatment and after withdrawal. Journal of Clinical Endocrinology and Metabolism. 2000;85:1492-7.

87. Recker RR, Delmas PD, Halse J, Reid IR, Boonen S, Garcia-Hernandez PA, et al. Effects of intravenous zoledronic acid once yearly on bone remodeling and bone structure. Journal of Bone and Mineral Research. 2008;23:6-16.

88. Recker RR, Ste-Marie LG, Chavassieux P, McClung MR, Lundy MW. Bone safety with risedronate: histomorphometric studies at different dose levels and exposure. OsteoporosInt. 2015;26:327-37.

89. Reginster JY. Risedronate increases bone mineral density and reduces the vertebral fracture incidence in postmenopausal women. Clin Exp Rheumatol. 2001;19(2):121-2.

90. Reid IR, Gamble GD, Mesenbrink P, Lakatos P, Black DM. Characterization of and risk factors for the acute-phase response after zoledronic acid. Obstet Gynecol Surv. 2011;66:97-9.

91. Reszka AA, Halasy-Nagy JM, Masarachia PJ, Rodan GA. Bisphosphonates act directly on the osteoclast to induce caspase cleavage of mst1 kinase during apoptosis. A link between inhibition of the mevalonate pathway and regulation of an apoptosis-promoting kinase. J Biol Chem. 1999;274(49):34967-73.

92. Ringe JD, Nitschmann S. Zoledronic acid for preventing fractures. HORIZON trial (Health Outcomes and Reduced Incidence with Zoledronic acid ONce yearly). Internist. 2008;49:502- 3.

93. Ross PD, Genant HK, Davis JW, Miller PD, Wasnich RD. Predicting vertebral fracture incidence from prevalent fractures and bone density among non-black, osteoporotic women. OsteoporosInt. 1993;3:120-6.

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94. Roux C, Seeman E, Eastell R, Adachi J, Jackson RD, Felsenberg D, et al. Efficacy of risedronate on clinical vertebral fractures within six months. Curr Med Res Opin. 2004;20:433- 9.

95. Rozkydal Z, Janicek P. The effect of alendronate in the treatment of postmenopausal osteoporosis. Bratisl Lek Listy. 2003;104(10):309-13.

96. Ryan PJ, Fogelman I. Clinical experience with etidronate in osteoporosis. Clin Rheumatol. 1994;13(3):455-8.

97. S. C. Papapoulos RB, M. Brown JC, E. Daizadeh NG, A. Krieg MM, Z. Mellstrom DR, S. Reginster JR, et al. Five years of denosumab treatment in women with postmenopausal osteoporosis: Preliminary results from the freedom extension study. Internal Medicine Journal. 2011;41(Suppl 1):26.

98. Sahin FI, Sahin I, Ergun MA, Saracoglu OF. Effects of estrogen and alendronate on sister chromatid exchange (SCE) frequencies in postmenopausal osteoporosis patients. International Journal of Gynecology and Obstetrics. 2000;71:49-52.

99. Sarli M, Fradinger E, Morillo S, Rey P, Zanchetta J. Treatment of post menopausal osteoporosis with intravenous pamidronate in patients with esophagogastric pathology. Medicina (Buenos Aires). 1998;58:446-52.

100. Sawka AM, Adachi JD, Ioannidis G, Olszynski WP, Brown JP, Hanley DA, et al. What predicts early fracture or bone loss on bisphosphonate therapy? J Clin Densitom. 2003;6(4):315-22.

101. Seibel MJ, Naganathan V, Barton I, Grauer A. Relationship between pretreatment bone resorption and vertebral fracture incidence in postmenopausal osteoporotic women treated with risedronate. Journal of Bone and Mineral Research. 2004;19:323-9.

102. Silberstein EB, Schnur W. Cyclic oral phosphate and etidronate increase femoral and lumbar bone mineral density and reduce lumbar spine fracture rate over three years. J Nucl Med. 1992;33(1):1-5.

103. Singer FR, Minoofar PN. Bisphosphonates in the treatment of disorders of mineral metabolism. Adv Endocrinol Metab. 1995;6:259-88.

104. Staa TPv, Abenhaim L, Cooper C. Bone safety of cyclical etidronate. Journal of Bone and Mineral Research. 1996;11(Suppl 1):S343.

105. Stepan JJ, Vokrouhlicka J. Comparison of biochemical markers of bone remodelling in the assessment of the effects of alendronate on bone in postmenopausal osteoporosis. Clin Chim Acta. 1999;288:121-35.

106. Storm T, Kollerup G, Thamsborg G, Genant HK, Sorensen OH. Five years of clinical experience with intermittent cyclical etidronate for postmenopausal osteoporosis. J Rheumatol. 1996;23:1560-4.

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107. Stovall DW, Beard MK, Barbier S, Chen E, Rosenberg E, e Papp AE. Response to oral bisphosphonates in subgroups of younger and older postmenopausal women. Journal of women's health / the official publication of the Society for the Advancementof Women's Health Research. 2010;19:491-7.

108. Sugimoto T, Matsumoto T, Hosoi T, Miki T, Gorai I, Yoshikawa H, et al. Three-year denosumab treatment in postmenopausal Japanese women and men with osteoporosis: results from a 1-year open-label extension of the Denosumab Fracture Intervention Randomized Placebo Controlled Trial (DIRECT). OsteoporosInt. 2014;26:765-74.

109. Sunyecz JA. Once-a-month risedronate in postmenopausal osteoporosis. PostgradMed. 2009;121:42-4.

110. Tanaka S. Effects of zoledronic acid on osteoporosis patients in Japan. Clinical Calcium. 2017;27:257-61.

111. Tanaka S, Miyazaki T, Uemura Y, Kuroda T, Miyakawa N, Nakamura T, et al. Design of a randomized clinical trial of concurrent treatment with vitamin K2 and risedronate compared with risedronate alone in osteoporotic patients: Japanese Osteoporosis Intervention Trial-03 (JOINT-03). J Bone MinerMetab. 2014;32:298-304.

112. Terranova R, Luca S. [Treatment of postmenopausal osteoporosis with etidronate]. Minerva Medica. 1999;90:85-90.

113. Uusi-Rasi K, Sievanen H, Heinonen A, Kannus P, Vuori I. Effect of discontinuation of alendronate treatment and exercise on bone mass and physical fitness: 15-month follow-up of a randomized, controlled trial. Bone. 2004;35:799-805.

114. Vasikaran SD, Khan S, McCloskey EV, Kanis JA. Sustained response to intravenous alendronate in postmenopausal osteoporosis. Bone. 1995;17(6):517-20.

115. Watts NB. Treatment of osteoporosis with bisphosphonates. Endocrinol Metab Clin North Am. 1998;27(2):419-39.

List of studies excluded: population not of interest, N=28 (116-143)

116. Akimitsu M, Toshio M, Toshitsugu S, Mika T, Margaret RW, Toshitaka N. Effects of teriparatide on bone mineral density and bone turnover markers in Japanese subjects with osteoporosis at high risk of fracture in a 24-month clinical study: 12-Month, randomized, placebo-controlled, double-blind and 12-month open-label phases. Bone. 2010;47(3):493.

117. Aro H, Moritz N, Timlin S, Lankinen P, Svedstrom E. A single dose of an intravenous bisphosphonate prevents periprosthetic bone loss but does not enhance rsa-evaluated osseointegration of uncemented femoral stems. HIP International. 2012;Conference:443- August.

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118. Barone A, Giusti A, Pioli G, Girasole G, Razzano M, Pizzonia M, et al. Secondary hyperparathyroidism due to hypovitaminosis D affects bone mineral density response to alendronate in elderly women with osteoporosis: a randomized controlled trial. J Am Geriatr Soc. 2007;55:752-7.

119. Brumsen C, Papapoulos SE, Lips P, Geelhoed-Duijvestijn PH, Hamdy NA, Landman JO, et al. Daily oral pamidronate in women and men with osteoporosis: a 3-year randomized placebo- controlled clinical trial with a 2-year open extension. Journal of Bone and Mineral Research. 2002;17:1057-64.

120. Carlino G, Cozzolongo A. Effects of intravenous zoledronic acid following subcutaneous teriparatide in postmenopausal osteoporosis. Bone. 2011;Conference:S220.

121. Cathleen SC-E, John C, Theodore TS, Carl FP, Cheri J, Jay M, et al. The HORIZON Recurrent Fracture Trial: design of a clinical trial in the prevention of subsequent fractures after low trauma hip fracture repair. Curr Med Res Opin. 2004;20:903-10.

122. Cesareo R, Di SE, Vescini F, Campagna G, Cianni R, Pasqualini V, et al. Effects of alendronate and vitamin D in patients with normocalcemic primary hyperparathyroidism. OsteoporosInt. 2015;26:1295-302.

123. Fujita T, Ohue M, Fujii Y, Miyauchi A, Takagi Y. Comparison of the analgesic effects of bisphosphonates: Etidronate, alendronate and risedronate by electroalgometry utilizing the fall of skin impedance. J Bone MinerMetab. 2009;27:234-9.

124. Fujita T, Orimo H, Inoue T, Kaneda K, Minoru S, Morita R, et al. Double-blind multicenter comparative study with alfacalcidol of etidronate disodium (EHDP) in involutional osteoporosis. Rinsho Hyoka (Clinical Evaluation). 1993;21:261-302.

125. Guan YT, Cai LL, Ding HX, Chen GD, Hu Y. [Clinical study on combination of multiple regimens in treatment of osteoporosis in perimenopause and postmenopausal women]. Zhonghua Fu Chan Ke Za Zhi. 2010;45:571-4.

126. Ikeda T, Manabe H, Iwata K. Clinical significance of alendronate in postmenopausal type 2 diabetes mellitus. Diabetes and Metabolism. 2004;30:355-8.

127. Kenneth WL, Cathleen SC-E. Zoledronic Acid and Clinical Fractures and Mortality after Hip Fracture. New England Journal of Medicine. 2007;357:1799-809.

128. Kushida K, Fukunaga M, Kishimoto H, Shiraki M, Itabashi A, Inoue T, et al. A comparison of incidences of vertebral fracture in Japanese patients with involutional osteoporosis treated with risedronate and etidronate: a randomized, double-masked trial. J Bone MinerMetab. 2004;22:469-78.

129. McComsey GA, Kendall MA, Tebas P, Swindells S, Hogg E, Alston-Smith B, et al. Alendronate with calcium and vitamin D supplementation is safe and effective for the treatment of decreased bone mineral density in HIV. AIDS (London, England). 2007;21:2473-82.

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130. Miller PD, Brown JP, Siris ES, Hoseyni MS, Axelrod DW, Bekker PJ. A randomized, double- blind comparison of risedronate and etidronate in the treatment of Paget’s disease of bone. Paget’s Risedronate/Etidronate Study Group. American Journal of Medicine. Am J Med. 1999;106(5):513–20.

131. Nakamura T, Fukunaga M, Nakano T, Kishimoto H, Ito M, Hagino H, et al. Efficacy and safety of once-yearly zoledronic acid in Japanese patients with primary osteoporosis: two-year results from a randomized placebo-controlled double-blind study (ZOledroNate treatment in Efficacy to osteoporosis ZONE study). OsteoporosInt. 2017;28(1):389-98.

132. Okazaki R, Hagino H, Ito M, Sone T, Nakamura T, Mizunuma H, et al. Efficacy and safety of monthly oral minodronate in patients with involutional osteoporosis. OsteoporosInt. 2012;23:1737-45.

133. Palomba S, Orio F, Manguso F, Falbo A, Russo T, Tolino A, et al. Efficacy of risedronate administration in osteoporotic postmenopausal women affected by inflammatory bowel disease. OsteoporosInt. 2005;16:1141-9.

134. Pearson EG, Nance PW, Leslie WD, Ludwig S. Cyclical etidronate: Its effect on bone density in patients with acute spinal cord injury. Arch Phys Med Rehabil. 1997;78:269-72.

135. R. N. Niimi AH, M. Kono TS. Efficacy of Switching From Teriparatide to Bisphosphonate or Denosumab: A Prospective, Randomized, Open-Label Trial. JBMR Plus. 2018;2(5):289-94.

136. Ringe JD, Farahmand P, Schacht E, Rozehnal A. Superiority of a combined treatment of Alendronate and Alfacalcidol compared with the combination of Alendronate and plain vitamin D or Alfacalcidol alone in established postmenopausal or male osteoporosis (AAC-Trial). Rheumatology International. 2007;27:425-34.

137. Ryan PJ, Blake GM, Davie M, Haddaway M, Gibson T, Fogelman I. Intermittent oral disodium pamidronate in established osteoporosis: a 2 year double-masked placebo-controlled study of efficacy and safety. OsteoporosInt. 2000;11:171-6.

138. Sato Y, Iwamoto J, Kanoko T, Satoh K. Alendronate and vitamin D2 for prevention of hip fracture in Parkinson's disease: a randomized controlled trial. Movement disorders : official journal of the Movement Disorder Society. 2006;21:924-9.

139. T. T. Yamamoto MH, E. Sowa H. Assessing the effect of baseline status of serum bone turnover markers and vitamin D levels on efficacy of teriparatide 20 mug/day administered subcutaneously in Japanese patients with osteoporosis. J Bone MinerMetab. 2013;31(2):199- 205.

140. Takuo F, Hajime O, Tetsuo I, Kiyoshi K, Minoru S, Rikushi M, et al. Clinical effect of bisphosphonate and vitamin D on osteoporosis: reappraisal of a multicenter double-blind clinical trial comparing etidronate and alfacalcidol. J Bone MinerMetab. 2007;25:130-7.

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141. Unnanuntana A, Jarusriwanna A, Songcharoen P. Randomized clinical trial comparing efficacy and safety of brand versus generic alendronate (Bonmax) for osteoporosis treatment. PLoS One. 2017;12:e0180325.

142. Vujasinovic-Stupar N, Pilipovic N, Brankovic S. Cyclic intravenous pamidronate in treatment of osteoporosis. Med Pregl. 2004;57:545-50.

143. Zhu XY, Zhang YQ, Pei LC, Li X, Yu WG. Effects of combined treatment of Rocaltrol, Etidronate and Sisterly on bone pain and bone mineral density in osteoporosis patients with vertebral fracture. Chinese Journal of Clinical Rehabilitation. 2004;8:5182-3.

List of studies excluded: intervention/comparator not of interest, N=184 (144- 327)

144. A double-blind, multicentric, multinational randomised study to assess the effects of one year administration of 2 g per day of strontium ranelate versus marketed bisphosphonates in women with postmenopausal osteoporosis on bone microarchitecture as measured by high- resolution peripheral-quantitative computed tomography (p-QCT). WHO ICTRP. 2017.

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250. Lozano-Tonkin C, Gonzalez MA. Long-term treatment of postmenopausal osteoporosis with sodium etidronate or calcitonin. Osteoporos-Int. 1996;6 Suppl 1:254.

251. Luckey M, Kagan R, Greenspan S, Bone H, Kiel RD, Simon J, et al. Once-weekly alendronate 70 mg and raloxifene 60 mg daily in the treatment of postmenopausal osteoporosis. Menopause (New York, N. 2004;Y.). 11:405-15.

252. Lunar LJ, Brakamonte MA, Serafin ME. Comparison of change in bone resorption and bone mineral density with onceweekly alendronate and daily strontium ranelate: A randomised, placebo-controlled study. OsteoporosInt. 2012;Conference:S138.

253. Masud T, Mulcahy B, Thompson AV, Donnelly S, Keen RW, Doyle DV, et al. Effects of cyclical etidronate combined with calcitriol versus cyclical etidronate alone on spine and femoral neck bone mineral density in postmenopausal osteoporotic women. Ann Rheum Dis. 1998;57:346- 9.

254. McClung MR, Lewiecki EM, Bolognese MA, Peacock M, Weinstein RL, Ding B, et al. Denosumab continues to affect bone mineral densityand biochemical markers of bone turnover for up to 8 years: Results of a phase 2 extension trial. OsteoporosInt. 2012;Conference:S74-S6.

255. McClung MR, Martin JS, Miller PD, Civitelli R, Bandeira F, Omizo M, et al. Opposite bone remodeling effects of teriparatide and alendronate in increasing bone mass. Arch Intern Med. 2005;165:1762-8.

256. Miller D, Ragi-Eis S, Mautalen C, Ramirez F, Jonkanski I. Effects of intravenous ibandronate injection on renal function in women with postmenopausal osteoporosis at high risk for renal disease - The DIVINE study. Bone. 2011;49:1317-22.

257. Miller P, Eis SR, Mautalen C, Ramirez F, Jonkanski I. Effects of intravenous ibandronate injection on renal function in postmenopausal women with osteoporosis at high risk for renal disease compared with ibandronate infusion or oral alendronate-the divine study. Journal of Bone and Mineral Research. 2010;Conference:S472.

258. Miller PD, Epstein S, Sedarati F, Reginster JY. Once-monthly oral ibandronate compared with weekly oral alendronate in postmenopausal osteoporosis: Results from the head-to-head MOTION study. Curr Med Res Opin. 2008;24:207-13.

259. Min YK, Lee DY, Choi SJ, Kim JH, Choi D, Yoon BK. Effects of adding alendronate to ongoing hormone therapy on bone mineral density in postmenopausal Korean women: a randomized, double-blind, placebo-controlled clinical trial. Menopause. 2013;20:761-6.

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260. Minisola SM, Kendler F, Geusens DL, Zerbini P, Russo CAF, Casado LA, et al. Serum 25- hydroxy-vitamin D and the risk of fractures in the teriparatide versus risedronate VERO clinical trial. Arch Osteoporos. 2019;14(1):10, 2019.

261. Muschitz C, Kocijan R, Fahrleitner-Pammer A, Pavo I, Haschka J, Schima W, et al. Overlapping and continued alendronate or raloxifene administration in patients on teriparatide: effects on areal and volumetric bone mineral density--the CONFORS Study. Journal of Bone and Mineral Research. 2014;29:1777-85.

262. Nabhan AF, Rabie NH. Isosorbide mononitrate versus alendronate for postmenopausal osteoporosis. International Journal of Gynecology and Obstetrics. 2008;103:213-6.

263. Nakamura YS, T. Kamimura MI, S. Murakami KU, S. Taguchi AK. Two-year clinical outcome of denosumab treatment alone and in combination with teriparatide in Japanese treatment- naive postmenopausal osteoporotic women. Bone Research. 2017;5:16055.

264. Narula R, Mujtaba T, Iraqi AA, Singh S. Effect of risedronate and strontium therapy on bone mineral density in postmenopausal osteoporosis. International Journal of Research in Ayurveda and Pharmacy. 2012;3:543-7.

265. NCT00365456. NCT00365456: Sequential Treatment of Postmenopausal Women With Primary Osteoporosis (FP-001-IM) (PEAK). Clinicaltrialsgov. 2012.

266. Nozaki M, Koera K, Egami R, Nagata H, Nakano H. Combination of intermittent cyclical etidronate and hormone replacement therapy for postmenopausal non-responders to estrogen. Clin Drug Invest. 2002;22:111-7.

267. Orimo H, Nakamura T, Fukunaga M, Ohta H, Hosoi T, Uemura Y, et al. Effects of alendronate plus alfacalcidol in osteoporosis patients with a high risk of fracture: The Japanese Osteoporosis Intervention Trial (JOINT)-02. Curr Med Res Opin. 2011;27:1273-84.

268. P. B. Chavassieux KZ, C. Pereira RDLP, P. Valter IH, T. Novosad PZ, J. Man ZS-M, L. G. Meunier PJC. Bone formation is significantly greater in women on strontium ranelate than in those on alendronate after 6 and 12 months of treatment: histomorphometric analysis from a large randomized controlled trial. OsteoporosInt. 2011;22:S104.

269. P. M. Geusens FK, L. Russo LZ, C. A. F. Greenspan SM, S. Bagur AL, P. Casado EF-P, A. Stepan JL, et al. Teriparatide compared with risedronate and the risk of fractures in subgroups of postmenopausal women with severe osteoporosis: The VERO Trial. Journal of Bone and Mineral Research. 2017;Conference:(Supplement 1):S22.

270. P. U. Wallace AB-B, S. A. Neer RL. Bone mineral density response rates with teriparatide, denosumab, or both: A responder analysis of the DATA study. Journal of Bone and Mineral Research. 2015;Conference:(Supplement 1).

271. Palacios S, Iolascon G, Agodoa I, Viswanathan H, Ghelani P, Ferreira I, et al. Treatment satisfaction in postmenopausal women previously treated with bisphosphonates who

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transitioned to denosumab vs ibandronate therapy in an open-label study. Arthritis and Rheumatism. 2012;Conference:S837-S8.

272. Palomba S, Orio, Jr., Colao A, Carlo CD, Sena T, Lombardi G, et al. Effect of estrogen replacement plus low-dose alendronate treatment on bone density in surgically postmenopausal women with osteoporosis. Journal of Clinical Endocrinology and Metabolism. 2002;87:1502-8.

273. Palomba S, Orio, Jr., Russo T, Falbo A, Tolino A, Manguso F, et al. BsmI vitamin D receptor genotypes influence the efficacy of antiresorptive treatments in postmenopausal osteoporotic women. A 1-year multicenter, randomized and controlled trial. OsteoporosInt. 2005;16:943-52.

274. Panico A, Lupoli GA, Marciello F, Lupoli R, Cacciapuoti M, Martinelli A, et al. Teriparatide vs. alendronate as a treatment for osteoporosis: Changes in biochemical markers of bone turnover, BMD and quality of life. Med Sci Monit. 2011;17:CR442-CR8.

275. Passeri M, Baroni MC, Pedrazzoni M, Pioli G, Barbagallo M, Costi D, et al. Intermittent treatment with intravenous 4-amino-1-hydroxybutylidene-1,1-bisphosphonate (AHBuBP) in the therapy of postmenopausal osteoporosis. Bone and Mineral. 1991;15:237-47.

276. Peretz A, Siderova V, Body JJ, Dumon JC, Rozenberg S, Fellemans C, et al. Response to alendronate in osteoporotic women previously treated with pamidronate. Maturitas. 2003;44:111-5.

277. R. N. Lindsay JF, C. Henneman EW, L. Shen VD, D. Cosman F. Randomised controlled study of effect of parathyroid hormone on vertebral-bone mass and fracture incidence among postmenopausal women on oestrogen with osteoporosis. Lancet. 1997;350(9077):550-5.

278. Ralston S, Binkley N, Boonen S, Kiel D, Roux C, Samanta S, et al. Weekly alendronate plus vitamin D3 5600 IU vs. usual care: Effect on serum hydroxyvitamin D in osteoporotic postmenopausal women with vitamin D inadequacy-6-month results of a randomized trial. Journal of Bone and Mineral Research. 2010;Conference:S212-S3.

279. Ralston SH, Binkley N, Boonen S, Kiel DP, Reginster JY, Roux C, et al. Randomized trial of alendronate plus vitamin D3 versus standard care in osteoporotic postmenopausal women with vitamin D insufficiency. Calcified Tissue International. 2011;88:485-94.

280. Recker RR, Kendler D, Recknor CP, Rooney TW, Lewiecki EM, Utian WH, et al. Comparative effects of raloxifene and alendronate on fracture outcomes in postmenopausal women with low bone mass. Bone. 2007;40:843-51.

281. Recknor C, Czerwinski E, Bone H, Bonnick S, Binkley N, Moffett A, et al. A randomized open- label study to evaluate the safety and efficacy of denosumab and ibandronate in postmenopausal women sub-optimally treated with daily or weekly bisphosphonates. Journal of Bone and Mineral Research. 2012;Conference

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282. Recknor C, Czerwinski E, Bone HG, Bonnick S, Binkley N, Moffett A, et al. Safetyand efficacy of denosumab (DMAB) and ibandronate (IBN) in postmenopausal women suboptimally treated with daily or weekly bisphosphonates: A randomized open-label study. OsteoporosInt. 2013;Conference:S217-S8.

283. Recknor C, Czerwinski E, Bone HG, Bonnick SL, Binkley N, Palacios S, et al. Denosumab compared with ibandronate in postmenopausal women previously treated with bisphosphonate therapy: a randomized open-label trial. ObstetGynecol. 2013;121:1291-9.

284. Reginster JY, Binkley N, Boonen S, Kiel DP, Ralston S, Roux C, et al. Correlations between 25(OH)D and bmd change in postmenopausal osteoporotic women: Secondary analyses of a 1-year trial of weekly alendronate (ALN) plus vitamin D3 5600 iu vs. standard care. OsteoporosInt. 2012;Conference:S238-S9.

285. Rittmaster RS, Bolognese M, Ettinger MP, Hanley DA, Hodsman AB, Kendler DL, et al. Enhancement of bone mass in osteoporotic women with parathyroid hormone followed by alendronate. Journal of Clinical Endocrinology and Metabolism. 2000;85:2129-34.

286. Rizzoli R, Chapurlat RD, Laroche JM, Krieg MA, Thomas T, Frieling I, et al. Effects of strontium ranelate and alendronate on bone microstructure in women with osteoporosis. Results of a 2-year study. OsteoporosInt. 2012;23:305-15.

287. Rizzoli R, Laroche M, Krieg MA, Frieling I, Thomas T, Delmas P, et al. Strontium ranelate and alendronate have differing effects on distal tibia bone microstructure in women with osteoporosis. Rheumatology International. 2010;30:1341-8.

288. Rubin C, Pouns K. Efficacy of treatment with slow-release sodium fluoride versus alendronate on bone mineral density and fractures in postmenopausal women. J Am Geriatr Soc. 2017;Conference:S111-S2.

289. S. M. Papapoulos ZM, D. Radominski SR, J. Y. Resch HR, J. Roux CC, S. Bone HC, R. Brandi MB, et al. Five-year denosumab treatment of postmenopausal women with osteoporosis: Results from the first two years of the freedom trial extension. OsteoporosInt. 2011;Conference:(22 Suppl 1):S107-S8.

290. Saag KGM, Cosman PD, Fitzpatrick F, Hattersley LA, Mitlak G, Bilezikian B, et al. Persistent Fracture Reduction with Abaloparatide-SC (TYMLOSTM) Followed by 24 Months of Alendronate. J Clin Densitometry. 2018;Conference:(4):43800.

291. Sambrook PN, Geusens P, Ribot C, Solimano JA, Ferrer-Barriendos J, Gaines K, et al. Alendronate produces greater effects than raloxifene on bone density and bone turnover in postmenopausal women with low bone density: Results of EFFECT (EFficacy of FOSAMAX versus EVISTA Comparison Trial) International. J Intern Med. 2004;255:503-11.

292. Sanad Z, Ellakwa H, Desouky B. Comparison of alendronate and raloxifene in postmenopausal women with osteoporosis. Climacteric. 2011;14:369-77.

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293. Sawada K, Morishige KI, Nishio Y, Hayakawa J, Mabuchi S, Isobe A, et al. Peripheral quantitative computed tomography is useful to monitor response to alendronate therapy in postmenopausal women. J Bone MinerMetab. 2009;27:175-81.

294. Seeman EZ, Zanchetta R, Hanley JR, Wang DA, Libanati A, Wagman C, et al. Bone microarchitecture after discontinuation of denosumab in postmenopausal women with low bone mass. Journal of Bone and Mineral Research. 2017;Conference:(Supplement 1).

295. Shiraki M, Kuroda T, Miyakawa N, Fujinawa N, Tanzawa K, Ishizuka A, et al. Design of a pragmatic approach to evaluate the effectiveness of concurrent treatment for the prevention of osteoporotic fractures : Rationale, aims and organization of a Japanese Osteoporosis Intervention Trial (JOINT) initiated by the Research Group of Adequate Treatment of Osteoporosis (A-TOP). J Bone MinerMetab. 2011;29:37-43.

296. Shiraki M, Kushida K, Fukunaga M, Kishimoto H. A Double-Masked Multicenter Comparative Study Between Alendronate and Alfacalcidol in Japanese Patients with Osteoporosis. Osteoporosis international : a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA. 1999;10:183-92.

297. Shiro T, Teruhiko M, Yukari U, Nobuaki M, Itsuo G, Toshitaka N, et al. Comparison of concurrent treatment with vitamin K 2 and risedronate compared with treatment with risedronate alone in patients with osteoporosis: Japanese Osteoporosis Intervention Trial-03. J Bone MinerMetab. 2017;35(4):385.

298. Silverman SL, Nasser K, Nattrass S, Drinkwater B. Impact of bone turnover markers and/or educational information on persistence to oral bisphosphonate therapy: a community setting- based trial. OsteoporosInt. 2012;23:1069-74.

299. Sosa M, Hernandez D, Segarra MC, Gomez A, e la Pena E, Betancor P. Effect of two forms of alendronate administration upon bone mass after two years of treatment. J Clin Densitometry. 2002;5:27-34.

300. Steiniche T, Hasling C, Charles P, Eriksen EF, Melsen F, Mosekilde L. The effects of etidronate on trabecular bone remodeling in postmenopausal spinal osteoporosis: A randomized study comparing intermittent treatment and an ADFR regime. Bone. 1991;12:155- 63.

301. Ste-Marie LGS, S. L. Hossain AD, D. Gaich GA. Effect of teriparatide [rhPTH(1-34)] on BMD when given to postmenopausal women receiving hormone replacement therapy. Journal of Bone and Mineral Research. 2006;21(2):283-91.

302. Stock JL, Bell NH, Chesnut Iii CH, Ensrud KE, Genant HK, Harris ST, et al. Increments in bone mineral density of the lumbar spine and hip and suppression of bone turnover are maintained after discontinuation of alendronate in postmenopausal women. Am J Med. 1997;103:291-7.

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303. Struijs A, Mulder H. Treatment of post-menopausal osteoporosis and low serum magnesium with intermittent cyclical EHDP and magnesium. Osteoporos-Int. 1996;6 Suppl 1:252.

304. Suzuki TN, Y. Kato H. Efficacy, safety, and compliance of ibandronate treatment for 3 years in postmenopausal Japanese women with primary osteoporosis. Osteoporosis and Sarcopenia. 2018;4(2):69-72.

305. Suzuki TN, Y. Tanaka MK, M. Ikegami SU, S. Kato H. Comparison of the effects of denosumab with either active vitamin D or native vitamin D on bone mineral density and bone turnover markers in postmenopausal osteoporosis. Mod Rheumatol. 2018;28(2):376-9.

306. T. N. Suzuki YK. Efficacy of 4-year denosumab treatment alone or in combination with teriparatide in Japanese postmenopausal osteoporotic women. Mod Rheumatol. 2018:43617.

307. Tira MB, Noyan V, Yildiz A, Yildirim M, Daya S. Effects of alendronate and hormone replacement therapy, alone or in combination, on bone mass in postmenopausal women with osteoporosis: A prospective, randomized study. Hum Reprod. 2000;15:2087-92.

308. Toshitaka N, Tetsuo N, Masako I, Hiroshi H, Junko H, Masato T, et al. Clinical Efficacy on Fracture Risk and Safety of 0.5 mg or 1 mg/month Intravenous Ibandronate Versus 2.5 mg/day Oral Risedronate in Patients with Primary Osteoporosis. Calcified Tissue International. 2013;93:137-46.

309. Tsai JN, Uihlein AV, Burnett-Bowie SA, Neer RM, Zhu Y, Derrico N, et al. Comparative effects of teriparatide, denosumab, and combination therapy on peripheral compartmental bone density, microarchitecture, and estimated strength: The DATA-HRpQCT study. Journal of Bone and Mineral Research. 2015;30:39-45.

310. Tsai JN, Uihlein AV, Lee H, Kumbhani R, Siwila-Sackman E, McKay EA, et al. Teriparatide and denosumab, alone or combined, in women with postmenopausal osteoporosis: the DATA study randomised trial. Lancet. 2013;382:50-6.

311. Tsai JNJ, Lee LA, Hans H, Leder D, B Z. Effects of Teriparatide, Denosumab, or Both on Spine Trabecular Microarchitecture in DATA-Switch: a Randomized Controlled Trial. J Clin Densitom. 2017;20(4):507-12.

312. Tsai JNU, Burnett-Bowie AV, Neer SM, Derrico RM, Lee NP, Bouxsein H, et al. Effects of Two Years of Teriparatide, Denosumab, or Both on Bone Microarchitecture and Strength (DATA- HRpQCT study). Journal of Clinical Endocrinology and Metabolism. 2016;101(5):2023-30.

313. Tsai JU, A. Burnett-Bowie SAN, R. Tuck PW, P. Bouxsein ML. Effect of denosumab (DMAB) and teriparatide (TPTD) transitions on peripheral bone mineral density (BMD) and microarchitecture: The DATA-Switch HR-pQCT study. Journal of Bone and Mineral Research. 2015(Supplement 1):S18.

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314. Tseng LN, Sheu WHH, Ho ESC, Lan HHC, Hu CC, Kao CH. Effects of alendronate combined with hormone replacement therapy on osteoporotic postmenopausal Chinese women. Metabolism: Clinical and Experimental. 2006;55:741-7.

315. Tutuncu L, Arslanhan N, Muhcu M, Ergur AR, Yergok YZ. Effectiveness of raloxifene and alendronate combination versus calcium and vitamin D usage: Effects on bone mineral density. Journal of the Turkish German Gynecology Association. 2005;6:139-45.

316. Um MJ, Cho EA, Jung H. Combination Therapy of Raloxifene and Alendronate for Treatment of Osteoporosis in Elderly Women. J Menopausal Med. 2017;23:56-62.

317. Wasnich RD, Bagger YZ, Hosking DJ, McClung MR, Wu M, Mantz AM, et al. Changes in bone density and turnover after alendronate or estrogen withdrawal. Menopause. 2004;11:622-30.

318. Watts NB, Chines A, Olszynski WP, McKeever CD, McClung MR, Zhou X, et al. Fracture risk remains reduced one year after discontinuation of risedronate. OsteoporosInt. 2008;19:365- 72.

319. Ylikorkala O, Evio S, Valimaki M, Tiitinen A. Effects of hormone therapy and alendronate on C- reactive protein, E-selectin, and sex hormone-binding globulin in osteoporotic women. Fertil Steril. 2003;80:541-5.

320. Yoon BK, Lee DY, Park MC, Cho SH, Park HM, Choi YM. Effects of Combination Therapy of Alendronate and Hormonal Therapy on Bone Mineral Density in Postmenopausal Korean Women: Multicenter, Randomized Controlled Clinical Trial. J Korean Med Sci. 2017;32:992-8.

321. You L, Sheng ZY, Chen JY, Pan L, Chen L. The safety and efficacy of early-stage bi-weekly alendronate to improve bone mineral density and bone turnover in Chinese post-menopausal women at risk of osteoporosis. J Int Med Res. 2011;39:302-10.

322. Z. L. L. Zhang EYX, W. B. Lin HC, Q. Wang LH, Y. Q. Chen DCT, H. De PYY, L. He LH, et al. Characteristics associated with bone mineral density increase by 1-year ALN/D5600 treatment in a randomized, controlled study on postmenopausal osteoporosis in Chinese women. Journal of Bone and Mineral Research. 2015;Conference:(Supplement 1).

323. Zhang Z, Liao EY, Wei BX, Lin H, Wang L, Chen DC, et al. Alendronate sodium/vitamin D3 combination tablet versus calcitriol for osteoporosis in Chinese postmenopausal women: A 6- month, randomized, open-label, active-comparator controlled study with a 6-month extension phase. Journal of Bone and Mineral Research. 2013;Conference

324. Zhang Z, Liao EY, Xia WB, Lin H, Wang L, Chen DC, et al. Effect of treatment for one yearwith alendronate/vitamin d3 combination on bone mineral density, bone biomarkers and 25(OH)D status in Chinese postmenopausal women with osteoporosis. OsteoporosInt. 2013;Conference:S606-S7.

325. Zhang ZL, Liao EY, Xia WB, Lin H, Cheng Q, Wang L, et al. Erratum to: Alendronate sodium/vitamin D3 combination tablet versus calcitriol for osteoporosis in Chinese

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postmenopausal women: a 6-month, randomized, open-label, active-comparator-controlled study with a 6-month extension. OsteoporosInt. 2015;26:2719-20.

326. Zhang ZL, Liao EY, Xia WB, Lin H, Cheng Q, Wang L, et al. Alendronate sodium/vitamin D3 combination tablet versus calcitriol for osteoporosis in Chinese postmenopausal women: a 6- month, randomized, open-label, active-comparator-controlled study with a 6-month extension. OsteoporosInt. 2015;26:2365-74.

327. Zhang ZL, Liao EY, Xia WB, Lin H, Cheng Q, Wang L, et al. Alendronate sodium/vitamin d3 combination tablet vs. calcitriol for osteoporosis in chinese postmenopausal women: A randomized, open-label study. OsteoporosInt. 2014;Conference:S411.

List of studies excluded: treatment duration less than one year, N=105 (328-432)

328. Adachi JD, Adami S, Miller PD, Olszynski WP, Kendler DL, Silverman SL, et al. Tolerability of risedronate in postmenopausal women intolerant of alendronate. Aging - Clinical and Experimental Research. 2001;13:347-54.

329. Adachi JD, Faraawi RY, O'Mahony MF, Nayar A, Massaad R, Evans JK, et al. Upper gastrointestinal tolerability of alendronate sodium monohydrate 10 mg once daily in postmenopausal women: a 12-week, randomized, double-blind, placebo-controlled, exploratory study. Clin Ther. 2009;31:1747-53.

330. Adolphson P, Abbaszadegan H, Boden H, Salemyr M, Henriques T. Clodronate increases mineralization of callus after Colles' fracture: a randomized, double-blind, placebo-controlled, prospective trial in 32 patients. Acta Orthop Scand. 2000;71:195-200.

331. Alka K, Agarwal N, Kulshrestha V, Jaiswal V. Weekly 70mg oral alendronate therapy in postmenopausal osteopenic women. Climacteric. 2011;Conference:147-8.

332. Altintas F, Ozkut AT, Beyzadeoglu T, Eren A, Guven M. [The effect of risedronate treatment on bone turnover markers in patients with hip fracture]. Acta orthopaedica et traumatologica turcica. 2007;41:132-5.

333. Anastasilakis AD, Goulis DG, Polyzos SA, Gerou S, Koukoulis G, Kita M, et al. Serum osteoprotegerin and RANKL are not specifically altered in women with postmenopausal osteoporosis treated with teriparatide or risedronate: a randomized, controlled trial. Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme. 2008;40:281-5.

334. Angsanuntsukh C, Wajanavisit W, Woratanarat P. Efficacy of Aldren 70 compared with Fosamax in terms of bone resorption marker in postmenopausal osteoporosis. J Med Assoc Thai. 2017;100:488-95.

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335. Bachmann G, Kriegman A, Goncalves J, Kianifard F, Warren M, Simon JA. Effect of zoledronic acid compared with raloxifene on bone turnover markers in postmenopausal women with low bone density. Menopause. 2011;18:851-6.

336. Bahlous A, Bouzid K, Sahli H, Sallami S, Abdelmoula J. Effects of risedronate on bone turnover markers in osteoporotic postmenopausal women: comparison of two protocols of treatment. La Tunisie medicale. 2009;87:380-1.

337. Bettica P, Bevilacqua M, Vago T, Masino M, Cucinotta E, Norbiato G. Short-term variations in bone remodeling biochemical markers: Cyclical etidronate and alendronate effects compared. Journal of Clinical Endocrinology and Metabolism. 1997;82:3034-9.

338. Binkley N, Silverman SL, Simonelli C, Santiago N, Kohles JD, Dasic G, et al. Monthly ibandronate suppresses serum CTX-I within 3 days and maintains a monthly fluctuating pattern of suppression. OsteoporosInt. 2009;20:1595-601.

339. Blumel JE, Castelo-Branco C, De La Cuadra G, Maciver L, Moreno M, Haya J. Alendronate daily, weekly in conventional tablets and weekly in enteric tablets: Preliminary study on the effects in bone turnover markers and incidence of side effects. Journal of Obstetrics and Gynaecology. 2003;23:278-81.

340. Bouts M, Van Den Bergh J, Bours S, Geusens P, Van GT. Comparing tolerability and efficacy of generic versus brand alendronate. A cross-over study in postmenopausal women with osteoporosis. Annals of the Rheumatic Disease. 2013;Conference

341. Buckwalter JG, Geiger AM, Parsons TD, Handler J, Howes J, Lehmer RR. Cognitive effects of short-term use of raloxifene: a randomized clinical trial. The International journal of neuroscience. 2007;117:1579-90.

342. C. K. Muschitz RF-P, A. Lung SR. Overlapping and follow-up of alendronate to teriparatide treatment results in maintenance of excess BMD gain. OsteoporosInt. 2013;Conference:(var.pagings). 24 (1 Suppl 1):S93.

343. C. K. Muschitz RF-P, A. Resch H. Overlapping and follow-up of alendronate to teriparatide treatment results in maintenance of excess BMD gain. OsteoporosInt. 2012;Conference:(var.pagings). 23 (7 Suppl 1):S750-S1.

344. Chesnut CH, Iii H. Short-term effect of alendronate on bone mass and bone remodeling in postmenopausal women. OsteoporosInt. 1993;3 Suppl 3:S17-9.

345. Choi HJ, Im JA, Kim SH. Changes in bone markers after once-weekly low-dose alendronate in postmenopausal women with moderate bone loss. Maturitas. 2008;60:170-6.

346. Chung YS, Lim SK, Chung HY, Lee IK, Park IH, Kim GS, et al. Comparison of monthly ibandronate versus weekly risedronate in preference, convenience, and bone turnover markers in Korean postmenopausal osteoporotic women. Calcified Tissue International. 2009;85:389-97.

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347. Cooper A, Drake J, Brankin E. Treatment persistence with once-monthly ibandronate and patient support vs. once-weekly alendronate: Results from the PERSIST study. Int J Clin Pract. 2006;60:896-905.

348. Cryer B, Binkley N, Simonelli C, Lewiecki EM, Lanza F, Chen E, et al. A randomized, placebo- controlled, 6-month study of once-weekly alendronate oral solution for postmenopausal osteoporosis. American Journal Geriatric Pharmacotherapy. 2005;3:127-36.

349. Daddona PEM, Mandema JA, Maa J, Y F. Parathyroid hormone (1-34)-coated microneedle patch system: clinical pharmacokinetics and pharmacodynamics for treatment of osteoporosis. Pharmaceutical Research. 2011;28(1):159-65.

350. D'Amelio P, Grimaldi A, Di BS, Tamone C, Brianza SZ, Ravazzoli MG, et al. Risedronate reduces osteoclast precursors and cytokine production in postmenopausal osteoporotic women. Journal of Bone and Mineral Research. 2008;23:373-9.

351. Dane C, Dane B, Cetin A, Erginbas M. Effect of risedronate on biochemical marker of bone resorption in postmenopausal women with osteoporosis or osteopenia. Gynecol Endocrinol. 2008;24:207-13.

352. Dempster D, Zhou H, Recker R, Brown JP, Bolognese M, Recknor C, et al. Differential effects of teriparatide and zoledronic acid on the outer and inner surfaces of cortical bone in postmenopausal women with osteoporosis: Results from the shotz trial. Journal of Bone and Mineral Research. 2012;Conference

353. Dempster DW, Zhou H, Recker RR, Brown JP, Bolognese MA, Recknor C, et al. Skeletal histomorphometry in patients on teriparatide or zoledronic acid therapy (SHOTZ) study: 6- month results of a randomized clinical trial. Journal of Bone and Mineral Research. 2011;Conference

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388. M. J. Bhandari LS, K. Burge RG, N. Witvrouw RK, K. D. Warner MRA, Q. I. Mitlak B. Does Teriparatide Improve Femoral Neck Fracture Healing: Results From A Randomized Placebo- controlled Trial. Clinical Orthopaedics and Related Research. 2016;474(5):1234-44.

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390. Marshall JK, Rainsford KD, James C, Hunt RH. A randomized controlled trial to assess alendronate-associated injury of the upper gastrointestinal tract. Alimentary Pharmacology and Therapeutics. 2000;14:1451-7.

391. Marshall JK, Thabane M, James C. Randomized active and placebo-controlled endoscopy study of a novel protected formulation of oral alendronate. Dig Dis Sci. 2006;51:864-8.

392. McClung M. Differential Effects of Teriparatide and Alendronate on Markers of Bone Remodeling and Areal and Volumetric Bone Density in Women with Osteoporosis. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research. 2003;18:S38.

393. McClung M, Miller P, Civitelli R. Distinctive effects of teriparatide [rhPTH(1-34)] and alendronate on bone turnover and lumbar spine bone density in women with osteoporosis. Osteoporosis international : a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA. 2003;13:S18.

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394. Miller PD, Woodson G, Licata AA, Ettinger MP, Mako B, Smith ME, et al. Rechallenge of patients who had discontinued alendronate therapy because of upper gastrointestinal symptoms. Clin Ther. 2000;22:1433-42.

395. Nieves J, Cosman F, Boutroy S, Barbuto N, Zion M, Shane E, et al. Teriparatide treatment for 24 months in postmenopausal women with osteoporosis differentially impacts cortical and trabecular bone at the tibia assessedby HRpQCT. Journal of Bone and Mineral Research. 2011;Conference

396. Ohtori S, Inoue G, Orita S, Yamauchi K, Eguchi Y, Ochiai N, et al. Teriparatide accelerates lumbar posterolateral fusion in women with postmenopausal osteoporosis: prospective study. Spine. 2012;37:E1464-E8.

397. Oktem M, Atar I, Zeyneloglu HB, Yildirir A, Kuscu E, Muderrisoglu H. Raloxifene has favourable effects on metabolic parameters but has no effect on left ventricular function in postmenopausal women. Pharmacological Research. 2008;57:364-8.

398. Oliveira LG, Eis SR, Neto HM, e Moraes FB, Pires LA, Vasconcelos JW. Use of risedronate for consolidation and callus formation in Colles fractures in postmenopausal women: SOLID study. RevBrasOrtop. 2015;50:274-82.

399. Oral A, Lorenc R, Flint-Act SI. Compliance, persistence, and preference outcomes of postmenopausal osteoporotic women receiving a flexible or fixed regimen of daily risedronate: A multicenter, prospective, parallel group study. Acta Orthop Traumatol Turc. 2015;49:67-74.

400. Pawlowski JW, Martin BR, McCabe GP, McCabe L, Jackson GS, Peacock M, et al. Impact of equol-producing capacity and soy-isoflavone profiles of supplements on bone calcium retention in postmenopausal women: a randomized crossover trial. Am J Clin Nutr. 2015;102:695-703.

401. Peris P, Atkinson EJ, Gossl M, Kane TL, McCready LK, Lerman A, et al. Effects of bisphosphonate treatment on circulating osteogenic endothelial progenitor cells in postmenopausal women. Mayo Clin Proc. 2013;88:46-55.

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404. Radicioni M, Cremonesi G, Baraldi E, Leuratti C, Mariotti F. Pharmacokinetic and tolerability of i.m. disodium clodronate 200 mg/lidocaine 1%, given twice monthly, in comparison with i.m. disodium clodronate 100 mg/lidocaine 1%, given weekly, in healthy postmenopausal female patients. Int J Clin Pharmacol Ther. 2013;51:313-22.

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405. Reginster JY, Lecart MP, Deroisy R, Sarlet N, Denis D, Ethgen D, et al. Prevention of postmenopausal bone loss by tiludronate. Lancet. 1989;2:1469-71.

406. Reginster JY, Wilson KM, Dumont E, Bonvoisin B, Barrett J. Monthly oral ibandronate is well tolerated and efficacious in postmenopausal women: Results from the Monthly Oral Pilot Study. Journal of Clinical Endocrinology and Metabolism. 2005;90:5018-24.

407. Rhee Y, Kang M, Min Y, Byun D, Chung Y, Ahn C, et al. Effects of a combined alendronate and calcitriol agent (Maxmarvil) on bone metabolism in Korean postmenopausal women: A multicenter, double-blind, randomized, placebo-controlled study. OsteoporosInt. 2006;17:1801-7.

408. Rossini M, Gatti D, Zamberlan N, Braga V, Dorizzi R, Adami S. Long-term effects of a treatment course with oral alendronate of postmenopausal osteoporosis. Journal of Bone and Mineral Research. 1994;9:1833-7.

409. Roux C, Deroisy R. Prevention of early postmenopausal bone loss with oral tiludronate. Osteoporos-Int. 1996;6 Suppl 1:249.

410. Saag K, Lindsay R, Kriegman A, Beamer E, Zhou W. A single zoledronic acid infusion reduces bone resorption markers more rapidly than weekly oral alendronate in postmenopausal women with low bone mineral density. Bone. 2007;40:1238-43.

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412. Schafer AL, Sellmeyer DE, Palermo L, Hietpas J, Eastell R, Shoback DM, et al. Six months of parathyroid Hormone (1-84) administered concurrently versus sequentially with monthly ibandronate over two years: the PTH and ibandronate combination study (PICS) randomized trial. Journal of Clinical Endocrinology and Metabolism. 2012;97:3522-9.

413. Shapses SA, Kendler DL, Robson R, Hansen KE, Sherrell RM, Field MP, et al. Effect of alendronate and vitamin D3 on fractional calcium absorption in a double-blind, randomized, placebo-controlled trial in postmenopausal osteoporotic women. Journal of Bone and Mineral Research. 2011;26:1836-44.

414. Shiraki M, Fukunaga M, Kushida K, Kishimoto H, Taketani Y, Minaguchi H, et al. A double- blind dose-ranging study of risedronate in Japanese patients with osteoporosis (a study by the Risedronate Late Phase II Research Group). OsteoporosInt. 2003;14:225-34.

415. Shiraki M, Kushida K, Fukunaga M, Kishimoto H, Kaneda K, Minaguchi H, et al. A placebo- controlled, single-blind study to determine the appropriate alendronate dosage in postmenopausal Japanese patients with osteoporosis. Endocrine Journal. 1998;45:191-201.

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416. Simon JA, Lewiecki EM, Smith ME, Petruschke RA, Wang L, Palmisano JJ. Patient preference for once-weekly alendronate 70 mg versus once-daily alendronate 10 mg: A multicenter, randomized, open-label, crossover study. Clin Ther. 2002;24:1871-86.

417. Smith ML, Fogelman I, Hart DM, Scott E, Bevan J, Leggate I. Effect of etidronate disodium on bone turnover following surgical menopause. Calcif Tissue Int. 1989;44(2):74-9.

418. Srividhya NB, Singh N, Goel N, Gambhir JK, Rathi V, Rajaram S. Comparison of antiresorptive effect of hormone therapy and ibandronate in postmenopausal osteoporotic women by assessing type I collagen C-telopeptide levels. Post Reprod Health. 2015;21:48-55.

419. Ste-Marie LG, Brown JP, Beary JF, Matzkin E, Darbie LM, Burgio DE, et al. Comparison of the effects of once-monthly versus once-daily risedronate in postmenopausal osteoporosis: a phase II, 6-month, multicenter, randomized, double-blind, active-controlled, dose-ranging study. Clin Ther. 2009;31:272-85.

420. Stuss M, Rieske P, Ceglowska A, Stepien-Klos W, Liberski PP, Brzezianska E, et al. Assessment of OPG/RANK/RANKL gene expression levels in peripheral blood mononuclear cells (PBMC) after treatment with strontium ranelate and ibandronate in patients with postmenopausal osteoporosis. Journal of Clinical Endocrinology and Metabolism. 2013;98:E1007-E11.

421. Takada J, Iba K, Imoto K, Yamashita T. Changes in bone resorption markers among Japanese patients with postmenopausal osteoporosis treated with alendronate and risedronate. J Bone MinerMetab. 2007;25:142-6.

422. Tanaka S, Yoshida A, Kono S, Ito M. Effectiveness of monotherapy and combined therapy with calcitonin and minodronic acid hydrate, a bisphosphonate, for early treatment in patients with new vertebral fractures: An open-label, randomized, parallel-group study. Journal of orthopaedic science : official journal of the Japanese Orthopaedic Association. 2017;22:536- 41.

423. Tanko LB, Mouritzen U, Lehmann HJ, Warming L, Moelgaard A, Christgau S, et al. Oral ibandronate: Changes in markers of bone turnover during adequately dosed continuous and weekly therapy and during different suboptimally dosed treatment regimens. Bone. 2003;32:687-93.

424. Thomson ABR, Marshall JK, Hunt RH, Provenza JM, Lanza FL, Royer MG, et al. 14 Day endoscopy study comparing risedronate and alendronate in postmenopausal women stratified by Helicobacter pylori status. J Rheumatol. 2002;29:1965-74.

425. van den Bergh JP, Bouts ME, van dV, van der Velde RY, Janssen MJ, Geusens PP, et al. Comparing tolerability and efficacy of generic versus brand alendronate: a randomized clinical study in postmenopausal women with a recent fracture. PLoS One. 2013;8:e78153.

426. Via MA, Potenza MV, Hollander J, Liu X, Peng Y, Li J, et al. Intravenous ibandronate acutely reduces bone hyperresorption in chronic critical illness. J Intensive Care Med. 2012;27:312-8.

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427. Wark J, Recknor C, Ryabitseva O, ChiodoIii J, Mesenbrink P, e VT. Treatment with acetaminophen/paracetamol or ibuprofen alleviates post-dose symptoms related to intravenous infusion with zoledronic acid 5 mg. Bone. 2010;Conference:S33.

428. Y. O. Kumagai AT, K. Sugimoto T. Safety Profiles, Pharmacokinetics, and Changes in Bone Turnover Markers After Twice-Weekly Subcutaneous Administration of Teriparatide in Healthy Japanese Postmenopausal Women: A Single-Blind Randomized Study. ClinPharmacolDrug Dev. 2019.

429. Yang TS, Tsan SH, Chen CR, Chang SP, Yuan CC. Effects of alendronate on bone turnover markers in early postmenopausal women. Chinese Medical Journal (Taipei). 1998;61:568-76.

430. Yeo MG, Song SH, Lee JG, Hur JY, Seo HS, Park YG. Clinical Usefulness of Alendronate for Osteoporosis in Postmenopausal women. Korean Journal of Obstetrics and Gynecology. 2000;43:2003-7.

431. Yoshioka T, Okimoto N, Okamoto K, Sakai A. A comparative study of the effects of daily minodronate and weekly alendronate on upper gastrointestinal symptoms, bone resorption, and back pain in postmenopausal osteoporosis patients. J Bone MinerMetab. 2013;31:153-60.

432. Zegels B, Eastell R, Russell RG, Ethgen D, Roumagnac I, Collette J, et al. Effect of high doses of oral risedronate (20 mg/day) on serum parathyroid hormone levels and urinary collagen cross-link excretion in postmenopausal women with spinal osteoporosis. Bone. 2001;28:108- 12.

List of studies excluded: duplicate publications, N=4 (433-436)

433. Bao L, Lin H, Li Y. Efficacy of monthly and weekly oral bisphosphonates in the treatment of postmenopausal osteoporsis. OsteoporosInt. 2012;Conference:S150.

434. Ishida Y, Soh H, Ogawa S, Kawahara S, Murata H. A one-year randomized controlled trial of hormone replacement therapy, bisphosphonate, calcitonin, vitamin D, and vitamin K, in women with postmenopausal osteoporosis. Journal of Bone and Mineral Research. 2000;15:S310, 2000.

435. Ishida Y, Soh H, Tsuchida S, Kawahara S, Murata H, Kawai S. Effectiveness of hormone replacement therapy, etidronate, calcitonin, vitamin D, and vitamin K in postmenopausal women with osteoporosis. Bone. 2002;3:S50.

436. K. G. P. Saag JB, M. L. Karaplis AL, M. Thomas TM, J. Fan MM, P. Grauer A. A randomized alendronate-controlled trial of romosozumab: Results of the phase 3 ARCH Study (Active- contRolled fraCture study in postmenopausal women with osteoporosis at High risk). Journal of Bone and Mineral Research. 2017;Conference:(Supplement 1):S54-S5.

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List of studies excluded: companion publications providing no further outcome data, N=220 (437-656)

437. Adachi JD, Adami S, Kulkarni PM, Wong M, Stock JL. Similar proportions of women lose bone mineral density with raloxifene or alendronate treatment. J Clin Densitometry. 2005;8:273-7.

438. Adami S, Baroni MC, Broggini M, Carratelli L, Caruso I, Gnessi L, et al. Treatment of postmenopausal osteoporosis with continuous daily oral alendronate in comparison with either placebo or intranasal salmon calcitonin. OsteoporosInt. 1993;3:21-7.

439. Antoniucci DM, Sellmeyer DE, Bilezikian JP, Palermo L, Ensrud KE, Greenspan SL, et al. Elevations in serum and urinary calcium with parathyroid hormone (1-84) with and without alendronate for osteoporosis. Journal of Clinical Endocrinology and Metabolism. 2007;92:942- 7.

440. Antoniucci DM, Vittinghoff E, Palermo L, Black DM, Sellmeyer DE. Vitamin D insufficiency does not affect response of bone mineral density to alendronate. OsteoporosInt. 2009;20:1259-66.

441. Bala Y, Barr CE, Boivin G. Daily and intermittent oral ibandronate improve bone tissue hardness and maintained its mineralization. OsteoporosInt. 2010;Conference:S155.

442. Bala Y, Chapurlat R, Felsenberg D, Thomas T, LaRoche M, Morris E, et al. Risedronate slows or partly reverses microarchitecture deterioration depending on whether remodelling is perturbed or in steady state. OsteoporosInt. 2013;24:S58-S9.

443. Bala Y, Kohles J, Recker RR, Boivin G. Oral ibandronate in postmenopausal osteoporotic women alters micromechanical properties independently of changes in mineralization. Calcified Tissue International. 2013;92:6-14.

444. Bauer DC, Garnero P, Hochberg MC, Santora A, Delmas P, Ewing SK, et al. Pretreatment levels of bone turnover and the antifracture efficacy of alendronate: the fracture intervention trial. Journal of Bone and Mineral Research. 2006;21:292-9.

445. Beck TJ, Michael LE, Miller PD, Felsenberg D, Liu Y, Ding B, et al. Effects of Denosumab on the Geometry of the Proximal Femur in Postmenopausal Women in Comparison with Alendronate. J Clin Densitometry. 2008;11:351-9.

446. Bettembuk P, Balogh A. The effect of a one-year alendronate therapy on postmenopausal osteoporosis. (Results in Hungarian of an international multicenter clinical study). Orvosi Hetilap. 1999;140(50):2799–803.

447. Black D, Delmas PD, Eastell R, Reid IR, Felsenberg D, Boonen S, et al. [Effect of an annual infusion with 5mg zoledronic acid in post-menopausal women with osteoporosis]. Medizinische Klinik. 2007;102:16.

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448. Black D, Reid I, Cauley J, Boonen S, Cosman F, Leung P, et al. The effect of 6 versus 9 years of zoledronic acid treatment in osteoporosis: A randomized extension to the horizon-pivotal fracture trial (PFT). Journal of Bone and Mineral Research. 2013;Conference

449. Black DD, Eastell PD, Reid R, Felsenberg IR, Boonen D, Cauley S, et al. Effect of an annual infusion with 5mg zoledronic acid in post-menopausal women with osteoporosis. Medizinische Klinik. 2007;102(4):16.

450. Black DM, Reiss TF, Nevitt MC, Cauley J, Karpf D, Cummings SR. Design of the Fracture Intervention Trial. OsteoporosInt. 1993;3:29-39.

451. Black DM, Thompson DE, Bauer DC, Ensrud K, Musliner T, Hochberg MC, et al. Fracture risk reduction with alendronate in women with osteoporosis: the Fracture Intervention Trial. FIT Research Group. The Journal of clinical endocrinology and metabolism. 2000;85:4118-24.

452. Blake GM, Herd RJM, Patel R, Fogelman I. The effect of weight change on total body dual- energy X-ray absorptiometry: Results from a clinical trial. OsteoporosInt. 2000;11:832-9.

453. Boivin GY, Chavassieux PM, Santora AC, Yates J, Meunier PJ. Alendronate increases bone strength by increasing the mean degree of mineralization of bone tissue in osteoporotic women. Bone. 2000;27:687-94.

454. Bolland M, Wattie D, Horne A, Gamble G, Reid IR, Grey A. Prolonged anti-resorptive activity of zoledronate-A randomized controlled trial. Bone. 2010;Conference:S56-S7.

455. Bolognese MA, Bone HG, Kendler DL, Brandi ML, Hodsman A, Orcel P, et al. Transitioning to denosumab leads to further increases in BMD throughout the skeleton in postmenopausal women who received 5 or more years of continuous alendronate therapy. Arthritis and Rheumatism. 2011;63.

456. Bolognese MAR, Bianchi C, Supronik G, Valter J, Vernejoul ID, Kendler MC, et al. Relationship of baseline bone turnover marker levels and month 12 bone mineral density change in postmenopausal women transitioned from alendronate to denosumab. Arthritis and Rheumatism. 2009;Conference:(60 Suppl 10):871.

457. Bone HG, Kendler DL, Bolognese MA, Brandi ML, Hodsman A, Orcel P, et al. Transitioning to denosumab further improves BMD in postmenopausal women who received 5 or more years of continuous alendronate therapy. EndocrRev. 2011;3.

458. Bonnick S, Rosen C, Mako B, DeLucca P, Byrned C, Melton M. Alendronate vs calcium for treatment of osteoporosis in postmenopausal women. Bone. 1998;350(5S):S476.

459. Boonen S, Sellmeyer DE, Lippuner K, Orlov-Morozov A, Abrams K, Mesenbrink P, et al. Renal safety of annual zoledronic acid infusions in osteoporotic postmenopausal women. Kidney International. 2008;74:641-8.

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APPENDIX 8: RISK OF BIAS ASSESSMENTS BY STUDY

Adami 2000 Unclear Unclear N/A Unclear N/A High Low Low

Adami 1995 Unclear Unclear N/A High N/A Low Low Low

Akyol 2006 Unclear Unclear Low N/A High High Unclear Unclear

Anastasilakis 2015 Low Low Low High Low Low Low Low

Ascott-Evans 2003 Low Unclear Low Low Low High Low Low

Atmaca 2006 Unclear Unclear N/A High N/A Unclear Low Low

Bai 2013 Unclear Unclear Low High Unclear Unclear Low Low

Bala 2014 Unclear Unclear N/A Unclear N/A Low Low Low

Bell 2002 Unclear Unclear N/A Unclear N/A High Low Low

Black 1996 Unclear Low Low Low Low Low High Low

Black 2007 Low Unclear Low Unclear Low Low Low Low

Bone 1997 Unclear Unclear Low Unclear Unclear Unclear Low Low

Bone 2000 Low Unclear Low Unclear High High Low Low

Bonnick 2007 Unclear Unclear N/A Unclear N/A High Low Low

Brown 2002 Unclear Unclear Low Low Low Low Low Low

Brown 2009 Unclear Unclear Low Low Low Low Low Low

Burghardt 2010 Unclear Unclear N/A Unclear N/A High Low Low

Chailurkit 2003 Unclear Unclear N/A Low N/A Low Low Low

Chao 2013 Unclear Unclear Low N/A Unclear Unclear Low Low

Incomplete Incomplete Blinding Blinding Selective Sequence Allocation Outcome Data Outcome Data Other Risk of Author Year (Objective (Subjective Outcome Generation Concealment (Efficacy (Safety Bias outcomes) outcomes) Reporting outcomes) outcomes) Chavez-Valencia Low Unclear Low N/A Low Low Low Low 2014 Chesnut 1995 Unclear Unclear Low High Low Low Low Low

Chilibeck 2002 Unclear Unclear N/A Unclear N/A Low Unclear Low

Clemmesen 1997 Unclear Unclear N/A N/A N/A N/A Low Low

Cosman 2016 Low Low N/A Low N/A High Low Low

Cummings 1998 Low Low Low Low Low Low High Low

Delmas 2008 Unclear Unclear Low Unclear Low Low Low Low

Delmas 2008 Unclear Unclear Low Low Low Low Low Low

Dobnig 2006 Unclear Unclear N/A High N/A Low High Low

Downs 2000 Unclear Unclear N/A High N/A Unclear Low Low

Dundar 2009 High Unclear N/A Low N/A Low Low Low

Dursun 2001 Unclear Unclear Low High Unclear Unclear Low Low

Eastell 2011 Unclear Unclear N/A Low N/A Unclear Low Low

Evans 1993 Low Unclear N/A N/A N/A N/A Low Low

Fogelman 2000 Unclear Unclear Low High High High Low Low

Frediani 1998 Low Unclear N/A High N/A Unclear Low Low

Freemantle 2012 Low Low Low High Low Low Low Low

Galesanu 2017 Unclear Unclear Low High Unclear Unclear Unclear High

Galesanu 2011 Unclear Unclear Low Unclear Unclear Unclear Unclear Unclear

Galesanu 2015 Unclear Unclear Low High Unclear Unclear High High

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Gonnelli 2002 Unclear Unclear N/A Unclear N/A Unclear Low Low

Gonnelli 1999 Unclear Unclear N/A High N/A Low Low Low

Greenspan 1998 Unclear Unclear Low Unclear High High High Low

Greenspan 2003 Low Low N/A Low N/A Low Low Low

Greenspan 2002 Low Unclear Low Low Unclear Unclear Low Low

Grey 2010 Low Low Low Low Low Low Low Low

Grey 2012 Low Low Low Low Low Low Low Low

Gu 2015 Low Unclear Low Low Low Low Low Low

Hadji 2012 Low Unclear Low High High High Low Unclear

Han 2016 Unclear Unclear N/A N/A N/A N/A Low Low

Harris 1999 Low Low Low Low High High Unclear Low

Heath 2000 Unclear Unclear N/A High N/A High Low Low

Herd 1997 Unclear Unclear Low Unclear Low Low Low Low

Ho 2005 Unclear Unclear N/A High N/A Low Low Low

Hooper 2005 Low Low Low Low High High Low Low

Hosking 2003 Low Low N/A Low N/A High Low Low

Hosking 1998 Unclear Low Low High Low Low Low Low

Hu 2005 Unclear Unclear N/A N/A N/A N/A High Low

Invernizzi 2013 Unclear Unclear N/A High N/A Low Unclear Unclear

Ishida 2004 Low Unclear Low Unclear Low Low Low Low

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Iwamoto 2001 Unclear Unclear Low High Unclear Unclear Low Low

Iwamoto 2005 High High Low High Low Low High Low

Johnell 2002 Low Low N/A Low N/A Low Low Low

Kendler 2010 Unclear Low Low Low Low Low Low Low

Kosus 2005 Unclear Unclear N/A High N/A Unclear Unclear Unclear

Kung 2000 Unclear Unclear N/A Low N/A Unclear Low Low

Lau 2000 Unclear Unclear N/A Unclear N/A Low Low Unclear

Leung 2005 Unclear Unclear Low Low Low Low Low Low

Leung 2006 Unclear Unclear N/A N/A N/A N/A Low Low

Lewiecki 2007 Unclear Unclear Low High Low Low Low Low

Li 2013 Unclear Unclear N/A High N/A Low Low Low

Li 2005 Unclear Unclear Low Low Low Low Low Low

Liang 2017 Unclear Unclear Low Low Low Low Low Unclear

Liberman 1995 Unclear Unclear Low Low Low Low Low Unclear

Luckey 2003 Low Unclear Low Low Low Low Low Low

Lyritis 1997 Unclear Unclear Low High High High Low Low

McClung 1998 Unclear Unclear Low Low High High Low Low

McClung 2009 Low Low N/A Low N/A Low Low Low

McClung 2007 Unclear Unclear N/A Unclear N/A Low Low Low

McClung 2001 Unclear Unclear Low Low High High High Low

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McClung 2014 Low Low N/A High N/A Low Low Low

McClung 2012 Unclear Unclear Low Low Low Low Low Low

Meunier 1997 Unclear Unclear Low Low Low Low Low Low

Michalska 2006 Unclear Unclear Low High Low Low Low Low

Miller 2016 Unclear Unclear Low Low Low Low Low Low

Montessori 1997 Low Unclear Low Unclear High High Unclear Low

Mortensen 1998 Unclear Unclear Low Low Low Low Low Low

Murphy 2001 Unclear Unclear Low N/A High N/A Low Low

Nakamura 2014 Unclear Unclear Low High Low Low Low Low

Ohtori 2013 High High N/A High N/A Low Low Low

Paggiosi 2014 Unclear Low Low High High High Unclear Low

Pols 1999 Unclear Unclear Low Unclear Low Low Low Low

Pouilles 1997 Unclear Unclear Low Unclear Low Low Low Low

Reginster 2000 Unclear Unclear Low Unclear High High Low Low

Reid 2006 Low Low N/A Low N/A Low Unclear Low

Reid 2002 Unclear Low Low Low Low Low Low Low Robles-Carranza Unclear Unclear Low N/A High N/A High Unclear 2013 Rosen 2005 Low Low N/A Low N/A High Low Low

Rossini 2000 Unclear Unclear N/A High N/A Low Low Low

Roux 2014 Unclear Unclear Low High Low Low Low Low

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Russo 1996 Unclear Unclear Low High Low Unclear Unclear Low

Sahota 2000 Low Unclear N/A High N/A Low Low Low

Sarioglu 2006 Unclear Unclear Low N/A Unclear Unclear Low Low

Schnitzer 2000 Low Unclear Low Low Low Low Low Low

Seeman 2010 Low Low N/A Low N/A Low Low Low

Shi 2017 Low Unclear N/A High N/A Low Low Low

Shilbayeh 2004 Low Unclear N/A Low N/A High High Low

Shiota 2001 Unclear Unclear Low High Unclear Unclear High Low

Storm 1990 Low Unclear Low Unclear High High Low High

Tan 2016 Low Unclear Low Unclear Low Low Low Low

Tobias 1997 Unclear Unclear N/A Unclear N/A Low Unclear Unclear

Uusi-Rasi 2003 Unclear Unclear N/A Unclear N/A Low Low Low

Välimäki 2007 Unclear Unclear Low Low Unclear Unclear Low Low

Watts 1990 Low Unclear Low Unclear Low Low Low High

Wimalawansa 1995 Unclear Unclear N/A High N/A Low Low Low

Wimalawansa 1998 Low Unclear Low High Low Low Low Low

Yan 2009 Low Unclear Low Low Low Low Low Low

Yang 2015 Unclear Unclear Low Unclear Low Low Low Low

Yanik 2008 Low Unclear N/A High N/A Unclear Unclear Low

Yen 2000 Unclear Unclear N/A Unclear N/A Low Low Low

TECHNOLOGY REVIEW Drugs for the Treatment and Prevention of Osteoporosis in Postmenopausal Women 213

Fukunaga 2002 Unclear Unclear Low Low Low Low Low Low

Qin 2007 Unclear Unclear Low Unclear Low Low Low Low

Pacifici 1988 Unclear Unclear Low N/A High N/A High Low

Nakamura 2012 Unclear Unclear Low Unclear Low Low Low Unclear

Bone 2008 Unclear Unclear Low Unclear Low Low Low Low

Reid 2018 Low Unclear Low Low Low Low Low Low

Aro 2018 Low Low Low Low Low Low Low Low

Cummings 2009 Unclear Unclear Low Low Low Low Low Low

Zhu 2017 Unclear Unclear N/A N/A N/A N/A Unclear Unclear

Zhang 2019 Low Low Low N/A Low N/A High Low

Susan 2015 Low Unclear Low Low Low High Low High EUCTR2008-001865- Unclear Unclear Low High Unclear Unclear Unclear Low 28 (Fogelman) 2015 NCT02063854 Unclear Unclear Low Unclear Low Low Unclear Unclear (Takeda) 2017 NCT02157948 Unclear Unclear N/A Unclear N/A Low Unclear Unclear (Amgen) 2017

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APPENDIX 9: STUDY CHARACTERISTICS

Primary

Author, Year, Trial Primary/ Time point* No. Background supplementation name Secondary (base case), Race Countries randomized (dose per day) (if known) Prevention months

Adami 1995 Primary 24 286 Caucasian (100%) Italy CAL 500 mg

Adami 2000 Primary 24 107 Caucasian (100%) Italy CAL 500 mg

Anastasilakis 2015 Primary 12 64 Caucasian (100%) Greece CAL 1000 mg + VID 800 IU

Aro 2018 Primary 12 49 NR Finland NR

Ascott Evans 2003 Primary 12 144 Caucasian (91.7%) Multinational CAL 500 mg

CAL ≥ 1000 mg + VID ≥ 400 IU (if United States baseline 25-[OH]D > 20 ng/ml) or ≥ Bone 2008 Primary 24 332 Caucasian (83%) and Canada 800 IU (if baseline 25-[OH]D was 12–20 ng/ml)

Burghardt 2010 Primary 24 53 NR NR CAL 1000 mg + VID 400 IU

Chesnut 1995 Primary 24 188 Caucasian (98%); Asian (2%) US CAL 500 mg

Chilibeck 2002 Primary 12 57 Caucasian (98%); Asian (2%) Canada CAL 500 mg + VID 400 IU

Author, Year, Trial Primary/ Time point* No. Background supplementation name Secondary (base case), Race Countries randomized (dose per day) (if known) Prevention months

Cummings 1998 Primary 48 4432 Caucasian (97%) US CAL 500 mg + VID 250 IU

Dursun 2001 Primary 12 151 NR Turkey CAL 1000 mg

Evans 1993 Primary 24 36 NR Australia CAL 600 mg

Galesanu 2015 Primary 36 105 NR NR CAL 1000 mg + ALF 1 μg

Greenspan 1998 Primary 30 120 NR US CAL 250 mg + VID 125 IU

CAL 890±437 mg + VID 252±230 Greenspan 2003 Primary 36 373 NR US IU

Grey 2010 Primary 24 50 NR New Zealand No

Grey 2012 Primary 24 180 NR New Zealand No

Gu 2015 Primary 12 290 NR China CAL 500 mg + VID 200 IU

Han 2016 Primary 12 639 Asian (100%) China CAL 600 mg + VID 125 IU

Heath 2000 Primary 24 77 NR UK No

CAL 500 mg for last 76 days of 90- Herd 1997 Primary 24 152 Caucasian (100%) UK day cycle

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Author, Year, Trial Primary/ Time point* No. Background supplementation name Secondary (base case), Race Countries randomized (dose per day) (if known) Prevention months

Hooper 2005 Primary 24 383 Caucasian (100%) Australia CAL 1000 mg

Caucasian (85%); Asian Hosking 1998 Primary 24 1609 (10%); Black/African- UK No American (0.6%)

Johnell 2002 Primary 12 331 Caucasian (95%) Multinational CAL 500 mg + VID 400-600 IU

Caucasian (86.2%); Asian Lewiecki 2007 Primary 24 412 (1.2%); Black/African- US CAL 1000 mg + VID 400 IU American (2.9%)

Li 2013 Primary 12 639 Asian (100%) China CAL 600 mg + VID 125 IU

Caucasian (96.2%); Luckey 2003 Primary 12 723 Black/African-American US CAL 500 mg + VID 250 IU (0.7%)

McClung 1998-1 Primary 36 447 NR Multinational CAL 500 mg

McClung 2007-3 Primary 12 225 Caucasian (97%) US CAL 1000 mg + VID 400 IU

Multinational McClung 2009 Primary 24 581 Caucasian (93%) (North America, NR Europe)

McClung 2014 Primary 12 410 Caucasian (86%) Multinational CAL 1000 mg + VID 800 IU

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Author, Year, Trial Primary/ Time point* No. Background supplementation name Secondary (base case), Race Countries randomized (dose per day) (if known) Prevention months

Meunier 1997 Primary 24 54 Caucasian (100%) France CAL 500 mg on days 15-91

Montessori 1997 Primary 36 80 Caucasian (100%) Netherlands CAL 500 mg

Denmark and Mortensen 1998 Primary 12 111 Caucasian (100%) No USA

Pols 1999 Primary 12 1908 NR Multinational CAL 500 mg

CAL 500 mg on days 15-91 in each Pouilles 1997 Primary 24 109 Caucasian (100%) France cycle Multinational (New Zealand, Canada, Reid 2002 Primary 12 351 Caucasian (99.4%) Switzerland, CAL ≤ 1000 mg + VID ≤ 1000 IU France, Belgium...10 countries) Cholecalciferol 1.25 mg once a month; Women not already taking VitD received 1-dose of Reid 2018 Primary 72 2000 Asian (2.0%) New Zealand chloecalciferol 2.5 mg (100,000 IU) ≥ 1 week before the first infusion of study medication

Robles-Carranza 2013 Primary 36 118 NR Mexico CAL 1200 mg + VID 400 IU

TECHNOLOGY REVIEW Drugs for the Treatment and Prevention of Osteoporosis in Postmenopausal Women 218

Author, Year, Trial Primary/ Time point* No. Background supplementation name Secondary (base case), Race Countries randomized (dose per day) (if known) Prevention months

Caucasian (95%), Asian (1%), Rosen 2005 Primary 24 1053 US CAL 1000 mg + VID 400 IU Black/African American (1%)

Seeman 2010 Primary 12 247 NR Multinational CAL > 500 mg + VID 400-800 IU

Shilbayeh 2004 Primary 12 118 NR Jordan CAL 500 mg + VID 0.25 μg

Tobias 1997 Primary 24 46 NR The UK No

Uusi-Rasi 2003 Primary 12 82 NR 0 CAL 630 mg + VID 400 IU

Multinational (Finland, Välimäki 2007 Primary 12 171 Caucasian (100%) Netherlands, CAL 1000 mg + VID 400 IU Norway, Spain, Sweden)

Wimalawansa 1995 Primary 48 58 Caucasian (100%) UK CAL 1000 mg

Yen 2000 Primary 12 60 Asian (100%) Taiwan CAL 500 mg

*Study duration may be longer than the time point extracted for base case if there is a long-term extension study

CAL=calcium, VID=vitamin D, 25-(OH)D= serum level of 25-hydroxyvitamin D, ALF= alfacalcidol, NR=not reported

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Secondary

Author, Year, Trial Primary/ Time point* No. Background supplementation name Secondary (base case), Race Countries randomized (dose per day) (if known) Prevention months

Akyol 2006 Secondary 12 112 NR Turkey CAL 1000 mg

Atmaca 2006 Secondary 12 30 NR Turkey CAL 600 mg + VID 400 IU

Bai 2013 Secondary 24 483 Asian (100%) China CAL 600 mg + VID 400 IU

Australia, France, Canada, Bala 2014 Secondary 12 324 NR Germany, UK, CAL 500 mg + VID 400 IU Argentina, and Switzerland

Bell 2002 Secondary 24 65 African-American (100%) US CAL 500 mg + VID 500 IU

CAL 500 mg (if Cal intake Caucasian (98%); Asian (1%); estimated by food-frequency Black 1996 Secondary 36 2027 US Black/African-American (1%) questionnaire was < 1000 mg/d) + VID 250 IU

Caucasian (79%); Asian CAL 1000-1500 mg + VID 400- Black 2007 Secondary 36 7765 (15%); Black/African- Multinational 1200 IU American (0.4%)

Bone 1997 Secondary 24 359 Caucasian (97.5%) US CAL 500 mg

Bone 2000 Secondary 24 425 Caucasian (89.9%) Multinational CAL 500 mg + VID <=400 IU

TECHNOLOGY REVIEW Drugs for the Treatment and Prevention of Osteoporosis in Postmenopausal Women 220

Author, Year, Trial Primary/ Time point* No. Background supplementation name Secondary (base case), Race Countries randomized (dose per day) (if known) Prevention months

Bonnick 2007 Secondary 24 701 Caucasian (97%) US CAL 800-1000 mg + VID 400 IU

CAL 1000 mg + VID (oral VID supplementation if baseline 25- Brown 2002 Secondary 24 1456 NR Canada and US (OH)D < 30nmol/l, dose not specified)

Caucasian (84.4%); Asian Brown 2009 Secondary 12 1189 (1.2%); Black/African- Multinational CAL ≥ 500 mg + VID ≥ 400 IU American (1.3%)

Chailurkit 2003 Secondary 12 80 NR Thailand CAL 500 mg

CAL 600-1500 mg + VID 400-1200 Chao 2013 Secondary 2 660 Asian (100%) China IU

Chavez-Valencia 2014 Secondary 12 104 NR Mexico CAL 600 mg + VID 200 IU

Denmark, Clemmensen 1997 Secondary 24 132 NR CAL 1000 mg Belgium

CAL >1200 mg + VID 2800 IU twice Cosman 2016 Secondary 12 526 Caucasian (86%) NR weekly

CAL ≥ 1000 mg + VID 800 IU (if baseline 25(OH)D was 12-20 Cummings 2009 Secondary 36 7868 Caucasian (92.7%) Multinational ng/mL) or 400 IU (if baseline 25(OH)D > 20 ng/mL)

TECHNOLOGY REVIEW Drugs for the Treatment and Prevention of Osteoporosis in Postmenopausal Women 221

Author, Year, Trial Primary/ Time point* No. Background supplementation name Secondary (base case), Race Countries randomized (dose per day) (if known) Prevention months

Multinational (USA, Canada, Delmas 2008a Secondary 24 1229 NR CAL 1000 mg + VID 400-800 IU France, Argentina)

CAL 1000 mg + VID 400–500 IU Delmas 2008b Secondary 24 1294 Caucasian (94%) Multinational (allowed to 1000 IU)

CAL 1000-1200 mg + VID 400-800 Dobnig 2006 Secondary 12 61 NR Germany IU

Downs 2000 Secondary 12 299 Caucasian (97%) US CAL 500 mg + VID 400 IU

Dundar 2009 Secondary 12 61 NR Turkey CAL 1000mg + VID 400IU

Eastell 2011 Secondary 24 285 Caucasian (100%) Multinational CAL 500 mg + VID 400 IU

EUCTR2008-001865- Secondary 24 26 NR UK CAL 600 mg + VID 400 IU 28 (Fogelman) 2018 France, the UK, the Netherlands, Fogelman 2000 Secondary 24 543 NR CAL 1000 mg Belgium, and Germany

Frediani 1998 Secondary 24 120 NR Italy No

Freemantle 2012 Secondary 12* 250 Caucasian (94%) US and Canada CAL 1000 mg + VID ≥ 400 IU

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Author, Year, Trial Primary/ Time point* No. Background supplementation name Secondary (base case), Race Countries randomized (dose per day) (if known) Prevention months

Fukunaga 2002 Secondary 48 235 Asian (100%) Japan CAL 200 mg

Galesanu 2011 Secondary 36 198 NR Romania No

Galesanu 2017 Secondary 24 62 NR NR CAL 1000 mg

Gonnelli 1999 Secondary 24 100 NR Italy CAL 1000 mg

Gonnelli 2002 Secondary 48 150 NR Italy CAL 1000 mg

Greenspan 2002 Secondary 24 327 Caucasian (97%) US CAL 500 mg + VID 400 IU

Greenspan 2015 Secondary 24 181 Caucasian (97.2%) USA CAL 1200 mg + VID 800 IU

Caucasian (98.7%); Asian Hadji 2012 Secondary 12 604 (0.17%); Black/African- Germany CAL 1200 mg + VID 800 IU American (0.33%)

CAL 1000 mg + cholecalciferol ≤ Harris 1999 Secondary 36 2458 Caucasian (96%) North America 500 IU (if baseline 25-(OH)D< 40 nmol/L)

Ho 2005 Secondary 12 58 Asian (100%) China CAL 500 mg

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Author, Year, Trial Primary/ Time point* No. Background supplementation name Secondary (base case), Race Countries randomized (dose per day) (if known) Prevention months

Hosking 2003 Secondary 12 549 Caucasian (99.5%) Multinational CAL 1000 mg + VID 400 IU

Hu 2005 Secondary 12 188 Asian (100%) China No

Invernizzi 2013 Secondary 12 104 NR Italy No

Ishida 2004 Secondary 24 396 Asian (100%) Japan No

Iwamoto 2001 Secondary 24 72 Asian (100%) Japan CAL 800 mg + VID 400 IU

Iwamoto 2005 Secondary 12 50 Asian (100%) Japan CAL 800 mg

Caucasian (93.3%); Asian Kendler 2010 Secondary 12 504 (0.4%); Black/African- Multinational CAL 1000 mg + VID 400 IU American (0.4%)

Köşüş 2005 Secondary 12 70 NR Turkey No

Kung 2000 Secondary 12 70 Asian (100%) China CAL 500 mg

Lau 2000 Secondary 12 100 Asian (100%) China CAL 500 mg

Leung 2005 Secondary 12 65 Asian (100%) China CAL 500 mg + VID 400 IU

TECHNOLOGY REVIEW Drugs for the Treatment and Prevention of Osteoporosis in Postmenopausal Women 224

Author, Year, Trial Primary/ Time point* No. Background supplementation name Secondary (base case), Race Countries randomized (dose per day) (if known) Prevention months

Leung 2006 Secondary 12 132 Asian (100%) China CAL 1200 mg

Li 2005 Secondary 12 60 Asian (100%) China CAL 600 mg + VID 125 U

CAL 600 mg + VID (dose not Liang 2017 Secondary 24 285 NR China specified)

Caucasian (87.4%); Liberman 1995 Secondary 36 994 Black/African-American US CAL 500 mg (0.4%) In a 90-day cyclic treatment: CAL Lyritis 1997 Secondary 48 100 NR Greece 500 mg for 85 days + 1,25- dihydroxyvitamin D3 for 5 days

North America, CAL 1000 mg + VID ≤ 500 IU (if Europe, New McClung 2001-2 Secondary 36 9331 Caucasian (98%) baseline serum 25-(OH)D< 16 Zealand, and ng/ml Australia

Multinational (North America, Caucasian (99.5%); Asian South America, McClung 2012 Secondary 24 922 CAL 1000 mg + VID 800–1000 IU (0.2%) and the European Union) Czech Republic, Michalska 2006 Secondary 24 100 NR CAL 500 mg + VID 800 IU Austria

TECHNOLOGY REVIEW Drugs for the Treatment and Prevention of Osteoporosis in Postmenopausal Women 225

Author, Year, Trial Primary/ Time point* No. Background supplementation name Secondary (base case), Race Countries randomized (dose per day) (if known) Prevention months

Spain, Denmark, Caucasian (97%); Asian US, Belgium, Miller 2016 Secondary 12 643 (1.4%); Black/African- Portland, CAL≥1000 mg + VID ≥ 800 IU American (0.2%) Canada and Australia

Murphy 2001 Secondary 12 292 NR US CAL 500 mg

Nakamura 2012 Secondary 12 226 Asian (100%) Japan CAL 600 mg + VID 400 IU

Nakamura 2014 Secondary 24 1262 Asian (100%) Japan CAL 600 mg + VID 400 IU

NCT02063854 Secondary 12 871 Asian (100%) Japan CAL lactate hydrate 195 mg (Takeda) 2017 Canada, USA, NCT02157948 Caucasian (98%); Asian Secondary 12 394 Denmark, No (Amgen) 2017 (1.3%) Poland

Ohtori 2013 Secondary 12 62 Asian (100%) Japan No

Pacifici 1988 Secondary 24 93 Caucasian (100%) US CAL 1000 mg

Paggiosi 2014 Secondary 24 172 NR UK CAL 1200 mg + VID 800 IU

Qin 2007 Secondary 12 47 Asian (100%) China CAL 1200 mg

CAL 1000 mg + VID ≤ 500 IU (if Reginster 2000 Secondary 36 1226 NR Multinational baseline 25-(OH)D< 40 nmol/l)

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Author, Year, Trial Primary/ Time point* No. Background supplementation name Secondary (base case), Race Countries randomized (dose per day) (if known) Prevention months

Reid 2006 Secondary 12* 936 Caucasian (79%), Asian (8%) Multinational CAL 1000 mg + VID 400 IU

CAL 500-1000 mg + VID 400-800 Rossini 2000 Secondary 12 124 NR Italy IU

Caucasian (97.6%); Asian Roux 2014 Secondary 12 870 Multimational CAL ≥ 1000 mg + VID ≥ 800 IU (0.9%)

Russo 1996 Secondary 12 77 NR Italy No

Sahota 2000 Secondary 12 140 NR UK No

Sarioglu 2006 Secondary 12 50 NR Turkey CAL 1000 mg + VID 400 IU

Schnitzer 2000 Secondary 12 1258 NR Multinational CAL 500 mg + VID 250 IU

Shi 2017 Secondary 12 240 Asian (100%) China CAL 800 mg of CAL daily in food

Shiota 2001 Secondary 24 40 Asian (100%) Japan CAL 2000 mg

Storm 1990 Secondary 36 66 NR Denmark CAL 500 mg + VID 400 IU

Tan 2016 Secondary 36 105 Asian (100%) China No

TECHNOLOGY REVIEW Drugs for the Treatment and Prevention of Osteoporosis in Postmenopausal Women 227

Author, Year, Trial Primary/ Time point* No. Background supplementation name Secondary (base case), Race Countries randomized (dose per day) (if known) Prevention months

CAL 500 mg on the days they did Watts 1990 Secondary 24 423 NR US not take phosphate or etidronate or placebo

NR (England or Wimalawansa 1998 Secondary 48 72 Caucasian (100%) CAL 1000 mg + VID 400 IU USA)

Yan 2009 Secondary 12 560 Asian (100%) China CAL 500 mg + VID 200 IU

Yang 2015 Secondary 12 100 Asian (100%) China CAL 1000 mg + VID 400 IU

Yanik 2008 Secondary 12 150 NR NR CAL 1200 mg + VID 800 IU

Zhang 2019 Secondary 12 101 Asian (100%) China CAL 1000 mg + VID 800 IU

Zhu 2017 Secondary 12 485 Asian (100%) China No

TECHNOLOGY REVIEW Drugs for the Treatment and Prevention of Osteoporosis in Postmenopausal Women 228

APPENDIX 10: PARTICIPANT CHARACTERISTICS

Primary

Age, FN T- LS T- Primary/ years score % Prior Author Year score Tr 1* Tr 2* Tr 3* Tr 4* Tr 5* Tr 6* Secondary mean mean VF BIS mean (SD) (SD) (SD)

ETI 400 51.9 0.78 -1.14 Adami 2000 Primary 0 No PBO mg/d (3.3) (0.10) (1.04) (cyclic)

59.5 ALE 10 ALE 20 CAC 100 Adami 1995 Primary NR NR 5 No PBO (6.0) mg/d mg/d IU/d, IN

Anastasilakis 63.2 -2.04 DEN 60 ZOL 5 Primary NR NR Yes 2015 (9.8) (1.15) mg/6m, SC mg/yr, IV

Ascott Evans 57.3 -2.27 ALE 10 Primary NR 0 NR PBO 2003 (6.6) (0.65) mg/d

Burghardt 55.6 -1.50 -1.20 ALE 70 Primary NR No PBO 2010 (3.6) (0.60) (0.70) mg/wk

ALE 20 ALE 40 ALE 40 Chesnut 63.0 ALE 5 ALE 10 Primary NR NR 0 NR PBO mg/d → mg/d mg/d→ 2.5 1995 (6.3) mg/d mg/d PBO → PBO mg/d

ETI 400 Chilibeck 57.5 -0.95 -1.04 Primary NR NR PBO mg/d 2002 (1.0) (1.06) (1.42) (cyclic)

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Age, FN T- LS T- Primary/ years score % Prior Author Year score Tr 1* Tr 2* Tr 3* Tr 4* Tr 5* Tr 6* Secondary mean mean VF BIS mean (SD) (SD) (SD)

Cummings 67.7 ALE 5-10 Primary NR NR 0 No PBO 1998 (6.2) mg/d

61.2 CAC 100 ALE 10 Dursun 2001 Primary NR NR NR No PBO (8.0) IU/d, IN mg/d

DEN 60 Galesanu 66.0 ALE 70 Primary NR NR NR NR mg/6m, 2015 (NR) mg/wk SC

Greenspan 70.0 ALE 5-10 Primary NR NR NR NR PBO 1998 (4.6) mg/d

ALE 10 Greenspan 71.5 -1.75 -2.30 ALE 10 Primary NR NR PBO HRT mg/d+ 2003 (5.5) (0.85) (1.37) mg/d HRT

ZOL 5 63.5 -1.15 Grey 2010 Primary NR 0 NR PBO mg/yr-s, (8.5) (0.76) IV

ZOL 1 ZOL 2.5 ZOL 5 65.3 -1.25 Grey 2012 Primary NR 0 No PBO mg/ yr-s, mg/yr yr- mg/yr yr-s, (8.5) (0.80) IV s, IV IV

63.0 RIS 35 RIS 5 Gu 2015 Primary NR NR NR NR (6.8) mg/wk mg/d

TECHNOLOGY REVIEW Drugs for the Treatment and Prevention of Osteoporosis in Postmenopausal Women 230

Age, FN T- LS T- Primary/ years score % Prior Author Year score Tr 1* Tr 2* Tr 3* Tr 4* Tr 5* Tr 6* Secondary mean mean VF BIS mean (SD) (SD) (SD)

ETI 400 52.5 Heath 2000 Primary NR NR 0 NR PBO mg/d (3.6) (cyclic)

ETI 400 54.8 Herd 1997 Primary NR NR 0 NR PBO mg/d (5.0) (cyclic)

52.7 -0.40 RIS 2.5 RIS 5 Hooper 2005 Primary NR 18 NR PBO (3.2) (0.11) mg/d mg/d

Hosking 53.0 ALE 2.5 ALE 5 Primary NR NR NR No PBO HRT 1998 (4.0) mg/d mg/d

ALE 10 63.7 ALE 10 RAL 60 Johnell 2002 Primary NR NR NR NR PBO mg/d+ RAL (6.0) mg/d mg/d 60 mg/d

DEN-7 Lewiecki 62.5 -1.90 -2.14 ALE 70 Primary NR NR PBO arms)†, 2007 (8.1) (0.50) (0.78) mg/wk SC

62.2 ALE 70 ALE 35 Li 2013 Primary NR NR 3 NR (7.0) mg/wk mg/wk

56.2 ALE 5 ALE 35 Luckey 2003 Primary NR NR NR No (5.9) mg/d mg/wk

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Age, FN T- LS T- Primary/ years score % Prior Author Year score Tr 1* Tr 2* Tr 3* Tr 4* Tr 5* Tr 6* Secondary mean mean VF BIS mean (SD) (SD) (SD)

ALE 20 McClung 51.8 ALE 1 ALE 5 ALE 10 Primary NR NR 0 No PBO mg/d→ 1998 (0.5) mg/d mg/d mg/d PBO

McClung 60.0 -1.43 -1.69 ZOL 5 ZOL 2.5 Primary NR NR PBO 2009 (7.9) (0.64) (0.44) mg/yr mg/yr

McClung 67.8 ALE 70 ZOL 5 Primary NR NR NR Yes 2007 (7.9) mg/wk mg/yr, IV

McClung 66.8 -1.93 -2.29 ALE 70 TER 20 ROM-5 Primary 0 NR PBO 2014 (6.4) (0.59) (0.68) mg/wk μg/d, SC arms ‡, SC

ETI 400 Meunier 52.7 Primary NR NR NR No PBO mg/d 1997 (0.5) (cyclic)

ETI 400 Montessori 62.5 Primary NR NR NR NR PBO mg/d 1997 (6.2) (cyclic)

RIS 5 Mortensen 51.5 RIS 5 Primary NR NR 0 NR PBO mg/d 1998 (3.8) mg/d (cyclic)

62.8 ALE 10 Pols 1999 Primary NR NR NR NR PBO (7.4) mg/d

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Age, FN T- LS T- Primary/ years score % Prior Author Year score Tr 1* Tr 2* Tr 3* Tr 4* Tr 5* Tr 6* Secondary mean mean VF BIS mean (SD) (SD) (SD)

ETI 400 Pouilles 53.8 Primary NR NR NR NR PBO mg/d 1997 (3.1) (cyclic)

ZOL 0.25 ZOL 0.5 ZOL 2 64.0 ZOL 1 ZOL 4 Reid 2002 Primary NR NR 0 No PBO mg/3m , mg/3m , mg/6m , (6.0) mg/3m , IV mg/yr , IV IV IV IV

Robles- 61.0 -1.90 ALE 70 ZOL 5 Carranza Primary NR NR NR (9.6) (0.74) mg/wk mg/yr, IV 2013

64.5 -2.14 -2.25 ALE 70 RIS 35 Rosen 2005 Primary NR NR (9.8) (0.67) (0.95) mg/wk mg/wk

DEN 60 Seeman 60.6 -2.40 ALE 70 Primary NR NR NR PBO mg/6m, 2010 (5.4) (0.30) mg/wk SC

Shilbayeh 57.6 ALE 5 or Primary NR NR NR NR PBO 2004 (8.1) 10 mg/d

ETI 400 49.5 Tobias 1997 Primary NR NR 0 NR mg/d PBO (NR) (cyclic)

Uusi-Rasi 53.7 ALE 5 Primary NR NR 0 NR PBO 2003 (2.5) mg/d

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Age, FN T- LS T- Primary/ years score % Prior Author Year score Tr 1* Tr 2* Tr 3* Tr 4* Tr 5* Tr 6* Secondary mean mean VF BIS mean (SD) (SD) (SD)

Välimäki 65.9 -1.23 -1.82 RIS 5 Primary NR NR PBO 2007 (6.8) (0.58) (0.42) mg/d

ETI 400 ETI 400 Wimalawans 52.6 mg/d Primary NR NR 0 No PBO mg/d HRT a 1995 (0.5) (cyclic)+HR (cyclic) T

59.7 ALE 10 Yen 2000 Primary -1.75 -1.90 0 No PBO (5.7) mg/d

DEN 60 59.4 -1.61 Bone 2008 Primary NR 0 NR PBO mg/6m, (7.5) (0.42) SC

71.0 -1.64 -0.89 ZOL 5 Reid 2018 Primary 13 NR PBO (5.0) (0.47) (1.14) mg/18, IV

68.1 ZOL 5 Aro 2018 Primary NR NR NR NR PBO (10.4) mg/yr, IV

PHO ETI 400 53.9 2g/d +ETI Evans 1993 Primary NR NR NR NR PBO mg/d (3.8) 400 mg/d (cyclic) (cyclic)

62.2 ALEW35/w ALE 70 Han 2016 Primary NR NR NR NR (7.0) k mg/wk

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* Orally administered unless otherwise specified. IV=intravenous, SC=subcutaneous, IN= intranasal; d=day, wk=week, yr=year, bim=two consecutive days each month; bid=twice a day; cyclic=3 monthly cycle, including 90-day cycle (14 days on treatment then followed by 76-day no treatment or calcium), or 12-week cycle ((14 days on treatment then followed by 76-day no treatment or calcium), SD=standard deviation, FN=femoral neck, LS=lumbar spine; VF=vertebral fracture, BIS=bisphosphonate, Tr=treatment ALE=Alendronate, RIS=risedronate, CAL=Calcium, VID=vitamin D, PBO=Placebo, CAC= Calcitonin, PTH= Parathyroid hormone, TER= Teriparatide, CEE= Conjugated equine estrogen, DEN= Denosumab, ZOL= Zoledronic acid, HRT= Hormone replace therapy, ALF= Alfacalcidol, DEN= Denosumab, IBA= Ibandronate, ETI= Etidronate, VIK1=vitamin K1, ROM=Romosozumab, CT=Calcitriol, QGY=QiangGuYin, PHO=Phosphate, CLO=Clodronate, PH=Phosphate; NR=not reported † including subcutaneous injection of denosumab 6 mg/3m, 14 mg/3m, 30 mg/3m, 14 mg/6m, 60 mg/6m,100 mg/6m, and 210 mg/6m ‡ including subcutaneous injection of romosuzumab 140 mg/3m, 210 mg/3m, 70 mg/m, 140 mg/m, and 210 mg.

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Secondary

Age, FN T- LS T- Primary/ years score % Prior Author Year score Tr 1* Tr 2* Tr 3* Tr 4* Tr 5* Tr 6* Secondary mean mean VF BIS mean (SD) (SD) (SD)

56.7 -1.44 -2.94 ALE 70 RIS 35 Akyol 2006 Secondary NR NR (8.0) (0.89) (0.81) mg/wk mg/wk

66.0 ALE 10 RIS 5 Atmaca 2006 Secondary NR NR NR NR (3.8) mg/d mg/d

56.8 ZOL 5 Bai 2013 Secondary NR NR 61 NR PBO (6.6) mg/yr, IV

57.0 -1.23 -1.76 RIS 35 Bala 2014 Secondary NR No PBO (6.0) (0.75) (0.52) mg/wk

66.2 ALE 10 Bell 2002 Secondary -1.94 -3.13 NR NR PBO (1.6) mg/d

ALE 70.8 Black 1996 Secondary NR NR 100 No PBO 5→10 (5.6) mg/d

73.1 ZOL 5 Black 2007 Secondary NR NR 63 NR PBO (5.4) mg/yr, IV

Age, FN T- LS T- Primary/ years score % Prior Author Year score Tr 1* Tr 2* Tr 3* Tr 4* Tr 5* Tr 6* Secondary mean mean VF BIS mean (SD) (SD) (SD)

70.6 ALE 1 ALE 2.5 Bone 1997 Secondary NR NR 37 NR PBO ALE 5 mg/d (5.9) mg/d mg/d

61.3 ALE 10 ALE 10 Bone 2000 Secondary NR -2.53 NR NR PBO HRT (8.0) mg/d CE mg/d+HRT

Bonnick 66.1 -2.31 ALE 10 Secondary -2.89 NR NR PBO 2007 (8.9) (0.04) mg/d

67.9 -2.30 -3.06 RIS 35 RIS 50 Brown 2002 Secondary 33 NR RIS 5 mg/d (8.2) (0.66) (0.67) mg/wk mg/wk

64.4 -2.57 DEN 60 ALE 70 Brown 2009 Secondary NR NR NR (8.5) (0.75) mg/6m, SC mg/wk

Chailurkit 62.0 ALE 10 Secondary NR NR NR NR PBO 2003 (5.9) mg/d

Chavez- 58.3 -2.18 ALE 70 ZOL 5 Valencia Secondary NR 0 NR (7.6) (0.79) mg/wk mg/yr, IV 2014

RIS 2.5 Clemmensen 68.3 RIS 2.5 Secondary NR NR 100 No PBO mg/d 1997 (5.7) mg/d (cyclic)

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Age, FN T- LS T- Primary/ years score % Prior Author Year score Tr 1* Tr 2* Tr 3* Tr 4* Tr 5* Tr 6* Secondary mean mean VF BIS mean (SD) (SD) (SD)

Cosman 67.5 -2.08 -2.50 ALE 70 MK-5442 MK-5442 MK-5442 MK-5442 Secondary NR Yes PBO 2016 (7.6) (0.62) (1.47) mg/wk 5 mg/d 7.5 mg/d 10 mg/d 15 mg/d

Delmas 64.8 -2.07 -3.17 RIS 75 Secondary 30 NR RIS 5 mg/d 2008a (7.8) (0.63) (0.55) mg/bim*

Delmas 64.9 -1.79 -3.15 RIS 150 Secondary 29 NR RIS 5 mg/d 2008b (7.5) (0.78) (0.57) mg/m

RIS 5 68.0 mg/d or Dobnig 2006 Secondary NR NR 34 NR PBO (5.3) ALE 10 mg/d

64.4 -2.66 -2.51 ALE 10 CAC 200 Downs 2000 Secondary 0 NR PBO (6.9) (0.60) (0.73) mg/d IU/d, IN

60.3 RIS 35 Dundar 2009 Secondary NR NR NR No PBO (9.0) mg/wk

ONO- ONO- 65.3 ALE 70 ONO-5334 Eastell 2011 Secondary NR NR NR NR PBO 5334 50 5334 300 (4.8) mg/wk 100 mg/d mg/bid mg/d

Fogelman 64.7 -2.90 RIS 2.5 RIS 5 Secondary NR 29 NR PBO 2000 (7.2) (0.70) mg/d mg/d

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Age, FN T- LS T- Primary/ years score % Prior Author Year score Tr 1* Tr 2* Tr 3* Tr 4* Tr 5* Tr 6* Secondary mean mean VF BIS mean (SD) (SD) (SD)

ALE 10 Frediani 63.0 -2.49 CT 0.5 ALE 10 Secondary NR NR NR PBO mg/d +CT 1998 (6.9) (0.30) µg/d mg/d 0.5 µg/d

60 Freemantle 65.2 -2.02 -1.97 ALE 70 Secondary NR No mg/6m, 2012 (7.6) (0.58) (1.15) mg/wk SC

DEN 60 Galesanu ZOL 5 Secondary NR NR NR NR NR mg/6m, 2017 mg/yr, IV SC

Galesanu 63.3 ALE 70 RIS 35 IBA 150 Secondary NR NR NR NR 2011 (3.1) mg/wk mg/wk mg/m

Gonnelli 59.5 ALE 10 Secondary NR NR NR No PBO 1999 (4.8) mg/d

Greenspan 78.5 ALE 10 Secondary NR NR NR NR PBO 2002 (19.3) mg/d

67.8 -2.07 -2.67 ZOL 5 ALE 70 Hadji 2012 Secondary NR NR (8.0) (0.86) (0.86) mg/yr, IV mg/wk

68.7 -2.60 -2.40 RIS 2.5 RIS 5 Harris 1999 Secondary 80 NR PBO (7.4) (1.10) (1.40) mg/d mg/d

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Age, FN T- LS T- Primary/ years score % Prior Author Year score Tr 1* Tr 2* Tr 3* Tr 4* Tr 5* Tr 6* Secondary mean mean VF BIS mean (SD) (SD) (SD)

61.3 -2.20 -3.30 ALE 70 Ho 2005 Secondary 38 NR PBO (4.8) (0.65) (0.65) mg/wk

Hosking 69.2 ALE 70 RIS 5 Secondary NR NR NR NR PBO 2003 (6.4) mg/wk mg/d

DEN 60 Invernizzi ZOL 5 Secondary NR NR NR NR NR mg/6m, 2013 mg/yr, IN SC

69.3 ETI 200 CAC 20 ALF 1 VIK 45 Ishida 2004 Secondary NR NR NR NR PBO HRT (13.3) mg/d IU/wk µg/d mg/d

ETI 200 Iwamoto 70.7 ALE 5 Secondary NR NR NR No mg/d 2005 (7.2) mg/d (cyclic)

DEN 60 67.6 -2.63 ALE 70 Kendler 2010 Secondary NR NR Yes mg/6m, (7.8) (0.77) mg/wk SC

64.5 -2.35 -3.40 ALE 10 Kung 2000 Secondary NR NR PBO (4.5) (0.61) (0.60) mg/d

74.0 ALE 10 Lau 2000 Secondary NR NR 6 No PBO (0.7) mg/d

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Age, FN T- LS T- Primary/ years score % Prior Author Year score Tr 1* Tr 2* Tr 3* Tr 4* Tr 5* Tr 6* Secondary mean mean VF BIS mean (SD) (SD) (SD)

67.0 -2.60 -3.20 RIS 5 Leung 2005 Secondary 28 NR PBO (6.0) (0.70) (0.50) mg/d

RIS 5 Li 2005 Secondary NR NR NR NR NR PBO mg/d

57.3 ZOL 5 Liang 2017 Secondary NR NR NR NR PBO (3.0) mg/yr, IV

Liberman 64.0 ALE 20→ Secondary NR NR 21 No PBO 1995 (NR) 5 mg/d

ETI 400 72.0 Lyritis 1997 Secondary NR NR 100 NR PBO mg/d (NR) (cyclic)

McClung 77.8 -3.70 RIS 2.5 or Secondary NR NR NR PBO 2001 (5.4) (0.60) 5 mg/d

RIS 35 RIS 35 mg/wk McClung 65.7 -2.95 -3.11 mg/wk Secondary 26 NR RIS 5 mg/d (Before 2012 (7.4) (1.38) (0.56) (After breakfast breakfast) )

Michalska 65.2 ALE 10 RAL 60 Secondary NR NR NR Yes PBO 2006 (6.7) mg/d mg/d

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Age, FN T- LS T- Primary/ years score % Prior Author Year score Tr 1* Tr 2* Tr 3* Tr 4* Tr 5* Tr 6* Secondary mean mean VF BIS mean (SD) (SD) (SD)

DEN 60 69.0 -2.69 ZOL 5 Miller 2016 Secondary NR 100 Yes mg/6m, (7.5) (0.85) mg/yr, IV SC

Nakamura 69.6 -2.33 -2.74 DEN 60 ALE 35 Secondary 98 NR PBO 2014 (7.5) (0.70) (0.90) mg/6m, SC mg/wk

77.6 RIS 2.5 TER 20 Ohtori 2013 Secondary NR NR NR NR PBO (6.0) mg/d μg/d, SC

Paggiosi 67.1 -2.23 ALE 70 IBA 150 RIS 35 Secondary NR 13 NR 2014 (7.2) (0.95) mg/wk mg/m mg/wk

Reginster 71.0 -2.77 RIS 2.5 RIS 5 Secondary NR 100 NR PBO 2000 (7.0) (1.35) mg/d mg/d

64.1 -2.12 -2.64 ALE 70 RIS 35 Reid 2006 Secondary NR NR (8.2) (0.75) (0.87) mg/wk mg/wk

ALE 10 mg/d, 1m 63.0 -2.49 -3.26 ALE 20 Rossini 2000 Secondary 0 NR PBO out of (5.4) (0.51) (0.63) mg/wk 3m, cyclic

DEN 60 67.8 -1.90 -2.20 RIS 150 Roux 2014 Secondary NR Yes* mg/6m, (6.9) (0.70) (1.20) mg/m SC

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Age, FN T- LS T- Primary/ years score % Prior Author Year score Tr 1* Tr 2* Tr 3* Tr 4* Tr 5* Tr 6* Secondary mean mean VF BIS mean (SD) (SD) (SD)

ETI 400 64.1 ALE 5 CLO 100- Russo 1996 Secondary NR NR 0 No mg/d (6.9) mg/d 400 mg/d (cyclic)

ALE 10 ETI 400 68.6 ALE 10 mg/d, 3m CT 250 ng Sahota 2000 Secondary NR NR 100 No mg/d (4.9) mg/d on/off, bid (cyclic) cyclic

Sarioglu 58.8 ALE 70 RIS 5 Secondary NR NR 10 NR 2006 (7.0) mg/wk mg/d

Schnitzer 66.5 ALE 10 ALEBW3 ALE 70 Secondary NR NR 10 No 2000 (NR) mg/d 5 mg/wk

ETI 200 61.7 Shiota 2001 Secondary NR NR 60 NR mg/d PBO (6.9) (cyclic)

ETI 400 68.3 Storm 1990 Secondary NR NR 100 No PBO mg/d (NR) (cyclic)

68.1 ALE 70 ZOL 5 Tan 2016 Secondary NR NR NR NR (8.7) mg/wk mg/yr, IV

ETI 400 ETI 400 65.1 PHO 2 mg/d Watts 1990 Secondary NR NR 100 No PBO mg/d (6.7) g/d +PHO 2 (cyclic) g/d (cyclic)

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Age, FN T- LS T- Primary/ years score % Prior Author Year score Tr 1* Tr 2* Tr 3* Tr 4* Tr 5* Tr 6* Secondary mean mean VF BIS mean (SD) (SD) (SD)

64.9 ALE 70 Yan 2009 Secondary NR NR 0 NR PBO (6.2) mg/wk

60.6 ZOL 5 Yang 2015 Secondary NR NR NR No PBO (9.3) mg/yr, IV

62.8 -1.78 -2.76 RAL 60 ALE 70 RIS 35 Yanik 2008 Secondary NR NR (6.8) (1.03) (0.73) mg/d mg/wk mg/wk

Fukunaga 62.6 -2.97 ETI 200 RIS 2.5 Secondary NR 14 NR 2002 (6.2) (0.44) mg/d mg/d

59.8 -1.62 -2.20 ALE 10 Qin 2007 Secondary NR NR PBO (6.3) (0.80) (0.80) mg/d

ETI 400 60.8 Pacifici 1988 Secondary NR NR 100 NR PBO mg/d HRT (8.2) (cyclic)

DEN 14 DEN 60 Nakamura 65.1 -1.85 -3.08 DEN 100 Secondary 16 NR PBO mg/6m, mg/6m, 2012 (6.8) (0.69) (0.41) mg/6m, SC SC SC

DEN 60 Cummings 72.3 -2.16 -2.83 Secondary 24 NR PBO mg/6m, 2009 (5.2) (0.72) (0.69) SC

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Age, FN T- LS T- Primary/ years score % Prior Author Year score Tr 1* Tr 2* Tr 3* Tr 4* Tr 5* Tr 6* Secondary mean mean VF BIS mean (SD) (SD) (SD)

DEN 60 69.4 Zhu 2017 Secondary NR NR NR NR PBO mg/6m, (0.5) SC

64.3 ZOL 5 Zhang 2019 Secondary NR NR 100 NR PBO (7.1) mg/yr, IV

ZOL 5 Greenspan 85.3 -2.20 Secondary NR 46 NR PBO mg/yr-s, 2015 (5.1) (0.14) IV

EUCTR2008 -001865-28 58.6 ALE 70 Secondary NR -2.49 NR NR PBO (Fogelman) (3.5) mg/wk 2018

NCT0206385 68.9 -2.86 -2.98 RIS 2.5 RIS 25 RIS 37.5 4 (Takeda) Secondary 39 NR (7.5) (0.86) (0.78) mg/d mg/m mg/m 2017

NCT0215794 DEN 60 DEN 60 68.1 -2.75 8 (Amgen) Secondary NR NR NR mg/6m mg/6m (7.0) (0.83) 2017 (CP2), SC (CP4), SC

Activated 55.0 Vitamin ZOL 5 Chao 2013 Secondary NR NR 55 NR (7.4) D3, 0.25 mg/yr, IV mg/yr

Gonnelli 59.6 -3.45 ALE 10 Secondary NR NR No PBO 2002 (5.3) (0.81) mg/d

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Age, FN T- LS T- Primary/ years score % Prior Author Year score Tr 1* Tr 2* Tr 3* Tr 4* Tr 5* Tr 6* Secondary mean mean VF BIS mean (SD) (SD) (SD)

ETI 400 Hu 2005 Secondary NR NR NR NR NR PBO HRT mg/d (cyclic)

Iwamoto 65.2 VIK 45 ETI 200 Secondary NR NR 31 No PBO 2001 (5.9) mg/d mg/d

ETI 400 ALE 10 ALE 10 Köşüş 2005 Secondary 50.0 NR NR NR NR mg/d mg/d mg/d (cyclic) (cyclic)

54.7 ALE 10 CAC 200 Leung 2006 Secondary NR NR NR NR PBO (3.4) mg/d IU/d, IN

MK-677 25 72.1 ALE 10 MK-677 mg/d + Murphy 2001 Secondary NR NR NR No PBO (5.0) mg/d 25 mg/d ALE 10 mg/d

59.3 -1.89 -3.30 ALE 70 QGY 20 Shi 2017 Secondary NR NR PBO (4.5) (0.65) (0.46) mg/wk g/d

ETI 400 ETI 400 Wimalawans 64.9 mg/d Secondary NR NR 49 No PBO mg/d HRT a 1998 (0.5) (cyclic)+HR (cyclic) T

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ALE=Alendronate, RIS=risedronate, CAL=Calcium, VID=vitamin D, PBO=Placebo, CAC= Calcitonin, PTH= Parathyroid hormone, TER= Teriparatide, CEE= Conjugated equine estrogen, DEN= Denosumab, ZOL= Zoledronic acid, HRT= Hormone replace therapy, ALF= Alfacalcidol, DEN= Denosumab, IBA= Ibandronate, ETI= Etidronate, VIK1=vitamin K1, ROM=Romosozumab, CT=Calcitriol, QGY=QiangGuYin, PHO=Phosphate, CLO=Clodronate, PH=Phosphate; NR=not reported † including subcutaneous injection of denosumab 6 mg/3m, 14 mg/3m, 30 mg/3m, 14 mg/6m, 60 mg/6m,100 mg/6m, and 210 mg/6m ‡ including subcutaneous injection of romosuzumab 140 mg/3m, 210 mg/3m, 70 mg/m, 140 mg/m, and 210 mg/

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APPENDIX 11: ANALYSIS RESULTS – BASE CASE, SUBGROUP AND SENSITIVITY ANALYSES FOR PRIMARY PREVENTION POPULATIONS

RADIOGRAPHIC VERTEBRAL FRACTURES

BASE CASE ANALYSIS

FIGURE 3: RADIOGRAPHIC VERTEBRAL FRACTURES, PRIMARY PREVENTION, BASE CASE

TABLE 42 : RADIOGRAPHIC VERTEBRAL FRACTURES, PRIMARY PREVENTION, BASE CASE: ODDS RATIO, RELATIVE RISK, AND RISK DIFFERENCE

Treatment Reference OR (95% CrI) RR (95% CrI) RD (95% Crl) ALED10 PBO 0.57 (0.32, 1.12) 0.60 (0.34, 1.10) -0.05 (-0.09, 0.01) RISD5 PBO 0.96 (0.32, 2.99) 0.96 (0.35, 2.49) -0.004 (-0.09, 0.15) RISD5 ALED10 1.67 (0.46, 6.00) 1.59 (0.49, 4.80) 0.04 (-0.05, 0.20)

Random-Effects Residual Deviance 5.4 vs 6 datapoints Model Deviance Information Criteria 38.501 PBO=placebo (includes no treatment or background supplementation); ALED10=oral alendronate 10 mg/day or 70 mg/week; RISD5=oral risedronate 5 mg/day or 35 mg/week or 150 mg/month.

SENSITIVITY ANALYSIS

FIGURE 4: NETWORK GEOMETRY: RADIOGRAPHIC VERTEBRAL FRACTURES, PRIMARY PREVENTION, SA2- EXCLUDING AGE-DEFINED STUDIES

TABLE 43: RADIOGRAPHIC VERTEBRAL FRACTURES, PRIMARY PREVENTION, SA2- EXCLUDING AGE-DEFINED STUDIES: ODDS RATIO, RELATIVE RISK, AND RISK DIFFERENCE

Treatment Reference OR (95% CrI) RR (95% CrI) RD (95% Crl) ALED10 PBO 0.55 (0.21, 1.53) 0.56 (0.21, 1.49) -0.02 (-0.05, 0.03) RISD5 PBO 0.96 (0.27, 3.41) 0.97 (0.28, 3.07) -0.002 (-0.05, 0.10) RISD5 ALED10 1.77 (0.36, 8.69) 1.72 (0.37, 7.71) 0.02 (-0.04, 0.11)

Random-Effects Residual Deviance 4.069 vs 4 datapoints Model Deviance Information Criteria 27.993 PBO=placebo (includes no treatment or background supplementation); ALED10=oral alendronate 10 mg/day or 70 mg/week; RISD5=oral risedronate 5 mg/day or 35 mg/week or 150 mg/month.

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NON-VERTEBRAL FRACTURES

BASE CASE ANALYSIS

FIGURE 5: NETWORK GEOMETRY: NON-VERTEBRAL FRACTURES, PRIMARY PREVENTION, BASE CASE

TABLE 44: NON-VERTEBRAL FRACTURES, PRIMARY PREVENTION, BASE CASE: ODDS RATIO, RELATIVE RISK AND RISK DIFFERENCE Treatment Reference OR (95% CrI) RR (95% CrI) RD (95% Crl) ALED5 PBO 1.26 (0.58, 2.54) 1.24 (0.60, 2.34) 0.01 (-0.02, 0.07) ALED10 PBO 0.77 (0.46, 1.13) 0.78 (0.48, 1.12) -0.01 (-0.03, 0.01) ETID400 PBO 0.50 (0.13, 1.61) 0.51 (0.14, 1.56) -0.03 (-0.06, 0.03) RISD5 PBO 0.66 (0.21, 2.10) 0.67 (0.22, 1.99) -0.02 (-0.05, 0.05) ZOLS5 PBO 2.13 (0.31, 15.16) 2.00 (0.32, 8.83) 0.06 (-0.04, 0.40) ZOLY5 PBO 0.78 (0.15, 3.82) 0.79 (0.16, 3.34) -0.01 (-0.05, 0.12) ALED10 ALED5 0.61 (0.27, 1.36) 0.63 (0.29, 1.34) -0.03 (-0.09, 0.01) ETID400 ALED5 0.40 (0.09, 1.63) 0.41 (0.10, 1.58) -0.04 (-0.11, 0.03) RISD5 ALED5 0.53 (0.13, 2.10) 0.54 (0.15, 2.01) -0.03 (-0.10, 0.05) ZOLS5 ALED5 1.71 (0.22, 14.32) 1.62 (0.24, 8.64) 0.04 (-0.08, 0.39) ZOLY5 ALED5 0.62 (0.11, 3.80) 0.64 (0.12, 3.32) -0.02 (-0.10, 0.12) ETID400 ALED10 0.65 (0.17, 2.34) 0.66 (0.18, 2.23) -0.01 (-0.05, 0.04) RISD5 ALED10 0.87 (0.25, 3.07) 0.87 (0.26, 2.87) -0.01 (-0.04, 0.07) ZOLS5 ALED10 2.82 (0.39, 20.94) 2.61 (0.40, 12.33) 0.07 (-0.03, 0.41) ZOLY5 ALED10 1.03 (0.19, 5.53) 1.03 (0.20, 4.76) 0.001 (-0.04, 0.14) RISD5 ETID400 1.34 (0.24, 7.44) 1.33 (0.26, 6.92) 0.01 (-0.06, 0.08) ZOLS5 ETID400 4.32 (0.45, 45.78) 3.90 (0.47, 28.45) 0.08 (-0.03, 0.42) ZOLY5 ETID400 1.60 (0.21, 12.68) 1.57 (0.22, 11.03) 0.01 (-0.05, 0.15) ZOLS5 RISD5 3.27 (0.34, 33.02) 2.99 (0.36, 20.35) 0.07 (-0.05, 0.42) ZOLY5 RISD5 1.18 (0.16, 8.30) 1.17 (0.17, 7.16) 0.01 (-0.07, 0.14) ZOLY5 ZOLS5 0.36 (0.03, 4.69) 0.40 (0.04, 4.18) -0.06 (-0.41, 0.10)

Random-Effects Residual Deviance 20.43 vs 23 datapoints Model Deviance Information Criteria 121.765 PBO=placebo (includes no treatment or background supplementation); ALED5=oral alendronate 5 mg/day or 35 mg/week; ALED10=oral alendronate 10 mg/day or 70 mg/week; RISD5=oral risedronate 5 mg/day or 35 mg/week or 150 mg/month; ETID400=oral cyclic etidronate 400 mg/day; ZOLY5=intravenous zoledronic acid 5 mg/year; ZOLS5=intravenous zoledronic acid 5 mg single dose.

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SUBGROUP ANALYSIS

SG 1: DENOSUMAB AND BISPHOSPHONATES

FIGURE 6: NETWORK GEOMETRY: Non-vertebral Fractures, Primary Prevention, SG1-denosumab compared with bisphosphonates

TABLE 45: NON-VERTEBRAL FRACTURES, PRIMARY PREVENTION, SG1- DENOSUMAB COMPARED WITH BISPHOSPHONATES: ODDS RATIOS, RELATIVE RISKS AND RISK DIFFERENCE FOR ALL TREATMENT COMPARISONS-RANDOM EFFECTS MODEL

Treatment Reference OR (95% CrI) RR (95% CrI) RD (95% Crl) ALED5 PBO 1.24 (0.58, 2.53) 1.23 (0.60, 2.34) 0.01 (-0.02, 0.07) ALED10 PBO 0.77 (0.47, 1.13) 0.78 (0.48, 1.12) -0.01 (-0.03, 0.01) ETID400 PBO 0.51 (0.13, 1.66) 0.53 (0.13, 1.61) -0.03 (-0.05, 0.03) RISD5 PBO 0.63 (0.20, 1.90) 0.65 (0.21, 1.81) -0.02 (-0.05, 0.04) ZOLS5 PBO 2.25 (0.36, 16.51) 2.10 (0.38, 9.41) 0.06 (-0.04, 0.41) DENBY60 PBO 0.25 (0.04, 1.19) 0.26 (0.04, 1.18) -0.04 (-0.06, 0.01) ZOLY5 PBO 0.80 (0.16, 4.06) 0.81 (0.17, 3.51) -0.01 (-0.05, 0.13) ALED10 ALED5 0.61 (0.27, 1.40) 0.63 (0.29, 1.38) -0.02 (-0.09, 0.01) ETID400 ALED5 0.41 (0.09, 1.65) 0.43 (0.10, 1.61) -0.04 (-0.10, 0.03) RISD5 ALED5 0.51 (0.13, 2.01) 0.53 (0.15, 1.92) -0.03 (-0.10, 0.04) ZOLS5 ALED5 1.81 (0.26, 15.50) 1.72 (0.28, 9.08) 0.05 (-0.07, 0.40) DENBY60 ALED5 0.20 (0.03, 1.15) 0.21 (0.03, 1.14) -0.05 (-0.11, 0.01) ZOLY5 ALED5 0.65 (0.11, 3.79) 0.66 (0.12, 3.32) -0.02 (-0.09, 0.12)

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Treatment Reference OR (95% CrI) RR (95% CrI) RD (95% Crl) ETID400 ALED10 0.68 (0.16, 2.44) 0.69 (0.16, 2.33) -0.01 (-0.05, 0.04) RISD5 ALED10 0.83 (0.25, 2.79) 0.84 (0.26, 2.63) -0.01 (-0.04, 0.06) ZOLS5 ALED10 2.96 (0.47, 22.90) 2.73 (0.49, 13.19) 0.07 (-0.02, 0.42) DENBY60 ALED10 0.33 (0.04, 1.65) 0.34 (0.05, 1.61) -0.03 (-0.05, 0.02) ZOLY5 ALED10 1.07 (0.20, 5.72) 1.06 (0.21, 4.90) 0.003 (-0.04, 0.14) RISD5 ETID400 1.25 (0.24, 7.20) 1.24 (0.25, 6.74) 0.01 (-0.06, 0.07) ZOLS5 ETID400 4.50 (0.47, 44.62) 4.04 (0.48, 26.26) 0.08 (-0.03, 0.43) DENBY60 ETID400 0.49 (0.05, 3.75) 0.50 (0.06, 3.62) -0.01 (-0.07, 0.04) ZOLY5 ETID400 1.61 (0.21, 13.63) 1.58 (0.22, 11.57) 0.02 (-0.05, 0.15) ZOLS5 RISD5 3.47 (0.42, 36.29) 3.17 (0.44, 21.42) 0.08 (-0.04, 0.43) DENBY60 RISD5 0.40 (0.04, 2.61) 0.41 (0.05, 2.53) -0.02 (-0.08, 0.03) ZOLY5 RISD5 1.26 (0.18, 9.88) 1.25 (0.19, 8.44) 0.01 (-0.06, 0.15) DENBY60 ZOLS5 0.11 (0.01, 1.15) 0.12 (0.01, 1.14) -0.10 (-0.45, 0.004) ZOLY5 ZOLS5 0.37 (0.03, 4.10) 0.40 (0.04, 3.65) -0.06 (-0.42, 0.10) ZOLY5 DENBY60 3.18 (0.36, 40.15) 3.07 (0.37, 35.24) 0.03 (-0.03, 0.17)

Random-Effect Model Residual Deviance 22.38 vs 25 datapoints Deviance 131.897 Information Criteria PBO=placebo (includes no treatment or background supplementation); ALED5=oral alendronate 5 mg/day or 35 mg/week; ALED10=oral alendronate 10 mg/day or 70 mg/week; RISD5=oral risedronate 5 mg/day or 35 mg/week or 150 mg/month; DENBY60= subcutaneous injection of denosumab 60 mg every 6 months; ETID400=oral cyclic etidronate 400 mg/day; ZOLY5=intravenous zoledronic acid 5 mg/year; ZOLS5=intravenous zoledronic acid 5 mg single dose.

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SG2- TREATMENT DURATIONS, 1 YEAR

FIGURE 7: NETWORK GEOMETRY: NON-VERTEBRAL FRACTURES, PRIMARY PREVENTION, SG2- 1 YEAR

TABLE 46: NON-VERTEBRAL FRACTURES, PRIMARY PREVENTION, SG2- 1YEAR: ODDS RATIOS, RELATIVE RISKS AND RISK DIFFERENCE FOR ALL TREATMENT COMPARISONS-RANDOM EFFECTS MODEL

Treatment Reference OR (95% CrI) RR (95% CrI) RD (95% Crl) ALED10 PBO 0.52 (0.22,1.37) 0.53 (0.23,1.35) -0.01 (-0.04,0.01) ZOLY5 PBO 0.38 (0.01,4.89) 0.39 (0.01,4.46) -0.02 (-0.05,0.09) ZOLY5 ALED10 0.72 (0.02,10.86) 0.72 (0.02,9.98) -0.004 (-0.04,0.10)

Random-Effect Residual 5.196 vs 6 datapoints Model Deviance Deviance Information Criteria 28.738 PBO=placebo (includes no treatment or background supplementation); ALED10=oral alendronate 10 mg/day or 70 mg/week; ZOLY5=intravenous zoledronic acid 5 mg/year.

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SG2- TREATMENT DURATIONS, 2 YEARS

FIGURE 8: NETWORK GEOMETRY: NON-VERTEBRAL FRACTURES, PRIMARY PREVENTION, SG2- 2 YEARS

TABLE 47: NON-VERTEBRAL FRACTURES, PRIMARY PREVENTION, SG2- 2 YEARS: ODDS RATIOS, RELATIVE RISKS AND RISK DIFFERENCE FOR ALL TREATMENT COMPARISONS-RANDOM EFFECTS MODEL

Treatment Reference OR (95% CrI) RR (95% CrI) RD (95% Crl) ALED5 PBO 1.58 (0.62,4.08) 1.53 (0.64,3.51) 0.03 (-0.02,0.14) RISD5 PBO 0.64 (0.20,2.03) 0.65 (0.21,1.94) -0.02 (-0.05,0.05) ETID400 PBO 0.51 (0.13,1.69) 0.53 (0.14,1.63) -0.03 (-0.06,0.03) ZOLY5 PBO 0.27 (0.01,2.43) 0.28 (0.02,2.27) -0.04 (-0.07,0.06) ZOLS5 PBO 1.62 (0.20,13.85) 1.56 (0.21,8.56) 0.03 (-0.05,0.36) RISD5 ALED5 0.41 (0.09,1.82) 0.43 (0.11,1.75) -0.05 (-0.17,0.03) ETID400 ALED5 0.32 (0.06,1.50) 0.34 (0.07,1.47) -0.05 (-0.17,0.02) ZOLY5 ALED5 0.17 (0.01,1.80) 0.18 (0.01,1.71) -0.07 (-0.18,0.04) ZOLS5 ALED5 1.01 (0.10,10.45) 1.01 (0.12,6.78) 0.0005 (-0.14,0.33) ETID400 RISD5 0.80 (0.14,4.08) 0.81 (0.15,3.85) -0.01 (-0.08,0.06) ZOLY5 RISD5 0.41 (0.02,4.71) 0.42 (0.02,4.33) -0.02 (-0.09,0.08) ZOLS5 RISD5 2.49 (0.21,29.72) 2.35 (0.23,18.32) 0.05 (-0.06,0.38) ZOLY5 ETID400 0.54 (0.02,7.28) 0.55 (0.02,6.68) -0.01 (-0.07,0.09) ZOLS5 ETID400 3.27 (0.30,37.31) 3.04 (0.32,23.25) 0.06 (-0.04,0.39) ZOLS5 ZOLY5 5.96 (0.30,263.70) 5.39 (0.32,194.90) 0.07 (-0.06,0.40)

Random-Effect Residual 12.31 vs 14 datapoints Model Deviance Deviance Information Criteria 67.748 PBO=placebo (includes no treatment or background supplementation); ALED5=oral alendronate 5 mg/day or 35 mg/week; ALED10=oral alendronate 10 mg/day or 70 mg/week; RISD5=oral risedronate 5 mg/day or 35 mg/week or 150 mg/month; ETID400=oral cyclic etidronate 400 mg/day; ZOLY5=intravenous zoledronic acid 5 mg/year; ZOLS5=intravenous zoledronic acid 5 mg single dose.

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SG2- TREATMENT DURATIONS, 3 YEARS

FIGURE 9: NETWORK GEOMETRY: NON-VERTEBRAL FRACTURES, PRIMARY PREVENTION, SG2- 3 YEARS

TABLE 48: NON-VERTEBRAL FRACTURES, PRIMARY PREVENTION, SG2- 3 YEARS: ODDS RATIOS, RELATIVE RISKS AND RISK DIFFERENCE FOR ALL TREATMENT COMPARISONS-RANDOM EFFECTS MODEL

Treatment Reference OR (95% Crl) RR (95% Crl) RD (95% Crl) ALED5 PBO 0.55 (0.08, 3.05) 0.57 (0.08, 2.77) -0.02 (-0.09, 0.09) ALED10 PBO 0.54 (0.09, 2.87) 0.56 (0.10, 2.63) -0.02 (-0.09, 0.09) ZOLS5 PBO 2.17 (0.32, 17.24) 2.01 (0.35, 10.98) 0.06 (-0.06, 0.37) ALED10 ALED5 0.97 (0.15, 7.77) 0.97 (0.16, 7.10) -0.001 (-0.09, 0.09) ZOLS5 ALED5 4.05 (0.31, 67.86) 3.61 (0.34, 44.63) 0.09 (-0.08, 0.39) ZOLS5 ALED10 4.14 (0.31, 57.06) 3.69 (0.34, 37.90) 0.09 (-0.08, 0.39)

Random-Effect Model Residual Deviance 5.104 vs 6 datapoints Deviance Information Criteria 24.913 PBO=placebo (includes no treatment or background supplementation); ALED5=oral alendronate 5 mg/day or 35 mg/week; ALED10=oral alendronate 10 mg/day or 70 mg/week; ZOLS5=intravenous zoledronic acid 5 mg single dose.

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SG3- PRIOR BISPHOSPHONATE EXPERIENCE, BISPHOSPHONATE-NAÏVE

FIGURE 10: NETWORK GEOMETRY: NON-VERTEBRAL FRACTURES, PRIMARY PREVENTION, SG3- BISPHOSPHONATE-NAÏVE

TABLE 49: NON-VERTEBRAL FRACTURES, PRIMARY PREVENTION, SG3- BISPHOSPHONATE-NAÏVE: ODDS RATIOS, RELATIVE RISKS AND RISK DIFFERENCE FOR ALL TREATMENT COMPARISONS- RANDOM EFFECTS MODEL

Treatment Reference OR (95% Crl) RR (95% Crl) RD (95% Crl) ALED5 PBO 1.29 (0.57, 2.58) 1.27 (0.59, 2.34) 0.02 (-0.03, 0.09) ALED10 PBO 0.87 (0.48, 1.50) 0.88 (0.50, 1.44) -0.01 (-0.04, 0.03) RISD5 PBO 0.76 (0.20, 3.08) 0.78 (0.21, 2.71) -0.02 (-0.06, 0.11) ETID400 PBO 0.51 (0.15, 1.64) 0.53 (0.16, 1.57) -0.03 (-0.07, 0.04) ZOLY5 PBO 0.83 (0.16, 4.14) 0.84 (0.17, 3.43) -0.01 (-0.07, 0.16) ZOLS5 PBO 2.30 (0.32, 16.88) 2.10 (0.34, 8.68) 0.08 (-0.05, 0.46) ALED10 ALED5 0.67 (0.29, 1.72) 0.69 (0.33, 1.65) -0.03 (-0.10, 0.03) RISD5 ALED5 0.59 (0.13, 2.98) 0.61 (0.15, 2.64) -0.03 (-0.12, 0.10) ETID400 ALED5 0.39 (0.10, 1.68) 0.42 (0.11, 1.61) -0.05 (-0.13, 0.03) ZOLY5 ALED5 0.64 (0.11, 3.88) 0.66 (0.12, 3.27) -0.03 (-0.12, 0.15) ZOLS5 ALED5 1.81 (0.23, 14.51) 1.68 (0.25, 7.85) 0.06 (-0.09, 0.44) RISD5 ALED10 0.88 (0.21, 3.93) 0.88 (0.22, 3.43) -0.01 (-0.07, 0.12) ETID400 ALED10 0.59 (0.15, 2.14) 0.61 (0.16, 2.03) -0.02 (-0.08, 0.05) ZOLY5 ALED10 0.96 (0.17, 5.24) 0.97 (0.18, 4.33) -0.002 (-0.07, 0.17) ZOLS5 ALED10 2.68 (0.34, 20.66) 2.42 (0.36, 10.81) 0.09 (-0.05, 0.47) ETID400 RISD5 0.67 (0.11, 3.86) 0.68 (0.12, 3.65) -0.02 (-0.15, 0.06) ZOLY5 RISD5 1.08 (0.12, 9.12) 1.07 (0.14, 7.65) 0.004 (-0.13, 0.18) ZOLS5 RISD5 2.97 (0.28, 35.23) 2.65 (0.31, 19.44) 0.09 (-0.09, 0.48) ZOLY5 ETID400 1.60 (0.21, 13.06) 1.56 (0.22, 10.73) 0.02 (-0.06, 0.19) ZOLS5 ETID400 4.63 (0.49, 46.13) 4.02 (0.51, 25.84) 0.11 (-0.04, 0.49)

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Treatment Reference OR (95% Crl) RR (95% Crl) RD (95% Crl) ZOLS5 ZOLY5 2.85 (0.21, 34.84) 2.54 (0.25, 20.43) 0.09 (-0.13, 0.47)

Random-Effect Residual Deviance 15.54 vs 17 datapoints Model Deviance Information Criteria 93.873 PBO=placebo (includes no treatment or background supplementation); ALED5=oral alendronate 5 mg/day or 35 mg/week; ALED10=oral alendronate 10 mg/day or 70 mg/week; RISD5=oral risedronate 5 mg/day or 35 mg/week or 150 mg/month; ETID400=oral cyclic etidronate 400 mg/day; ZOLY5=intravenous zoledronic acid 5 mg/year; ZOLS5=intravenous zoledronic acid 5 mg single dose.

SENSITIVITY ANALYSIS

SA1- STUDIES WITH HIGH METHODOLOGICAL QUALITY

FIGURE 11: NETWORK GEOMETRY: NON-VERTEBRAL FRACTURES, PRIMARY PREVENTION, SA1- STUDIES WITH HIGH METHODOLOGICAL QUALITY

Treatment Reference OR (95% Crl) RR (95% Crl) RD (95% Crl) ALED5 PBO 1.59 (0.55,4.77) 1.53 (0.57,3.73) 0.04 (-0.03,0.20) ALED10 0.87 (0.36,2.11) 0.88 (0.37,1.95) -0.01 (-0.05,0.07) ZOLY5 0.77 (0.14,4.51) 0.78 (0.15,3.71) -0.02 (-0.08,0.17) ALED10 ALED5 2.04 (0.31,17.86) 1.88 (0.33,9.34) 0.07 (-0.06,0.46) ZOLY5 0.55 (0.13,2.10) 0.58 (0.17,1.97) -0.05 (-0.21,0.06) ZOLY5 ALED10 0.48 (0.06,3.82) 0.51 (0.08,3.21) -0.05 (-0.23,0.14)

Random-Effect Residual Deviance 8.015 vs 8 datapoints Model Deviance Information Criteria 51.812 PBO=placebo (includes no treatment or background supplementation); ALED5=oral alendronate 5 mg/day or 35 mg/week; ALED10=oral alendronate 10 mg/day or 70 mg/week; ZOLY5=intravenous zoledronic acid 5 mg/year.

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SA2- EXCLUDING AGE-DEFINED STUDIES

FIGURE 12: NETWORK GEOMETRY: NON-VERTEBRAL FRACTURES, PRIMARY PREVENTION, SA2- EXCLUDING AGE-DEFINED STUDIES

TABLE 51: NON-VERTEBRAL FRACTURES, PRIMARY PREVENTION SA2- EXCLUDING AGE-DEFINED STUDIES: ODDS RATIOS, RELATIVE RISKS AND RISK DIFFERENCE FOR ALL TREATMENT COMPARISONS-RANDOM EFFECTS MODEL

Treatment Reference OR (95% Crl) RR (95% Crl) RD (95% Crl) ALED5 PBO 0.63 (0.14, 2.56) 0.65 (0.15, 2.35) -0.02 (-0.06, 0.08) ALED10 PBO 0.85 (0.46, 1.42) 0.86 (0.48, 1.39) -0.01 (-0.03, 0.02) RISD5 PBO 0.68 (0.22, 1.95) 0.69 (0.23, 1.86) -0.02 (-0.06, 0.05) ETID400 PBO 0.55 (0.06, 4.61) 0.57 (0.06, 3.88) -0.03 (-0.07, 0.15) ZOLY5 PBO 0.78 (0.15, 3.93) 0.79 (0.16, 3.40) -0.01 (-0.06, 0.13) ZOLS5 PBO 2.17 (0.34, 14.74) 2.03 (0.36, 8.74) 0.06 (-0.04, 0.40) ALED10 ALED5 1.33 (0.32, 6.15) 1.31 (0.35, 5.84) 0.01 (-0.08, 0.05) RISD5 ALED5 1.08 (0.17, 6.82) 1.07 (0.19, 6.37) 0.00 (-0.10, 0.07) ETID400 ALED5 0.87 (0.06, 12.31) 0.88 (0.07, 10.59) 0.00 (-0.11, 0.17) ZOLY5 ALED5 1.23 (0.15, 10.63) 1.22 (0.17, 9.33) 0.01 (-0.09, 0.15) ZOLS5 ALED5 3.42 (0.31, 41.58) 3.09 (0.34, 26.20) 0.08 (-0.07, 0.42) RISD5 ALED10 0.81 (0.23, 2.68) 0.81 (0.24, 2.52) -0.01 (-0.06, 0.06) ETID400 ALED10 0.65 (0.07, 5.88) 0.67 (0.07, 4.90) -0.02 (-0.07, 0.16) ZOLY5 ALED10 0.93 (0.17, 5.14) 0.93 (0.18, 4.37) 0.00 (-0.06, 0.14) ZOLS5 ALED10 2.61 (0.38, 18.90) 2.40 (0.39, 11.27) 0.07 (-0.04, 0.40) ETID400 RISD5 0.82 (0.08, 8.99) 0.83 (0.08, 7.48) -0.01 (-0.08, 0.17) ZOLY5 RISD5 1.17 (0.16, 8.41) 1.16 (0.17, 7.10) 0.01 (-0.07, 0.15) ZOLS5 RISD5 3.22 (0.38, 30.26) 2.93 (0.40, 18.55) 0.08 (-0.04, 0.41) ZOLY5 ETID400 1.39 (0.09, 21.13) 1.36 (0.11, 18.47) 0.01 (-0.17, 0.15)

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Treatment Reference OR (95% Crl) RR (95% Crl) RD (95% Crl) ZOLS5 ETID400 4.11 (0.25, 66.23) 3.64 (0.28, 44.12) 0.08 (-0.11, 0.41) ZOLS5 ZOLY5 2.88 (0.24, 37.20) 2.60 (0.27, 23.59) 0.07 (-0.10, 0.40)

Random-Effect Residual Deviance 14.53 vs 17 datapoints Model Deviance 85.738 Information Criteria PBO=placebo (includes no treatment or background supplementation); ALED5=oral alendronate 5 mg/day or 35 mg/week; ALED10=oral alendronate 10 mg/day or 70 mg/week; RISD5=oral risedronate 5 mg/day or 35 mg/week or 150 mg/month; ETID400=oral cyclic etidronate 400 mg/day; ZOLY5=intravenous zoledronic acid 5 mg/year; ZOLS5=intravenous zoledronic acid 5 mg single dose.

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HIP FRACTURES

BASE CASE ANALYSIS

FIGURE 13: HIP FRACTURES, PRIMARY PREVENTION, BASE CASE

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WRIST FRACTURES

BASE CASE ANALYSIS

FIGURE 14: NETWORK GEOMETRY: WRIST FRACTURE, PRIMARY PREVENTION, BASE CASE

TABLE 52: WRIST FRACTURE, PRIMARY PREVENTION, BASE CASE: ODDS RATIO, RELATIVE RISK AND RISK DIFFERENCE Treatment Reference OR (95% CrI) RR (95% CrI) RD (95% Crl) ALED10 PBO 1.01 (0.45, 2.44) 1.01 (0.45, 2.39) 0.0002 (-0.01, 0.02) RISD5 PBO 0.46 (0.02, 9.62) 0.46 (0.02, 8.73) -0.01 (-0.03, 0.09) RISD5 ALED10 0.45 (0.02, 10.51) 0.46 (0.02, 9.61) -0.01 (-0.04, 0.09)

Random-Effects Residual 11.79 vs 8 datapoints Model Deviance Deviance Information Criteria 46.115 PBO=placebo (includes no treatment or background supplementation); ALED10=oral alendronate 10 mg/day or 70 mg/week; RISD5=oral risedronate 5 mg/day or 35 mg/week or 150 mg/month.

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SENSITIVITY ANALYSIS

SA2- EXCLUDING AGE-DEFINED STUDIES

FIGURE 15: NETWORK GEOMETRY: WRIST FRACTURES, PRIMARY PREVENTION, SA2- EXCLUDING AGE-DEFINED STUDIES

TABLE 53: WRIST FRACTURES, PRIMARY PREVENTION, SA2- EXCLUDING AGE-DEFINED STUDIES: ODDS RATIOS, RELATIVE RISKS AND RISK DIFFERENCE FOR ALL TREATMENT COMPARISONS- RANDOM EFFECTS MODEL

Treatment Reference OR (95% CrI) RR (95% CrI) RD (95% Crl) ALED10 PBO 1.19 (0.45,3.04) 1.18 (0.46,2.90) 0.003 (-0.01,0.05) RISD5 PBO 0.40 (0.02,8.25) 0.40 (0.02,7.76) -0.01 (-0.04,0.06) RISD5 ALED10 0.33 (0.01,8.11) 0.34 (0.01,7.52) -0.02 (-0.07,0.06)

Random-Effect Residual 3.799 vs 4 datapoints Model Deviance Deviance Information Criteria 23.893 PBO=placebo (includes no treatment or background supplementation); ALED10=oral alendronate 10 mg/day or 70 mg/week; RISD5=oral risedronate 5 mg/day or 35 mg/week or 150 mg/month.

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WITHDRAWAL DUE TO ADVERSE EVENTS

BASE CASE ANALYSIS

FIGURE 16: NETWORK GEOMETRY: WITHDRAWAL DUE TO ADVERSE EVENTS, PRIMARY PREVENTION, BASE CASE

TABLE 54: WITHDRAWAL DUE TO ADVERSE EVENTS, PRIMARY PREVENTION (BASE CASE): ODDS RATIO, RELATIVE RISK AND RISK DIFFERENCE Treatment Reference OR (95% CrI) RR (95% CrI) RD (95% Crl) ALED5 PBO 1.38 (0.77,2.36) 1.35 (0.78,2.22) 0.02 (-0.01,0.06) ALED10 0.87 (0.61,1.16) 0.88 (0.63,1.15) -0.01 (-0.02,0.01) RISD5 0.75 (0.44,1.19) 0.76 (0.46,1.18) -0.01 (-0.03,0.01) ETID400 1.49 (0.78,2.98) 1.46 (0.79,2.75) 0.02 (-0.01,0.07) ZOLY5 2.39 (0.67,10.58) 2.24 (0.68,7.36) 0.06 (-0.02,0.29) ZOLS5 0.66 (0.03,10.39) 0.67 (0.03,7.33) -0.02 (-0.05,0.28) ALED10 ALED5 0.63 (0.34,1.17) 0.65 (0.36,1.16) -0.02 (-0.07,0.01) RISD5 0.55 (0.26,1.13) 0.57 (0.28,1.12) -0.03 (-0.07,0.005) ETID400 1.09 (0.47,2.72) 1.08 (0.49,2.54) 0.01 (-0.05,0.07) ZOLY5 1.75 (0.43,8.57) 1.67 (0.45,6.25) 0.04 (-0.05,0.27) ZOLS5 0.48 (0.02,7.85) 0.50 (0.02,5.65) -0.03 (-0.09,0.26) RISD5 ALED10 0.86 (0.53,1.40) 0.87 (0.54,1.37) -0.01 (-0.02,0.01) ETID400 1.70 (0.84,3.68) 1.65 (0.85,3.37) 0.03 (-0.01,0.08) ZOLY5 2.74 (0.77,12.19) 2.55 (0.78,8.44) 0.06 (-0.01,0.30) ZOLS5 0.76 (0.03,12.05) 0.77 (0.03,8.44) -0.01 (-0.05,0.29) ETID400 RISD5 1.99 (0.91,4.76) 1.92 (0.92,4.36) 0.03 (-0.004,0.09) ZOLY5 3.20 (0.84,14.51) 2.97 (0.85,10.21) 0.07 (-0.01,0.30) ZOLS5 0.89 (0.04,14.73) 0.89 (0.04,10.29) -0.004 (-0.04,0.29) ZOLY5 ETID400 1.63 (0.36,7.94) 1.56 (0.38,5.79) 0.04 (-0.06,0.27) ZOLS5 0.45 (0.02,7.22) 0.47 (0.02,5.12) -0.03 (-0.10,0.26) ZOLS5 ZOLY5 0.27 (0.01,5.78) 0.30 (0.01,4.42) -0.07 (-0.30,0.23)

Random-Effects 59.13 vs 55 Model datapoints 59.13 vs 55 datapoints Deviance Information Criteria 261.465 PBO=placebo (includes no treatment or background supplementation); ALED5=oral alendronate 5 mg/day or 35 mg/week; ALED10=oral alendronate 10 mg/day or 70 mg/week; RISD5=oral risedronate 5 mg/day or 35 mg/week or 150 mg/month; ETID400=oral cyclic etidronate 400 mg/day; ZOLY5=intravenous zoledronic acid 5 mg/year, ZOLS5=single intravenous injection of zoledronic acid 5 mg.

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FIGURE16-1: CONSISTENCY PLOT FOR WITHDRAWAL DUE TO ADVERSE EVENTS, PRIMARY PREVENTION, BASE CASE

4.5 4 3.5 3 2.5 2 1.5

InconsistencyModel 1 0.5 0 0 1 2 3 4 5 Consistency Model

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SERIOUS ADVERSE EVENTS

BASE CASE ANALYSIS

FIGURE 17: NETWORK GEOMETRY: SERIOUS ADVERSE EVENTS, PRIMARY PREVENTION, BASE CASE

TABLE 55: SERIOUS ADVERSE EVENTS, PRIMARY PREVENTION, BASE CASE: ODDS RATIO, RELATIVE RISK AND RISK DIFFERENCE

Treatment Reference OR (95% CrI) RR (95% CrI) RD (95% Crl) ALED5 PBO 1.10 (0.64,1.80) 1.09 (0.67,1.69) 0.01 (-0.03,0.06) ALED10 0.98 (0.70,1.35) 0.98 (0.72,1.31) -0.002 (-0.03,0.02) RISD5 0.93 (0.58,1.50) 0.94 (0.60,1.45) -0.01 (-0.04,0.04) ETID400 0.86 (0.46,1.66) 0.87 (0.48,1.58) -0.01 (-0.05,0.04) ZOLY5 0.87 (0.48,1.52) 0.88 (0.50,1.46) -0.01 (-0.04,0.04) ZOLS5 0.94 (0.44,1.88) 0.94 (0.46,1.76) -0.005 (-0.05,0.06) ALED10 ALED5 0.89 (0.51,1.60) 0.90 (0.54,1.54) -0.01 (-0.06,0.03) RISD5 0.85 (0.44,1.72) 0.86 (0.47,1.64) -0.01 (-0.07,0.04) ETID400 0.79 (0.35,1.77) 0.81 (0.38,1.69) -0.02 (-0.08,0.04) ZOLY5 0.80 (0.38,1.68) 0.81 (0.41,1.60) -0.02 (-0.08,0.04) ZOLS5 0.85 (0.34,2.05) 0.86 (0.37,1.91) -0.01 (-0.08,0.06) RISD5 ALED10 0.95 (0.60,1.49) 0.96 (0.62,1.44) -0.003 (-0.03,0.03) ETID400 0.88 (0.44,1.82) 0.89 (0.46,1.73) -0.01 (-0.05,0.05) ZOLY5 0.90 (0.48,1.60) 0.90 (0.50,1.54) -0.01 (-0.05,0.04) ZOLS5 0.96 (0.43,2.00) 0.96 (0.46,1.87) -0.003 (-0.05,0.06) ETID400 RISD5 0.93 (0.43,2.05) 0.93 (0.45,1.93) -0.01 (-0.06,0.05) ZOLY5 0.94 (0.45,1.87) 0.94 (0.48,1.77) -0.004 (-0.05,0.05) ZOLS5 1.00 (0.43,2.32) 1.00 (0.45,2.14) -0.00005 (-0.05,0.07) ZOLY5 ETID400 1.02 (0.43,2.32) 1.01 (0.46,2.18) 0.001 (-0.06,0.06) ZOLS5 1.08 (0.41,2.76) 1.07 (0.44,2.53) 0.01 (-0.06,0.08) ZOLS5 ZOLY5 1.07 (0.50,2.21) 1.06 (0.52,2.07) 0.004 (-0.04,0.07)

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Random-Effects Residual 36.37 vs 40 datapoints Model Deviance Deviance Information Criteria 214.253 PBO=placebo (includes no treatment or background supplementation); ALED5=oral alendronate 5 mg/day or 35 mg/week; ALED10=oral alendronate 10 mg/day or 70 mg/week; RISD5=oral risedronate 5 mg/day or 35 mg/week or 150 mg/month; ETID400=oral cyclic etidronate 400 mg/day; ZOLY5=intravenous zoledronic acid 5 mg/year.

FIGURE 17-1: CONSISTENCY PLOT FOR SERIOUS ADVERSE EVENTS, PRIMARY PREVENTION, BASE CASE

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GASTROINTESTINAL ADVERSE EVENTS

BASE CASE ANALYSIS

FIGURE 18: NETWORK GEOMETRY: GASTROINTESTINAL ADVERSE EVENTS, PRIMARY PREVENTION, BASE CASE

TABLE 56: GASTROINTESTINAL ADVERSE EVENTS, PRIMARY PREVENTION, BASE CASE: ODDS RATIO, RELATIVE RISK AND RISK DIFFERENCE

Treatment Reference OR (95% CrI) RR (95% CrI) RD (95% Crl) ALED5 PBO 0.87 (0.61, 1.16) 0.90 (0.68, 1.12) -0.03 (-0.08, 0.03) ALED10 1.05 (0.87, 1.27) 1.04 (0.90, 1.19) 0.01 (-0.03, 0.05) RISD5 0.95 (0.67, 1.34) 0.96 (0.73, 1.24) -0.01 (-0.07, 0.06) ETID400 0.47 (0.18, 1.18) 0.55 (0.23, 1.13) -0.11 (-0.20, 0.03) ALED10 ALED5 1.21 (0.87, 1.77) 1.15 (0.90, 1.55) 0.03 (-0.03, 0.10) RISD5 1.09 (0.70, 1.78) 1.07 (0.76, 1.55) 0.02 (-0.06, 0.10) ETID400 0.54 (0.20, 1.46) 0.61 (0.25, 1.33) -0.09 (-0.19, 0.07) RISD5 ALED10 0.91 (0.64, 1.27) 0.93 (0.71, 1.19) -0.02 (-0.08, 0.05) ETID400 0.45 (0.17, 1.14) 0.53 (0.22, 1.10) -0.12 (-0.22, 0.02) ETID400 RISD5 0.50 (0.18, 1.32) 0.57 (0.23, 1.23) -0.11 (-0.21, 0.05)

Random-Effects Residual Deviance 25.5 vs 27 datapoints Model Deviance Information Criteria 181.388 PBO=placebo (includes no treatment or background supplementation); ALED5=oral alendronate 5 mg/day or 35 mg/week; ALED10=oral alendronate 10 mg/day or 70 mg/week; RISD5=oral risedronate 5 mg/day or 35 mg/week or 150 mg/month.

FIGURE 18-1: CONSISTENCY PLOT FOR GASTROINTESTINAL ADVERSE EVENTS, PRIMARY PREVENTION, BASE CASE

0 0 1 2 3

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APPENDIX 12: RESULTS – BASE CASE, SUBGROUP AND SENSITIVITY ANALYSES FOR SECONDARY PREVENTION POPULATIONS

RADIOGRAPHIC VERTEBRAL FRACTURES

BASE CASE ANALYSIS

FIGURE 19: NETWORK GEOMETRY: RADIOGRAPHIC VERTEBRAL FRACTURES, SECONDARY PREVENTION, BASE CASE

TABLE 57: RADIOGRAPHIC VERTEBRAL FRACTURES, SECONDARY PREVENTION, BASE CASE: ODDS RATIO, RELATIVE RISK, AND RISK DIFFERENCE

Treatment Reference OR (95% CrI) RR (95% CrI) RD (95% Crl) ALED5 PBO 0.53 (0.31, 0.88) 0.56 (0.33, 0.89) -0.04 (-0.07, -0.01) ALED10 0.47 (0.30, 0.68) 0.49 (0.33, 0.70) -0.05 (-0.07, -0.03) RISD5 0.55 (0.40, 0.76) 0.58 (0.42, 0.78) -0.04 (-0.06, -0.02) ETID400 0.38 (0.14, 0.89) 0.41 (0.16, 0.90) -0.06 (-0.09, -0.01) ZOLY5 0.30 (0.21, 0.47) 0.32 (0.22, 0.49) -0.07 (-0.08, -0.05) ZOLS5 0.71 (0.23, 2.21) 0.73 (0.25, 1.98) -0.03 (-0.08, 0.09) ALED10 ALED5 0.88 (0.47, 1.65) 0.88 (0.49, 1.62) -0.01 (-0.04, 0.02) RISD5 1.04 (0.57, 1.96) 1.04 (0.59, 1.90) 0.002 (-0.03, 0.03) ETID400 0.72 (0.24, 2.00) 0.73 (0.25, 1.92) -0.01 (-0.06, 0.04) ZOLY5 0.56 (0.30, 1.13) 0.57 (0.32, 1.13) -0.02 (-0.06, 0.00) ZOLS5 1.34 (0.38, 4.79) 1.32 (0.39, 4.14) 0.02 (-0.04, 0.14) RISD5 ALED10 1.18 (0.71, 2.02) 1.17 (0.73, 1.95) 0.01 (-0.02, 0.03) ETID400 0.82 (0.28, 2.12) 0.82 (0.30, 2.03) -0.01 (-0.04, 0.04)

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ZOLY5 0.63 (0.38, 1.21) 0.64 (0.39, 1.20) -0.02 (-0.04, 0.01) ZOLS5 1.53 (0.46, 5.27) 1.49 (0.48, 4.47) 0.02 (-0.03, 0.15) ETID400 RISD5 0.69 (0.25, 1.71) 0.70 (0.26, 1.65) -0.02 (-0.05, 0.03) ZOLY5 0.54 (0.33, 0.95) 0.55 (0.35, 0.95) -0.02 (-0.05, 0.00) ZOLS5 1.29 (0.39, 4.20) 1.27 (0.41, 3.62) 0.02 (-0.04, 0.13) ZOLY5 ETID400 0.78 (0.31, 2.26) 0.79 (0.33, 2.22) -0.01 (-0.05, 0.02) ZOLS5 1.87 (0.42, 9.05) 1.81 (0.44, 7.77) 0.03 (-0.04, 0.15) ZOLS5 ZOLY5 2.40 (0.71, 7.78) 2.30 (0.72, 6.55) 0.04 (-0.01, 0.16)

Random- Residual 22.12 vs 31 datapoints Effects Model Deviance Deviance Information Criteria 162.558 PBO=placebo (includes no treatment or background supplementation); ALED5=oral alendronate 5 mg/day or 35 mg/week; ALED10=oral alendronate 10 mg/day or 70 mg/week; RISD5=oral risedronate 5 mg/day or 35 mg/week or 150 mg/month; ETID400=oral cyclic etidronate 400 mg/day; ZOLY5=intravenous zoledronic acid 5 mg/year; ZOLS5=intravenous zoledronic acid 5 mg single dose.

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SUBGROUP ANALYSIS

SG1- DENOSUMAB COMPARED WITH BISPHOSPHONATES

FIGURE 20: NETWORK GEOMETRY: RADIOGRAPHIC VERTEBRAL FRACTURES, SECONDARY PREVENTION, SG1-DENOSUMAB COMPARED WITH BISPHOSPHONATES

Treatment Reference OR (95% CrI) RR (95% CrI) RD (95% Crl) ALED5 PBO 0.56(0.32,0.92) 0.58(0.34,0.92) -0.04(-0.06,-0.01) ALED10 0.46(0.31,0.67) 0.49(0.33,0.69) -0.05(-0.06,-0.03) RISD5 0.55(0.40,0.76) 0.58(0.42,0.77) -0.04(-0.05,-0.02) ETID400 0.38(0.16,0.85) 0.40(0.17,0.86) -0.05(-0.08,-0.01) ZOLY5 0.29(0.21,0.46) 0.31(0.22,0.48) -0.06(-0.08,-0.04) ZOLS5 0.71(0.22,2.15) 0.73(0.24,1.95) -0.02(-0.07,0.08) DENBY60 0.29(0.20,0.40) 0.31(0.21,0.43) -0.06(-0.08,-0.05) ALED10 ALED5 0.83(0.44,1.61) 0.84(0.46,1.57) -0.01(-0.04,0.02) RISD5 0.99(0.55,1.90) 0.99(0.57,1.85) -0.0004(-0.03,0.03) ETID400 0.68(0.24,1.81) 0.69(0.26,1.75) -0.02(-0.06,0.03) ZOLY5 0.53(0.29,1.06) 0.54(0.30,1.06) -0.02(-0.06,0.002) ZOLS5 1.28(0.36,4.50) 1.26(0.38,3.93) 0.01(-0.04,0.12) DENBY60 0.52(0.29,0.96) 0.53(0.30,0.97) -0.02(-0.06,-0.001) RISD5 ALED10 1.20(0.73,2.00) 1.19(0.75,1.94) 0.01(-0.01,0.03) ETID400 0.82(0.31,2.03) 0.83(0.33,1.95) -0.01(-0.04,0.04) ZOLY5 0.64(0.38,1.18) 0.65(0.40,1.17) -0.02(-0.04,0.01) ZOLS5 1.53(0.47,5.02) 1.50(0.48,4.35) 0.02(-0.03,0.13) DENBY60 0.63(0.37,1.06) 0.64(0.38,1.06) -0.02(-0.04,0.002) ETID400 RISD5 0.68(0.27,1.66) 0.69(0.28,1.61) -0.02(-0.05,0.03)

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ZOLY5 0.53(0.33,0.91) 0.55(0.35,0.92) -0.02(-0.04,-0.004) ZOLS5 1.29(0.39,4.06) 1.27(0.40,3.54) 0.01(-0.04,0.12) DENBY60 0.52(0.32,0.83) 0.54(0.33,0.84) -0.02(-0.04,-0.01) ZOLY5 ETID40 0.79(0.32,2.04) 0.79(0.34,2.01) -0.01(-0.05,0.02) ZOLS5 1.93(0.46,7.84) 1.86(0.48,6.84) 0.03(-0.03,0.14) DENBY60 0.77(0.31,1.94) 0.77(0.33,1.91) -0.01(-0.05,0.02) ZOLS5 ZOLY5 2.40(0.72,7.60) 2.31(0.73,6.52) 0.04(-0.01,0.14) DENBY60 0.99(0.54,1.59) 0.99(0.55,1.57) -0.0003(-0.02,0.01) DENBY60 ZOLS5 0.41(0.13,1.38) 0.43(0.15,1.37) -0.04(-0.14,0.01)

Random-Effect Residual 25.47 vs 30 datapoints Model Deviance Deviance Information Criteria 183.968 PBO=placebo (includes no treatment or background supplementation); ALED5=oral alendronate 5 mg/day or 35 mg/week; ALED10=oral alendronate 10 mg/day or 70 mg/week; RISD5=oral risedronate 5 mg/day or 35 mg/week or 150 mg/month; DENBY60= subcutaneous injection of denosumab 60 mg every 6 months; ETID400=oral cyclic etidronate 400 mg/day; ZOLY5=intravenous zoledronic acid 5 mg/year; ZOLS5=intravenous zoledronic acid 5 mg single dose.

FIGURE 20-1 CONSISTENCY PLOT FOR RADIOGRAPHIC VERTEBRAL FRACTURES, SECONDARY PREVENTION, SG1-DENOSUMAB COMPARED WITH BISPHOSPHONATES

1.5

0.5

0 0 0.5 1 1.5 2

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SG2- TREATMENT DURATIONS, 1 YEAR

FIGURE 21: NETWORK GEOMETRY: RADIOGRAPHIC VERTEBRAL FRACTURES, SECONDARY PREVENTION, SG2-1 YEAR

TABLE 59: RADIOGRAPHIC VERTEBRAL FRACTURES, SECONDARY PREVENTION, SG2- 1 YEAR: ODDS RATIO, RELATIVE RISK, AND RISK DIFFERENCE

Treatment Reference OR (95% Crl) RR (95% Crl) RD (95% Crl) ALED5 PBO 0.53 (0.27, 1.03) 0.55 (0.29, 1.02) -0.03 (-0.06, 0.002) ETID400 0.11 (0.01, 0.85) 0.12 (0.01, 0.85) -0.07 (-0.09, -0.01) RISD5 0.37 (0.21, 0.68) 0.39 (0.22, 0.69) -0.05 (-0.06, -0.02) ZOLY5 0.39 (0.19, 0.81) 0.41 (0.21, 0.82) -0.04 (-0.06, -0.01) ETID400 ALED5 0.22 (0.01, 1.81) 0.22 (0.01, 1.76) -0.03 (-0.07, 0.02) RISD5 0.71 (0.30, 1.71) 0.72 (0.31, 1.68) -0.01 (-0.05, 0.02) ZOLY5 0.74 (0.28, 1.96) 0.75 (0.30, 1.91) -0.01 (-0.05, 0.03) RISD5 ETID400 3.28 (0.40, 61.14) 3.21 (0.42, 58.95) 0.02 (-0.03, 0.04) ZOLY5 3.45 (0.41, 67.18) 3.36 (0.43, 64.30) 0.02 (-0.03, 0.05) ZOLY5 RISD5 1.04 (0.41, 2.63) 1.04 (0.42, 2.54) 0.001 (-0.03, 0.03)

Random-Effect Model Residual Deviance 9.392 vs 10 datapoints Deviance Information Criteria 70.382 PBO=placebo (includes no treatment or background supplementation); ALED5=oral alendronate 5 mg/day or 35 mg/week; ALED10=oral alendronate 10 mg/day or 70 mg/week; RISD5=oral risedronate 5 mg/day or 35 mg/week or 150 mg/month; ETID400=oral cyclic etidronate 400 mg/day; ZOLY5=intravenous zoledronic acid 5 mg/year.

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SG2- TREATMENT DURATIONS, 2 YEARS

FIGURE 22: NETWORK GEOMETRY: RADIOGRAPHIC VERTEBRAL FRACTURES, SECONDARY PREVENTION, SG2-2 YEARS

TABLE 60: RADIOGRAPHIC VERTEBRAL FRACTURES, SECONDARY PREVENTION, SG2- 2 YEARS: ODDS RATIO, RELATIVE RISK, AND RISK DIFFERENCE

Treatment Reference OR (95% Crl) RR (95% Crl) RD (95% Crl) ALED5 PBO 0.56 (0.26, 1.18) 0.58 (0.28, 1.17) -0.03 (-0.06, 0.01) ALED10 0.36 (0.17, 0.71) 0.38 (0.18, 0.72) -0.05 (-0.07, -0.02) ETID400 0.26 (0.09, 0.67) 0.28 (0.10, 0.69) -0.06 (-0.08, -0.02) RISD5 0.47 (0.15, 1.36) 0.49 (0.16, 1.32) -0.04 (-0.07, 0.03) ZOLY5 0.55 (0.16, 1.79) 0.57 (0.18, 1.69) -0.03 (-0.07, 0.05) ZOLS5 0.72 (0.2, 2.58) 0.74 (0.21, 2.29) -0.02 (-0.07, 0.10) ALED10 ALED5 0.64 (0.22, 1.74) 0.65 (0.24, 1.71) -0.02 (-0.07, 0.02) ETID400 0.47 (0.13, 1.58) 0.48 (0.14, 1.55) -0.02 (-0.07, 0.02) RISD5 0.83 (0.22, 3.12) 0.84 (0.24, 2.92) -0.01 (-0.06, 0.06) ZOLY5 0.99 (0.24, 3.96) 0.99 (0.26, 3.59) -0.0003 (-0.06, 0.09) ZOLS5 1.3 (0.28, 5.78) 1.28 (0.30, 4.97) 0.01 (-0.05, 0.14) ETID400 ALED10 0.73 (0.21, 2.45) 0.74 (0.22, 2.37) -0.01 (-0.04, 0.03) RISD5 1.3 (0.36, 4.86) 1.29 (0.37, 4.46) 0.01 (-0.03, 0.08) ZOLY5 1.55 (0.4, 6.21) 1.52 (0.41, 5.60) 0.02 (-0.03, 0.11) ZOLS5 2.03 (0.48, 8.82) 1.96 (0.49, 7.52) 0.03 (-0.02, 0.15) RISD5 ETID400 1.8 (0.42, 8.08) 1.77 (0.43, 7.46) 0.02 (-0.03, 0.09) ZOLY5 2.14 (0.48, 10.30) 2.09 (0.49, 9.20) 0.02 (-0.02, 0.11) ZOLS5 2.78 (0.53, 14.14) 2.67 (0.54, 12.14) 0.04 (-0.02, 0.16) ZOLY5 RISD5 1.18 (0.23, 6.06) 1.17 (0.24, 5.51) 0.01 (-0.07, 0.10) ZOLS5 1.53 (0.28, 8.40) 1.49 (0.30, 7.27) 0.02 (-0.06, 0.14) ZOLS5 ZOLY5 1.28 (0.22, 7.74) 1.26 (0.25, 6.68) 0.01 (-0.09, 0.14)

Random-Effect Model Residual Deviance 16.49 vs 18 datapoints Deviance Information Criteria 101.371 PBO=placebo (includes no treatment or background supplementation); ALED5=oral alendronate 5 mg/day or 35 mg/week; ALED10=oral alendronate 10 mg/day or 70 mg/week; RISD5=oral risedronate 5 mg/day or 35 mg/week or 150 mg/month; ETID400=oral cyclic etidronate 400 mg/day; ZOLY5=intravenous zoledronic acid 5 mg/year; ZOLS5=intravenous zoledronic acid 5 mg single dose.

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SG2- TREATMENT DURATIONS, 3 YEARS

FIGURE 23: NETWORK GEOMETRY: RADIOGRAPHIC VERTEBRAL FRACTURES, SECONDARY PREVENTION, SG2-3 YEARS

TABLE 61: RADIOGRAPHIC VERTEBRAL FRACTURES, SECONDARY PREVENTION, SG2- 3 YEARS: ODDS RATIO, RELATIVE RISK, AND RISK DIFFERENCE

Treatment Reference OR (95% CrI) RR (95% CrI) RD (95% Crl) ALED5 PBO 0.46 (0.16, 1.20) 0.50 (0.18, 1.17) -0.08 (-0.13, 0.02) ALED10 0.47 (0.29, 0.74) 0.51 (0.32, 0.77) -0.07 (-0.11, -0.03) ETID400 0.21 (0.05, 0.76) 0.24 (0.06, 0.78) -0.12 (-0.15, -0.03) RISD5 0.56 (0.37, 0.86) 0.60 (0.41, 0.88) -0.06 (-0.09, -0.02) ZOLY5 0.28 (0.17, 0.47) 0.31 (0.19, 0.51) -0.10 (-0.13, -0.07) ALED10 ALED5 1.02 (0.37, 3.08) 1.01 (0.41, 2.88) 0.001 (-0.10, 0.06) ETID400 0.46 (0.08, 2.43) 0.48 (0.09, 2.28) -0.04 (-0.14, 0.05) RISD5 1.22 (0.43, 3.89) 1.20 (0.48, 3.59) 0.02 (-0.09, 0.08) ZOLY5 0.60 (0.20, 1.98) 0.62 (0.23, 1.93) -0.03 (-0.13, 0.03) ETID400 ALED10 0.44 (0.10, 1.77) 0.46 (0.11, 1.69) -0.04 (-0.09, 0.04) RISD5 1.20 (0.65, 2.31) 1.18 (0.68, 2.15) 0.01 (-0.03, 0.06) ZOLY5 0.59 (0.30, 1.24) 0.61 (0.32, 1.22) -0.03 (-0.07, 0.01) RISD5 ETID400 2.70 (0.69, 12.07) 2.53 (0.72, 10.83) 0.05 (-0.03, 0.11) ZOLY5 1.33 (0.33, 6.17) 1.31 (0.36, 5.86) 0.01 (-0.07, 0.05) ZOLY5 RISD5 0.49 (0.25, 0.96) 0.52 (0.28, 0.96) -0.04 (-0.09, -0.003)

Random-Effect Model Residual Deviance 11.8 vs 13 datapoints Deviance Information Criteria 92.708 PBO=placebo (includes no treatment or background supplementation); ALED5=oral alendronate 5 mg/day or 35 mg/week; ALED10=oral alendronate 10 mg/day or 70 mg/week; RISD5=oral risedronate 5 mg/day or 35 mg/week or 150 mg/month; ETID400=oral cyclic etidronate 400 mg/day; ZOLY5=intravenous zoledronic acid 5 mg/year.

TECHNOLOGY REVIEW Drugs for the Treatment and Prevention of Osteoporosis in Postmenopausal Women 274

SG3- PRIOR BISPHOSPHONATE EXPERIENCE, BISPHOSPHONATE-NAÏVE

FIGURE 24: NETWORK GEOMETRY: RADIOGRAPHIC VERTEBRAL FRACTURES, SECONDARY PREVENTION, SG3- BISPHOSPHONATE-NAÏVE

TABLE 62: RADIOGRAPHIC VERTEBRAL FRACTURES, SECONDARY PREVENTION, SG3- BISPHOSPHONATE-NAÏVE: ODDS RATIO, RELATIVE RISK, AND RISK DIFFERENCE

Treatment Reference OR (95% CrI) RR (95% CrI) RD (95% Crl) ALED5 PBO 0.52 (0.22, 1.16) 0.54 (0.24, 1.15) -0.04 (-0.07, 0.01) ALED10 0.46 (0.26, 0.74) 0.49 (0.28, 0.76) -0.04 (-0.07, -0.02) RISD5 0.52 (0.27, 1.04) 0.55 (0.29, 1.04) -0.04 (-0.07, 0.003) ETID400 0.42 (0.11, 1.43) 0.44 (0.12, 1.38) -0.05 (-0.08, 0.03) ALED10 ALED5 0.89 (0.35, 2.17) 0.89 (0.37, 2.11) -0.005 (-0.05, 0.03) RISD5 1.00 (0.36, 3.01) 1.00 (0.38, 2.86) 0.0001 (-0.05, 0.05) ETID400 0.81 (0.18, 3.49) 0.82 (0.19, 3.25) -0.01 (-0.07, 0.07) RISD5 ALED10 1.13 (0.51, 2.85) 1.12 (0.52, 2.69) 0.005 (-0.03, 0.05) ETID400 0.92 (0.23, 3.54) 0.92 (0.24, 3.28) -0.003 (-0.04, 0.07) ETID400 RISD5 0.80 (0.19, 3.22) 0.81 (0.20, 3.00) -0.01 (-0.06, 0.07)

Random-Effect Model Residual Deviance 10.69 vs 13 datapoints Deviance Information Criteria 75.394 PBO=placebo (includes no treatment or background supplementation); ALED5=oral alendronate 5 mg/day or 35 mg/week; ALED10=oral alendronate 10 mg/day or 70 mg/week; RISD5=oral risedronate 5 mg/day or 35 mg/week or 150 mg/month; ETID400=oral cyclic etidronate 400 mg/day.

TECHNOLOGY REVIEW Drugs for the Treatment and Prevention of Osteoporosis in Postmenopausal Women 275

SENSITIVITY ANALYSIS

SA3-STUDIES RE-DEFINED USING CAROC CALCULATOR, MODERATE LEVEL OF 10-YEAR FRACTURE RISK FIGURE 25: NETWORK GEOMETRY: RADIOGRAPHIC VERTEBRAL FRACTURES, SA3 CAROC- MODERATE 10-YEAR fracture risk

TABLE 63: RADIOGRAPHIC VERTEBRAL FRACTURES, SA3 CAROC- MODERATE 10-YEAR FRACTURE RISK: ODDS RATIO, RELATIVE RISK, AND RISK DIFFERENCE

Treatment Reference OR (95% CrI) RR (95% CrI) RD (95% Crl) ALED5 PBO 0.55 (0.27, 1.04) 0.58 (0.29, 1.03) -0.04 (-0.08, 0.00) RISD5 0.60 (0.43, 0.85) 0.63 (0.45, 0.86) -0.04 (-0.06, -0.01) ZOLS5 0.74 (0.23, 2.22) 0.76 (0.26, 2.02) -0.02 (-0.09, 0.09) RISD5 ALED5 1.10 (0.53, 2.42) 1.09 (0.56, 2.32) 0.01 (-0.04, 0.04) ZOLS5 1.34 (0.37, 4.95) 1.31 (0.39, 4.34) 0.02 (-0.05, 0.13) ZOLS5 RISD5 1.22 (0.37, 3.86) 1.21 (0.38, 3.39) 0.01 (-0.05, 0.12)

Random-Effect Model Residual Deviance 6.04 vs 6 datapoints Deviance Information Criteria 41.287 PBO=placebo (includes no treatment or background supplementation); ALED5=oral alendronate 5 mg/day or 35 mg/week; ALED10=oral alendronate 10 mg/day or 70 mg/week; RISD5=oral risedronate 5 mg/day or 35 mg/week or 150 mg/month; ZOLS5=intravenous zoledronic acid 5 mg single dose.

TECHNOLOGY REVIEW Drugs for the Treatment and Prevention of Osteoporosis in Postmenopausal Women 276

CLINICAL VERTEBRAL FRACTURES

BASE CASE ANALYSIS

FIGURE 26: NETWORK GEOMETRY: CLINICAL VERTEBRAL FRACTURES, SECONDARY PREVENTION, BASE CASE

TABLE 64: CLINICAL VERTEBRAL FRACTURES, SECONDARY PREVENTION, BASE CASE: ODDS RATIO, RELATIVE RISK, AND RISK DIFFERENCE

Treatment Reference OR (95% CrI) RR (95% CrI) RD (95% Crl) ALED10 PBO 0.43 (0.19, 0.98) 0.44 (0.20, 0.98) -0.02 (-0.04, -0.001) ZOLY5 0.20 (0.08, 0.41) 0.21 (0.08, 0.42) -0.03 (-0.05, -0.02) ZOLY5 ALED10 0.46 (0.13, 1.36) 0.47 (0.14, 1.36) -0.01 (-0.03, 0.004)

Random-Effects Model Residual Deviance 6.816 vs 8 datapoints Deviance Information Criteria 43.637 PBO=placebo (includes no treatment or background supplementation); ALED10=oral alendronate 10 mg/day or 70 mg/week; ZOLY5=intravenous zoledronic acid 5 mg/year.

TECHNOLOGY REVIEW Drugs for the Treatment and Prevention of Osteoporosis in Postmenopausal Women 277

SUBGROUP ANALYSIS

SG1- DENOSUMAB COMPARED WITH BISPHOSPHONATES

FIGURE 27: NETWORK GEOMETRY: CLINICAL VERTEBRAL FRACTURES, SECONDARY PREVENTION, SG1- DENOSUMAB COMPARED WITH BISPHOSPHONATES

TABLE 65: CLINICAL VERTEBRAL FRACTURES, SECONDARY PREVENTION, SG1- DENOSUMAB COMPARED WITH BISPHOSPHONATES: ODDS RATIO, RELATIVE RISK, AND RISK DIFFERENCE

Treatment Reference OR (95% CrI) RR (95% CrI) RD (95% Crl)

ALED10 PBO 0.46 (0.22, 1.02) 0.47 (0.23, 1.02) -0.02 (-0.03, 0.0005) ZOLY5 0.20 (0.08, 0.40) 0.21 (0.09, 0.41) -0.03 (-0.04, -0.02) DENBY60 0.29 (0.13, 0.60) 0.30 (0.14, 0.61) -0.02 (-0.04, -0.01) ZOLY5 ALED10 0.44 (0.13, 1.14) 0.45 (0.13, 1.14) -0.01 (-0.03, 0.001) DENBY60 0.64 (0.21, 1.63) 0.64 (0.22, 1.62) -0.01 (-0.02, 0.01) DENBY60 ZOLY5 1.46 (0.52, 4.62) 1.45 (0.53, 4.55) 0.003 (-0.01, 0.02)

Random-Effect Residual Deviance 9.79 vs 12 datapoints Model Deviance Information Criteria 65.29 PBO=placebo (includes no treatment or background supplementation); ALED10=oral alendronate 10 mg/day or 70 mg/week; DENBY60= subcutaneous injection of denosumab 60 mg every 6 months; ZOLY5=intravenous zoledronic acid 5 mg/year.

FIGURE 27-1: INCONSISTENCY PLOT FOR CLINICAL VERTEBRAL FRACTURES, SECONDARY PREVENTION, SG1- DENOSUMAB COMPARED WITH BISPHOSPHONATES

1.5

0.5

0 0 0.5 1 1.5

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SG2- TREATMENT DURATIONS, 3 YEARS

FIGURE 28: NETWORK GEOMETRY: CLINICAL VERTEBRAL FRACTURES, SECONDARY PREVENTION, SG2- 3 YEARS

TABLE 66: CLINICAL VERTEBRAL FRACTURES, SG2- 3 YEARS: ODDS RATIO, RELATIVE RISK, AND RISK DIFFERENCE

Treatment Reference OR (95% CrI) RR (95% CrI) RD (95% Crl) ALED10 PBO 0.44 (0.17,1.18) 0.45 (0.17,1.17) -0.02 (-0.03,0.005) ZOLY5 0.22 (0.08,0.61) 0.23 (0.08,0.62) -0.03 (-0.03,-0.01) ZOLY5 ALED10 0.51 (0.13,2.01) 0.51 (0.13,2.07) -0.007 (-0.03,0.008)

Random-Effect Model Residual Deviance 4.089 vs 4 datapoints Deviance Information Criteria 29.854 PBO=placebo (includes no treatment or background supplementation); ALED10=oral alendronate 10 mg/day or 70 mg/week; ZOLY5=intravenous zoledronic acid 5 mg/year.

TECHNOLOGY REVIEW Drugs for the Treatment and Prevention of Osteoporosis in Postmenopausal Women 279

SG3- PRIOR BISPHOSPHONATE EXPERIENCE, BISPHOSPHONATE-NAÏVE

FIGURE 29: CLINICAL VERTEBRAL FRACTURES, SECONDARY PREVENTION, SG3- BISPHOSPHONATE-NAÏVE

TECHNOLOGY REVIEW Drugs for the Treatment and Prevention of Osteoporosis in Postmenopausal Women 280

NON-VERTEBRAL FRACTURES

BASE CASE ANALYSIS

FIGURE 30: NETWORK GEOMETRY: NON-VERTEBRAL FRACTURES, SECONDARY PREVENTION, BASE CASE

TABLE 67: NON-VERTEBRAL FRACTURES, SECONDARY PREVENTION, BASE CASE: ODDS RATIO, RELATIVE RISK AND RISK DIFFERENCE

Treatment Reference OR (95% CrI) RR (95% CrI) RD (95% Crl) ALED5 PBO 0.56 (0.18, 1.44) 0.58 (0.19, 1.40) -0.03 (-0.06, 0.03) ALED10 0.72 (0.42, 1.05) 0.73 (0.44, 1.05) -0.02 (-0.04, 0.003) ETID400 0.65 (0.24, 1.72) 0.66 (0.25, 1.64) -0.02 (-0.06, 0.04) RISD5 0.74 (0.52, 0.94) 0.75 (0.54, 0.94) -0.02 (-0.03, -0.004) ZOLY5 0.73 (0.47, 1.14) 0.74 (0.49, 1.13) -0.02 (-0.04, 0.01) ALED10 ALED5 1.27 (0.44, 4.24) 1.26 (0.46, 4.05) 0.01 (-0.05, 0.05) ETID400 1.17 (0.28, 5.28) 1.16 (0.30, 4.92) 0.01 (-0.06, 0.07) RISD5 1.31 (0.48, 4.12) 1.30 (0.50, 3.95) 0.01 (-0.05, 0.04) ZOLY5 1.30 (0.46, 4.34) 1.29 (0.48, 4.12) 0.01 (-0.05, 0.05) ETID400 ALED10 0.92 (0.32, 2.70) 0.92 (0.33, 2.53) -0.004 (-0.04, 0.06) RISD5 1.03 (0.63, 1.80) 1.03 (0.64, 1.75) 0.001 (-0.02, 0.03) ZOLY5 1.01 (0.59, 2.11) 1.01 (0.60, 2.03) 0.0005 (-0.03, 0.04) RISD5 ETID400 1.13 (0.41, 3.15) 1.12 (0.43, 3.03) 0.01 (-0.06, 0.04) ZOLY5 1.13 (0.39, 3.34) 1.12 (0.41, 3.18) 0.01 (-0.06, 0.05) ZOLY5 RISD5 0.98 (0.61, 1.79) 0.98 (0.63, 1.73) -0.001 (-0.02, 0.03)

Random-Effects Residual 20.99 vs 24 datapoints Model Deviance Deviance Information Criteria 147.415 PBO=placebo (includes no treatment or background supplementation); ALED5=oral alendronate 5 mg/day or 35 mg/week; ALED10=oral alendronate 10 mg/day or 70 mg/week; RISD5=oral risedronate 5 mg/day or 35 mg/week or 150 mg/month; ETID400=oral cyclic etidronate 400 mg/day; ZOLY5=intravenous zoledronic acid 5 mg/year

TECHNOLOGY REVIEW Drugs for the Treatment and Prevention of Osteoporosis in Postmenopausal Women 281

SUBGROUP ANALYSIS

SG1- DENOSUMAB COMPARED WITH BISPHOSPHONATES

FIGURE 31: NETWORK GEOMETRY: NON-VERTEBRAL FRACTURES, SECONDARY PREVENTION, SG1- DENOSUMAB COMPARED WITH BISPHOSPHONATES

Treatment Reference OR (95% Crl) RR (95% Crl) RD (95% Crl) ALED5 PBO 0.54 (0.19,1.30) 0.56 (0.20,1.28) -0.03 (-0.06,0.02) ALED10 0.70 (0.46,0.99) 0.71 (0.48,0.99) -0.02 (-0.04,-0.001) ETID400 0.67 (0.23,1.84) 0.68 (0.24,1.74) -0.02 (-0.06,0.05) RISD5 0.74 (0.55,0.93) 0.76 (0.56,0.93) -0.02 (-0.03,-0.005) DENBY60 0.84 (0.63,1.18) 0.85 (0.64,1.17) -0.01 (-0.03,0.01) ZOLY5 0.73 (0.50,1.07) 0.74 (0.52,1.07) -0.02 (-0.04,0.005) ALED10 ALED5 1.29 (0.50,3.85) 1.28 (0.52,3.70) 0.01 (-0.04,0.04) ETID400 1.24 (0.31,5.42) 1.23 (0.33,4.99) 0.01 (-0.05,0.08) RISD5 1.36 (0.55,3.99) 1.34 (0.57,3.82) 0.01 (-0.04,0.04) DENBY60 1.55 (0.65,4.50) 1.52 (0.67,4.27) 0.02 (-0.03,0.05) ZOLY5 1.35 (0.52,4.15) 1.33 (0.54,3.96) 0.01 (-0.04,0.05) ETID400 ALED10 0.96 (0.31,2.78) 0.96 (0.32,2.58) -0.002 (-0.04,0.07) RISD5 1.06 (0.68,1.67) 1.06 (0.69,1.64) 0.003 (-0.02,0.02) DENBY60 1.21 (0.79,2.03) 1.19 (0.80,1.95) 0.01 (-0.01,0.04) ZOLY5 1.04 (0.63,1.88) 1.04 (0.65,1.82) 0.002 (-0.02,0.03) RISD5 ETID400 1.10 (0.39,3.30) 1.09 (0.42,3.17) 0.004 (-0.07,0.04)

TECHNOLOGY REVIEW Drugs for the Treatment and Prevention of Osteoporosis in Postmenopausal Women 282

Treatment Reference OR (95% Crl) RR (95% Crl) RD (95% Crl) DENBY60 1.26 (0.45,3.86) 1.25 (0.47,3.67) 0.01 (-0.06,0.05) ZOLY5 1.09 (0.38,3.36) 1.08 (0.41,3.21) 0.004 (-0.07,0.04) DENBY60 RISD5 1.13 (0.79,1.83) 1.12 (0.80,1.77) 0.01 (-0.01,0.03) ZOLY5 0.98 (0.65,1.65) 0.98 (0.66,1.60) -0.001 (-0.02,0.03) ZOLY5 DENBY60 0.87 (0.52,1.41) 0.87 (0.54,1.38) -0.01 (-0.03,0.02)

Random-Effects Residual Deviance 26.21 vs 31 datapoints Model Deviance Information Criteria 187.601 PBO=placebo (includes no treatment or background supplementation); ALED5=oral alendronate 5 mg/day or 35 mg/week; ALED10=oral alendronate 10 mg/day or 70 mg/week; RISD5=oral risedronate 5 mg/day or 35 mg/week or 150 mg/month; DENBY60= subcutaneous injection of denosumab 60 mg every 6 months; ETID400=oral cyclic etidronate 400 mg/day; ZOLY5=intravenous zoledronic acid 5 mg/year.

FIGURE 31-1: CONSISTENCY PLOT FOR NON-VERTEBRAL FRACTURES, SECONDARY PREVENTION, SG1- DENOSUMAB COMPARED WITH BISPHOSPHONATES

1.5

0.5

0 0 0.5 1 1.5

TECHNOLOGY REVIEW Drugs for the Treatment and Prevention of Osteoporosis in Postmenopausal Women 283

SG2- TREATMENT DURATIONS, 1 YEAR

FIGURE 32: NETWORK GEOMETRY: NON-VERTEBRAL FRACTURES, PRIMARY PREVENTION, SG2- 1 YEAR

TABLE 69: NON-VERTEBRAL FRACTURES, SECONDARY PREVENTION, SG2- 1 YEAR: ODDS RATIOS, RELATIVE RISKS AND RISK DIFFERENCE FOR ALL TREATMENT COMPARISONS-RANDOM EFFECTS MODEL

Treatment Reference OR (95% Crl) RR (95% Crl) RD (95% Crl) ALED5 PBO 0.96 (0.47,2.00) 0.96 (0.48,1.94) -0.001 (-0.02,0.03) ALED10 0.26 (0.03,1.15) 0.27 (0.03,1.14) -0.02 (-0.04,0.004) RISD5 0.75 (0.39,1.48) 0.76 (0.40,1.46) -0.01 (-0.02,0.01) ZOLY5 0.87 (0.42,1.79) 0.87 (0.42,1.75) -0.004 (-0.02,0.02) ALED10 ALED5 0.27 (0.03,1.40) 0.28 (0.03,1.39) -0.02 (-0.06,0.01) RISD5 0.78 (0.30,2.08) 0.78 (0.31,2.03) -0.01 (-0.04,0.02) ZOLY5 0.90 (0.32,2.45) 0.90 (0.34,2.38) -0.003 (-0.04,0.03) RISD5 ALED10 2.87 (0.57,26.82) 2.82 (0.58,25.94) 0.01 (-0.01,0.04) ZOLY5 3.29 (0.64,30.62) 3.22 (0.64,29.22) 0.02 (-0.01,0.05) ZOLY5 RISD5 1.15 (0.44,3.02) 1.15 (0.44,2.91) 0.003 (-0.02,0.03)

Random-Effect Model Residual Deviance 11.11 vs 12 datapoints Deviance Information Criteria 74.725 PBO=placebo (includes no treatment or background supplementation); ALED5=oral alendronate 5 mg/day or 35 mg/week; ALED10=oral alendronate 10 mg/day or 70 mg/week; RISD5=oral risedronate 5 mg/day or 35 mg/week or 150 mg/month; ZOLY5=intravenous zoledronic acid 5 mg/year.

TECHNOLOGY REVIEW Drugs for the Treatment and Prevention of Osteoporosis in Postmenopausal Women 284

SG2- TREATMENT DURATIONS, 2 YEARS

FIGURE 33: NETWORK GEOMETRY: NON-VERTEBRAL FRACTURES, PRIMARY PREVENTION, SG2- 2 YEAR

TABLE 70: NON-VERTEBRAL FRACTURES, SECONDARY PREVENTION, SG2- 2 YEARS: ODDS RATIOS, RELATIVE RISKS AND RISK DIFFERENCE FOR ALL TREATMENT COMPARISONS-RANDOM EFFECTS MODEL

Treatment Reference OR (95% Crl) RR (95% Crl) RD (95% Crl) ALED5 PBO 0.56 (0.18, 1.57) 0.58 (0.18, 1.52) -0.02 (-0.05, 0.03) ALED10 0.39 (0.01, 4.35) 0.40 (0.01, 3.74) -0.04 (-0.07, 0.14) RISD5 0.64 (0.40, 0.98) 0.65 (0.42, 0.98) -0.02 (-0.04, -0.001) ALED10 ALED5 0.70 (0.02, 10.25) 0.71 (0.02, 8.76) -0.01 (-0.07, 0.16) RISD5 1.15 (0.36, 3.94) 1.14 (0.38, 3.81) 0.005 (-0.05, 0.04) RISD5 ALED10 1.64 (0.14, 48.09) 1.61 (0.16, 46.16) 0.01 (-0.15, 0.05)

Random-Effect Residual Deviance 8.837 vs 10 datapoints Model Deviance Information Criteria 59.515 PBO=placebo (includes no treatment or background supplementation); ALED5=oral alendronate 5 mg/day or 35 mg/week; ALED10=oral alendronate 10 mg/day or 70 mg/week; RISD5=oral risedronate 5 mg/day or 35 mg/week or 150 mg/month.

TECHNOLOGY REVIEW Drugs for the Treatment and Prevention of Osteoporosis in Postmenopausal Women 285

SG2- TREATMENT DURATIONS, 3 YEARS

FIGURE 34: NETWORK GEOMETRY: NON-VERTEBRAL FRACTURES, PRIMARY PREVENTION, SG2- 3 YEAR

TABLE 71: NON-VERTEBRAL FRACTURES, SECONDARY PREVENTION, SG2- 3 YEARS: ODDS RATIOS, RELATIVE RISKS AND RISK DIFFERENCE FOR ALL TREATMENT COMPARISONS-RANDOM EFFECTS MODEL

Treatment Reference OR (95% Crl) RR (95% Crl) RD (95% Crl) ALED10 PBO 0.79 (0.46,1.35) 0.81 (0.49,1.30) -0.02 (-0.06,0.03) RISD5 0.75 (0.52,1.01) 0.77 (0.55,1.01) -0.03 (-0.05,0.001) ETID400 0.81 (0.19,3.25) 0.83 (0.21,2.63) -0.02 (-0.10,0.17) ZOLY5 0.73 (0.44,1.22) 0.75 (0.47,1.19) -0.03 (-0.06,0.02) RISD5 ALED10 0.95 (0.48,1.72) 0.96 (0.52,1.65) -0.004 (-0.07,0.04) ETID400 1.03 (0.22,4.58) 1.02 (0.24,3.62) 0.002 (-0.09,0.19) ZOLY5 0.93 (0.45,1.91) 0.93 (0.48,1.80) -0.01 (-0.07,0.05) ETID400 RISD5 1.08 (0.24,4.48) 1.08 (0.26,3.56) 0.01 (-0.08,0.19) ZOLY5 0.97 (0.55,1.86) 0.97 (0.58,1.75) -0.003 (-0.04,0.06) ZOLY5 ETID400 0.90 (0.21,4.24) 0.91 (0.26,3.89) -0.01 (-0.20,0.08)

Random-Effect Residual Deviance 11.45 vs 12 datapoints Model Deviance Information Criteria 95.194 PBO=placebo (includes no treatment or background supplementation); ALED5=oral alendronate 5 mg/day or 35 mg/week; ALED10=oral alendronate 10 mg/day or 70 mg/week; RISD5=oral risedronate 5 mg/day or 35 mg/week or 150 mg/month; ETID400=oral cyclic etidronate 400 mg/day; ZOLY5=intravenous zoledronic acid 5 mg/year.

TECHNOLOGY REVIEW Drugs for the Treatment and Prevention of Osteoporosis in Postmenopausal Women 286

SG3- PRIOR BISPHOSPHONATE EXPERIENCE, BISPHOSPHONATE-NAÏVE

FIGURE 35: NETWORK GEOMETRY: NON-VERTEBRAL FRACTURES, PRIMARY PREVENTION, SG3- BISPHOSPHONATE-NAÏVE

TABLE 72: NON-VERTEBRAL FRACTURES, SECONDARY PREVENTION, SG3- BISPHOSPHONATE- NAÏVE: ODDS RATIOS, RELATIVE RISKS AND RISK DIFFERENCE FOR ALL TREATMENT COMPARISONS-RANDOM EFFECTS MODEL

Treatment Reference OR (95% CrI) RR (95% CrI) RD (95% Crl) ALED10 PBO 0.75 (0.26,1.56) 0.77 (0.28,1.49) -0.02 (-0.08,0.04) RISD5 0.68 (0.26,1.77) 0.70 (0.28,1.65) -0.03 (-0.08,0.06) ETID400 0.81 (0.15,3.91) 0.83 (0.17,3.16) -0.01 (-0.10,0.18) RISD5 ALED10 0.90 (0.28,4.06) 0.90 (0.31,3.57) -0.01 (-0.08,0.10) ETID400 1.11 (0.18,7.17) 1.10 (0.20,5.71) 0.01 (-0.09,0.20) ETID400 RISD5 1.21 (0.18,7.54) 1.20 (0.20,6.00) 0.01 (-0.10,0.21)

Random-Effect Residual Deviance 7.913 vs 8 datapoints Model Deviance Information Criteria 47.858 PBO=placebo (includes no treatment or background supplementation); ALED10=oral alendronate 10 mg/day or 70 mg/week; RISD5=oral risedronate 5 mg/day or 35 mg/week or 150 mg/monthETID400=oral cyclic etidronate 400 mg/day.

TECHNOLOGY REVIEW Drugs for the Treatment and Prevention of Osteoporosis in Postmenopausal Women 287

SENSITIVITY ANALYSIS

SA3-STUDIES RE-DEFINED USING CAROC CALCULATOR, LOW LEVEL OF 10-YEAR FRACTURE RISK

FIGURE 36: NETWORK GEOMETRY: NON-VERTEBRAL FRACTURES, SA3 CAROC-LOW 10-YEAR FRACTURE RISK

TABLE 73: NON-VERTEBRAL FRACTURES, SECONDARY PREVENTION, SA3 CAROC- LOW 10-YEAR FRACTURE: ODDS RATIOS, RELATIVE RISKS AND RISK DIFFERENCE FOR ALL TREATMENT COMPARISONS-RANDOM EFFECTS MODEL

Treatment Reference OR (95% CrI) RR (95% CrI) RD (95% Crl)

ALED10 PBO 0.80 (0.03,19.30) 0.81 (0.03,16.35) -0.004 (-0.05,0.16)

RISD5 0.43 (0.05,4.02) 0.44 (0.05,3.86) -0.01 (-0.05,0.04)

RISD5 ALED10 0.54 (0.01,33.23) 0.55 (0.02,31.40) -0.01 (-0.17,0.06)

Random-Effect Model Residual Deviance 3.872 vs 4 datapoints

Deviance Information Criteria 16.606 PBO=placebo (includes no treatment or background supplementation); ALED10=oral alendronate 10 mg/day or 70 mg/week; RISD5=oral risedronate 5 mg/day or 35 mg/week or 150 mg/month.

TECHNOLOGY REVIEW Drugs for the Treatment and Prevention of Osteoporosis in Postmenopausal Women 288

SA3-STUDIES RE-DEFINED USING CAROC CALCULATOR, MODERATE LEVEL OF 10-YEAR FRACTURE RISK

FIGURE 37: NETWORK GEOMETRY: NON-VERTEBRAL FRACTURES, SA3 CAROC-MODERATE 10- YEAR FRACTURE RISK

TABLE 74: NON-VERTEBRAL FRACTURES, SECONDARY PREVENTION, SA3 CAROC- MODERATE 10- YEAR FRACTURE: ODDS RATIOS, RELATIVE RISKS AND RISK DIFFERENCE FOR ALL TREATMENT COMPARISONS-RANDOM EFFECTS MODEL

Treatment Reference OR (95% CrI) RR (95% CrI) RD (95% Crl) ALED10 PBO 0.56 (0.14,1.95) -0.02 (-0.05,0.04) -0.02 (-0.05,0.04) RISD5 0.61 (0.23,1.70) -0.02 (-0.04,0.03) -0.02 (-0.04,0.03) RISD5 ALED10 1.11 (0.23,5.99) 0.003 (-0.06,0.06) 0.003 (-0.06,0.06)

Random-Effect Model Residual Deviance 4.055 vs 4 datapoints Deviance Information Criteria 27.512 PBO=placebo (includes no treatment or background supplementation); ALED10=oral alendronate 10 mg/day or 70 mg/week; RISD5=oral risedronate 5 mg/day or 35 mg/week or 150 mg/month.

TECHNOLOGY REVIEW Drugs for the Treatment and Prevention of Osteoporosis in Postmenopausal Women 289

HIP FRACTURES

BASE CASE ANALYSIS

FIGURE 38: NETWORK GEOMETRY: HIP FRACTURE, SECONDARY PREVENTION, BASE CASE

TABLE 75: HIP FRACTURE, SECONDARY PREVENTION, BASE CASE: ODDS RATIO, RELATIVE RISK AND RISK DIFFERENCE Treatment Reference OR (95% CrI) RR (95% CrI) RD (95% Crl) ALED10 PBO 0.44 (0.20, 0.87) 0.45 (0.21, 0.87) -0.01 (-0.02, -0.003) RISD5 0.72 (0.43, 1.22) 0.73 (0.43, 1.21) -0.01 (-0.01, 0.005) ETID400 0.78 (0.09, 4.82) 0.78 (0.10, 4.51) -0.01 (-0.02, 0.07) ZOLY5 0.58 (0.37, 0.87) 0.58 (0.38, 0.88) -0.01 (-0.02, -0.003) RISD5 ALED10 1.65 (0.69, 4.17) 1.64 (0.70, 4.10) 0.01 (-0.01, 0.02) ETID400 1.77 (0.19, 12.28) 1.76 (0.19, 11.42) 0.01 (-0.01, 0.08) ZOLY5 1.30 (0.60, 3.22) 1.30 (0.60, 3.18) 0.003 (-0.01, 0.01) ETID400 RISD5 1.08 (0.13, 7.19) 1.08 (0.13, 6.72) 0.001 (-0.02, 0.07) ZOLY5 0.80 (0.40, 1.53) 0.80 (0.41, 1.52) -0.003 (-0.02, 0.01) ZOLY5 ETID400 0.74 (0.11, 6.49) 0.74 (0.12, 6.41) -0.005 (-0.07, 0.01)

Random-Effects Residual Model Deviance 14.76 vs 18 datapoints Deviance Information Criteria 98.912 PBO=placebo (includes no treatment or background supplementation); ALED10=oral alendronate 10 mg/day or 70 mg/week; RISD5=oral risedronate 5 mg/day or 35 mg/week or 150 mg/month; ETID400=oral cyclic etidronate 400 mg/day; ZOLY5=intravenous zoledronic acid 5 mg/year.

TECHNOLOGY REVIEW Drugs for the Treatment and Prevention of Osteoporosis in Postmenopausal Women 290

SUBGROUP ANALYSIS

SG1- DENOSUMAB COMPARED WITH BISPHOSPHONATES

FIGURE 39 NETWORK GEOMETRY: HIP FRACTURES, SECONDARY PREVENTION, SG1-DENOSUMAB COMPARED WITH BISPHOSPHONATES

TABLE 76: HIP FRACTURES, SECONDARY PREVENTION, SG1-DENOSUMAB COMPARED WITH BISPHOSPHONATES: ODDS RATIOS, RELATIVE RISKS AND RISK DIFFERENCE FOR ALL TREATMENT COMPARISONS-RANDOM EFFECTS MODEL

Treatment Reference OR (95% CrI) RR (95% CrI) RD (95% Crl) ALED10 PBO 0.43 (0.20, 0.87) 0.44 (0.20, 0.87) -0.01 (-0.02, -0.003) RISD5 0.73 (0.44, 1.21) 0.73 (0.44, 1.21) -0.01 (-0.01, 0.004) ETID400 0.76 (0.12, 3.96) 0.77 (0.12, 3.77) -0.005 (-0.02, 0.05) ZOLY5 0.58 (0.38, 0.86) 0.58 (0.38, 0.86) -0.01 (-0.01, -0.003) DENBY60 0.59 (0.31, 1.09) 0.60 (0.31, 1.09) -0.01 (-0.02, 0.002) RISD5 ALED10 1.68 (0.71, 4.38) 1.67 (0.71, 4.30) 0.01 (-0.005, 0.02) ETID400 1.79 (0.23, 12.06) 1.77 (0.23, 11.30) 0.01 (-0.01, 0.06) ZOLY5 1.32 (0.60, 3.21) 1.32 (0.60, 3.17) 0.003 (-0.01, 0.01) DENBY60 1.37 (0.54, 3.63) 1.37 (0.54, 3.58) 0.003 (-0.01, 0.02) ETID400 RISD5 1.05 (0.16, 5.98) 1.05 (0.16, 5.63) 0.001 (-0.02, 0.06) ZOLY5 0.79 (0.41, 1.49) 0.79 (0.41, 1.48) -0.003 (-0.01, 0.01) DENBY60 0.81 (0.36, 1.77) 0.81 (0.37, 1.75) -0.003 (-0.01, 0.01) ZOLY5 ETID400 0.75 (0.14, 5.13) 0.76 (0.15, 5.06) -0.004 (-0.06, 0.01) DENBY60 0.78 (0.12, 5.27) 0.78 (0.13, 5.19) -0.004 (-0.06, 0.02)

TECHNOLOGY REVIEW Drugs for the Treatment and Prevention of Osteoporosis in Postmenopausal Women 291

DENBY60 ZOLY5 1.03 (0.48, 2.18) 1.03 (0.48, 2.15) 0.0004 (-0.01, 0.01)

Random-Effects Model Residual Deviance 17.49 vs 22 datapoints Deviance Information Criteria 119.448 PBO=placebo (includes no treatment or background supplementation); ALED5=oral alendronate 5 mg/day or 35 mg/week; ALED10=oral alendronate 10 mg/day or 70 mg/week; RISD5=oral risedronate 5 mg/day or 35 mg/week or 150 mg/month; DENBY60= subcutaneous injection of denosumab 60 mg every 6 months; ETID400=oral cyclic etidronate 400 mg/day; ZOLY5=intravenous zoledronic acid 5 mg/year.

FIGURE 39-1: CONSISTENCY PLOT FOR HIP FRACTURES, SECONDARY PREVENTION, SG1- DENOSUMAB COMPARED WITH BISPHOSPHONATES

1.4 1.2 1 0.8 0.6

0.4 InconsistencyModel 0.2 0 0 0.5 1 1.5 Consistency Model

TECHNOLOGY REVIEW Drugs for the Treatment and Prevention of Osteoporosis in Postmenopausal Women 292

SG2- TREATMENT DURATIONS, 2 YEARS Figure 40: NETWORK GEOMETRY: Hip Fractures, Secondary Prevention, SG2- 2 years

TABLE 77: HIP FRACTURES, SECONDARY PREVENTION, SG2- 2 YEARS: ODDS RATIOS, RELATIVE RISKS AND RISK DIFFERENCE FOR ALL TREATMENT COMPARISONS-RANDOM EFFECTS MODEL

Treatment Reference OR (95% CrI) RR (95% CrI) RD (95% Crl) ALED10 PBO 0.47 (0.06, 3.05) 0.06 (0.06, 2.86) -0.06 (-0.06, 0.06) ZOLY5 0.54 (0.17, 1.66) 0.17 (0.17, 1.62) -0.05 (-0.05, 0.03) ZOLY5 ALED10 1.13 (0.13, 12.23) 0.14 (0.14, 11.49) -0.08 (-0.08, 0.06)

Random-Effects Residual Deviance 3.966 vs 4 datapoints Model Deviance Information Criteria 22.752 PBO=placebo (includes no treatment or background supplementationALED10=oral alendronate 10 mg/day or 70 mg/week; ZOLY5=intravenous zoledronic acid 5 mg/year.

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SG2- TREATMENT DURATIONS, 3 YEARS

FIGURE 41 NETWORK GEOMETRY: HIP FRACTURES, SECONDARY PREVENTION, SG2- 3 YEARS

TABLE 78: HIP FRACTURES, SECONDARY PREVENTION, SG2- 3YEARS: ODDS RATIOS, RELATIVE RISKS AND RISK DIFFERENCE FOR ALL TREATMENT COMPARISONS-RANDOM EFFECTS MODEL Treatment Reference OR (95% CrI) RR (95% CrI) RD (95% Crl) ALED10 PBO 0.42 (0.17, 0.95) 0.43 (0.18, 0.95) -0.01 (-0.02, -0.001) RISD5 0.72 (0.37, 1.40) 0.73 (0.38, 1.39) -0.01 (-0.01, 0.01) ZOLY5 0.59 (0.33, 1.03) 0.59 (0.34, 1.03) -0.01 (-0.01, 0.001) RISD5 ALED10 1.72 (0.63, 5.17) 1.71 (0.64, 5.08) 0.01 (-0.01, 0.02) ZOLY5 1.39 (0.53, 4.03) 1.39 (0.53, 3.98) 0.003 (-0.01, 0.01) ZOLY5 RISD5 0.81 (0.34, 1.92) 0.81 (0.35, 1.90) -0.003 (-0.02, 0.01)

Random-Effect Model Residual Deviance 8.687 vs 10 datapoints Deviance Information Criteria 64.596

PBO=placebo (includes no treatment or background supplementation); ALED10=oral alendronate 10 mg/day or 70 mg/week; RISD5=oral risedronate 5 mg/day or 35 mg/week or 150 mg/month; ZOLY5=intravenous zoledronic acid 5 mg/year.

TECHNOLOGY REVIEW Drugs for the Treatment and Prevention of Osteoporosis in Postmenopausal Women 294

SG3- PRIOR BISPHOSPHONATE EXPERIENCE, BISPHOSPHONATE-NAÏVE Figure 42: Hip Fractures, Secondary Prevention, SG3- bisphosphonate-naïve

TECHNOLOGY REVIEW Drugs for the Treatment and Prevention of Osteoporosis in Postmenopausal Women 295

SENSITIVITY ANALYSIS

SA2- EXCLUDING AGE-DEFINED STUDIES Figure 43: NETWORK GEOMETRY: Hip Fractures, Secondary Prevention, SA2- excluding age- defined studies

TABLE 79: HIP FRACTURES, SECONDARY PREVENTION, SA2- EXCLUDING AGE-DEFINED STUDIES: ODDS RATIOS, RELATIVE RISKS AND RISK DIFFERENCE FOR ALL TREATMENT COMPARISONS- RANDOM EFFECTS MODEL

Treatment Reference OR (95% CrI) RR (95% CrI) RD (95% Crl) ALED10 PBO 0.43 (0.19,0.93) 0.43 (0.19,0.93) -0.01 (-0.02,-0.001) RISD5 0.72 (0.43,1.24) 0.73 (0.44,1.23) -0.01 (-0.01,0.01) ETID400 0.84 (0.10,5.23) 0.84 (0.11,4.88) -0.004 (-0.02,0.07) ZOLY5 0.58 (0.38,0.88) 0.58 (0.38,0.88) -0.01 (-0.02,-0.003) RISD5 ALED10 1.69 (0.68,4.50) 1.67 (0.68,4.41) 0.01 (-0.01,0.02) ETID400 2.01 (0.22,14.83) 1.99 (0.22,13.71) 0.01 (-0.01,0.08) ZOLY5 1.34 (0.56,3.50) 1.33 (0.56,3.46) 0.003 (-0.01,0.01) ETID400 RISD5 1.18 (0.14,7.77) 1.17 (0.14,7.21) 0.003 (-0.02,0.07) ZOLY5 0.80 (0.41,1.56) 0.80 (0.41,1.55) -0.003 (-0.02,0.01) ZOLY5 ETID400 0.68 (0.11,5.74) 0.69 (0.11,5.66) -0.01 (-0.08,0.01)

Random-Effect Residual 13.6 vs 16 datapoints Model Deviance Deviance Information Criteria 90.843 PBO=placebo (includes no treatment or background supplementation); ALED10=oral alendronate 10 mg/day or 70 mg/week; RISD5=oral risedronate 5 mg/day or 35 mg/week or 150 mg/month; ZOLY5=intravenous zoledronic acid 5 mg/year.

TECHNOLOGY REVIEW Drugs for the Treatment and Prevention of Osteoporosis in Postmenopausal Women 296

WRIST FRACTURES

BASE CASE ANALYSIS

FIGURE 44: NETWORK GEOMETRY: WRIST FRACTURES, SECONDARY PREVENTION, BASE CASE

TABLE 80: WRIST FRACTURE, SECONDARY PREVENTION, BASE CASE: ODDS RATIO, RELATIVE RISK AND RISK DIFFERENCE

Treatment Reference OR (95% CrI) RR (95% CrI) RD (95% Crl) ALED10 PBO 0.64 (0.30,2.36) 0.64 (0.31,2.32) -0.01 (-0.02,0.02) RISD5 0.62 (0.20,2.00) 0.63 (0.20,1.97) -0.01 (-0.02,0.01) ETID400 0.88 (0.08,8.45) 0.88 (0.09,7.71) -0.002 (-0.02,0.09) RISD5 ALED10 0.98 (0.16,3.56) 0.98 (0.16,3.48) -0.0002 (-0.02,0.02) ETID400 1.34 (0.10,14.43) 1.33 (0.10,13.16) 0.003 (-0.02,0.09) ETID400 RISD5 1.40 (0.11,17.43) 1.39 (0.11,15.83) 0.004 (-0.02,0.09)

Random-Effects 12.13 vs 10 12.13 vs 10 datapoints Model datapoints Deviance Information Criteria 50.001 PBO=placebo (includes no treatment or background supplementation); ALED10=oral alendronate 10 mg/day or 70 mg/week; RISD5=oral risedronate 5 mg/day or 35 mg/week or 150 mg/month; ETID400=oral cyclic etidronate 400 mg/day; ZOLY5=intravenous zoledronic acid 5 mg/year

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SUBGROUP ANALYSIS

SG1-DENOSUMAB COMPARED WITH BISPHOSPHONATES Figure 45: NETWORK GEOMETRY: Wrist Fractures, Secondary Prevention, SG1-denosumab compared with bisphosphonates

TABLE 81: WRIST FRACTURES, SECONDARY PREVENTION, SG1-DENOSUMAB COMPARED WITH BISPHOSPHONATES: ODDS RATIOS, RELATIVE RISKS AND RISK DIFFERENCE FOR ALL TREATMENT COMPARISONS-RANDOM EFFECTS MODE

Treatment Reference OR (95% CrI) RR (95% CrI) RD (95% Crl) ALED10 PBO 0.72 (0.34,3.47) 0.73 (0.35,3.36) -0.004 (-0.01,0.03) ETID400 0.91 (0.08,8.70) 0.91 (0.09,7.86) -0.001 (-0.02,0.09) RISD5 0.61 (0.17,2.19) 0.62 (0.17,2.15) -0.01 (-0.02,0.02) DENBY60 0.78 (0.21,1.92) 0.79 (0.21,1.89) -0.004 (-0.01,0.01) ETID400 ALED10 1.20 (0.07,12.22) 1.20 (0.07,11.04) 0.002 (-0.03,0.10) RISD5 0.85 (0.09,3.03) 0.85 (0.10,2.97) -0.002 (-0.03,0.02) DENBY60 1.08 (0.11,2.90) 1.08 (0.11,2.85) 0.001 (-0.03,0.02) RISD5 ETID400 0.67 (0.05,9.84) 0.67 (0.06,9.64) -0.005 (-0.10,0.02) DENBY60 0.83 (0.06,10.32) 0.83 (0.07,10.11) -0.002 (-0.10,0.02) DENBY60 RISD5 1.27 (0.19,5.53) 1.26 (0.19,5.41) 0.003 (-0.02,0.02)

Random-Effect Residual Deviance 15.73 vs 14 datapoints Model Deviance Information Criteria 71.922 PBO=placebo (includes no treatment or background supplementation); ALED5=oral alendronate 5 mg/day or 35 mg/week; ALED10=oral alendronate 10 mg/day or 70 mg/week; RISD5=oral risedronate 5 mg/day or 35 mg/week or 150 mg/month; DENBY60= subcutaneous injection of denosumab 60 mg every 6 months; ETID400=oral cyclic etidronate 400 mg/day.

TECHNOLOGY REVIEW Drugs for the Treatment and Prevention of Osteoporosis in Postmenopausal Women 298

SG2- TREATMENT DURATIONS, 3 YEARS

FIGURE 46: NETWORK GEOMETRY: WRIST FRACTURES, SECONDARY PREVENTION, SG2- 3 YEARS

TABLE 82: WRIST FRACTURES, SECONDARY PREVENTION, SG2- 3 YEARS: ODDS RATIOS, RELATIVE RISKS AND RISK DIFFERENCE FOR ALL TREATMENT COMPARISONS-RANDOM EFFECTS MODE Treatment Reference OR (95% CrI) RR (95% CrI) RD (95% Crl) ALED10 PBO 0.51 (0.19, 1.44) 0.52 (0.19, 1.42) -0.02 (-0.03, 0.01) RISD5 0.63 (0.21, 1.86) 0.64 (0.21, 1.81) -0.01 (-0.03, 0.02) RISD5 ALED10 1.23 (0.27, 5.49) 1.22 (0.28, 5.26) 0.004 (-0.03, 0.04)

Random-Effects Model Residual Deviance 4.041 vs 9 datapoints Deviance Information Criteria 27.859 PBO=placebo (includes no treatment or background supplementation); ALED10=oral alendronate 10 mg/day or 70 mg/week; RISD5=oral risedronate 5 mg/day or 35 mg/week or 150 mg/month.

TECHNOLOGY REVIEW Drugs for the Treatment and Prevention of Osteoporosis in Postmenopausal Women 299

SG3- PRIOR BISPHOSPHONATE EXPERIENCE, BISPHOSPHONATE-NAÏVE Figure 47: Wrist Fractures, Secondary Prevention, SG3- bisphosphonate-naïve

TECHNOLOGY REVIEW Drugs for the Treatment and Prevention of Osteoporosis in Postmenopausal Women 300

HEALTH RELATED QUALITY OF LIFE

BASE CASE ANALYSIS

FIGURE 48: NETWORK GEOMETRY: HEALTH RELATED QUALITY OF LIFE, SECONDARY PREVENTION, BASE CASE

TABLE 83: HEALTH RELATED QUALITY OF LIFE, BASE CASE: STANDARDIZED MEAN DIFFERENCE (SMD) FOR ALL TREATMENT COMPARISONS

Treatment Reference SMD (95% CrI)

ALED10 PBO 0.15 (-8.68,8.98) ZOLY5 0.06 (-6.22,6.27) ZOLY5 ALED10 -0.09 (-6.39,6.12)

Total Residual Deviance 1.979 Deviance Information Criteria -3.082 PBO=placebo (includes no treatment or background supplementation); ALED10=oral alendronate 10 mg/day or 70 mg/week; ZOLY5=intravenous zoledronic acid 5 mg/year.

TECHNOLOGY REVIEW Drugs for the Treatment and Prevention of Osteoporosis in Postmenopausal Women 301

WITHDRAWAL DUE TO ADVERSE EVENTS

BASE CASE ANALYSIS

FIGURE 49: NETWORK GEOMETRY: WITHDRAWAL DUE TO ADVERSE EVENTS, SECONDARY PREVENTION, BASE CASE

TABLE 84: WITHDRAWAL DUE TO ADVERSE EVENTS, SECONDARY PREVENTION, BASE CASE: ODDS RATIO, RELATIVE RISK AND RISK

Treatment Reference OR (95% CrI) RR (95% CrI) RD (95% Crl) ALED5 PBO 1.69 (0.17,14.30) 1.63 (0.18,8.78) 0.03 (-0.04,0.37) ALED10 1.32 (0.94,1.89) 1.30 (0.94,1.82) 0.02 (-0.003,0.04) RISD5 1.15 (0.79,1.74) 1.14 (0.80,1.68) 0.01 (-0.01,0.03) ETID400 0.63 (0.23,1.66) 0.64 (0.24,1.61) -0.02 (-0.04,0.03) ZOLY5 0.65 (0.29,1.17) 0.66 (0.30,1.16) -0.02 (-0.04,0.01) ALED10 ALED5 0.78 (0.09,8.18) 0.79 (0.15,7.70) -0.02 (-0.36,0.06) RISD5 0.68 (0.08,7.25) 0.70 (0.13,6.89) -0.02 (-0.36,0.06) ETID400 0.37 (0.04,4.47) 0.39 (0.06,4.32) -0.05 (-0.39,0.04) ZOLY5 0.37 (0.04,4.09) 0.39 (0.06,3.96) -0.05 (-0.39,0.03) RISD5 ALED10 0.87 (0.56,1.37) 0.88 (0.58,1.35) -0.01 (-0.03,0.02) ETID400 0.47 (0.16,1.29) 0.49 (0.17,1.26) -0.03 (-0.06,0.02) ZOLY5 0.49 (0.21,0.91) 0.50 (0.23,0.92) -0.03 (-0.06,-0.005) ETID400 RISD5 0.55 (0.18,1.53) 0.56 (0.19,1.49) -0.02 (-0.06,0.02) ZOLY5 0.56 (0.22,1.09) 0.57 (0.24,1.09) -0.02 (-0.06,0.004) ZOLY5 ETID400 1.02 (0.29,3.20) 1.02 (0.31,3.11) 0.001 (-0.05,0.03)

Random-Effect Residual Model Deviance 58.76 vs 60 datapoints Deviance Information Criteria 302.529 PBO=placebo (includes no treatment or background supplementation); ALED5=oral alendronate 5 mg/day or 35 mg/week; ALED10=oral alendronate 10 mg/day or 70 mg/week; RISD5=oral risedronate 5 mg/day or 35 mg/week or 150 mg/month; ETID400=oral cyclic etidronate 400 mg/day; ZOLY5=intravenous zoledronic acid 5 mg/year.

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FIGURE 49-1: CONSISTENCY PLOT FOR WITHDRAWAL DUE TO ADVERSE EVENTS, SECONDARY PREVENTION, BASE CASE

TECHNOLOGY REVIEW Drugs for the Treatment and Prevention of Osteoporosis in Postmenopausal Women 303

SERIOUS ADVERSE EVENTS

BASE CASE ANALYSIS

FIGURE 50: NETWORK GEOMETRY: SERIOUS ADVERSE EVENTS, SECONDARY PREVENTION, BASE CASE

TABLE 85: SERIOUS ADVERSE EVENTS, SECONDARY PREVENTION, BASE CASE: ODDS RATIO, RELATIVE RISK AND RISK DIFFERENCE Treatment Reference OR (95% CrI) RR (95% CrI) RD (95% Crl) ALED5 PBO 0.74 (0.49, 1.10) 0.77 (0.54, 1.08) -0.04 (-0.08, 0.01) ALED10 0.81 (0.65, 1.01) 0.84 (0.69, 1.01) -0.03 (-0.05, 0.001) RISD5 1.02 (0.88, 1.19) 1.01 (0.89, 1.15) 0.002 (-0.02, 0.02) ZOLY5 0.94 (0.73, 1.15) 0.95 (0.77, 1.12) -0.01 (-0.04, 0.02) ZOLS5 1.40 (0.73, 2.70) 1.32 (0.76, 2.12) 0.05 (-0.04, 0.18) ALED10 ALED5 1.10 (0.70, 1.68) 1.08 (0.74, 1.59) 0.01 (-0.04, 0.05) RISD5 1.37 (0.90, 2.13) 1.31 (0.92, 1.93) 0.04 (-0.01, 0.08) ZOLY5 1.27 (0.80, 2.00) 1.22 (0.83, 1.84) 0.03 (-0.03, 0.08) ZOLS5 1.90 (0.86, 4.05) 1.71 (0.88, 3.09) 0.09 (-0.02, 0.22) RISD5 ALED10 1.26 (0.99, 1.61) 1.21 (0.99, 1.50) 0.03 (-0.002, 0.06) ZOLY5 1.15 (0.86, 1.53) 1.13 (0.88, 1.44) 0.02 (-0.02, 0.05) ZOLS5 1.73 (0.87, 3.48) 1.58 (0.89, 2.65) 0.08 (-0.02, 0.21) ZOLY5 RISD5 0.92 (0.69, 1.18) 0.94 (0.73, 1.15) -0.01 (-0.05, 0.02) ZOLS5 1.38 (0.71, 2.69) 1.30 (0.74, 2.12) 0.05 (-0.04, 0.18) ZOLS5 ZOLY5 1.51 (0.76, 2.98) 1.40 (0.79, 2.32) 0.06 (-0.03, 0.19)

Random-Effects Residual Deviance 40.26 vs 42 datapoints Model Deviance Information Criteria 276.449 PBO=placebo (includes no treatment or background supplementation); ALED5=oral alendronate 5 mg/day or 35 mg/week; ALED10=oral alendronate 10 mg/day or 70 mg/week; RISD5=oral risedronate 5 mg/day or 35 mg/week or 150 mg/month; ZOLY5=intravenous zoledronic acid 5 mg/year.

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FIGURE 50-1: CONSISTENCY PLOT FOR SERIOUS ADVERSE EVENTS, SECONDARY PREVENTION, BASE CASE

2.5

1.5

0.5

0 0 0.5 1 1.5 2 2.5

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GASTROINTESTINAL ADVERSE EVENTS

BASE CASE ANALYSIS

FIGURE 51: NETWORK GEOMETRY: GASTROINTESTINAL ADVERSE EVENTS, SECONDARY PREVENTION, BASE CASE

TABLE 86: GASTROINTESTINAL ADVERSE EVENTS, SECONDARY PREVENTION, BASE CASE: ODDS RATIO, RELATIVE RISK AND RISK DIFFERENCE Treatment Reference OR (95% CrI) RR (95% CrI) RD (95% Crl) ALED5 PBO 0.87 (0.62, 1.20) 0.90 (0.68, 1.15) -0.02 (-0.07, 0.03) ALED10 1.07 (0.93, 1.22) 1.05 (0.94, 1.17) 0.01 (-0.01, 0.04) RISD5 1.00 (0.87, 1.14) 1.00 (0.90, 1.11) -0.001 (-0.02, 0.02) ZOLY5 0.58 (0.36, 0.92) 0.64 (0.42, 0.93) -0.08 (-0.13, -0.01) ALED10 ALED5 1.22 (0.87, 1.74) 1.17 (0.90, 1.57) 0.03 (-0.02, 0.09) RISD5 1.14 (0.81, 1.63) 1.11 (0.85, 1.49) 0.02 (-0.04, 0.08) ZOLY5 0.66 (0.37, 1.15) 0.71 (0.44, 1.12) -0.06 (-0.13, 0.02) RISD5 ALED10 0.93 (0.79, 1.11) 0.95 (0.83, 1.09) -0.01 (-0.04, 0.02) ZOLY5 0.54 (0.34, 0.85) 0.60 (0.41, 0.88) -0.09 (-0.14, -0.03) ZOLY5 RISD5 0.58 (0.36, 0.93) 0.64 (0.42, 0.94) -0.08 (-0.13, -0.01)

Random-Effects Residual Deviance 37.42 vs 44 datapoints Model Deviance Information Criteria 289.931 PBO=placebo (includes no treatment or background supplementation); ALED5=oral alendronate 5 mg/day or 35 mg/week; ALED10=oral alendronate 10 mg/day or 70 mg/week; RISD5=oral risedronate 5 mg/day or 35 mg/week or 150 mg/month.

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FIGURE 51-1: CONSISTENCY PLOT FOR GASTROINTESTINAL ADVERSE EVENTS, SECONDARY PREVENTION, BASE CASE

3.5

2.5

1.5

0.5

0 0 1 2 3 4

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ATRIAL FIBRILLATION

BASE CASE ANALYSIS

FIGURE 52: NETWORK GEOMETRY: ATRIAL FIBRILLATION, SECONDARY PREVENTION, BASE CASE

TABLE 87: ATRIAL FIBRILLATION, SECONDARY PREVENTION (BASE CASE): ODDS RATIO, RELATIVE RISK AND RISK DIFFERENCE Treatment Reference OR (95% CrI) RR (95% CrI) RD (95% Crl) ZOLY5 PBO 1.29 (0.50, 3.27) 1.28 (0.51, 3.05) 0.01 (-0.02, 0.06) ZOLS5 1.00 (0.20, 4.64) 1.00 (0.21, 4.27) -0.0001 (-0.03, 0.08) ZOLS5 ZOLY5 0.77 (0.13, 4.54) 0.78 (0.13, 4.22) -0.01 (-0.07, 0.07)

Random-Effects Residual Model Deviance 4.014 vs 4 datapoints Deviance Information Criteria 27.28 PBO=placebo (includes no treatment or background supplementation); ZOLY5=intravenous zoledronic acid 5 mg/year; ZOLS5= single intravenous injection of zoledronic acid 5 mg.

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APPENDIX 13: INVESTIGATION OF NETWORK INCONSISTENCY

TABLE 88: COMPARISON OF BASE CASE NMA AND BASE CASE NMA EXCLUDING QUESTIONABLE STUDY, WITHDRAWAL DUE TO ADVERSE EVENTS, SECONDARY PREVENTION

Original NMA NMA Excluding Sahota 2000 study Treatment Reference OR (95% CrI) OR (95% CrI)

ALED5 PBO 1.69 (0.17,14.30) 1.62 (0.15,14.12) ALED10 1.32 (0.94,1.89) 1.25 (0.90,1.76) RISD5 1.15 (0.79,1.74) 1.13 (0.79,1.69) ETID400 0.63 (0.23,1.66) 1.11 (0.37,3.43) ZOLY5 0.65 (0.29,1.17) 0.66 (0.30,1.16) ALED10 ALED5 0.78 (0.09,8.18) 0.78 (0.09,8.32) RISD5 0.68 (0.08,7.25) 0.70 (0.08,7.35) ETID400 0.37 (0.04,4.47) 0.68 (0.06,9.60) ZOLY5 0.37 (0.04,4.09) 0.40 (0.04,4.60) RISD5 ALED10 0.87 (0.56,1.37) 0.90 (0.59,1.41) ETID400 0.47 (0.16,1.29) 0.89 (0.28,2.88) ZOLY5 0.49 (0.21,0.91) 0.52 (0.24,0.95) ETID400 RISD5 0.55 (0.18,1.53) 0.99 (0.30,3.22) ZOLY5 0.56 (0.22,1.09) 0.58 (0.24,1.11) ZOLY5 ETID400 1.02 (0.29,3.20) 0.58 (0.15,2.02)

Random-Effect Residual Deviance 56.82 vs 58 datapoints 51.33 vs 56 datapoints Model Deviance Information Criteria 292.667 281.957

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TABLE 89: COMPARISON OF BASE CASE NMA AND BASE CASE NMA EXCLUDING QUESTIONABLE STUDY, SERIOUS ADVERSE EVENTS, PRIMARY PREVENTION

Base Case NMA Excluding Base Case NMA Treatment Reference Hooper 2005 study OR (95% CrI) OR (95% CrI) ALED5 PBO 1.10 (0.64,1.80) 1.12 (0.68,1.83) ALED10 0.98 (0.70,1.35) 1.06 (0.76,1.48) RISD5 0.93 (0.58,1.50) 1.28 (0.74,2.22) ETID400 0.86 (0.46,1.66) 0.87 (0.45,1.57) ZOLY5 0.87 (0.48,1.52) 0.90 (0.51,1.56) ZOLS5 0.94 (0.44,1.88) 0.95 (0.46,1.88) ALED10 ALED5 0.89 (0.51,1.60) 0.96 (0.54,1.66) RISD5 0.85 (0.44,1.72) 1.14 (0.56,2.36) ETID400 0.79 (0.35,1.77) 0.78 (0.33,1.66) ZOLY5 0.80 (0.38,1.68) 0.80 (0.38,1.72) ZOLS5 0.85 (0.34,2.05) 0.85 (0.35,2.03) RISD5 ALED10 0.95 (0.60,1.49) 1.20 (0.74,1.98) ETID400 0.88 (0.44,1.82) 0.82 (0.40,1.61) ZOLY5 0.90 (0.48,1.60) 0.85 (0.46,1.53) ZOLS5 0.96 (0.43,2.00) 0.90 (0.41,1.84) ETID400 RISD5 0.93 (0.43,2.05) 0.68 (0.29,1.54) ZOLY5 0.94 (0.45,1.87) 0.71 (0.33,1.47) ZOLS5 1.00 (0.43,2.32) 0.75 (0.30,1.72) ZOLY5 ETID400 1.02 (0.43,2.32) 1.05 (0.46,2.41) ZOLS5 1.08 (0.41,2.76) 1.09 (0.42,2.82) ZOLS5 ZOLY5 1.07 (0.50,2.21) 1.06 (0.51,2.07)

Random-Effect Model Residual Deviance 36.37 vs 40 datapoints 31.69 vs 38 datapoints Deviance Information Criteria 214.253 198.897

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