© Copyright 2012 Oregon State University. All Rights Reserved Drug Use Research & Management Program Oregon State University, 500 Summer Street NE, E35 Salem, Oregon 97301-1079 Phone 503-947-5220 | Fax 503-947-1119 Literature Scan: Bone Resorption Inhibitors and Related Agents Date of Review: July 2016 Date of Last Review: May 2014 Literature Search: April 2014 – April 2016 Current Status of PDL Class: See Appendix 1. Conclusions: The Endocrine Society recommends intravenous (IV) zoledronic acid 5 mg in a single dose for most patients with active Paget’s disease who are at risk for complications unless contraindications exist.1 One systematic review with meta‐analysis found no statistically significant and consistent difference in vertebral and nonvertebral fracture risk reduction between bisphosphonates, denosumab, or teriparatide.2 Denosumab had lower rates of nonvertebral fracture compared to other bisphosphonates or placebo in one systematic review with meta‐analysis but with increased risk for infections.2,3 A systematic review with meta‐analysis found no benefit in terms of risk for vertebral or nonvertebral fractures with bisphosphonate use at 12 months in patients with cystic fibrosis, though a significant increase in percent change in bone mineral density (BMD) of the lumbar spine, hip and femur was found.4 In patients with osteogenesis imperfecta, oral alendronate and IV pamidronate showed no difference in fracture incidence.5 A significant increase was seen in Z‐score BMD between patients dosed 0.2 mg/kg versus 2 mg/kg of IV risedronate.5 No difference in fracture risk was seen in patients treated with zoledronic acid versus pamidronate.5 Bisphosphonate‐treated patients with inflammatory bowel disease had improvements in BMD at the lumbar spine and total hip and lower rates of vertebral and nonvertebral fractures when compared to control groups.6 Early breast cancer patients scheduled to receive aromatase inhibitors had a greater increase in BMD in the lumbar spine in terms of percent change and absolute change when treated with a bisphosphonate compared to calcium or vitamin D supplementation.7 Patients with Parkinson’s disease and previous stroke had reduced rates of hip fractures when treated with bisphosphonates compared to controls.8 Raloxifene was not found to prevent nonvertebral fractures and is associated with a significant rate of severe side effects including thromboembolic events, pulmonary embolism, and fatal strokes.2 Cases of osteonecrosis of the jaw have been reported with bisphosphonate use but are associate much more significantly with IV bisphosphonates versus oral formulations and in patients being treated for malignant conditions.2 No statistically significant difference among any bisphosphonates in terms of gastrointestinal (GI) safety outcomes were found in one systematic review.2 In addition, no significant relationship was discovered between oral alendronate and risedronate for risk of upper GI harms.2 Another systematic review found that zoledronic acid had the highest probability of GI‐related adverse events (91%) followed by etidronate (8%) and alendronate (1%).9 Etidronate (56%) had Authors: K. Delach/ A. Gibler Date: July 2016 the highest rate of upper GI adverse events followed by alendronate (40%) and risedronate (1%).9 The incidence of nausea was highest with zoledronic acid (70%) followed by alendronate (29%), placebo (1%), and risedronate (0%).9 Absolute rates of cardiovascular (CV) events were slightly higher in bisphosphonate‐treated patients (6.5%) versus controls (6.2%) over 25‐36 months.10 The absolute risk of atrial fibrillation conversely was minimally lower in bisphosphonate treated patients (1.4%) versus controls (1.5%) over 25‐36 months though the risk associated with zoledronic acid was somewhat elevated compared to controls (OR 1.24; 95% CI: 0.96 to 1.61).10 Rates of myocardial infarction, stroke, and death from cardiovascular causes were similar at between patients treated with bisphosphonates versus controls.10 Recommendations: No further review or research needed at this time. After the executive session, no changes to the PDL were made. Previous Conclusions and Recommendations: There is no new comparative evidence that suggests changes to previous recommendations are needed: o Consider inclusion of denosumab, zoledronic acid, risedronate, alendronate in various routes and dosing schedules for osteoporosis treatment based upon cost. o Include at least one nitrogen‐containing bisphosphonate for Paget ’s disease (zoledronic acid, pamidronate, risedronate, alendronate or ibandronate). o Make calcitonin, raloxifene and teriparatide non‐preferred due to limited evidence to reduce non‐vertebral and hip fracture risk in post‐menopausal women. Calcitonin has limited evidence for Paget ’s disease. o Make tiludronate non‐preferred as it is only indicated for Paget’s, is not a nitrogen containing bisphosphonate and it has insufficient evidence for osteoporosis treatment. No further review or research needed at this time. Methods: A Medline literature search for new systematic reviews and randomized controlled trials (RCTs) assessing clinically relevant outcomes to active controls, or placebo if needed, was conducted. A summary of the clinical trials is available in Appendix 2 with abstracts presented in Appendix 3. The Medline search strategy used for this literature scan is available in Appendix 4, which includes dates, search terms and limits used. The OHSU Drug Effectiveness Review Project, Agency for Healthcare Research and Quality (AHRQ), Cochrane Collection, National Institute for Health and Clinical Excellence (NICE), Department of Veterans Affairs, BMJ Clinical Evidence, and the Canadian Agency for Drugs and Technologies in Health (CADTH) resources were manually searched for high quality and relevant systematic reviews. When necessary, systematic reviews are critically appraised for quality using the AMSTAR tool and clinical practice guidelines using the AGREE tool. The FDA website was searched for new drug approvals, indications, and pertinent safety alerts. Finally, the AHRQ National Guideline Clearinghouse (NGC) was searched for updated and recent evidence‐based guidelines. The primary focus of the evidence is on high quality systematic reviews and evidence‐based guidelines. Randomized controlled trials will be emphasized if evidence is lacking or insufficient from those preferred sources. Authors: Delach/ Gibler Date: July 2016 New Systematic Reviews: Efficacy: Crandall C, et al. Ann Intern Med. (2014)2 The purpose of this systematic review was to update a previous review on the benefits and harms of pharmacologic treatments used to prevent fractures in at‐ risk adults.2 Three‐hundred and fifteen RCTs and systematic reviews were included.2 Five network meta‐analyses of placebo‐controlled or head‐to‐head trials found that differences in reduction of vertebral and nonvertebral fracture risk among any of the bisphosphonates, denosumab, or teriparatide were not consistent or statistically significant.2 There was also agreement amongst the meta‐analyses that raloxifene does not prevent nonvertebral fractures. In addition, there is less evidence supporting efficacy for nonvertebral fracture reduction for ibandronate than for the other bisphosphonates, denosumab, or teriparatide.2 An increase rate of atypical subtrochanteric fractures is seen in those treated with bisphosphonates but the association has only been established in observational studies, case studies, and case series.2 A meta‐analysis of 5 case‐control studies and 6 cohort studies found an overall pooled risk ratio (RR) of 1.70 (95% CI: 1.22 to 2.37).2 Data are sufficient to conclude that bisphosphonate use increases the risk for atypical femoral fractures though the strength of evidence is low.2 The risk of atypical femoral fracture is lower (30‐100 fold) than the risk of hip fracture among untreated persons with osteoporosis. Use of denosumab has also been linked to occurrences of atypical femoral fractures.2 An increased risk of esophageal cancer was seen in 2 observational studies but was not seen in 2 others.2 Several observational studies have found no increased risk or statistically significant decreases in risk for all types of cancer in general.2 A meta‐analysis of 4 studies found no statistically significant risks (OR 1.74; 95% CI: not reported) for esophageal cancer in patients with bisphosphonate treatment.2 An evaluation of teriparatide found no association with osteosarcoma after 7 years of follow‐up.2 Five studies (2 observational studies, 2 meta‐analyses, and 1 systematic review) did not find an increased risk of atrial fibrillation and 1 meta‐analysis found an increased risk of atrial fibrillation with bisphosphonate use.2 The previous review showed an increased risk for mild upper gastrointestinal side effects with use of alendronate (OR 1.07; 95% CI: 1.01 to 1.14), teriparatide (OR 3.26; 95% CI: 2.82 o 3.78), and denosumab (OR 1.74; 95% CI: 1.29 to 2.38).2 A network meta‐analysis did not find any statistically significant differences among any bisphosphonates in terms of gastrointestinal safety outcomes.2 A case‐control study found no significant relationship between oral alendronate or risedronate for the risk of subsequent hospitalizations for serious upper gastrointestinal harms (e.g., perforations, ulcers, and bleeding).2 Pooled data from 4 trials of denosumab showed an increased risk for infection (RR 1.28; 95% CI: 1.02 to 1.60).2 Twenty‐three publications and 2408