Expert Opinion On Pharmacotherapy

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Management of Severe

Journal: Expert Opinion On Pharmacotherapy

Manuscript ID EOOP-2015-0304.R1

Manuscript Type: Review

severe osteoporosis, management of severe osteoporosis, treatment of Keywords: high risk osteoporotic patients, pharmacological therapy of severe osteoporosis

URL: http://mc.manuscriptcentral.com/eoop Email: [email protected] Page 1 of 111 Expert Opinion On Pharmacotherapy

1 2 3 Reviewer Comments: 4 5 6 Referee 1: 7 8 9 This review focuses on recognition and treatment of severe osteoporosis. The high risk patients have 10 11 been defined according to author opinion and appropriate treatment to reduce their fracture risk was 12 13 revised. 14 For Peer Review Only 15 16 Several points need to be clarified: 17 18 1) Page 3; I have some concerns about the definition of severe osteoporosis and the categorization 19 20 provided by the author. In fact, at point 3, “pre-menopausal women or young men with lower extremity 21 22 fractures” are included in the group of “Osteoporosis associated with systemic diseases that are also 23 24 25 associated with low bone formation and turnover”, but it is not clear which systemic diseases the author 26 27 refers to. Moreover, chronic kidney disease are considered to be associated with low bone formation 28 29 and turnover, but this is not always the case, since in chronic kidney disease a large spectrum of 30 31 32 different bone involvement can be observed, including high bone turnover. Moreover, regarding 33 34 multiple myeloma and MGUS, multiple factors that either increase osteoclast-mediated bone loss or 35 36 suppress osteoblast-mediated bone formation have been described, but this does not imply low bone 37 38 39 turnover (see Drake MT, J Bone Miner Res, 2014). 40 41 2) Page 8 lines-55-58. The sentence seems to affirm that “first line” vs “second line” therapies are 42 43 exclusively based on health-economics; put this way, this statement appear to be rather simplistic and I 44 45 believe that reasons related to efficacy, safety, potency may concur to discriminate a first vs. a second 46 47 48 line therapy. Please, clarify. 49 50 3) Page 9, lines 39-47. This paragraph seems too generic. I do not believe that in considering parenteral 51 52 therapy for osteoporosis zoledronate, ibandronate, and are alternative choices 53 54 55 to be put at the same level. 56 57 4) Page 11, lines 43-45. The author writes that “There is no greater risk for a second fracture once the 58 59 60 URL: http://mc.manuscriptcentral.com/eoop Email: [email protected] Expert Opinion On Pharmacotherapy Page 2 of 111

1 2 3 first fracture has occurred”; this is probably a mistake, since this is contrary to what known and also to 4 5 6 what is stated by the author himself several times in the text – please correct. 7 8 5) Page 11, lines 45-53. This statement is too strong. It is obvious that an intravenous route of 9 10 administration ensures that the drug is delivered to the site of action, but this applies to all drugs. The 11 12 13 sentence regarding oral that “their absorbability is so erratic and uncertain” is an 14 For Peer Review Only 15 author’s opinion and this should be outlined. To my knowledge, there are no clinical trials comparing 16 17 oral and intravenous bisphosphonates in terms of how predictable are of their serum levels – please 18 19 provide supporting evidence for your statement or revise your paper appropriately. 20 21 22 6) Page 17, lines 41. Figure X regarding is lacking – please ensure all figures are provided/ or 23 24 correctly cited throughout the text. 25 26 7) There are several typing errors and errors in grammar throughout the text, please carefully review 27 28 29 your paper to address these mistakes. 30 31 8) Some references mentioned in the text are incomplete and not listed in the references section, please 32 33 carefully review your paper and address these changes 34 35 36 37 38 Referee 2: 39 40 In this paper, the treatment of severe osteoporosis is reviewed. The topic is of interest, particularly at a 41 42 time when secondary fracture prevention is becoming a management priority. 43 44 45 1. The review is very US centred, please can the author provide information regarding Europe and the 46 47 Rest of World management 48 49 2. May be the WHO definition of severe osteoporosis could be extended in the future, by including other 50 51 52 risk factors. It would be interesting to know the author’s opinion with this respect – please discuss 53 54 3. « IOF and NBHA » should be read instead of the opposite (p 3). 55 56 4. p 7, line 17, the sentence should be rewritten, to provide clarity to the reader 57 58 59 60 URL: http://mc.manuscriptcentral.com/eoop Email: [email protected] Page 3 of 111 Expert Opinion On Pharmacotherapy

1 2 3 5. p 8, medical societies other than ACR have also taken positions regarding GIOP, please discuss. 4 5 6 6. Please comment that the FDA, EMA and other agencies also have registration guidelines. 7 8 7. p 9, the registration of generics is based on similar PK and PD, and not necessarily on BMD efficacy 9 10 similarity. Could the author verify this point? 11 12 13 8. p 11, ibandronate is not registered for non-vertebral fracture. This should be specified. 14 For Peer Review Only 15 9. The spelling of denosumab should be corrected. 16 17 10. p 16, the right reference is likely Seeman and Martin, and not Eisman and Seeman, please can the 18 19 author review and correct as appropriate. 20 21 22 11. How could a wide use of bone turnover markers contribute to a better management of severe 23 24 osteoporosis? Please discuss. 25 26 12. p 20, depending on the experimental system, areal BMD could account for up to 80% of bone 27 28 29 strength variance. The 50% mentioned is not the rule, please correct. 30 31 13. How does the drug efficacy review specifically pertain to severe osteoporosis and not to 32 33 osteoporosis in general? Please make sure this is clear to the reader 34 35 36 37 38 39 40 Referee 3: 41 42 1. The review seems inaccurate, there are a lot of typos and copy and paste errors, see for example line 43 44 45 19: "Finally, the number one cause of the loss of independence in" - please carefully review your paper 46 47 for quality of English language and grammar. 48 49 2. The figures are of low quality and need to be improved before publication 50 51 52 3. Figure X cited within the text does not exist, please cite the correct figure 53 54 4. Table II is not cited, please add a citation. 55 56 5. Reference citations within the text are inaccurate, please carefully review and make changes where 57 58 59 60 URL: http://mc.manuscriptcentral.com/eoop Email: [email protected] Expert Opinion On Pharmacotherapy Page 4 of 111

1 2 3 necessary. 4 5 6 6. The author does not consider SERMs in the treatment of severe osteoporosis – please can authors 7 8 provide discussion on SERMs. 9 10 11 12 13 Editorial Comments: 14 For Peer Review Only 15 1. Please number your section headings and subheadings. 16 17 2. Small figures should be 300 dpi and large figures should be 72 dpi. 18 19 3. Please provide a copy of permission to use for each of your figures and tables from previous 20 21 22 publications 23 24 4. Please provide an article highlights box, in the form of a bulleted list of five or six statements, covering 25 26 the key aspects of your paper. 27 28 29 5. Please use “et al.” in place of fourth and subsequent authors in the reference list, and delete periods 30 31 from the end of each reference in the list. 32 33 6. Please provide a few reference annotations (*=of importance, **= of considerable importance, 34 35 36 followed by a brief sentence explaining why the reference is considered to be of interest). 37 38 39 40 41 42 Response to reviewer comments: 43 44 45 Reviewer #1 : Thank you. 46 47 48 I have removed the reference to pre-menopausal women with lower extremity fractures. For general 49 50 information, while these young otherwise healthy patients with spontaneous mid-shaft femur fractures 51 52 do represent a form of severe disease (and on bone biopsy do have very low bone formation) as 53 54 published by The Columbia University (NYC) group (Cohen A et al), and, whom I myself have 6 such 55 56 57 58 59 60 URL: http://mc.manuscriptcentral.com/eoop Email: [email protected] Page 5 of 111 Expert Opinion On Pharmacotherapy

1 2 3 patients with similar fractures and histomorphometric findings, I am also sensitive to overstating a very 4 5 6 rare condition. 7 8 9 I have also clarified what, in my opinion constitutes “severe” osteoporosis. 10 11 12 As a nephrologist, this author is well aware of the spectrum of bone turnover in chronic kidney disease 13 14 (CKD) but the statementFor under Peer item #3 was specificaReviewlly discussing low Only bone turnover. 15 16 17 Finally, I have added reference to the osteoblast dysfunction in multiple myeloma and MGUS, including 18 19 Dr. Drake’s work. 20 21 22 I have expanded the basis for pharmacy formularies of insurance plans giving a hierarchy of first line vs 23 24 second line therapies to include evidence for safety and efficacy in these decisions. In addition, I have 25 26 27 added a sentence stressing that among the parenteral therapies, and denosumab have 28 29 the most robust evidence for global fracture reduction. 30 31 32 I have removed the sentence: “There is no greater risk for a second fracture once the first fracture has 33 34 occurred.” 35 36 37 I have expanded the issue of the bioavailability of oral as opposed to intravenous bisphosphonates, 38 39 40 added the sentence that, as suggested, there are no head-to-head studies comparing the efficacy of oral 41 42 vs intravenous preparations; and, added a reference to these data. 43 44 45 I have removed the figure (that was missing anyway-my apologies) to Cathepsin K. Since I don’t provide 46 47 figures for the other agents it would also make the paper imbalanced to only provide a MOA for one 48 49 50 agent. 51 52 53 The grammar, and references have been improved and updated. 54 55 56 Reviewer #2 : Thank you. 57 58 59 60 URL: http://mc.manuscriptcentral.com/eoop Email: [email protected] Expert Opinion On Pharmacotherapy Page 6 of 111

1 2 3 My apologies if it appeared that the paper is too USA centered. That was never an intention. In fact, the 4

5 st nd 6 1 and 2 paragraphs comment on Canadian and the IOF (FLS) work. I have expanded the European 7 8 phrases; given credit as proper to the IOF and, of course, the WHO (FRAX) which were included in the 9 10 original draft. In addition 88 of the 178 references have non-USA persons as the first author. 11 12 13 I have added the reference (Siris E et al) referring to the work of attempting to expand the definition of 14 For Peer Review Only 15 16 osteoporosis, and put the IOF ahead of the NBHA in the Introduction commenting on FLS; and, added 17 18 EULAR to the European leaders providing guidance on GIOP. 19 20 21 I have corrected the reference to Seeman and Martin, clarified the point that ibandronate is not 22 23 registered for the reduction in non-vertebral fractures, and expanded the use of bone turnover markers. 24 25 26 Reviewer #3 : Thank you. 27 28 29 I have diligently been careful to correct typos and misspellings. There is nowhere in this original article 30 31 that I “copied and pasted” except the Figures. 32 33 34 I have provided improved imaging for the figures 35 36 37 Tables I and II are original 38 39 40 Thanks to each and every reviewer for their time and very constructive comments. 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 URL: http://mc.manuscriptcentral.com/eoop Email: [email protected] Page 7 of 111 Expert Opinion On Pharmacotherapy

1 2 3 Management of Severe Osteoporosis 4 5 6 Abstract: 7 8 9 Introduction 10 11 12 Severe osteoporosis represents a disease of high mortality and morbidity. Recognition of what 13 14 For Peer Review Only 15 constitutes and causes severe osteoporosis and aggressive intervention with pharmacological agents 16 17 with evidence to reduce fracture risk are outlined in this review. 18 19 20 Areas Covered 21 22 23 This review is a blend of evidence obtained from literature searches from PubMed and The National 24 25 Library of Medicine (USA), clinical experience and the author’s opinions. The review covers the 26 27 recognition of what constitutes severe osteoporosis, and provides up-to-date references on this sub-set 28 29 30 of high risk patients 31 32 33 Expert Opinion 34 35 36 Severe osteoporosis can be classified by using measurements of bone densitometry, identification of 37 38 prevalent fractures, and, knowledge of what additional risk factors contribute to high fracture risk. Once 39 40 recognized, the potential consequences of severe osteoporosis can be mitigated by appropriate 41 42 43 selection of pharmacological therapies and modalities to reduce the risk for falling. 44 45 46 47 48 49 Article Highlights: 50 51 52 1. Osteoporosis is largely underdiagnosed and undertreated 53 54 2. The annual costs of osteoporotic fractures exceeds and annual costs of caring for myocardial 55 56 infarction, cerebrovascular accidents and breast cancer 57 58 59 60 URL: http://mc.manuscriptcentral.com/eoop Email: [email protected] Expert Opinion On Pharmacotherapy Page 8 of 111

1 2 3 3. The underdiagnoses of osteoporosis is largely due to the declining utilization of bone mineral 4 5 6 density; the under detection of vertebral compression fractures; and the under appreciation 7 8 that a low trauma fracture is women or men after the age of 50 years is a strong risk factor for 9 10 future fragility fractures in untreated people. 11 12 13 4. Severe osteoporosis constitutes a sub-group where the fracture risk is extraordinarily high. 14 For Peer Review Only 15 5. There are a number of registered pharmacological choices that can be considered in severe 16 17 osteoporosis. 18 19 6. New therapies in development will offer an even wider variety of therapies for severe 20 21 22 osteoporosis with new mechanisms of action. 23 24 25 26 27 28 29 30 31 1. Introduction 32 33 34 Osteoporosis is both an underdiagnosed and undertreated disease [1, 2]. The annual costs in the 35 36 United States of America (USA) of caring for osteoporotic-related fractures parallels or exceeds 37 38 39 the annual costs of caring for myocardial infarction, breast cancer and/or cerebrovascular 40 41 accident [3](Figure I). Globally, addition, in a large Manitoba, Canada study the ratio of the 42 43 total annual costs of either prevalent or incident osteoporotic related fractures exceeds the same 44 45 46 ratio calculation for many other serious chronic diseases [3, 4]. Furthermore, recently published 47 48 by Oden and colleagues demonstrated that individuals with a high probability of osteoporotic 49 50 fractures compromise a very significant disease burden to society and that this burden is set to 51 52 53 increase markedly in the future. Equally as disturbing is the data showing that the percent of 54 55 patients receiving a registered therapy for osteoporosis, even after sustaining a hip fracture, has 56 57 58 59 60 URL: http://mc.manuscriptcentral.com/eoop Email: [email protected] Page 9 of 111 Expert Opinion On Pharmacotherapy

1 2 3 declined from 41% in 2001 to 21% in 2010 Figure[5]. Finally, a major contributor to the loss of 4 5 6 independence in subjects 70 years of age and older are falls at home and fragility fractures [6, 7]. 7 8 9 There are many opinions regarding our decline in the awareness and treatment of osteoporosis. 10 11 The international movement to develop Fracture Liaison Services (FLS), spearheaded 12 13 internationally by The International Osteoporosis Foundation (IOF) and in the USA by The 14 For Peer Review Only 15 16 National Bone Health Alliance (NBHA), is a multi-disciplinary effort to reduce the incidence of 17 18 the second osteoporotic fracture [8, 9]. The FLS relies on developing mechanisms and pathways 19 20 21 to identify patients admitted to hospitals, emergency rooms, or urgent care clinics with an 22 23 osteoporotic fracture and direct those patients into a well-developed osteoporotic management 24 25 and treatment plan. 26 27 28 The greatest risk factor for developing a second osteoporotic fracture is the occurrence of the 29 30 31 first osteoporotic fracture [10-14]. There is broad international agreement that a low trauma 32 33 fracture after the age of 50 years of age in post-menopausal women or men merits first, an 34 35 36 evaluation for secondary causes of osteoporosis; and, second, pharmacological therapy for 37 38 osteoporosis in addition to adequate and [15-18] . Justifications for these 39 40 recommendations are based on the population data previously cited showing the high risk of a 41 42 43 second fracture flowing the first fracture in untreated subjects; and, the clinical trial data 44 45 providing evidence that fracture reduction with pharmacological agents for osteoporosis reduces 46 47 fractures above and beyond that reduction in fracture seen with vitamin D and calcium alone [19- 48 49 50 22]. This manuscript will define in the author’s opinion what constitutes severe osteoporosis, 51 52 and, what this author’s opinion is regarding approaches’ to management of the high risk patient. 53 54 55 1. Severe Osteoporosis 56 57 58 59 60 URL: http://mc.manuscriptcentral.com/eoop Email: [email protected] Expert Opinion On Pharmacotherapy Page 10 of 111

1 2 3 The word severe in Webster’s dictionary can mean “critical or grave”. This term is appropriate 4 5 6 for a certain magnitude of severity in bone strength which is comprised of bone mineral density 7 8 (BMD) and/or bone quality. While clinicians can measure BMD by dual energy x-ray 9 10 11 absorptiometry (DXA), we lack the clinical tools to quantitate bone quality. Bone quality can be 12 13 measured at the current time by a number of research methods (high resolution central or 14 For Peer Review Only 15 peripheral quantitative computerized tomography, micro-magnetic imaging resolution [23, 24]. 16 17 18 Recently, an office based methodology that is based on a grey-scale derived from the spine DXA 19 20 imaging, trabecular bone score (TBS) has been approved by international registration agencies 21 22 and offers a point-of-care means to quantitate a portion of bone quality [25-27]. TBS values 23 24 25 increase fracture risk prediction above and beyond that risk calculated by DXA alone and has 26 27 been added to the World Health organization’s (WHO) risk calculator, FRAX™ (Figure III) [28, 28 29 29]. 30 31 32 Severe osteoporosis constitutes a wide spectrum of skeletal disorders that all carry the common 33 34 35 term, osteoporosis. The categories of severe osteoporosis should be made distinct from 36 37 osteoporosis in general due to the very high risk for fracture high mortality and morbidity that 38 39 40 accompanies severe osteoporosis [30-32]. There are a broad range of conditions that might be 41 42 associated with severe osteoporosis: 43 44 45 1. Severe postmenopausal osteoporosis or severe male osteoporosis [33, 34] 46 47 2. Glucocorticoid-induced osteoporosis [35-38] 48 49 50 3. Osteoporosis associated with systemic diseases that may also be associated with low bone 51 52 formation and turnover such as diabetes mellitus; chronic kidney disease, multiple 53 54 myeloma and MGUS (monoclonal gamopathy of undetermined significance). Each of 55 56 57 these conditions may have low bone formation associated with elevation in the serum of 58 59 60 URL: http://mc.manuscriptcentral.com/eoop Email: [email protected] Page 11 of 111 Expert Opinion On Pharmacotherapy

1 2 3 inhibitors of osteoblast function [39-45]. These diseases are also associated with poor 4 5 6 bone quality. 7 8 4. Osteoporosis associated with systemic diseases that are also associated with high bone 9 10 11 turnover: e.g. severe primary hyperparathyroidism; immobilization (e.g. quadriplegia) 12 13 [46-50]. Osteoporosis associated with systemic diseases associated with frailty and a high 14 For Peer Review Only 15 risk for fractures from falls: e.g. Parkinson’s disease, multiple sclerosis, polio, 16 17 18 amyotrophic lateral sclerosis (ALS), and diseases associated with marked sarcopenia 19 20 (deficiency of muscle mass and strength), particularly malabsorption syndromes, age- 21 22 related sarcopenia, and myopathies of diffuse etiologies [51-55]. 23 24 25 2. Severe Postmenopausal and male osteoporosis 26 27 28 There are certain risk factors that place a patient of either gender into the severe category 29 30 regardless of underlying mechanisms of osteoporosis disease: 31 32 33 1. A prior low trauma fracture after the age of 50 years 34 35 36 2. Very low BMD (or T-scores) in older patients 37 38 3. A very high FRAX™ score 39 40 The presence of a low trauma fracture in women or men past the age of 50 years is greatest 41 42 43 risk factor for a second fracture in untreated individuals [10, 56, 57]. Fractures of the hands, 44 45 feet, and skull are currently not considered osteoporotic fractures since they do not predict 46 47 future fracture risk in untreated patients. One exception before discounting metatarsal 48 49 50 fractures: metatarsal fractures may suggest the presence of adult hypophosphatasia (HPP), 51 52 which is becoming increasingly diagnosed due to greater awareness of examining laboratory 53 54 reports for low or low-normal serum total alkaline phosphatase [58]. The underlying 55 56 57 pathophysiology of HPP is a decrease in osteoblast production of alkaline phosphatase and 58 59 60 URL: http://mc.manuscriptcentral.com/eoop Email: [email protected] Expert Opinion On Pharmacotherapy Page 12 of 111

1 2 3 the adult patients can present with a singular skeletal manifestation (e.g. metatarsal fractures, 4 5 6 lower extremity large bone (mid-shaft femur) fractures and/or poor dentation. The total 7 8 serum alkaline phosphatase is often below 40 IU/l in these patients; and, if suspected can be 9 10 11 followed up by looking for an elevated serum phosphorus and elevated pyridoxal phosphate 12 13 (vitamin B6). 14 For Peer Review Only 15 16 The most common, and often unrecognized low trauma fracture that conveys a high risk for 17 18 future fracture are vertebral compression fractures (VCF). The reality is that most VCF are 19 20 21 missed by clinicians [59-61]. The reasons behind this under diagnosis and under treatment of 22 23 VCF include: 24 25 26 1. A lack of awareness that the majority of VCF are asymptomatic. Clinicians are looking 27 28 for pain as the clue to the possible presence of a VCF [62-64]. 29 30 31 32 2. The under- appreciation that even morphometric (radiological detected) VCF convey a 33 34 high risk, not only for more VCF but also for other further fractures at other skeletal sites [65- 35 36 69]. 37 38 39 3. That vertebral compression fractures may exists even though the T-score is normal [70, 40 41 42 71] [72]. 43 44 45 4. That simple height measurements are often not done in physician offices; or rather, if 46 47 done, are often done on inaccurate scales (e.g. the “metal rod”) rather than the wall mounted and 48 49 inexpensive stadiometer [33, 73]. 50 51 52 5. Height loss should be the alerting signal that a VCF may be present. Both The Canadian 53 54 55 practice guidelines as well as The International Society for Clinical Densitometry (ISCD) has 56 57 58 59 60 URL: http://mc.manuscriptcentral.com/eoop Email: [email protected] Page 13 of 111 Expert Opinion On Pharmacotherapy

1 2 3 established specific prevalent or interval height loss values that has a high probability of 4 5 6 detecting either a prevalent or incident VCF [74, 75]. 7 8 9 6. The underreporting of the presence of VCF by radiologists examining routine PA and 10 11 lateral chest-x-ray [76-79]. 12 13 14 When an asymptomaticFor VCF Peer is detected, Revieweven though the date ofOnly when the VCF occurred is 15 16 17 unknown, there is a high risk for global fracture risk in untreated patients. Vertebral compression 18 19 fractures are graded by severity according to the degree of vertebral compression [80-82] (Figure 20 21 IV). The greater the severity of compression or the greater the number of prevalent VCF, the 22 23 24 greater the risk for future fractures [13, 83-85]. 25 26 27 While low BMD is a strong predictor for future fracture risk, fracture risk as a function of low 28 29 BMD is highly age dependent [86] (Figure V). For every decade above the age of 50 years, 30 31 32 future fracture risk approximately doubles by decade at the same BMD. While more elderly 33 34 patients may fall more, and this greater risk for falling is certainly a partial reason for the greater 35 36 fracture risk as age increases, the relationship between increased age and fracture risk is also 37 38 39 independent of falls. Bone strength, a composite of BMD and bone quality, is poorer in older 40 41 patients as compared to younger patients. Practically, management recommendations for 42 43 osteoporosis therapy should be different in a patient at 50 years of age with a T-score of -2.5 as 44 45 46 compared to a patient of 80 year with the same T-score of -2.5. The fracture risk is ~6X greater 47 48 in the 80 year old at the same BMD. 49 50 51 The WHO Fracture Risk Assessment Model (FRAX™) is a health-economic model to assess the 52 53 risk for a major osteoporotic fracture or hip fracture over a 10 year period in untreated 54 55 56 postmenopausal women and older men [86]. Based on a robust dataset, FRAX™ has provided a 57 58 59 60 URL: http://mc.manuscriptcentral.com/eoop Email: [email protected] Expert Opinion On Pharmacotherapy Page 14 of 111

1 2 3 validated model to help guide clinicians as to which patients may need pharmacological therapy 4 5 6 to reduce the risk of future fracture. While the provision of 20% for major fracture or 3% for hip 7 8 fracture to consider treatment is based on a cost-effective analysis using the annual cost of 9 10 11 alendronate at the time FRAX™ was developed, it is also know that broad clinical judgement 12 13 must be incorporated along with FRAX™ to make treatment decisions[87-89]. For example, 14 For Peer Review Only 15 FRAX™ did not capture fall rates or doses of glucocorticoids into the model; nor a number of 16 17 18 additional diseases that may contribute to greater skeletal fragility, such as chronic kidney failure 19 20 or diabetes mellitus. Hence while prevalent fracture, low BMD and increased age constitute the 21 22 most robust 3 risk factors for future fracture risk, clinicians must incorporate a wide range of risk 23 24 25 factors, some captured and some not captured in FRAX™ to make treatment decisions. The 26 27 National Osteoporosis Foundation’s Clinician’s Guide for the management of osteoporosis and 28 29 The European guidance for the diagnosis and management of osteoporosis in post-menopausal 30 31 32 women also provide evidence-based as well as opinion-based recommendations for initiating 33 34 pharmacological therapy [15, 16, 90]. One of the hindrances to physician management and 35 36 37 decisions to initiate therapy in today’s changing health-economic environment are the 38 39 restrictions imposed on physician judgement by insurance company “phantom” physicians or 40 41 administrators who have no accountability for the patient’s health. Payer’s often base their 42 43 44 decisions on simple economic numbers such as in the FRAX™ model without knowledge of the 45 46 broad clinical issues that modulate individual patient management. Expanding the definition of 47 48 osteoporosis by using the risk for fracture as a threshold and /or the expansion of diagnostic sub- 49 50 51 categories for the diagnosis by a new International Classification of Disease 10 (ICD-10) has 52 53 been suggested [90]. Whether or not these expanded criteria simplify diagnosis and management 54 55 or make it more complex will be measured by quantitating if these newer approached increase 56 57 58 59 60 URL: http://mc.manuscriptcentral.com/eoop Email: [email protected] Page 15 of 111 Expert Opinion On Pharmacotherapy

1 2 3 the proportion of patients treated. The patient and her/his health care management lie in the 4 5 6 hands of the physician who not only has medical, moral, and legal accountability for their 7 8 patient’s care, but also the broad knowledge of the patient’s clinical situations. 9 10 11 4. Glucocorticoid-Induced Osteoporosis (GIOP) 12 13 14 GlucocorticoidsFor inhibit osteoblast Peer activity Review [36, 90]. In that regard, Only a major effect of 15 16 17 glucocorticoids on fracture risk is a decrease in bone formation. The effect of glucocorticoids on 18 19 bone strength is both dose and duration related. Low dose prednisone, even at a dose of 2.5 20 21 mg/day will convey a great risk for fractures than no dose and not as great as 5.0 mg/day. Even 22 23 24 higher (> 15 mg/day) sustained doses of glucocorticoids may induce fractures, particularly 25 26 multiple VCF within a short (months) period of time [91-92]. 27 28 29 While low BMD is a strong predictor of fracture risk in PMO and male osteoporosis, BMD is not 30 31 32 as strong a predictor for fracture in GIOP. In part, this is related to the fact that glucocorticoids 33 34 inhibit osteoblast function and bone formation. Hence, impaired bone quality rather than low 35 36 BMD is a major component of the fracture risk in GIOP. While patients who have already 37 38 39 sustained a GIOP related fracture, or those with very low BMD (T-scores of -2.5 and lower) and 40 41 older age certainly constitute a high risk group, the challenge for clinicians is in deciding what 42 43 patients may need pharmacological therapy who are younger, have not fractured and have higher 44 45 46 BMD that are committed to chronic glucocorticoid therapy. Risk factors are not as predictive for 47 48 future fracture risk in GIOP as they are in PMO [93]. Certainly the higher the dose of 49 50 glucocorticoid and the longer the duration of use are strong considerations for the timing of the 51 52 53 initiation of therapy for GIOP. Like all guidelines, the both European as well as USA guidelines 54 55 recognize the role that broad clinical judgement plays in ultimate management decisions [94]. 56 57 58 59 60 URL: http://mc.manuscriptcentral.com/eoop Email: [email protected] Expert Opinion On Pharmacotherapy Page 16 of 111

1 2 3 5. Other Categories of Severe Osteoporosis 4 5 6 The other categories representing severe osteoporosis listed in the introduction of this manuscript 7 8 9 have been previously dealt with in individual peer-reviewed publications. The use of specific 10 11 pharmacological agents for any specific condition will be included in the choices of 12 13 pharmacological agents in the remainder of this paper. 14 For Peer Review Only 15 16 17 6. Treatment of Severe Osteoporosis 18 19 20 The list of Food and Drug Administration (FDA) and European Medicine Agency (MEA) 21 22 approved pharmacological agents for the treatment of PMO are shown in Table I. In general, 23 24 pharmacological agents are divided into drugs that inhibit (anti-resorptive) and 25 26 27 drugs that stimulate bone formation (anabolic) [95-99]. To date, there are no published data 28 29 comparing the efficacy between or among these agents on the most important outcome-fracture 30 31 32 risk reduction. While there are comparative studies examining important surrogate markers of 33 34 bone strength (BMD and/or bone turnover markers {BTM} between or among agents that have 35 36 been published, suggesting differences between or among pharmacological agents, it is unknown 37 38 39 if these differences in BMD or BTM translate into differences in fracture risk as compared to 40 41 placebo since the criteria for registration are fracture end-point [99] [101, 102]. 42 43 44 Opinions about what is “first line” vs “second-line” therapies, the terminology created by payers 45 46 and/or professional organization practice guidelines, are based on a combination of 47 48 49 efficacy/safety and costs. As pharmacological agents become “generic” and costs for therapies 50 51 decline, it is logical for payers to prefer a generic agent. Generics agents in the osteoporosis field 52 53 do not require the same stringent evidence for efficacy for registration as is required for the 54 55 56 initial registration of the branded drug (e.g. fracture risk reduction). The generics only have to 57 58 59 60 URL: http://mc.manuscriptcentral.com/eoop Email: [email protected] Page 17 of 111 Expert Opinion On Pharmacotherapy

1 2 3 show that as compared to the original registered agent, the BMD increases in a non-inferiority 4 5 6 manner to the same degree as the branded formulation [103]. While this non-fracture end-point 7 8 seems acceptable, it is important to recognize that due to the nature of the very poor absorption 9 10 11 of oral bisphosphonates [104,105], patients with gastrointestinal diseases that may affect 12 13 absorption such as celiac disease, malabsorption syndromes, small bowel 14 For Peer Review Only 15 resections, and gastric bypass differ from the subjects in clinical trials. For this reason alone, 16 17 18 monitoring the biological effect of oral bisphosphonates on bone metabolism is important [44, 19 20 106, 107 ]. 21 22 23 Measuring serial BMD and BTM is one way of gaining some assurance that the oral generic 24 25 bisphosphonate, the most widely prescribed therapy for osteoporosis, is “working”. Increases in 26 27 28 BMD or declines in BTM with pharmacological therapy using anti-resorptive agents are 29 30 associated with reductions in fracture risk [108-110 ]; and, increases in bone formation 31 32 (osteoblast activity markers) with teriparatide are associated with improvements in BMD and 33 34 35 bone microarchitecture. 36 37 38 The selective estrogen receptor modulators (SERMS) have evidence for reduction in vertebral 39 40 fracture but not for non-vertebral fractures [111]. Certainly in patients with severe osteoporosis 41 42 43 and a high risk for non-vertebral fractures, a SERM should not be a viable treatment option. 44 45 46 While the oral bisphosphonates, alendronate, risedronate and ibandronate are all effective and 47 48 worthy, and, have variable evidence for either reduction in vertebral, non-vertebral and/or hip 49 50 fracture risk, they may have compliance issues as well as gastrointestinal tolerability issues that 51 52 53 mitigate their effectiveness. Ibandronate is also not registered for the reduction in non-vertebral 54 55 fractures [112]. 56 57 58 59 60 URL: http://mc.manuscriptcentral.com/eoop Email: [email protected] Expert Opinion On Pharmacotherapy Page 18 of 111

1 2 3 When the physician has concerns about compliance, absorption, tolerability or effectiveness, the 4 5 6 administration of a parenteral therapy for osteoporosis is a viable option. Parenteral therapies 7 8 guarantee that the delivery of the drug to the bone site, include intravenous bisphosphonates 9 10 11 (zoledronic acid or ibanadronate), subcutaneous administration of denosumab and the anabolic 12 13 agent, teriparatide. Each agent has evidence for efficacy in reducing the risk of fractures and 14 For Peer Review Only 15 different mechanisms of action (MOA) for strengthening bone [116-119]. On examining 16 17 18 individual clinical trial data, intravenous zoledronic acid and denosumab have the most robust 19 20 evidence for reduction in all fractures: vertebral, non-vertebral including hip fractures [120-121]. 21 22 23 7. Pharmacological Choices in Severe Osteoporosis 24 25 26 While all of the pharmacological agents have efficacy for fracture risk reduction, there are 27 28 circumstances where the physician believes it is important to intervene in a severe situation 29 30 31 where the risk is very high. These situations would include: 32 33 34 1. A recent (<12 months) fracture 35 36 2. Fractures occurring while already receiving an osteoporotic agent 37 38 39 3. Fractures that have a “cascade” pattern, e.g. recurrent vertebral compression fractures 40 41 4. Fractures occurring in the setting of high dose glucocorticoid use 42 43 44 Recent fractures or cascade fracture events require immediate treatment. Both situations are very 45 46 serious and can be life-threatening since they represent the extremes of risk. The terrible cascade 47 48 49 vertebral fracture clinical situation is unusual but is associated with tremendous and rapid loss of 50 51 height, pulmonary function, pain and a very high morbidity and mortality [34, 69, 122-123] . For 52 53 any acute fracture the risk for the 2 nd fracture is greatest in the first 12 months following a 54 55 56 fracture [124]. 57 58 59 60 URL: http://mc.manuscriptcentral.com/eoop Email: [email protected] Page 19 of 111 Expert Opinion On Pharmacotherapy

1 2 3 Fractures occurring while on a previous osteoporotic (usually an oral bisphosphonate) are 4 5 6 common. In part, this observation is due to the fact that no pharmacological agent abolishes 7 8 fracture risk-they reduce risk. Second, issues with compliance are prevalent; and, there are 9 10 11 situations where compliance and bioavailability of the bisphosphonate are insured yet the patient 12 13 does not respond. While “non-response” may be unusual, there are reversible factors that could 14 For Peer Review Only 15 mitigate a non-response such as vitamin D deficiency or celiac disease. Since oral 16 17 18 bisphosphonate blood levels cannot be measured in clinical practice the physician must use serial 19 20 BMD and BTM to assess biological effects of the drug. While a decline in BMD beyond the least 21 22 significant change (LSC) of the precision of DXA is unacceptable, a stable or increasing BMD is 23 24 25 acceptable since both are associated with fracture risk reduction. Likewise, for anti-resorptive 26 27 agents, a decline in bone turnover markers beyond their LSC is also an indicator of response 28 29 [125-126]. Though the bone resorption marker, serum collagen-crosslink, C-telopeptide (CTX) 30 31 32 declines sooner than serum bone formation markers (bone specific alkaline phosphatase 33 34 {BSAP}, osteocalcin {OC}, and pro-peptide type I collagen {PINP} all are indicators of 35 36 37 response. Bone formation markers decline with anti-resorptive therapies since the osteoclast- 38 39 osteoblast cells are coupled in their activity, e.g. a decline (or an increase) in the activity of one 40 41 cell line will be followed by a directional change in the other cell line. The preferred marker by 42 43 44 the American Association of Clinical Chemistry and The National Bone Health Alliance for 45 46 bone resorption applications is the CTX and the preferred formation marker is PINP [127]. 47 48 While serum CTX must be drawn fasting before 10AM, the PINP can be drawn at any time of 49 50 51 the day. 52 53 54 8. Specific Osteoporosis Pharmacological Agents for Severe Osteoporosis 55 56 57 58 59 60 URL: http://mc.manuscriptcentral.com/eoop Email: [email protected] Expert Opinion On Pharmacotherapy Page 20 of 111

1 2 3 All of the registered osteoporosis agents are effective to reduce the risk for fracture. Since there 4 5 6 are no head to head comparative fracture studies to demonstrate superiority of anyone agent over 7 8 another, there are reasons that merit strong consideration for choosing the following agents as 9 10 11 first line therapies, not requiring that the patient “fail” the most widely prescribed osteoporosis 12 13 agent worldwide-----oral bisphosphonates. These “first-line” choices in my opinion are 14 For Peer Review Only 15 recommended according to the individual patient clinical situation, and the knowledge that 16 17 18 achieving a rapid onset of action on bone may be a priority in severe osteoporosis. 19 20 21 9. Intravenous zoledronic acid and intravenous ibandronate 22 23 24 Assuring that a bisphosphonate is delivered to bone seems, clinically, to be a desirable goal in 25 26 the patient population described as having severe osteoporosis. In these more severe patients, 27 28 halting the cascade of vertebral fractures or reducing the risk of a 2 nd non-vertebral fracture in the 29 30 31 immediate period following the first fracture is a desirable goal. Oral bisphosphonates have been 32 33 shown to have a rapid onset of pharmacological effect to reduce VCF within 6 months [128]. If 34 35 36 absorbability is uncertain and when a physician desires to guarantee that the bisphosphonate is 37 38 being delivered to bone, an intravenous route of administration is the most confident means to 39 40 guarantee this skeletal delivery. There are no head to head studies comparing the biological 41 42 43 effects of oral as opposed to intravenous bisphosphonates. Yet with the knowledge that under the 44 45 best circumstances of compliance and proper dosing instructions that 0.6% of an oral 46 47 bisphosphonate is absorbed, achieving a secure and rapid delivery to the bone site is a desirable 48 49 50 goal [103. 129-131] 51 52 53 Both intravenous zoledronic acid (5mg/yr) as well as intravenous ibandronate (3mg every 3 54 55 months) achieve this end. While intravenous (as well as oral) bisphosphonates have either FDA 56 57 58 contraindications or warnings not to administer for patients were more severe reductions in renal 59 60 URL: http://mc.manuscriptcentral.com/eoop Email: [email protected] Page 21 of 111 Expert Opinion On Pharmacotherapy

1 2 3 function (e.g. glomerular filtration rates (GFR) < 35 ml/min it seems ibandronate may have less 4 5 6 of a risk for renal toxicity than zoledronic acid [132]. It has been suggested from broad clinical 7 8 experience that if one is concerned at all about renal function, slowing the infusion rate down 9 10 11 with zoledronic acid to 30 or 60 minutes from the FDA label of 15 minutes may offer less renal 12 13 toxicity. 14 For Peer Review Only 15 16 17 In a prospective study we did show that every 3 month IV ibandronate “push” via a 5 minute 18 19 20 slower drip showed no differences in changes in GFR, even in diabetics with marginal GFR to 21 22 begin with [132]. There is more robust fracture data with zoledronic acid than ibandronate from 23 24 individual clinical trials and ibandronate is not registered for the reduction of non-vertebral 25 26 27 fractures. In addition, extension data suggest that 6 annual doses of zoledronic acid may have 28 29 additional morphometric vertebral fracture benefit than in specific severe osteoporotic 30 31 populations (e.g. femoral neck T-score of -2.5 and with prevalent VCF [133]. In this regard, the 32 33 34 extension of alendronate clinical trials, the Fosamax long term extension (FLEX) trial also 35 36 showed some additional benefit, from the initial data analysis, for continuing oral alendronate 37 38 beyond 5 years in subjects with a prevalent VCF or “very low” BMD [134]. However, in the 39 40 41 FLEX interaction table (Table 4 in the FLEX manuscript) actually shows that the fracture risk 42 43 reduction benefit of continuing alendronate beyond 5 years was independent of the baseline 44 45 46 BMD (down to a femoral neck T-score of -2.0) or the presence of VCF. Both fracture 47 48 intervention trials (FIT trials) either had randomized subjects with either a prevalent VCF (severe 49 50 osteoporosis) or in FIT 2 without prevalent VFC but a T-score of -2.0 or lower. Perhaps age is 51 52 53 the risk factor that constitutes severe osteoporosis even with a non-osteoporotic (e.g. osteopenic) 54 55 T-score, since the FLEX population were between 66-91 years old when they entered FLEX. 56 57 58 59 60 URL: http://mc.manuscriptcentral.com/eoop Email: [email protected] Expert Opinion On Pharmacotherapy Page 22 of 111

1 2 3 10. Denosumab 4 5 6 Parenteral denosumab, 60 mg SQ every 6 months, is another first line choice in severe 7 8 9 osteoporosis or in situations where oral administrations of agents are unacceptable, or 10 11 uncertainty of absorption is a clinical concern or poor compliance with oral is an 12 13 issue. 14 For Peer Review Only 15 16 17 Densoumab js a fully human monoclonal antibody to an activator of osteoclastic differentiation 18 19 and activity, soluble Rank-Ligand (Rank-L). Rank-Ligand is receptor activator (Rank being the 20 21 receptor on osteoclasts, also called NF-kB). Rank-L, a glycoprotein produced in the osteoblast, is 22 23 24 a member of the superfamily of ligands, and is also known as TNF –activation-induced cytokine 25 26 and osteoclast activator [135]. 27 28 29 Denosumab has robust fracture data with fracture risk reduction at all (vertebral, non-vertebral 30 31 32 and hip) skeletal sites [136, 137]. In addition, denosumab has robust extension BMD, safety and 33 34 fracture data showing continual fracture efficacy up to eight years, data that does not exist with 35 36 any other osteoporosis pharmacological agent [138]. 37 38 39 Denosumab is metabolized by the reticuloendothelial system and the biological effect of 40 41 42 increasing BMD or lowering bone turnover is nearly gone by the end of the 6 month of 43 44 administration. Thus, every 6 month administration is needed to maintain efficacy [139-142]. 45 46 47 The FDA label for the postmenopausal osteoporosis indication does not have any lower cut-off 48 49 50 for renal function. This is because denosumab is not cleared by the kidney but by the 51 52 53 reticuloendothelial system, and may not have any adverse renal effects as may be seen, though 54 55 56 rarely, with intravenous bisphosphonates. In a post-hoc analysis of FREEDOM where the 57 58 59 60 URL: http://mc.manuscriptcentral.com/eoop Email: [email protected] Page 23 of 111 Expert Opinion On Pharmacotherapy

1 2 3 registration population had estimated glomerular filtration rates (eGFR) divided into quartiles (> 4 5 6 90 ml/min to 15-29 ml/min), densoumab had evidence of reduction in incident vertebral fractures 7 8 9 10 across these quartiles without any adverse renal effects (e.g. change in eGFR over 3 years) [143]. 11 12 13 There are no data on changes in BMD or fractures in patients with GFR < 15 ml/min. 14 For Peer Review Only 15 16 In this latter population, the diagnosis of osteoporosis becomes far more difficult to establish; 17 18 19 and, there is concern that in patients with pre-existing adynamic renal bone disease reducing 20 21 bone turnover further may be associated with an increase in cardiovascular calcification [144- 22 23 148]. This theoretical interaction is predicated on the knowledge that absorbed calcium and/or 24 25 26 phosphorus cannot be adequately eliminated by renal clearance; and, if bone turnover is low, the 27 28 capacity of bone to take up these ions is restricted, leaving vascular tissue exposed to calcium- 29 30 31 phosphorus and risk for vascular calcification. One study has examined the effect of denosumab 32 33 on vascular calcification in the FREEDOM trial and found that across the quartiles of eGFR 34 35 there was no greater increase in vascular calcification with denosumab vs placebo, at least when 36 37 38 assessed by lateral lumbar x-ray assessment of aortic calcification [149]. The FDA label cautions 39 40 the physician concerning the possibility of hypocalcemia after denosumab administration. While 41 42 all anti-resorptive agents may induce a small and transient hypocalcemia after administration, 43 44 45 clinically significant hypocalcemia (associated with tetany or paresthesias) is not observed in 46 47 patients with adequate calcium and vitamin D intake; and, with intact parathyroid hormone 48 49 (PTH) responses to normalize the transient hypocalcemia. In that regard, hypocalcemia in the 50 51 52 FREEDOM trial was no different between the treated vs placebo groups either in the registration 53 54 (1 st 3 years) or the extension trial. It is important in patient management to ensure that an 55 56 57 58 59 60 URL: http://mc.manuscriptcentral.com/eoop Email: [email protected] Expert Opinion On Pharmacotherapy Page 24 of 111

1 2 3 adequate amount of calcium and vitamin D are provided. Symptomatic hypocalcemia has been 4 5 6 seen in patients on hemodialysis given denosumab [150]. 7 8 9 Denosumab, since FDA registration in June 2010 for the treatment of PMO, has had an 10 11 impressive safety and efficacy track record. 12 13 14 11. TeriparatideFor Peer Review Only 15 16 17 Teriparatide (recombinant human 1-34 parathyroid hormone) marketed under the brand name 18 19 20 Forteo™ is the first anabolic agent registered for the treatment of osteoporosis [116]. 21 22 Teriparatide has FDA registration for severe postmenopausal, male and glucocorticoid-induced 23 24 osteoporosis [151-153]. In many restricted health plans, both in the USA as well as in Europe, 25 26 27 most patient have to have “failed” a less expensive oral bisphosphonate before approval of 28 29 teriparatide. 30 31 32 This restrictive approach, based purely on health economics is a hindrance to effective and 33 34 35 humanistic patient care. Patients with severe osteoporosis and at extremely high risk for more 36 37 fractures than they have already had, deserve consideration, first line, to receive an anabolic 38 39 agent. Many clinical bone specialists and bone biologists feel that first providing an anabolic 40 41 42 agent to initially build new bone first in treatment naïve patients is the approach that should be 43 44 taken. Then after new bone is formed, follow anabolic therapy with an ant-resorptive agent to 45 46 maintain the newly formed bone in many patients with severe osteoporosis seems logical. 47 48 49 There remains a “black-box” warning on the FDA labels for the lifetime duration of teriparatide 50 51 52 use to more than 24 months. This restriction, which is based on the lifespan of the rat model and 53 54 the appearance of osteogenic sarcoma toward the end of the life span in the rat, should be 55 56 57 removed now that teriparatide has been on the USA market for 15 years. During this time period 58 59 60 URL: http://mc.manuscriptcentral.com/eoop Email: [email protected] Page 25 of 111 Expert Opinion On Pharmacotherapy

1 2 3 osteogenic sarcoma has not been seen in 4 other animal models that remodel bone similar to 4 5 6 human beings: dog, sheep, pig and monkey. In the human population, validated osteogenic 7 8 sarcoma has only been reported in < 5 cases with an exposure window of 15 years and over 1.5 9 10 11 million patients [154-157]. The natural background incident rate of osteogenic sarcoma in adult 12 13 human beings is 4/million/year, meaning that teriparatide does not increase the incident rate of 14 For Peer Review Only 15 this tumor. There is evidence that teriparatide continues to be effective beyond 2 years and the 16 17 18 glucocorticoid-induced osteoporosis data demonstrated this point in the clinical trials of 19 20 teriparatide in GIOP. The biomarker data, especially the osteoblast activity marker, pro-peptide 21 22 type I collagen (PINP) also demonstrates that osteoblast stimulation may continue to occur 23 24 25 beyond 2 years such that the “anabolic window”, where bone formation and subsequent bone 26 27 resorption biomarker lines cross, may be quite heterogeneous [158-161]. Modulating the 28 29 anabolic window may allow for a longer period of bone formation before bone resorption 30 31 32 “catches up” This can be done with combination therapy, an anabolic combined with an anti- 33 34 resortpive; perhaps by sequential therapy where, or by drug development of agents that induce a 35 36 37 less osteoblast stimulation of Rank-Ligand [162-169] . While combination therapy has appeal, it 38 39 is unlikely in today’s more restrictive health care economy that payer’s will pay for combination 40 41 therapies unless combination therapy shows greater fracture reduction than monotherapy. 42 43 44 12. New Pharmacological Agents 45 46 47 12. 1 48 49 50 Abaloparatide (Parathyroid hormone related peptide analogue, PTHrP analogue) is a parathyroid 51 52 hormone related peptide analogue with altered amino acid sequencing that conveys unique 53 54 biological actions that differ from either parathyroid hormone, parathyroid hormone related 55 56 57 peptide, or teriparatide. Abaloparatide preferentially binds to the osteoblast parathyroid receptor, 58 59 60 URL: http://mc.manuscriptcentral.com/eoop Email: [email protected] Expert Opinion On Pharmacotherapy Page 26 of 111

1 2 3 RO, more than the RG osteoblast receptor, where teripataide or parathyroid hormone related 4 5 6 peptide preferentially bind [168]. Greater stimulation of the RO receptor may induce a less rise 7 8 on osteoblast derived Rank- Ligand, leading to less bone resorption than teriparatide; yet similar 9 10 11 increases in bone formation markers leading in this way to an expanded anabolic window. 12 13 In the pivotal registration clinical trial comparing abaloparatide to placebo to teriparatide, 80ug 14 For Peer Review Only 15 16 SQ/day of abaloparatide significantly reduced the incidence of vertebral compression fractures 17 18 compared to placebo (the primary end-point) and significantly reduced the incidence of non- 19 20 21 vertebral and all clinical fractures as well (Miller PD et al. Endocrine Society 2015 abstract, 22 23 submitted for publication). Fracture reduction between abaloparatide and teriparatide, by Kaplan- 24 25 Meier (time to first event) the reduction in non-vertebral and all clinical fractures occurred 26 27 28 sooner with abaloparatide than teriparatide and the increase in cortical bone site bone mineral 29 30 density (BMD) was significantly greater with abaloparatide. Finally, there was significantly 31 32 lower incident rates of hypercalcemia with abaloparatide than teriparatide. Thus, this novel 33 34 35 PTHrP analogue may offer some distinct advantages as a new anabolic agent than teriparatide. 36 37 38 12.2 39 40 41 The mono-clonal antibody to , romosozumab, has impressive data with regard to 42 43 increases in BMD and bone formation with little increase in serum CTX or bone resorption [170- 44 45 46 ]. Hence, even a wider anabolic window may be seen with romosozumab. Sclerostin, a product 47 48 of the osteocyte, binds to the osteoblast and inhibits osteoblast activity. The discovery of 49 50 sclerostin and the development of a monoclonal antibody to sclerostin represents an achievement 51 52 53 in basic bone biology [40, 170-171]. The phase III registration studies are currently ongoing. 54 55 56 12.3 Odanacatib 57 58 59 60 URL: http://mc.manuscriptcentral.com/eoop Email: [email protected] Page 27 of 111 Expert Opinion On Pharmacotherapy

1 2 3 Cathepsin K is an enzyme that has ubiquitous presence throughout the human body but its bone 4 5 6 presence acts as a mediator of bone resorption. Cathepsin K works outside the osteoclast to 7 8 induce bone resorption [172-173]. The discovery of cathepsin K inhibitors allowed targeting of 9 10 11 bone resorption without altering the structural integrity of the osteoclast, resulting in 12 13 maintenance of osteoclast cell membrane signaling back to the osteoblast. Hence osteoblast bone 14 For Peer Review Only 15 formation is maintained with odanacatib administration, thus providing another mechanism 16 17 18 whereby “uncoupling” bone resorption to bone formation [174]. A number of well-designed 19 20 phase II clinical trials have consistently documented the large increases in BMD and other 21 22 structural parameters of improvement in bone strength as well as safety over a long study period 23 24 25 [175-178]. The phase III registration study given the acronym LOFT (long term odanacatib 26 27 fracture trial) in unpublished data shows that 50mg/week of oral odanacatib provides significant 28 29 incident fracture reduction at all skeletal sites as compared to placebo with a very favorable 30 31 32 safety profile. 33 34 35 13 Conclusions 36 37 38 Severe osteoporosis is a devastating systemic disease with a high mortality, morbidity, and 39 40 economic cost. The important message to convey in this review is that fractures can be prevented 41 42 43 by appropriate treatment and fall prevention strategies. Both current and emerging 44 45 pharmacological treatments have evidence for efficacy and safety when used in the right 46 47 population. As longer term (extension) studies of newer osteoporosis therapies continue to 48 49 50 provide reassurance of maintenance of efficacy and safety, the acceptance by patients of 51 52 osteoporosis treatments should be attended by a reduction in the incidence of all fragility 53 54 fractures. 55 56 57 58 59 60 URL: http://mc.manuscriptcentral.com/eoop Email: [email protected] Expert Opinion On Pharmacotherapy Page 28 of 111

1 2 3 14 Expert Opinion 4 5 6 Severe osteoporosis remains a challenge in terms of recognition and treatment. The challenge is 7 8 9 largely due to the underutilization of bone densitometry (DXA), the utilization of which is 10 11 declining worldwide; and, the under-identification of asymptomatic vertebral fractures which 12 13 constitute a very high risk population independent of that risk measured by BMD alone. 14 For Peer Review Only 15 16 17 Populations are living longer, and associated with increased longevity is an increase in both the 18 19 number and the severity of the consequences of all forms of low trauma fractures. Osteoporotic 20 21 fractures cost more than the costs of caring for myocardial infarction, breast cancer, or 22 23 24 cerebrovascular accidents (3). The declining treatment of patients with pharmacological agents 25 26 even with severe osteoporosis is disturbing (5). The challenge to reverse these health-economic 27 28 and under treatment patterns is a great one and will only be resolved when governments and 29 30 31 health care policy decision makers focus enough resources into wider support for professional 32 33 societies charged with increasing awareness and education about osteoporosis. The international 34 35 36 movement to develop fracture liaison services (FLS) throughout all communities offers a great 37 38 opportunity to reduce the risk of the second osteoporotic fracture. 39 40 41 Existing and newer pharmacological agents for the treatment of osteoporosis offer great hope in 42 43 reducing the burden of osteoporotic fractures and their consequences. The scientific limitations 44 45 46 of these agents that show evidence to reduce fracture risk vs placebo is to provide evidence that 47 48 one agent is superior to another by greater reduction in fracture risk. This may never be 49 50 accomplished given the enormous costs of performing head-to-head fractures trials and should be 51 52 53 the impetus for international drug registration agencies to accept solid surrogate markers of bone 54 55 strength as sufficient evidence that fractures would be reduced in order for head-to-head 56 57 58 comparisons to be provided registration language of either superiority or non-inferiority (103). 59 60 URL: http://mc.manuscriptcentral.com/eoop Email: [email protected] Page 29 of 111 Expert Opinion On Pharmacotherapy

1 2 3 The wider utilization of bone turnover markers will provide physicians with the ability to 4 5 6 measure early responses to therapies rather than wait 2 years until a BMD change occurs. 7 8 9 Newer emerging therapies ( PTHrp analogue (abaloparatide), mono-clonal antibody to sclerostin 10 11 (romoozumab), and the cathepsin K inhibitor ( odanacatib) offer unique mechanisms of action 12 13 on bone remodeling in that they may provide some uncoupling of remodeling for a period of 14 For Peer Review Only 15 16 time resulting in a greater period of either bone formation or continual maintenance of bone 17 18 formation as opposed to current pharmacological agents that have not been shown to uncouple 19 20 21 the normal coupling patterns of bone remodeling. 22 23 24 In addition to emerging pharmacological therapies the field of osteoporosis has been handed the 25 26 opportunity to show the links between muscle and bone; and, by doing so, develop means to 27 28 improve muscle strength and reduce the risk of falls. These advances will recognize the 29 30 31 increasingly important challenge to quantitate muscle mass and strength in order to provide a 32 33 consensus on the definition of sarcopenia; and integrate physicians with other professional 34 35 36 bodies in order to create a team dedicated to reducing falls. 37 38 39 The field of osteoporosis has to develop an office based bone quality measurement tool that 40 41 compliments BMD tests to enhance risk prediction. Since nearly 50% of bone strength is due to 42 43 bone quality and not bone density; and, there is an increasing recognition that many diseases 44 45 46 impair bone quality more than bone density, the capacity to measure bone quality as a point-of- 47 48 care modality will be a great step forward. 49 50 51 Finally, this author has a large interest in improving the science and ultimately the acceptability 52 53 of bone turnover markers. Bone turnover markers have other potential utilization beyond 54 55 56 enhancing fracture risk prediction, predicting rates of bone loss and response to therapies. They 57 58 59 60 URL: http://mc.manuscriptcentral.com/eoop Email: [email protected] Expert Opinion On Pharmacotherapy Page 30 of 111

1 2 3 may be able to identify, to still an imperfect degree of positive predictive value, patients with low 4 5 6 bone turnover or even adynamic bone disease, an increasing form of bone disease seen in 7 8 diabetics and the growing population of chronic kidney disease. The “gold-standard” of 9 10 11 identification of adynamic bone disease is quantitative bone histomorphometry, a field of great 12 13 science but underutilized mostly related to fewer and fewer institutions providing quantitative 14 For Peer Review Only 15 histomorphometry reading. In the end, our field of osteoporosis will need the development of 16 17 18 sub-specialty boards in Metabolic Bone Disease in order to train young physicians in this 19 20 increasingly important and often complex field; and, provide professional/governmental 21 22 licensing to support recognition of competence and proper reimbursement. 23 24 25 Legends for Figures and Tables 26 27 28 Figure 1 The annual costs of osteoporotic fractures as compared to the annual costs of 3 other major 29 30 31 disease states (reference # 3) 32 33 34 Figure 2 The declining annual probability of treatment with an osteoporosis agent after hospital 35 36 discharge for hip fractures (reference # 5) 37 38 39 Figure 3 The predictive value of TBS (trabecular bone score) used in the FRAX™ calculator (reference # 40 41 28) 42 43 44 Figure 4 The semiquantitative classification of morphometric vertebral compression fractures according 45 46 to the Genant method (reference # 82) 47 48 49 Figure 5 The effect of age on the risk of hip fractures (reference # 87 ) 50 51 52 Table 1 The currently available pharmacological therapies for postmenopausal osteoporosis (P Miller) 53 54 55 Table 2 The emerging new therapies for postmenopausal osteoporosis (P Miller) 56 57 58 59 60 URL: http://mc.manuscriptcentral.com/eoop Email: [email protected] Page 31 of 111 Expert Opinion On Pharmacotherapy

1 2 3 4 5 6 Figure 1 7 8 9 10 11 12 13 14 For Peer Review Only 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32

33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 URL: http://mc.manuscriptcentral.com/eoop Email: [email protected] Expert Opinion On Pharmacotherapy Page 32 of 111

1 2 3 Figure 2 4 5 6 7 8 9 10 11 12 13 14 For Peer Review Only 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 URL: http://mc.manuscriptcentral.com/eoop Email: [email protected] Page 33 of 111 Expert Opinion On Pharmacotherapy

1 2 3 Figure III 4 5 6 7 8 9 10 11 12 13 14 For Peer Review Only 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 URL: http://mc.manuscriptcentral.com/eoop Email: [email protected] Expert Opinion On Pharmacotherapy Page 34 of 111

1 2 3 Figure 4 4 5 6 Classification of the Grades of Vertebral Fractures 7 8 9 10 11 12 13 14 For Peer Review Only 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 URL: http://mc.manuscriptcentral.com/eoop Email: [email protected] Page 35 of 111 Expert Opinion On Pharmacotherapy

1 2 3 Figure 5 4 5 6 7 8 9 10 11 12 13 14 For Peer Review Only 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 URL: http://mc.manuscriptcentral.com/eoop Email: [email protected] Expert Opinion On Pharmacotherapy Page 36 of 111

1 2 3 Table 1 4 5 6 7 Osteoporosis Treatment Options – 2015 8 9 Anti -remodeling agents (inhibit bone turnover) 10 11 - Bisphosphonates (oral and IV) 12 13 - Estrogen agonists/ antagonist (raloxifene) 14 For Peer- RANK Reviewligand inhibitor (denosumab) Only 15 Bone activating agent (stimulates formation and resorption) 16 17 - Parathyroid hormone (1-34) (Teriparatide) 18 - Parathyroid hormone (1-84) (not available in the USA) 19 Other (no effect on bone turnover) 20 21 - (not available in the USA) 22 23 24 25 26 Table 2 27 28 29 30 Emerging Treatment for Osteoporosis 31 32 A New ‘anti -resorptive’ 33 34 - Odanacatib 35 New anabolics 36 37 - PTHrP analogues (abaloparatide) 38 - Monoclonal antibody to sclerostin (romosozumab) 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 URL: http://mc.manuscriptcentral.com/eoop Email: [email protected] Page 37 of 111 Expert Opinion On Pharmacotherapy

1 2 3 References 4 5 6 1. Morris, C.A., et al., Patterns of bone mineral density testing: current guidelines, testing 7 8 9 rates, and interventions. J Gen.Intern.Med., 2004. 19(7): p. 783-790. 10 11 12 2. Cooper, C., et al., Epidemiology of childhood fractures in Britain: a study using the 13 14 general practiceFor research database.Peer J.Bone Review Miner.Res., 2004. 19(12): Only p. 1976-1981. 15 16 17 3. Singer, A., et al., Burden of illness for osteoporotic fractures compared with other serious 18 19 20 diseases among postmenopausal women in the United States. Mayo Clin Proc, 2015. 90(1): p. 21 22 53-62. 23 24 25 4. Watts, N.B., Insights from the Global Longitudinal Study of Osteoporosis in Women 26 27 (GLOW). Nat Rev Endocrinol, 2014. 10(7): p. 412-22. 28 29 30 31 5. Solomon, D.H., et al., Osteoporosis use after hip fracture in U.S. patients 32 33 between 2002 and 2011. J Bone Miner Res, 2014. 29(9): p. 1929-37. 34 35 36 6. Trombetti, A., et al., Effect of a multifactorial fall-and-fracture risk assessment and 37 38 management program on gait and balance performances and disability in hospitalized older 39 40 41 adults: a controlled study. Osteoporos Int, 2013. 24(3): p. 867-76. 42 43 44 7. Karlsson, M.K., et al., Prevention of falls in the elderly--a review. Osteoporos Int, 2013. 45 46 24(3): p. 747-62. 47 48 49 8. Akesson, K., et al., Capture the Fracture: a Best Practice Framework and global campaign 50 51 to break the fragility fracture cycle. Osteoporos Int, 2013. 24(8): p. 2135-52. 52 53 54 55 9. Lee, D.B., et al., National Bone Health Alliance: an innovative public-private partnership 56 57 improving America's bone health. Curr Osteoporos Rep, 2013. 11(4): p. 348-53. 58 59 60 URL: http://mc.manuscriptcentral.com/eoop Email: [email protected] Expert Opinion On Pharmacotherapy Page 38 of 111

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1 2 3 46. Lewiecki, E.M. and P.D. Miller, Skeletal effects of primary hyperparathyroidism: bone 4 5 6 mineral density and fracture risk. J Clin Densitom, 2013. 16(1): p. 28-32. 7 8 9 47. Vestergaard, P. and S. Thomsen, Medical treatment of primary, secondary, and tertiary 10 11 hyperparathyroidism. Curr Drug Safety, 2011. 6(2): p. 108-13. 12 13 14 48. Bjorkman,For M., A. Sorva,Peer and R. Tilvis,Review Parathyroid hormone Only as a mortality predictor in 15 16 17 frail aged inpatients. Gerontology, 2009. 55(6): p. 601-606. 18 19 20 49. Parisien, M., et al., Bone disease in primary hyperparathyroidism. Endocrinol.Metab Clin 21 22 North Am., 1990. 19(1): p. 19-34. 23 24 25 50. Rejnmark, L., et al., Increased fracture risk in normocalcemic postmenopausal women 26 27 with high parathyroid hormone levels: a 16-year follow-up study. Calcif.Tissue Int., 2011. 88(3): 28 29 30 p. 238-245. 31 32 33 51. Cole, M.H., et al., Use of a short-form balance confidence scale to predict future 34 35 recurrent fallers in Parkinson's disease. Arch Phys Med Rehabil, 2015. 36 37 38 52. Chalhoub, D., et al., Risk of Nonspine Fractures in Older Adults with Sarcopenia, Low 39 40 41 Bone Mass, or Both. J Am Geriatr Soc, 2015. 42 43 44 53. Sternberg, S.A., et al., Frailty and osteoporosis in older women--a prospective study. 45 46 Osteoporos Int, 2014. 25(2): p. 763-8. 47 48 49 54. Cooper, C., et al., Frailty and sarcopenia: definitions and outcome parameters. 50 51 Osteoporos Int, 2012. 23(7): p. 1839-48. 52 53 54 55 56 57 58 59 60 URL: http://mc.manuscriptcentral.com/eoop Email: [email protected] Page 43 of 111 Expert Opinion On Pharmacotherapy

1 2 3 55. Binkley, N., D. Krueger, and B. Buehring, What's in a name revisited: should 4 5 6 osteoporosis and sarcopenia be considered components of "dysmobility syndrome?". Osteoporos 7 8 Int, 2013. 24(12): p. 2955-9. 9 10 11 56. Bliuc, D., et al., The impact of nonhip nonvertebral fractures in elderly women and men. 12 13 J Clin Endocrinol Metab, 2014. 99(2): p. 415-23. 14 For Peer Review Only 15 16 17 57. Huntjens, K.M., et al., Risk of subsequent fracture and mortality within 5 years after a 18 19 non-vertebral fracture. Osteoporos Int, 2010. 21(12): p. 2075-82. 20 21 22 58. Whyte, M.P., Hypophosphatasia. 2013: p. 337-360. 23 24 25 59. Rea, J.A., et al., Vertebral morphometry: a comparison of long-term precision of 26 27 morphometric X-ray absorptiometry and morphometric radiography in normal and osteoporotic 28 29 30 subjects. Osteoporos Int, 2001. 12(2): p. 158-166. 31 32 33 60. El Maghraoui, A., et al., Systematic vertebral fracture assessment in asymptomatic 34 35 postmenopausal women. Bone, 2013. 52(1): p. 176-80. 36 37 38 61. Lewiecki, E.M., Bone densitometry and vertebral fracture assessment. Curr.Osteoporos 39 40 41 Rep., 2010. 8(3): p. 123-130. 42 43 44 62. Link, T.M., Radiology of Osteoporosis. Can Assoc Radiol J, 2015. 45 46 47 63. Bertoldo, F., et al., Prevalence of asymptomatic vertebral fractures in late-onset Pompe 48 49 disease. J Clin Endocrinol Metab, 2015. 100(2): p. 401-6. 50 51 52 64. Angeli, A., et al., High prevalence of asymptomatic vertebral fractures in post- 53 54 55 menopausal women receiving chronic glucocorticoid therapy: a cross-sectional outpatient study. 56 57 Bone, 2006. 39(2): p. 253-9. 58 59 60 URL: http://mc.manuscriptcentral.com/eoop Email: [email protected] Expert Opinion On Pharmacotherapy Page 44 of 111

1 2 3 65. Schousboe, J.T., et al., Prediction of Incident Major Osteoporotic and Hip Fractures by 4 5 6 Trabecular Bone Score (TBS) and Prevalent Radiographic Vertebral Fracture in Older Men. J 7 8 Bone Miner Res, 2015. 9 10 11 66. Rosen, H.N., et al., The Official Positions of the International Society for Clinical 12 13 Densitometry: vertebral fracture assessment. J Clin Densitom, 2013. 16(4): p. 482-8. 14 For Peer Review Only 15 16 17 67. Kaptoge, S., et al., Whom to treat? The contribution of vertebral X-rays to risk-based 18 19 algorithms for fracture prediction. Results from the European Prospective Osteoporosis Study. 20 21 Osteoporos Int, 2006. 17(9): p. 1369-81. 22 23 24 68. Kanis, J.A., et al., A meta-analysis of previous fracture and subsequent fracture risk. 25 26 27 Bone, 2004. 35(2): p. 375-382. 28 29 30 69. Johnell, O., et al., Fracture risk following an osteoporotic fracture. Osteoporos Int, 2004. 31 32 15(3): p. 175-179. 33 34 35 70. Gluer, M.G., et al. Prospective identification of postmenopausal osteoporotic women at 36 37 38 high vertebral fracture risk by radiography, bone densitometry, quantitative ultrasound, and 39 40 laboratory findings: results from the PIOS study. J Clin Densitom, 2005. 8(4): p. 386-95. 41 42 43 71. Greenspan, S.L., et al., Instant vertebral assessment: a noninvasive dual X-ray 44 45 absorptiometry technique to avoid misclassification and clinical mismanagement of osteoporosis. 46 47 48 J Clin Densitom, 2001. 4(4): p. 373-80. 49 50 51 72. Schousboe, J.T., et al., Prediction models of prevalent radiographic vertebral fractures 52 53 among older women. J Clin Densitom, 2014. 17(3): p. 378-85. 54 55 56 57 58 59 60 URL: http://mc.manuscriptcentral.com/eoop Email: [email protected] Page 45 of 111 Expert Opinion On Pharmacotherapy

1 2 3 73. Siminoski, K., et al., The accuracy of historical height loss for the detection of vertebral 4 5 6 fractures in postmenopausal women. Osteoporos Int, 2006. 17(2): p. 290-296. 7 8 9 74. Vokes, T., et al., Vertebral Fracture Assessment: The 2005 ISCD Official Positions. J 10 11 Clin Densitom, 2006. 9(1): p. 37-46. 12 13 14 75. Lentle,For B., et al., OsteoporosisPeer Canada Review 2010 guidelines forOnly the assessment of fracture 15 16 17 risk. Can Assoc Radiol J, 2011. 62(4): p. 243-50. 18 19 20 76. Delmas, P.D., et al., Underdiagnosis of vertebral fractures is a worldwide problem: the 21 22 IMPACT study. J Bone Miner Res, 2005. 20(4): p. 557-63. 23 24 25 77. Fink, H.A., et al., What proportion of incident radiographic vertebral deformities is 26 27 clinically diagnosed and vice versa? J Bone Miner Res, 2005. 20(7): p. 1216-22. 28 29 30 31 78. Kim, N., et al., Underreporting of vertebral fractures on routine chest radiography. AJR 32 33 Am J Roentgenol, 2004. 182(2): p. 297-300. 34 35 36 79. Mujumdar SR, et al. Incidental vertebral fractures discovered with chest radiography in 37 38 the emergency department: prevalence, recognition, and osteoporosis management in a cohort of 39 40 41 elderly patients. Arch Int Med 2005; 165(8):905-909. 42 43 44 45 46 47 80. Siris, E.S., et al., Enhanced prediction of fracture risk combining vertebral fracture status 48 49 and BMD. Osteoporos Int, 2007. 18(6): p. 761-70. 50 51 52 81. Leidig-Bruckner, G., et al., Comparison of a semiquantitative and a quantitative method 53 54 55 for assessing vertebral fractures in osteoporosis. Osteoporos Int, 1994. 4(3): p. 154-61. 56 57 58 59 60 URL: http://mc.manuscriptcentral.com/eoop Email: [email protected] Expert Opinion On Pharmacotherapy Page 46 of 111

1 2 3 82. Genant HK , Jergas M. Assessment of prevalent and incident vertebral fractures in 4 5 6 osteoporosis research. Osteoporos Int. 2003;14 Suppl 3:S43-55. 7 8 9 83. Cauley, J.A., et al., Long-term risk of incident vertebral fractures. JAMA, 2007. 298(23): 10 11 p. 276-277 12 13 14 84. van Geel,For T.A., et al.,Peer Timing of subsequentReview fractures after Only an initial fracture. Current 15 16 17 Osteoporos Reports, 2010. 8(3): p. 118-22. 18 19 20 85. Schousboe JT, Fink HA, Lui LY, et al. Association between prior non-spine non-hip 21 22 fractures or prevalent radiographic vertebral deformities known to be at least 10 years old and 23 24 incident hip fracture. J Bone Miner Res 2006; 21(10): 1557e1564. 25 26 27 86. Kanis, J.A., et al., Interpretation and use of FRAX in clinical practice. Osteoporos Int, 28 29 30 2011. 22(9): p. 2395-2411. 31 32 33 87. Kanis, J.A., et al., FRAX(R) and its applications to clinical practice. Bone, 2009. 44(5): 34 35 p. 734-743. 36 37 38 88. Lewiecki, E.M., Bone density measurement and assessment of fracture risk. Clin Obstet 39 40 41 Gynecol, 2013. 56(4): p. 667-76. 42 43 44 89. Kanis, J.A., et al., FRAX with and without bone mineral density. Calcif.Tissue Int, 2012. 45 46 90(1): p. 1-13. 47 48 49 90. Siris, E.S., et al., The clinical diagnosis of osteoporosis: a position statement from the 50 51 National Bone Health Alliance Working Group. Osteoporos Int, 2014. 25(5): p. 1439-43. 52 53 54 55 91. Canalis, E. and A. Giustina, Glucocorticoid-induced osteoporosis: Summary of a 56 57 workshop. Journal of Clinical Endocrinology and Metabolism, 2001. 86(12): p. 5681-5685. 58 59 60 URL: http://mc.manuscriptcentral.com/eoop Email: [email protected] Page 47 of 111 Expert Opinion On Pharmacotherapy

1 2 3 92. van Staa, T.P., The pathogenesis, epidemiology and management of glucocorticoid- 4 5 6 induced osteoporosis. Calcif.Tissue Int, 2006. 79(3): p. 129-137. 7 8 9 93. Saag, K.G., Glucocorticoid-induced osteoporosis. Endocrinol Metab Clin North Am, 10 11 2003. 32(1): p. 135-57, vii. 12 13 14 94. Leib, E.S.,For et al., OfficialPeer Positions Review for FRAX((R)) Clinical Only Regarding Glucocorticoids: 15 16 17 The impact of the Use of Glucocorticoids on the Estimate by FRAX((R)) of the 10 Year Risk of 18 19 Fracture From Joint Official Positions Development Conference of the International Society for 20 21 Clinical Densitometry and International Osteoporosis Foundation on FRAX((R)). 22 23 24 J.Clin.Densitom., 2011. 14(3): p. 212-219. 25 26 27 95. Levis, S. and G. Theodore, Summary of AHRQ's comparative effectiveness review of 28 29 treatment to prevent fractures in men and women with low bone density or osteoporosis: update 30 31 32 of the 2007 report. J Manag.Care Pharm., 2012. 18(4 Suppl B): p. S1-15. 33 34 35 96. Reid, I.R., Short-term and long-term effects of osteoporosis therapies. Nat Rev 36 37 Endocrinol, 2015. 11(7): p. 418-28. 38 39 40 97. Crandall, C.J., et al., Comparative effectiveness of pharmacologic treatments to prevent 41 42 fractures: an updated systematic review. Ann Intern Med, 2014. 161(10): p. 711-23. 43 44 45 98. Reginster, J.Y., et al., Efficacy and safety of currently marketed anti-osteoporosis 46 47 48 medications. Best Pract Res Clin Endocrinol Metab, 2014. 28(6): p. 809-34. 49 50 51 99. Litwic, A., C. Cooper, and E. Dennison, Osteoporosis therapies in 2014. Panminerva 52 53 Med, 2014. 56(4): p. 273-83. 54 55 56 57 58 59 60 URL: http://mc.manuscriptcentral.com/eoop Email: [email protected] Expert Opinion On Pharmacotherapy Page 48 of 111

1 2 3 101. Miller, P.D., et al., Once-monthly oral ibandronate compared with weekly oral 4 5 6 alendronate in postmenopausal osteoporosis: results from the head-to-head MOTION study. 7 8 Current Medical Research and Opinion, 2008. 24(1): p. 207-213. 9 10 11 102. Bonnick, S., et al., Comparison of weekly treatment of postmenopausal osteoporosis with 12 13 alendronate versus risedronate over two years. J Clin Endocrinol Metab, 2006. 91(7): p. 2631-7. 14 For Peer Review Only 15 16 17 103. Miller, P.D., Bone strength and surrogate markers: the first, second, and third fiddle. J 18 19 Bone Miner Res, 2012. 27(8): p. 1623-6. 20 21 22 104. Russell, R.G., Pharmacological diversity among drugs that inhibit bone resorption. Curr 23 24 Opin Pharmacol, 2015. 22: p. 115-30. 25 26 27 105. Russell, R.G.G. and M.J. Rogers, Bisphosphonates: From the laboratory to the clinic and 28 29 30 back again. Bone, 1999. 25(1): p. 97-106. 31 32 33 106. Bonnick, S.L. and L. Shulman, Monitoring osteoporosis therapy: bone mineral density, 34 35 bone turnover markers, or both? Am J Med, 2006. 119(4 Suppl 1): p. S25-31. 36 37 38 107. Miller, P.D., Monitoring osteoporosis therapies. Curr Osteoporos Rep, 2007. 5(1): p. 38- 39 40 41 43. 42 43 44 108. Wasnich, R.D. and P.D. Miller, Antifracture efficacy of antiresorptive agents are related 45 46 to changes in bone density. Journal of Clinical Endocrinology and Metabolism, 2000. 85(1): p. 47 48 231-236. 49 50 51 109. Hochberg, M.C., et al., Changes in bone density and turnover explain the reductions in 52 53 54 incidence of nonvertebral fractures that occur during treatment with antiresorptive agents. J Clin 55 56 Endocrinol.Metab, 2002. 87(4): p. 1586-1592. 57 58 59 60 URL: http://mc.manuscriptcentral.com/eoop Email: [email protected] Page 49 of 111 Expert Opinion On Pharmacotherapy

1 2 3 110. Austin, M., et al., Relationship between bone mineral density changes with denosumab 4 5 6 treatment and risk reduction for vertebral and nonvertebral fractures. J.Bone Miner.Res., 2012. 7 8 27(3): p. 687-693. 9 10 11 111. Delmas, P.D., et al., Efficacy of raloxifene on vertebral fracture risk reduction in 12 13 postmenopausal women with osteoporosis: Four-year results from a randomized clinical trial. 14 For Peer Review Only 15 16 Journal of Clinical Endocrinology and Metabolism, 2002. 87(8): p. 3609-3617. 17 18 19 112. Vestergaard, P., L. Mosekilde, and B. Langdahl, Fracture prevention in postmenopausal 20 21 women. BMJ Clin Evid, 2011. 2011. 22 23 24 113. Harris, S.T., et al., Risk of fracture in women treated with monthly oral ibandronate or 25 26 27 weekly bisphosphonates: the eValuation of IBandronate Efficacy (VIBE) database fracture 28 29 study. Bone, 2009. 44(5): p. 758-65. 30 31 32 114. Harris, S.T., W.A. Blumentals, and P.D. Miller, Ibandronate and the risk of non-vertebral 33 34 35 and clinical fractures in women with postmenopausal osteoporosis: results of a meta-analysis of 36 37 phase III studies. Curr.Med Res Opin., 2008. 24(1): p. 237-245. 38 39 40 115. Miller, P.D., Non-vertebral fracture risk reduction with oral bisphosphonates: challenges 41 42 with interpreting clinical trial data. Curr Med Res Opin, 2008. 24(1): p. 107-19. 43 44 45 116. Zebaze, R.M., et al., Differing effects of denosumab and alendronate on cortical and 46 47 48 trabecular bone. Bone, 2014. 59: p. 173-9. 49 50 51 117. Bilezikian, J.P., Efficacy of bisphosphonates in reducing fracture risk in postmenopausal 52 53 osteoporosis. Am.J Med, 2009. 122(2 Suppl): p. S14-S21. 54 55 56 57 58 59 60 URL: http://mc.manuscriptcentral.com/eoop Email: [email protected] Expert Opinion On Pharmacotherapy Page 50 of 111

1 2 3 118. Neer, R.M., et al., Effect of parathyroid hormone (1-34) on fractures and bone mineral 4 5 6 density in postmenopausal women with osteoporosis. N Engl J Med, 2001. 344: p. 1434-1441. 7 8 9 119. Eriksen, E.F., et al., Literature review: The effects of teriparatide therapy at the hip in 10 11 patients with osteoporosis. Bone, 2014. 67: p. 246-56. 12 13 14 120. Black, ForD.M., et al., Peer Once-yearly zoledronicReview acid for treatment Only of postmenopausal 15 16 17 osteoporosis. N.Engl.J.Med., 2007. 356(18): p. 1809-1822. 18 19 20 121. Austin, M., et al., Relationship between bone mineral density changes with denosumab 21 22 treatment and risk reduction for vertebral and nonvertebral fractures. J Bone Miner Res, 2012. 23 24 27(3): p. 687-93. 25 26 27 122. Bours, S.P., et al., Contributors to secondary osteoporosis and metabolic bone diseases in 28 29 30 patients presenting with a clinical fracture. J.Clin.Endocrinol.Metab, 2011. 96(5): p. 1360-1367. 31 32 33 123. van Geel, T.A., et al., Timing of subsequent fractures after an initial fracture. Curr 34 35 Osteoporos Rep, 2010. 8(3): p. 118-22. 36 37 38 123. Kanis, J.A., et al., Excess mortality after hospitalisation for vertebral fracture. Osteoporos 39 40 41 Int, 2004. 15(2): p. 108-112. 42 43 44 124. Lindsay, R., et al., Increased risk of new vertebral fracture within 1 year of an incident 45 46 vertebral fracture. Osteoporos Int, 2000. 11 (Suppl 2): p. S112. 47 48 49 125. Civitelli, R., R. Armamento-Villareal, and N. Napoli, Bone turnover markers: 50 51 understanding their value in clinical trials and clinical practice. Osteoporos Int, 2009. 20(6): p. 52 53 54 843-851. 55 56 57 58 59 60 URL: http://mc.manuscriptcentral.com/eoop Email: [email protected] Page 51 of 111 Expert Opinion On Pharmacotherapy

1 2 3 126. Glover, S.J., et al., Establishing a reference range for bone turnover markers in young, 4 5 6 healthy women. Bone, 2008. 42(4): p. 623-630. 7 8 9 127. Bauer, D., et al., National Bone Health Alliance Bone Turnover Marker Project: current 10 11 practices and the need for US harmonization, standardization, and common reference ranges. 12 13 Osteoporos.Int, 2012. 23(10): p. 2425-2433. 14 For Peer Review Only 15 16 17 128. Watts, N.B., et al., Risedronate prevents new vertebral fractures in postmenopausal 18 19 women at high risk. J Clin Endocrinol Metab, 2003. 88(2): p. 542-9. 20 21 22 129. Rogers, M.J., et al., Cellular and molecular mechanisms of action of bisphosphonates. 23 24 Cancer., 2000. 88(12:Suppl): p. Suppl-78. 25 26 27 130. Fleisch, H., et al. Introduction to bisphosphonates. History and functional mechanisms. 28 29 30 Orthopade, 2007. 36(2): p. 103-4, 106-9. 31 32 33 131. Fleisch, H.A., Bisphosphonates: preclinical aspects and use in osteoporosis. Ann Med, 34 35 1997. 29(1): p. 55-62. 36 37 38 132. Miller, P.D., et al., Effects of intravenous ibandronate injection on renal function in 39 40 41 women with postmenopausal osteoporosis at high risk for renal disease--the DIVINE study. 42 43 Bone, 2011. 49(6): p. 1317-22. 44 45 46 133. Black, D.M., et al., The effect of 3 versus 6 years of zoledronic acid treatment of 47 48 osteoporosis: a randomized extension to the HORIZON-Pivotal Fracture Trial (PFT). J Bone 49 50 51 Miner Res, 2011. 52 53 54 55 56 57 58 59 60 URL: http://mc.manuscriptcentral.com/eoop Email: [email protected] Expert Opinion On Pharmacotherapy Page 52 of 111

1 2 3 134. Black, D.M., et al., Effects of continuing or stopping alendronate after 5 years of 4 5 6 treatment: the Fracture Intervention Trial Long-term Extension (FLEX): a randomized trial. 7 8 JAMA; 2006: 296(24): p. 2927-38. 9 10 11 135. Body, J.J., et al., A Study of the Biological Receptor Activator of Nuclear Factor- 12 13 {kappa}B Ligand Inhibitor, Denosumab, in Patients with Multiple Myeloma or Bone Metastases 14 For Peer Review Only 15 16 from Breast Cancer. Clin Cancer Res, 2006. 12(4): p. 1221-1228. 17 18 19 136. Cummings, S.R., et al., Denosumab for prevention of fractures in postmenopausal 20 21 women with osteoporosis. N Engl J Med, 2009. 361(8): p. 756-765. 22 23 24 137. Papapoulos, S., et al., Five years of denosumab exposure in women with postmenopausal 25 26 27 osteoporosis: results from the first two years of the FREEDOM extension. J Bone Miner Res, 28 29 2012. 27(3): p. 694-701. 30 31 32 138. McClung, M.R., et al., Effect of denosumab on bone mineral density and biochemical 33 34 35 markers of bone turnover: 8-year results of a phase 2 clinical trial. Osteoporos Int, 2013. 24(1): 36 37 p. 227-35. 38 39 40 139. Miller, P.D., Denosumab: anti-RANKL antibody. Curr Osteoporos Rep., 2009. 7(1): p. 41 42 18-22. 43 44 45 140. Miller, P.D., et al., Effect of denosumab on bone density and turnover in postmenopausal 46 47 48 women with low bone mass after long-term continued, discontinued, and restarting of therapy: a 49 50 randomized blinded phase 2 clinical trial. Bone, 2008. 43(2): p. 222-9. 51 52 53 54 55 56 57 58 59 60 URL: http://mc.manuscriptcentral.com/eoop Email: [email protected] Page 53 of 111 Expert Opinion On Pharmacotherapy

1 2 3 141. Bone, H.G., et al., Effects of denosumab treatment and discontinuation on bone mineral 4 5 6 density and bone turnover markers in postmenopausal women with low bone mass. J Clin 7 8 Endocrinol Metab, 2011. 96(4): p. 972-80. 9 10 11 142. Peterson, M.C., et al., The pharmacokinetics of denosumab (AMG 162) following 12 13 various multiple subcutaneous dosing regimens in postmenopausal women with low bone mass. 14 For Peer Review Only 15 16 J Bone Miner Res, 2005. 20(Suppl 1): p. S293. 17 18 19 143. Jamal, S.A., et al., Effects of denosumab on fracture and bone mineral density by level of 20 21 kidney function. J Bone Miner Res, 2011. 26(8): p. 1829-35. 22 23 24 144. Jamal, S.A., S.L. West, and P.D. Miller, Bone and Kidney Disease: Diagnostic and 25 26 27 Therapeutic Implications. Curr.Rheumatol.Rep., 2012. 28 29 30 145. Fang, Y., et al., Early chronic kidney disease-mineral bone disorder stimulates vascular 31 32 calcification. Kidney Int, 2014. 85(1): p. 142-150. 33 34 35 146. Reid, I., et al. Effects of denosumab on bone histology and histomorphometry: the 36 37 38 FREEDOM and STAND studies. J Bone Miner Res, 2009. 24. 39 40 41 147 Cannata-Andia, J.B., P. Roman-Garcia, and K. Hruska, The connections between 42 43 vascular calcification and bone health. Nephrol Dial Transplant, 2011. 26(11): p. 3429-36. 44 45 46 148. Hruska, K.A., et al., The pathogenesis of vascular calcification in the chronic kidney 47 48 disease mineral bone disorder: the links between bone and the vasculature. Semin Nephrol, 2009. 49 50 51 29(2): p. 156-65. 52 53 54 149. Samelson, E.J., et al., RANKL inhibition with denosumab does not influence 3-year 55 56 progression of aortic calcification or incidence of adverse cardiovascular events in 57 58 59 60 URL: http://mc.manuscriptcentral.com/eoop Email: [email protected] Expert Opinion On Pharmacotherapy Page 54 of 111

1 2 3 postmenopausal women with osteoporosis and high cardiovascular risk.. J Bone Miner Res, 4 5 6 2014. 29(2):450-7.. 7 8 9 150. Block GA, Bone HG, Fang L, Lee E, Padhi D. A single-dose study of denosumab in 10 11 patients with various degrees of renal impairment J Bone Miner Res. 2012 ;27(7):1471-9 12 13 14 151. Orwoll,For E.S., et al.,Peer The effect of Review teriparatide [human parathyroid Only hormone (1-34)] 15 16 17 therapy on bone density in men with osteoporosis. J Bone Miner Res, 2003. 18(1): p. 9-17. 18 19 20 152. Gluer, C.C., et al., Comparative effects of teriparatide and risedronate in glucocorticoid- 21 22 induced osteoporosis in men: 18-month results of the Euro GIOPs trial. J Bone Miner Res, 2013. 23 24 28(6): p. 1355-68. 25 26 27 153. Saag, K.G., et al., Teriparatide or alendronate in glucocorticoid-induced osteoporosis. N 28 29 30 Engl J Med, 2007. 357(20): p. 2028-2039. 31 32 33 154. Harper, K.D., et al., Comments on Initial experience with teriparatide in the United 34 35 States. Curr Med Res Opin, 2006. 22(10): p. 1927. 36 37 38 155. Harper, K.D., et al., Osteosarcoma and teriparatide? J Bone Miner Res, 2007. 22(2): p. 39 40 41 334. 42 43 44 156. Andrews, E.B., et al., The US postmarketing surveillance study of adult osteosarcoma 45 46 and teriparatide: study design and findings from the first 7 years. J Bone Miner Res, 2012. 47 48 27(12): p. 2429-37. 49 50 51 157. Miller, P.D., Safety of parathyroid hormone for the treatment of osteoporosis. Curr 52 53 54 Osteoporos Rep., 2008. 6(1): p. 12-16. 55 56 57 58 59 60 URL: http://mc.manuscriptcentral.com/eoop Email: [email protected] Page 55 of 111 Expert Opinion On Pharmacotherapy

1 2 3 158. Muschitz, C., et al., Antiresorptives overlapping ongoing teriparatide treatment result in 4 5 6 additional increases in bone mineral density. J Bone Miner Res, 2013. 28(1): p. 196-205. 7 8 9 159. Eastell, R., et al., Development of an algorithm for using PINP to monitor treatment of 10 11 patients with teriparatide. Curr Med Res Opin, 2006. 22(1): p. 61-6. 12 13 14 160. Dempster,For D.W., etPeer al., Anabolic actionsReview of parathyroid hormoneOnly on bone. Endocr.Rev., 15 16 17 1993. 14: p. 690-709. 18 19 20 161. Tsujimoto, M., et al., PINP as an aid for monitoring patients treated with teriparatide. Bone, 21 22 2011. 48(4): p. 798-803. 23 24 25 162. Cosman, F., et al., Effects of teriparatide in postmenopausal women with osteoporosis on 26 27 prior alendronate or raloxifene: differences between stopping and continuing the antiresorptive 28 29 30 agent. J Clin Endocrinol Metab, 2009. 94(10): p. 3772-3780. 31 32 33 163. Cosman, F., et al., Effects of intravenous zoledronic acid plus subcutaneous teriparatide 34 35 [rhPTH(1-34)] in postmenopausal osteoporosis. J Bone Miner Res, 2011. 26(3): p. 503-511. 36 37 38 164. Cosman, F., Anabolic and antiresorptive therapy for osteoporosis: combination and 39 40 41 sequential approaches. Curr Osteoporos Rep, 2014. 12(4): p. 385-95. 42 43 44 165. Cosman, F., et al., Daily and cyclic parathyroid hormone in women receiving 45 46 alendronate. N.Engl.J Med, 2005. 353(6): p. 566-575. 47 48 49 166. Cosman, F., et al., Effects of intravenous zoledronic acid plus subcutaneous teriparatide 50 51 [(1-34)rhPTH] in postmenopausal osteoporosis. J Bone Miner Res, 2010. 52 53 54 55 56 57 58 59 60 URL: http://mc.manuscriptcentral.com/eoop Email: [email protected] Expert Opinion On Pharmacotherapy Page 56 of 111

1 2 3 167. Leder, B., et al., The effects of combined denosumab and teriparatide administration on 4 5 6 bone mineral density in postmenopausal women: the DATA (Denosumab And Teriparatide 7 8 Administration) study. J Bone Miner Res, 2012. 27(Suppl 1): p. S31. 9 10 11 168. Hattersley, G., et al., Bone Anabolic Efficacy and Safety of BA058, a Novel Analog of 12 13 hPTHrP: Results from a Phase 2 Clinical Trial in Postmenopausal Women with Osteoporosis. 14 For Peer Review Only 15 16 Endocr Rev, 2012. 33(03_MeetingAbstracts): p. OR08-1. 17 18 19 169. Seeman E, Martin TJ. Co-administration of antiresorptive and anabolic agents: a missed 20 21 opportunity. J Bone Miner Res. 2015 ;30(5):753-64. 22 23 24 170. McClung, M.R. and A. Grauer, Romosozumab in postmenopausal women with 25 26 27 osteopenia. N Engl J Med, 2014. 370(17): p. 1664-5. 28 29 30 171. Bonewald, L.F., The amazing osteocyte. J Bone Miner Res, 2011. 26(2): p. 229-38. 31 32 33 172. Rodan, S.B. and L.T. Duong, Cathepsin K – A new molecular target for osteoporosis. 34 35 IBMS BoneKEy, 2008. 5(1): p. 16-24. 36 37 38 173. Costa, A.G., et al., Cathepsin K: its skeletal actions and role as a therapeutic target in 39 40 41 osteoporosis. Nat.Rev.Rheumatol., 2011. 7(8): p. 447-456. 42 43 44 174 . Sims NA, Martin TJ. Coupling Signals between the Osteoclast and Osteoblast: How are 45 46 Messages Transmitted between These Temporary Visitors to the Bone Surface? Front 47 48 Endocrinol (Lausanne). 2015;6:41. doi: 10.3389/fendo.2015.00041. eCollection 2015. Review 49 50 51 175. Adami, S., et al., Effect of one year treatment with the cathepsin-K inhibitor, balicatib, on 52 53 54 bone mineral density (BMD) in postmenopausal women with osteopenia/osteoporosis. J Bone 55 56 Miner Res, 2006. 21(Suppl 1): p. S24. 57 58 59 60 URL: http://mc.manuscriptcentral.com/eoop Email: [email protected] Page 57 of 111 Expert Opinion On Pharmacotherapy

1 2 3 176. Langdahl, B., et al., Odanacatib in the treatment of postmenopausal women with low 4 5 6 bone mineral density: 5 years of continued therapy in a phase 2 study. J Bone Miner Res, 2012. 7 8 Epub. 9 10 11 177. Eastell, R., et al., Safety and efficacy of the cathepsin K inhibitor ONO-5334 in 12 13 postmenopausal osteoporosis: the OCEAN study. J Bone Miner Res, 2011. 26(6): p. 1303-1312. 14 For Peer Review Only 15 16 17 178. Eisman, J.A., et al., Odanacatib in the treatment of postmenopausal women with low 18 19 bone mineral density: three-year continued therapy and resolution of effect. J Bone Miner Res, 20 21 2011. 26(2): p. 242-51. 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 URL: http://mc.manuscriptcentral.com/eoop Email: [email protected] Expert Opinion On Pharmacotherapy Page 58 of 111

1 2 3 References of Considerable Importance 4 5 6 1. Reference #5: This data from the USA shows the declining rates of osteoporosis medication use even 7 8 9 after hospitalization for a hip fracture. 10 11 2. Reference #8: The international movement Fracture Liaison Service (FLS), which is aimed at 12 13 developing pathways for patients admitted to various care stings with a fracture to receive 14 For Peer Review Only 15 16 osteoporosis evaluation and management. 17 18 3. Reference #16: The European guidelines for the diagnosis and management of osteoporosis in 19 20 postmenopausal women. 21 22 4. Reference 23: Understanding the issues surrounding bone quality which explains a large proportion 23 24 25 of the fracture risk independent of bone density 26 27 5. Reference #54: A perspective on the definition of frailty and sarcopenia, and strategies to manage 28 29 this age related phenomena which lead to high risk for falls and fractures. 30 31 32 6. Reference: #66: The ISCD Official Position Development statements on the detection and 33 34 importance of vertebral compression fractures. 35 36 7. Reference #86: The clinical application of FRAX™ in clinical practice 37 38 39 8. Reference #90: A novel approach for ways to broaden the diagnosis of osteoporosis from The 40 41 National Bone Health Alliance. 42 43 9. Reference # 123: The importance of the excessive high risk for a 2 nd fracture following the 1 st 44 45 fracture. 46 47 48 10. Reference # 144: The importance of understanding the spectrum of bone diseases in chronic kidney 49 50 disease and how to discriminate among them. 51 52 11. Reference # 171: The importance of the osteocyte in bone biology 53 54 55 56 57 58 59 60 URL: http://mc.manuscriptcentral.com/eoop Email: [email protected] Page 59 of 111 Expert Opinion On Pharmacotherapy

1 2 3 Management of Severe Osteoporosis 4 5 6 Paul D. Miller, M.D. 7 8 9 10 11 12 13 14 For Peer Review Only 15 16 17 18 19 20 21 22 23 24 Paul D. Miller, M.D. 25 26 27 Distinguished Clinical Professor of Medicine 28 29 30 University of Colorado Health Sciences Center 31 32 33 Medical Director 34 35 36 Colorado Center for Bone Research 37 38 39 3190 S. Wadsworth Blvd 40 41 42 Lakewood, Colorado, USA 80227 43 44 45 Phone: 303-980-9985 46 47 48 Fax: 303-980-1367 49 50 51 E-mail: [email protected] 52 53 54 55 56 57 58 59 60 URL: http://mc.manuscriptcentral.com/eoop Email: [email protected] Expert Opinion On Pharmacotherapy Page 60 of 111

1 2 3 Article Highlights: 4 5 6 1. Osteoporosis is largely underdiagnosed and undertreated 7 8 9 2. The annual costs of osteoporotic fractures exceeds and annual costs of caring for myocardial 10 11 infarction, cerebrovascular accidents and breast cancer 12 13 3. The underdiagnoses of osteoporosis is largely due to the declining utilization of bone mineral 14 For Peer Review Only 15 16 density; the under detection of vertebral compression fractures; and the under appreciation 17 18 that a low trauma fracture is women or men after the age of 50 years is a strong risk factor for 19 20 future fragility fractures in untreated people. 21 22 4. Severe osteoporosis constitutes a sub-group where the fracture risk is extraordinarily high. 23 24 25 5. There are a number of registered pharmacological choices that can be considered in severe 26 27 osteoporosis. 28 29 6. New therapies in development will offer an even wider variety of therapies for severe 30 31 32 osteoporosis with new mechanisms of action. 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 URL: http://mc.manuscriptcentral.com/eoop Email: [email protected] Page 61 of 111 Expert Opinion On Pharmacotherapy

1 2 3 4 5 6 1. Introduction 7 8 9 10 11 12 13 14 For Peer Review Only 15 16 17 18 19 Osteoporosis is both an underdiagnosed and undertreated disease [1, 2]. The annual costs in the 20 21 United States of America (USA) of caring for osteoporotic-related fractures parallels or exceeds 22 23 the annual costs of caring for myocardial infarction, breast cancer and/or cerebrovascular 24 25 26 accident [3](Figure I). Globally, addition, in a large Manitoba, Canada study the ratio of the 27 28 total annual costs of either prevalent or incident osteoporotic related fractures exceeds the same 29 30 ratio calculation for many other serious chronic diseases [3, 4]. Furthermore, recently published 31 32 33 by Oden and colleagues demonstrated that individuals with a high probability of osteoporotic 34 35 fractures compromise a very significant disease burden to society and that this burden is set to 36 37 increase markedly in the future. Equally as disturbing is the data showing that the percent of 38 39 40 patients receiving a registered therapy for osteoporosis, even after sustaining a hip fracture, has 41 42 declined from 41% in 2001 to 21% in 2010 Figure[5]. Finally, a major contributor to the loss of 43 44 45 independence in subjects 70 years of age and older are falls at home and fragility fractures [6, 7]. 46 47 48 There are many opinions regarding our decline in the awareness and treatment of osteoporosis. 49 50 The international movement to develop Fracture Liaison Services (FLS), spearheaded 51 52 internationally by The International Osteoporosis Foundation (IOF) and in the USA by The 53 54 55 National Bone Health Alliance (NBHA), is a multi-disciplinary effort to reduce the incidence of 56 57 the second osteoporotic fracture [8, 9]. The FLS relies on developing mechanisms and pathways 58 59 60 URL: http://mc.manuscriptcentral.com/eoop Email: [email protected] Expert Opinion On Pharmacotherapy Page 62 of 111

1 2 3 to identify patients admitted to hospitals, emergency rooms, or urgent care clinics with an 4 5 6 osteoporotic fracture and direct those patients into a well-developed osteoporotic management 7 8 and treatment plan. 9 10 11 The greatest risk factor for developing a second osteoporotic fracture is the occurrence of the 12 13 first osteoporotic fracture [10-14]. There is broad international agreement that a low trauma 14 For Peer Review Only 15 16 fracture after the age of 50 years of age in post-menopausal women or men merits first, an 17 18 evaluation for secondary causes of osteoporosis; and, second, pharmacological therapy for 19 20 21 osteoporosis in addition to adequate vitamin D and calcium [15-18] . Justifications for these 22 23 recommendations are based on the population data previously cited showing the high risk of a 24 25 second fracture flowing the first fracture in untreated subjects; and, the clinical trial data 26 27 28 providing evidence that fracture reduction with pharmacological agents for osteoporosis reduces 29 30 fractures above and beyond that reduction in fracture seen with vitamin D and calcium alone [19- 31 32 22]. This manuscript will define in the author’s opinion what constitutes severe osteoporosis, 33 34 35 and, what this author’s opinion is regarding approaches’ to management of the high risk patient. 36 37 Literature searches were completed from PubMed, Medscape and National Institutes of Health 38 39 40 reference databases. 41 42 43 1. Severe Osteoporosis 44 45 46 The word severe in Webster’s dictionary can mean “critical or grave”. This term is appropriate 47 48 for a certain magnitude of severity in bone strength which is comprised of bone mineral density 49 50 (BMD) and/or bone quality. While clinicians can measure BMD by dual energy x-ray 51 52 53 absorptiometry (DXA), we lack the clinical tools to quantitate bone quality. Bone quality can be 54 55 measured at the current time by a number of research methods (high resolution central or 56 57 58 peripheral quantitative computerized tomography, micro-magnetic imaging resolution [23, 24]. 59 60 URL: http://mc.manuscriptcentral.com/eoop Email: [email protected] Page 63 of 111 Expert Opinion On Pharmacotherapy

1 2 3 Recently, an office based methodology that is based on a grey-scale derived from the spine DXA 4 5 6 imaging, trabecular bone score (TBS) has been approved by international registration agencies 7 8 and offers a point-of-care means to quantitate a portion of bone quality [25-27]. TBS values 9 10 11 increase fracture risk prediction above and beyond that risk calculated by DXA alone and has 12 13 been added to the World Health organization’s (WHO) risk calculator, FRAX™ (Figure III) [28, 14 For Peer Review Only 15 29]. 16 17 18 Severe osteoporosis constitutes a wide spectrum of skeletal disorders that all carry the common 19 20 21 term, osteoporosis. The categories of severe osteoporosis should be made distinct from 22 23 osteoporosis in general due to the very high risk for fracture high mortality and morbidity that 24 25 accompanies severe osteoporosis [30-32]. There are a broad range of conditions that might be 26 27 28 associated with severe osteoporosis: 29 30 31 1. Severe postmenopausal osteoporosis or severe male osteoporosis [33, 34] 32 33 2. Glucocorticoid-induced osteoporosis [35-38] 34 35 36 3. Osteoporosis associated with systemic diseases that may also be associated with low bone 37 38 formation and turnover such as diabetes mellitus; chronic kidney disease, multiple 39 40 myeloma and MGUS (monoclonal gamopathy of undetermined significance). Each of 41 42 43 these conditions may have low bone formation associated with elevation in the serum of 44 45 inhibitors of osteoblast function [39-45]. These diseases are also associated with poor 46 47 bone quality. 48 49 50 4. Osteoporosis associated with systemic diseases that are also associated with high bone 51 52 turnover: e.g. severe primary hyperparathyroidism; immobilization (e.g. quadriplegia) 53 54 [46-50]. Osteoporosis associated with systemic diseases associated with frailty and a high 55 56 57 risk for fractures from falls: e.g. Parkinson’s disease, multiple sclerosis, polio, 58 59 60 URL: http://mc.manuscriptcentral.com/eoop Email: [email protected] Expert Opinion On Pharmacotherapy Page 64 of 111

1 2 3 amyotrophic lateral sclerosis (ALS), and diseases associated with marked sarcopenia 4 5 6 (deficiency of muscle mass and strength), particularly malabsorption syndromes, age- 7 8 related sarcopenia, and myopathies of diffuse etiologies [51-55]. 9 10 11 2. Severe Postmenopausal and male osteoporosis 12 13 There are certain risk factors that place a patient of either gender into the severe category 14 For Peer Review Only 15 16 regardless of underlying mechanisms of osteoporosis disease: 17 18 19 1. A prior low trauma fracture after the age of 50 years 20 21 2. Very low BMD (or T-scores) in older patients 22 23 24 3. A very high FRAX™ score 25 26 The presence of a low trauma fracture in women or men past the age of 50 years is greatest 27 28 risk factor for a second fracture in untreated individuals [10, 56, 57]. Fractures of the hands, 29 30 31 feet, and skull are currently not considered osteoporotic fractures since they do not predict 32 33 future fracture risk in untreated patients. One exception before discounting metatarsal 34 35 36 fractures: metatarsal fractures may suggest the presence of adult hypophosphatasia (HPP), 37 38 which is becoming increasingly diagnosed due to greater awareness of examining laboratory 39 40 reports for low or low-normal serum total alkaline phosphatase [58]. The underlying 41 42 43 pathophysiology of HPP is a decrease in osteoblast production of alkaline phosphatase and 44 45 the adult patients can present with a singular skeletal manifestation (e.g. metatarsal fractures, 46 47 lower extremity large bone (mid-shaft femur) fractures and/or poor dentation. The total 48 49 50 serum alkaline phosphatase is often below 40 IU/l in these patients; and, if suspected can be 51 52 followed up by looking for an elevated serum phosphorus and elevated pyridoxal phosphate 53 54 (vitamin B6). 55 56 57 58 59 60 URL: http://mc.manuscriptcentral.com/eoop Email: [email protected] Page 65 of 111 Expert Opinion On Pharmacotherapy

1 2 3 The most common, and often unrecognized low trauma fracture that conveys a high risk for 4 5 6 future fracture are vertebral compression fractures (VCF). The reality is that most VCF are 7 8 missed by clinicians [59-61]. The reasons behind this under diagnosis and under treatment of 9 10 11 VCF include: 12 13 1. A lack of awareness that the majority of VCF are asymptomatic. Clinicians are looking 14 For Peer Review Only 15 16 for pain as the clue to the possible presence of a VCF [62-64]. 17 18 19 2. The under- appreciation that even morphometric (radiological detected) VCF convey a 20 21 high risk, not only for more VCF but also for other further fractures at other skeletal sites [65- 22 23 24 69]. 25 26 27 3. That vertebral compression fractures may exists even though the T-score is normal [70, 28 29 71] [72]. 30 31 32 4. That simple height measurements are often not done in physician offices; or rather, if 33 34 35 done, are often done on inaccurate scales (e.g. the “metal rod”) rather than the wall mounted and 36 37 inexpensive stadiometer [33, 73]. 38 39 40 5. Height loss should be the alerting signal that a VCF may be present. Both The Canadian 41 42 practice guidelines as well as The International Society for Clinical Densitometry (ISCD) has 43 44 45 established specific prevalent or interval height loss values that has a high probability of 46 47 detecting either a prevalent or incident VCF [74, 75]. 48 49 50 6. The underreporting of the presence of VCF by radiologists examining routine PA and 51 52 lateral chest-x-ray [76-79]. 53 54 55 56 57 58 59 60 URL: http://mc.manuscriptcentral.com/eoop Email: [email protected] Expert Opinion On Pharmacotherapy Page 66 of 111

1 2 3 When an asymptomatic VCF is detected, even though the date of when the VCF occurred is 4 5 6 unknown, there is a high risk for global fracture risk in untreated patients. Vertebral compression 7 8 fractures are graded by severity according to the degree of vertebral compression [80-82] (Figure 9 10 11 IV). The greater the severity of compression or the greater the number of prevalent VCF, the 12 13 greater the risk for future fractures [13, 83-85]. 14 For Peer Review Only 15 16 While low BMD is a strong predictor for future fracture risk, fracture risk as a function of low 17 18 BMD is highly age dependent [86] (Figure V). For every decade above the age of 50 years, 19 20 21 future fracture risk approximately doubles by decade at the same BMD. While more elderly 22 23 patients may fall more, and this greater risk for falling is certainly a partial reason for the greater 24 25 fracture risk as age increases, the relationship between increased age and fracture risk is also 26 27 28 independent of falls. Bone strength, a composite of BMD and bone quality, is poorer in older 29 30 patients as compared to younger patients. Practically, management recommendations for 31 32 osteoporosis therapy should be different in a patient at 50 years of age with a T-score of -2.5 as 33 34 35 compared to a patient of 80 year with the same T-score of -2.5. The fracture risk is ~6X greater 36 37 in the 80 year old at the same BMD. 38 39 40 The WHO Fracture Risk Assessment Model (FRAX™) is a health-economic model to assess the 41 42 43 risk for a major osteoporotic fracture or hip fracture over a 10 year period in untreated 44 45 postmenopausal women and older men [86]. Based on a robust dataset, FRAX™ has provided a 46 47 validated model to help guide clinicians as to which patients may need pharmacological therapy 48 49 50 to reduce the risk of future fracture. While the provision of 20% for major fracture or 3% for hip 51 52 fracture to consider treatment is based on a cost-effective analysis using the annual cost of 53 54 alendronate at the time FRAX™ was developed, it is also know that broad clinical judgement 55 56 57 must be incorporated along with FRAX™ to make treatment decisions[87-89]. For example, 58 59 60 URL: http://mc.manuscriptcentral.com/eoop Email: [email protected] Page 67 of 111 Expert Opinion On Pharmacotherapy

1 2 3 FRAX™ did not capture fall rates or doses of glucocorticoids into the model; nor a number of 4 5 6 additional diseases that may contribute to greater skeletal fragility, such as chronic kidney failure 7 8 or diabetes mellitus. Hence while prevalent fracture, low BMD and increased age constitute the 9 10 11 most robust 3 risk factors for future fracture risk, clinicians must incorporate a wide range of risk 12 13 factors, some captured and some not captured in FRAX™ to make treatment decisions. The 14 For Peer Review Only 15 National Osteoporosis Foundation’s Clinician’s Guide for the management of osteoporosis and 16 17 18 The European guidance for the diagnosis and management of osteoporosis in post-menopausal 19 20 women also provide evidence-based as well as opinion-based recommendations for initiating 21 22 pharmacological therapy [15, 16, 90]. One of the hindrances to physician management and 23 24 25 decisions to initiate therapy in today’s changing health-economic environment are the 26 27 restrictions imposed on physician judgement by insurance company “phantom” physicians or 28 29 administrators who have no accountability for the patient’s health. Payer’s often base their 30 31 32 decisions on simple economic numbers such as in the FRAX™ model without knowledge of the 33 34 broad clinical issues that modulate individual patient management. Expanding the definition of 35 36 37 osteoporosis by using the risk for fracture as a threshold and /or the expansion of diagnostic sub- 38 39 categories for the diagnosis by a new International Classification of Disease 10 (ICD-10) has 40 41 been suggested [90]. Whether or not these expanded criteria simplify diagnosis and management 42 43 44 or make it more complex will be measured by quantitating if these newer approached increase 45 46 the proportion of patients treated. The patient and her/his health care management lie in the 47 48 hands of the physician who not only has medical, moral, and legal accountability for their 49 50 51 patient’s care, but also the broad knowledge of the patient’s clinical situations. 52 53 54 4. Glucocorticoid-Induced Osteoporosis (GIOP) 55 56 57 58 59 60 URL: http://mc.manuscriptcentral.com/eoop Email: [email protected] Expert Opinion On Pharmacotherapy Page 68 of 111

1 2 3 Glucocorticoids inhibit osteoblast activity [36, 90]. In that regard, a major effect of 4 5 6 glucocorticoids on fracture risk is a decrease in bone formation. The effect of glucocorticoids on 7 8 bone strength is both dose and duration related. While not all patients on glucocorticoids have 9 10 11 severe osteoporosis unless they have fractured, the severity increases with the dose and/or 12 13 duration of glucocorticoid use. Low dose prednisone, even at a dose of 2.5 mg/day will convey a 14 For Peer Review Only 15 great risk for fractures than no dose and not as great as 5.0 mg/day. Even higher (> 15 mg/day) 16 17 18 sustained doses of glucocorticoids may induce fractures, particularly multiple VCF within a short 19 20 (months) period of time [91-92]. 21 22 23 While low BMD is a strong predictor of fracture risk in PMO and male osteoporosis, BMD is not 24 25 as strong a predictor for fracture in GIOP. In part, this is related to the fact that glucocorticoids 26 27 28 inhibit osteoblast function and bone formation. Hence, impaired bone quality rather than low 29 30 BMD is a major component of the fracture risk in GIOP. While patients who have already 31 32 sustained a GIOP related fracture, or those with very low BMD (T-scores of -2.5 and lower) and 33 34 35 older age certainly constitute a high risk group, the challenge for clinicians is in deciding what 36 37 patients may need pharmacological therapy who are younger, have not fractured and have higher 38 39 40 BMD that are committed to chronic glucocorticoid therapy. Risk factors are not as predictive for 41 42 future fracture risk in GIOP as they are in PMO [93]. Certainly the higher the dose of 43 44 glucocorticoid and the longer the duration of use are strong considerations for the timing of the 45 46 47 initiation of therapy for GIOP. Like all guidelines, the both European as well as USA guidelines 48 49 recognize the role that broad clinical judgement plays in ultimate management decisions [94]. 50 51 52 5. Other Categories of Severe Osteoporosis 53 54 55 The other categories representing severe osteoporosis listed in the introduction of this manuscript 56 57 58 have been previously dealt with in individual peer-reviewed publications. The use of specific 59 60 URL: http://mc.manuscriptcentral.com/eoop Email: [email protected] Page 69 of 111 Expert Opinion On Pharmacotherapy

1 2 3 pharmacological agents for any specific condition will be included in the choices of 4 5 6 pharmacological agents in the remainder of this paper. 7 8 9 6. Treatment of Severe Osteoporosis 10 11 12 The list of Food and Drug Administration (FDA) and European Medicine Agency (MEA) 13 14 approved pharmacologicalFor Peer agents for the treatmentReview of PMO are shownOnly in Table I. In general, 15 16 17 pharmacological agents are divided into drugs that inhibit bone resorption (anti-resorptive) and 18 19 drugs that stimulate bone formation (anabolic) [95-99]. To date, there are no published data 20 21 comparing the efficacy between or among these agents on the most important outcome-fracture 22 23 24 risk reduction. While there are comparative studies examining important surrogate markers of 25 26 bone strength (BMD and/or bone turnover markers {BTM} between or among agents that have 27 28 been published, suggesting differences between or among pharmacological agents, it is unknown 29 30 31 if these differences in BMD or BTM translate into differences in fracture risk as compared to 32 33 placebo since the criteria for registration are fracture end-point [99] [101, 102]. 34 35 36 Opinions about what is “first line” vs “second-line” therapies, the terminology created by payers 37 38 39 and/or professional organization practice guidelines, are based on a combination of 40 41 efficacy/safety and costs. As pharmacological agents become “generic” and costs for therapies 42 43 decline, it is logical for payers to prefer a generic agent. Generics agents in the osteoporosis field 44 45 46 do not require the same stringent evidence for efficacy for registration as is required for the 47 48 initial registration of the branded drug (e.g. fracture risk reduction). The generics only have to 49 50 show that as compared to the original registered agent, the BMD increases in a non-inferiority 51 52 53 manner to the same degree as the branded formulation [103]. While this non-fracture end-point 54 55 seems acceptable, it is important to recognize that due to the nature of the very poor absorption 56 57 58 of oral bisphosphonates [104,105], patients with gastrointestinal diseases that may affect 59 60 URL: http://mc.manuscriptcentral.com/eoop Email: [email protected] Expert Opinion On Pharmacotherapy Page 70 of 111

1 2 3 bisphosphonate absorption such as celiac disease, malabsorption syndromes, small bowel 4 5 6 resections, and gastric bypass differ from the subjects in clinical trials. For this reason alone, 7 8 monitoring the biological effect of oral bisphosphonates on bone metabolism is important [44, 9 10 11 106, 107 ]. 12 13 Measuring serial BMD and BTM is one way of gaining some assurance that the oral generic 14 For Peer Review Only 15 16 bisphosphonate, the most widely prescribed therapy for osteoporosis, is “working”. Increases in 17 18 BMD or declines in BTM with pharmacological therapy using anti-resorptive agents are 19 20 21 associated with reductions in fracture risk [108-110 ]; and, increases in bone formation 22 23 (osteoblast activity markers) with teriparatide are associated with improvements in BMD and 24 25 bone microarchitecture. 26 27 28 The selective estrogen receptor modulators (SERMS) have evidence for reduction in vertebral 29 30 31 fracture but not for non-vertebral fractures [111]. Certainly in patients with severe osteoporosis 32 33 and a high risk for non-vertebral fractures, a SERM should not be a viable treatment option. 34 35 36 While the oral bisphosphonates, alendronate, risedronate and ibandronate are all effective and 37 38 39 worthy, and, have variable evidence for either reduction in vertebral, non-vertebral and/or hip 40 41 fracture risk, they may have compliance issues as well as gastrointestinal tolerability issues that 42 43 mitigate their effectiveness. Ibandronate is also not registered for the reduction in non-vertebral 44 45 46 fractures [112]. 47 48 49 When the physician has concerns about compliance, absorption, tolerability or effectiveness, the 50 51 administration of a parenteral therapy for osteoporosis is a viable option. Parenteral therapies 52 53 guarantee that the delivery of the drug to the bone site, include intravenous bisphosphonates 54 55 56 (zoledronic acid or ibanadronate), subcutaneous administration of denosumab and the anabolic 57 58 59 60 URL: http://mc.manuscriptcentral.com/eoop Email: [email protected] Page 71 of 111 Expert Opinion On Pharmacotherapy

1 2 3 agent, teriparatide. Each agent has evidence for efficacy in reducing the risk of fractures and 4 5 6 different mechanisms of action (MOA) for strengthening bone [116-119]. On examining 7 8 individual clinical trial data, intravenous zoledronic acid and denosumab have the most robust 9 10 11 evidence for reduction in all fractures: vertebral, non-vertebral including hip fractures [120-121]. 12 13 14 7. PharmacologicalFor PeerChoices in Severe Review Osteoporosis Only 15 16 17 While all of the pharmacological agents have efficacy for fracture risk reduction, there are 18 19 circumstances where the physician believes it is important to intervene in a severe situation 20 21 where the risk is very high. These situations would include: 22 23 24 1. A recent (<12 months) fracture 25 26 27 2. Fractures occurring while already receiving an osteoporotic agent 28 29 3. Fractures that have a “cascade” pattern, e.g. recurrent vertebral compression fractures 30 31 32 4. Fractures occurring in the setting of high dose glucocorticoid use 33 34 35 Recent fractures or cascade fracture events require immediate treatment. Both situations are very 36 37 serious and can be life-threatening since they represent the extremes of risk. The terrible cascade 38 39 vertebral fracture clinical situation is unusual but is associated with tremendous and rapid loss of 40 41 42 height, pulmonary function, pain and a very high morbidity and mortality [34, 69, 122-123] . For 43 44 any acute fracture the risk for the 2 nd fracture is greatest in the first 12 months following a 45 46 fracture [124]. 47 48 49 Fractures occurring while on a previous osteoporotic (usually an oral bisphosphonate) are 50 51 52 common. In part, this observation is due to the fact that no pharmacological agent abolishes 53 54 fracture risk-they reduce risk. Second, issues with compliance are prevalent; and, there are 55 56 57 situations where compliance and bioavailability of the bisphosphonate are insured yet the patient 58 59 60 URL: http://mc.manuscriptcentral.com/eoop Email: [email protected] Expert Opinion On Pharmacotherapy Page 72 of 111

1 2 3 does not respond. While “non-response” may be unusual, there are reversible factors that could 4 5 6 mitigate a non-response such as vitamin D deficiency or celiac disease. Since oral 7 8 bisphosphonate blood levels cannot be measured in clinical practice the physician must use serial 9 10 11 BMD and BTM to assess biological effects of the drug. While a decline in BMD beyond the least 12 13 significant change (LSC) of the precision of DXA is unacceptable, a stable or increasing BMD is 14 For Peer Review Only 15 acceptable since both are associated with fracture risk reduction. Likewise, for anti-resorptive 16 17 18 agents, a decline in bone turnover markers beyond their LSC is also an indicator of response 19 20 [125-126]. Though the bone resorption marker, serum collagen-crosslink, C-telopeptide (CTX) 21 22 declines sooner than serum bone formation markers (bone specific alkaline phosphatase 23 24 25 {BSAP}, osteocalcin {OC}, and pro-peptide type I collagen {PINP} all are indicators of 26 27 response. Bone formation markers decline with anti-resorptive therapies since the osteoclast- 28 29 osteoblast cells are coupled in their activity, e.g. a decline (or an increase) in the activity of one 30 31 32 cell line will be followed by a directional change in the other cell line. The preferred marker by 33 34 the American Association of Clinical Chemistry and The National Bone Health Alliance for 35 36 37 bone resorption applications is the CTX and the preferred formation marker is PINP [127]. 38 39 While serum CTX must be drawn fasting before 10AM, the PINP can be drawn at any time of 40 41 the day. 42 43 44 8. Specific Osteoporosis Pharmacological Agents for Severe Osteoporosis 45 46 47 All of the registered osteoporosis agents are effective to reduce the risk for fracture. Since there 48 49 50 are no head to head comparative fracture studies to demonstrate superiority of anyone agent over 51 52 another, there are reasons that merit strong consideration for choosing the following agents as 53 54 first line therapies, not requiring that the patient “fail” the most widely prescribed osteoporosis 55 56 57 agent worldwide-----oral bisphosphonates. These “first-line” choices in my opinion are 58 59 60 URL: http://mc.manuscriptcentral.com/eoop Email: [email protected] Page 73 of 111 Expert Opinion On Pharmacotherapy

1 2 3 recommended according to the individual patient clinical situation, and the knowledge that 4 5 6 achieving a rapid onset of action on bone may be a priority in severe osteoporosis. 7 8 9 9. Intravenous zoledronic acid and intravenous ibandronate 10 11 12 Assuring that a bisphosphonate is delivered to bone seems, clinically, to be a desirable goal in 13 14 the patient populationFor described Peer as having Review severe osteoporosis. InOnly these more severe patients, 15 16 nd 17 halting the cascade of vertebral fractures or reducing the risk of a 2 non-vertebral fracture in the 18 19 immediate period following the first fracture is a desirable goal. Oral bisphosphonates have been 20 21 shown to have a rapid onset of pharmacological effect to reduce VCF within 6 months [128]. If 22 23 24 absorbability is uncertain and when a physician desires to guarantee that the bisphosphonate is 25 26 being delivered to bone, an intravenous route of administration is the most confident means to 27 28 guarantee this skeletal delivery. There are no head to head studies comparing the biological 29 30 31 effects of oral as opposed to intravenous bisphosphonates. Yet with the knowledge that under the 32 33 best circumstances of compliance and proper dosing instructions that 0.6% of an oral 34 35 36 bisphosphonate is absorbed, achieving a secure and rapid delivery to the bone site is a desirable 37 38 goal [103. 129-131] 39 40 41 Both intravenous zoledronic acid (5mg/yr) as well as intravenous ibandronate (3mg every 3 42 43 months) achieve this end. While intravenous (as well as oral) bisphosphonates have either FDA 44 45 46 contraindications or warnings not to administer for patients were more severe reductions in renal 47 48 function (e.g. glomerular filtration rates (GFR) < 35 ml/min it seems ibandronate may have less 49 50 of a risk for renal toxicity than zoledronic acid [132]. It has been suggested from broad clinical 51 52 53 experience that if one is concerned at all about renal function, slowing the infusion rate down 54 55 with zoledronic acid to 30 or 60 minutes from the FDA label of 15 minutes may offer less renal 56 57 58 toxicity. 59 60 URL: http://mc.manuscriptcentral.com/eoop Email: [email protected] Expert Opinion On Pharmacotherapy Page 74 of 111

1 2 3 4 5 In a prospective study we did show that every 3 month IV ibandronate “push” via a 5 minute 6 7 8 slower drip showed no differences in changes in GFR, even in diabetics with marginal GFR to 9 10 begin with [132]. There is more robust fracture data with zoledronic acid than ibandronate from 11 12 individual clinical trials and ibandronate is not registered for the reduction of non-vertebral 13 14 For Peer Review Only 15 fractures. In addition, extension data suggest that 6 annual doses of zoledronic acid may have 16 17 additional morphometric vertebral fracture benefit than in specific severe osteoporotic 18 19 20 populations (e.g. femoral neck T-score of -2.5 and with prevalent VCF [133]. In this regard, the 21 22 extension of alendronate clinical trials, the Fosamax long term extension (FLEX) trial also 23 24 showed some additional benefit, from the initial data analysis, for continuing oral alendronate 25 26 27 beyond 5 years in subjects with a prevalent VCF or “very low” BMD [134]. However, in the 28 29 FLEX interaction table (Table 4 in the FLEX manuscript) actually shows that the fracture risk 30 31 reduction benefit of continuing alendronate beyond 5 years was independent of the baseline 32 33 34 BMD (down to a femoral neck T-score of -2.0) or the presence of VCF. Both fracture 35 36 intervention trials (FIT trials) either had randomized subjects with either a prevalent VCF (severe 37 38 osteoporosis) or in FIT 2 without prevalent VFC but a T-score of -2.0 or lower. Perhaps age is 39 40 41 the risk factor that constitutes severe osteoporosis even with a non-osteoporotic (e.g. osteopenic) 42 43 T-score, since the FLEX population were between 66-91 years old when they entered FLEX. 44 45 46 10. Denosumab 47 48 49 Parenteral denosumab, 60 mg SQ every 6 months, is another first line choice in severe 50 51 52 osteoporosis or in situations where oral administrations of agents are unacceptable, or 53 54 uncertainty of absorption is a clinical concern or poor compliance with oral medications is an 55 56 issue. 57 58 59 60 URL: http://mc.manuscriptcentral.com/eoop Email: [email protected] Page 75 of 111 Expert Opinion On Pharmacotherapy

1 2 3 Densoumab js a fully human monoclonal antibody to an activator of osteoclastic differentiation 4 5 6 and activity, soluble Rank-Ligand (Rank-L). Rank-Ligand is receptor activator (Rank being the 7 8 receptor on osteoclasts, also called NF-kB). Rank-L, a glycoprotein produced in the osteoblast, is 9 10 11 a member of the superfamily of ligands, and is also known as TNF –activation-induced cytokine 12 13 and osteoclast activator [135]. 14 For Peer Review Only 15 16 Denosumab has robust fracture data with fracture risk reduction at all (vertebral, non-vertebral 17 18 and hip) skeletal sites [136, 137]. In addition, denosumab has robust extension BMD, safety and 19 20 21 fracture data showing continual fracture efficacy up to eight years, data that does not exist with 22 23 any other osteoporosis pharmacological agent [138]. 24 25 26 Denosumab is metabolized by the reticuloendothelial system and the biological effect of 27 28 increasing BMD or lowering bone turnover is nearly gone by the end of the 6 month of 29 30 31 administration. Thus, every 6 month administration is needed to maintain efficacy [139-142]. 32 33 34 The FDA label for the postmenopausal osteoporosis indication does not have any lower cut-off 35 36 37 for renal function. This is because denosumab is not cleared by the kidney but by the 38 39 40 reticuloendothelial system, and may not have any adverse renal effects as may be seen, though 41 42 43 rarely, with intravenous bisphosphonates. In a post-hoc analysis of FREEDOM where the 44 45 46 registration population had estimated glomerular filtration rates (eGFR) divided into quartiles (> 47 48 49 90 ml/min to 15-29 ml/min), densoumab had evidence of reduction in incident vertebral fractures 50 51 52 across these quartiles without any adverse renal effects (e.g. change in eGFR over 3 years) [143]. 53 54 55 There are no data on changes in BMD or fractures in patients with GFR < 15 ml/min. 56 57 58 59 60 URL: http://mc.manuscriptcentral.com/eoop Email: [email protected] Expert Opinion On Pharmacotherapy Page 76 of 111

1 2 3 In this latter population, the diagnosis of osteoporosis becomes far more difficult to establish; 4 5 6 and, there is concern that in patients with pre-existing adynamic renal bone disease reducing 7 8 9 bone turnover further may be associated with an increase in cardiovascular calcification [144- 10 11 148]. This theoretical interaction is predicated on the knowledge that absorbed calcium and/or 12 13 phosphorus cannot be adequately eliminated by renal clearance; and, if bone turnover is low, the 14 For Peer Review Only 15 16 capacity of bone to take up these ions is restricted, leaving vascular tissue exposed to calcium- 17 18 phosphorus and risk for vascular calcification. One study has examined the effect of denosumab 19 20 21 on vascular calcification in the FREEDOM trial and found that across the quartiles of eGFR 22 23 there was no greater increase in vascular calcification with denosumab vs placebo, at least when 24 25 assessed by lateral lumbar x-ray assessment of aortic calcification [149]. The FDA label cautions 26 27 28 the physician concerning the possibility of hypocalcemia after denosumab administration. While 29 30 all anti-resorptive agents may induce a small and transient hypocalcemia after administration, 31 32 clinically significant hypocalcemia (associated with tetany or paresthesias) is not observed in 33 34 35 patients with adequate calcium and vitamin D intake; and, with intact parathyroid hormone 36 37 (PTH) responses to normalize the transient hypocalcemia. In that regard, hypocalcemia in the 38 39 40 FREEDOM trial was no different between the treated vs placebo groups either in the registration 41 st 42 (1 3 years) or the extension trial. It is important in patient management to ensure that an 43 44 adequate amount of calcium and vitamin D are provided. Symptomatic hypocalcemia has been 45 46 47 seen in patients on hemodialysis given denosumab [150]. 48 49 50 Denosumab, since FDA registration in June 2010 for the treatment of PMO, has had an 51 52 impressive safety and efficacy track record. 53 54 55 11. Teriparatide 56 57 58 59 60 URL: http://mc.manuscriptcentral.com/eoop Email: [email protected] Page 77 of 111 Expert Opinion On Pharmacotherapy

1 2 3 Teriparatide (recombinant human 1-34 parathyroid hormone) marketed under the brand name 4 5 6 Forteo™ is the first anabolic agent registered for the treatment of osteoporosis [116]. 7 8 Teriparatide has FDA registration for severe postmenopausal, male and glucocorticoid-induced 9 10 11 osteoporosis [151-153]. In many restricted health plans, both in the USA as well as in Europe, 12 13 most patient have to have “failed” a less expensive oral bisphosphonate before approval of 14 For Peer Review Only 15 teriparatide. 16 17 18 This restrictive approach, based purely on health economics is a hindrance to effective and 19 20 21 humanistic patient care. Patients with severe osteoporosis and at extremely high risk for more 22 23 fractures than they have already had, deserve consideration, first line, to receive an anabolic 24 25 agent. Many clinical bone specialists and bone biologists feel that first providing an anabolic 26 27 28 agent to initially build new bone first in treatment naïve patients is the approach that should be 29 30 taken. Then after new bone is formed, follow anabolic therapy with an ant-resorptive agent to 31 32 maintain the newly formed bone in many patients with severe osteoporosis seems logical. 33 34 35 36 There remains a “black-box” warning on the FDA labels for the lifetime duration of teriparatide 37 38 use to more than 24 months. This restriction, which is based on the lifespan of the rat model and 39 40 the appearance of osteogenic sarcoma toward the end of the life span in the rat, should be 41 42 43 removed now that teriparatide has been on the USA market for 15 years. During this time period 44 45 osteogenic sarcoma has not been seen in 4 other animal models that remodel bone similar to 46 47 human beings: dog, sheep, pig and monkey. In the human population, validated osteogenic 48 49 50 sarcoma has only been reported in < 5 cases with an exposure window of 15 years and over 1.5 51 52 million patients [154-157]. The natural background incident rate of osteogenic sarcoma in adult 53 54 human beings is 4/million/year, meaning that teriparatide does not increase the incident rate of 55 56 57 this tumor. There is evidence that teriparatide continues to be effective beyond 2 years and the 58 59 60 URL: http://mc.manuscriptcentral.com/eoop Email: [email protected] Expert Opinion On Pharmacotherapy Page 78 of 111

1 2 3 glucocorticoid-induced osteoporosis data demonstrated this point in the clinical trials of 4 5 6 teriparatide in GIOP. The biomarker data, especially the osteoblast activity marker, pro-peptide 7 8 type I collagen (PINP) also demonstrates that osteoblast stimulation may continue to occur 9 10 11 beyond 2 years such that the “anabolic window”, where bone formation and subsequent bone 12 13 resorption biomarker lines cross, may be quite heterogeneous [158-161]. Modulating the 14 For Peer Review Only 15 anabolic window may allow for a longer period of bone formation before bone resorption 16 17 18 “catches up” This can be done with combination therapy, an anabolic combined with an anti- 19 20 resortpive; perhaps by sequential therapy where, or by drug development of agents that induce a 21 22 less osteoblast stimulation of Rank-Ligand [162-169] . While combination therapy has appeal, it 23 24 25 is unlikely in today’s more restrictive health care economy that payer’s will pay for combination 26 27 therapies unless combination therapy shows greater fracture reduction than monotherapy. 28 29 30 12. New Pharmacological Agents 31 32 33 12. 1 Abaloparatide 34 35 36 Abaloparatide (Parathyroid hormone related peptide analogue, PTHrP analogue) is a parathyroid 37 38 hormone related peptide analogue with altered amino acid sequencing that conveys unique 39 40 biological actions that differ from either parathyroid hormone, parathyroid hormone related 41 42 43 peptide, or teriparatide. Abaloparatide preferentially binds to the osteoblast parathyroid receptor, 44 45 RO, more than the RG osteoblast receptor, where teripataide or parathyroid hormone related 46 47 peptide preferentially bind [168]. Greater stimulation of the RO receptor may induce a less rise 48 49 50 on osteoblast derived Rank- Ligand, leading to less bone resorption than teriparatide; yet similar 51 52 increases in bone formation markers leading in this way to an expanded anabolic window. 53 54 55 In the pivotal registration clinical trial comparing abaloparatide to placebo to teriparatide, 80ug 56 57 58 SQ/day of abaloparatide significantly reduced the incidence of vertebral compression fractures 59 60 URL: http://mc.manuscriptcentral.com/eoop Email: [email protected] Page 79 of 111 Expert Opinion On Pharmacotherapy

1 2 3 compared to placebo (the primary end-point) and significantly reduced the incidence of non- 4 5 6 vertebral and all clinical fractures as well (Miller PD et al. Endocrine Society 2015 abstract, 7 8 submitted for publication). Fracture reduction between abaloparatide and teriparatide, by Kaplan- 9 10 11 Meier (time to first event) the reduction in non-vertebral and all clinical fractures occurred 12 13 sooner with abaloparatide than teriparatide and the increase in cortical bone site bone mineral 14 For Peer Review Only 15 density (BMD) was significantly greater with abaloparatide. Finally, there was significantly 16 17 18 lower incident rates of hypercalcemia with abaloparatide than teriparatide. Thus, this novel 19 20 PTHrP analogue may offer some distinct advantages as a new anabolic agent than teriparatide. 21 22 23 12.2 Romosozumab 24 25 26 The mono-clonal antibody to sclerostin, romosozumab, has impressive data with regard to 27 28 increases in BMD and bone formation with little increase in serum CTX or bone resorption [170- 29 30 31 ]. Hence, even a wider anabolic window may be seen with romosozumab. Sclerostin, a product 32 33 of the osteocyte, binds to the osteoblast and inhibits osteoblast activity. The discovery of 34 35 36 sclerostin and the development of a monoclonal antibody to sclerostin represents an achievement 37 38 in basic bone biology [40, 170-171]. The phase III registration studies are currently ongoing. 39 40 41 12.3 Odanacatib 42 43 44 Cathepsin K is an enzyme that has ubiquitous presence throughout the human body but its bone 45 46 presence acts as a mediator of bone resorption. Cathepsin K works outside the osteoclast to 47 48 49 induce bone resorption [172-173]. The discovery of cathepsin K inhibitors allowed targeting of 50 51 bone resorption without altering the structural integrity of the osteoclast, resulting in 52 53 maintenance of osteoclast cell membrane signaling back to the osteoblast. Hence osteoblast bone 54 55 56 formation is maintained with odanacatib administration, thus providing another mechanism 57 58 59 60 URL: http://mc.manuscriptcentral.com/eoop Email: [email protected] Expert Opinion On Pharmacotherapy Page 80 of 111

1 2 3 whereby “uncoupling” bone resorption to bone formation [174]. A number of well-designed 4 5 6 phase II clinical trials have consistently documented the large increases in BMD and other 7 8 structural parameters of improvement in bone strength as well as safety over a long study period 9 10 11 [175-178]. The phase III registration study given the acronym LOFT (long term odanacatib 12 13 fracture trial) in unpublished data shows that 50mg/week of oral odanacatib provides significant 14 For Peer Review Only 15 incident fracture reduction at all skeletal sites as compared to placebo with a very favorable 16 17 18 safety profile. 19 20 21 13 Conclusions 22 23 24 Severe osteoporosis is a devastating systemic disease with a high mortality, morbidity, and 25 26 economic cost. The important message to convey in this review is that fractures can be prevented 27 28 by appropriate treatment and fall prevention strategies. Both current and emerging 29 30 31 pharmacological treatments have evidence for efficacy and safety when used in the right 32 33 population. As longer term (extension) studies of newer osteoporosis therapies continue to 34 35 36 provide reassurance of maintenance of efficacy and safety, the acceptance by patients of 37 38 osteoporosis treatments should be attended by a reduction in the incidence of all fragility 39 40 fractures. 41 42 43 Legends for Figures and Tables 44 45 46 Figure 1 The annual costs of osteoporotic fractures as compared to the annual costs of 3 other major 47 48 49 disease states (reference # 3) 50 51 52 Figure 2 The declining annual probability of treatment with an osteoporosis agent after hospital 53 54 discharge for hip fractures (reference # 5) 55 56 57 58 59 60 URL: http://mc.manuscriptcentral.com/eoop Email: [email protected] Page 81 of 111 Expert Opinion On Pharmacotherapy

1 2 3 Figure 3 The predictive value of TBS (trabecular bone score) used in the FRAX™ calculator (reference # 4 5 6 28) 7 8 9 Figure 4 The semiquantitative classification of morphometric vertebral compression fractures according 10 11 to the Genant method (reference # 82) 12 13 14 Figure 5 The effectFor of age on Peer the risk of hip fracturesReview (reference # 87 )Only 15 16 17 Table 1 The currently available pharmacological therapies for postmenopausal osteoporosis (P Miller) 18 19 20 Table 2 The emerging new therapies for postmenopausal osteoporosis (P Miller) 21 22 23 24 25 26 27 28 29 Figure 1 30 31 32 33 34 35 36 37 38 39 40 41

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1 2 3 4 5 6 7 8 9 10 11 12 13 14 For Peer Review Only 15 16 17 18 19 20 21 22 23 24 25 26 Figure 2 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 URL: http://mc.manuscriptcentral.com/eoop Email: [email protected] Page 83 of 111 Expert Opinion On Pharmacotherapy

1 2 3 4 5 6 7 8 9 10 11 12 13 14 For Peer Review Only 15 16 17 18 19 20 21 22 23 24 25 26 27 Figure III 28 29 30

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1 2 3 4 5 6 7 8 9 10 11 12 13 14 For Peer Review Only 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 Figure 4 31 32 33 Classification of the Grades of Vertebral Fractures 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 URL: http://mc.manuscriptcentral.com/eoop Email: [email protected] Page 87 of 111 Expert Opinion On Pharmacotherapy

1 2 3 4 5 6 7 8 9 10 11 12 13 14 For Peer Review Only 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 URL: http://mc.manuscriptcentral.com/eoop Email: [email protected] Expert Opinion On Pharmacotherapy Page 88 of 111

1 2 3 Figure 5 4 5 6 7 8 9 10 11 12 13 14 For Peer Review Only 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 Table 1 53 54 55 56 Osteoporosis Treatment Options – 2015 57 58 59 60 URL: http://mc.manuscriptcentral.com/eoop Email: [email protected] Page 89 of 111 Expert Opinion On Pharmacotherapy

1 2 3 Anti -remodeling agents (inhibit bone turnover) 4 5 - Bisphosphonates (oral and IV) 6 - Estrogen agonists/ antagonist (raloxifene) 7 8 - RANK ligand inhibitor (denosumab) 9 Bone activating agent (stimulates formation and resorption) 10 11 - Parathyroid hormone (1-34) (Teriparatide) 12 - Parathyroid hormone (1-84) (not available in the USA) 13 Other (no effect on bone turnover) 14 For Peer Review Only 15 - Strontium ranelate (not available in the USA) 16 17 18 19 20 Table 2 21 22 23 24 Emerging Treatment for Osteoporosis 25 26 A New ‘anti -resorptive’ 27 28 - Odanacatib 29 New anabolics 30 31 - PTHrP analogues (abaloparatide) 32 - Monoclonal antibody to sclerostin (romosozumab) 33 34 35 36 37 38 39 40 References 41 42 43 1. Morris, C.A., et al., Patterns of bone mineral density testing: current guidelines, testing 44 45 rates, and interventions. J Gen.Intern.Med., 2004. 19(7): p. 783-790. 46 47 48 2. Cooper, C., et al., Epidemiology of childhood fractures in Britain: a study using the 49 50 51 general practice research database. J.Bone Miner.Res., 2004. 19(12): p. 1976-1981. 52 53 54 55 56 57 58 59 60 URL: http://mc.manuscriptcentral.com/eoop Email: [email protected] Expert Opinion On Pharmacotherapy Page 90 of 111

1 2 3 3. Singer, A., et al., Burden of illness for osteoporotic fractures compared with other serious 4 5 6 diseases among postmenopausal women in the United States. Mayo Clin Proc, 2015. 90(1): p. 7 8 53-62. 9 10 11 4. Watts, N.B., Insights from the Global Longitudinal Study of Osteoporosis in Women 12 13 (GLOW). Nat Rev Endocrinol, 2014. 10(7): p. 412-22. 14 For Peer Review Only 15 16 17 5. Solomon, D.H., et al., Osteoporosis medication use after hip fracture in U.S. patients 18 19 between 2002 and 2011. J Bone Miner Res, 2014. 29(9): p. 1929-37. 20 21 22 6. Trombetti, A., et al., Effect of a multifactorial fall-and-fracture risk assessment and 23 24 management program on gait and balance performances and disability in hospitalized older 25 26 27 adults: a controlled study. Osteoporos Int, 2013. 24(3): p. 867-76. 28 29 30 7. Karlsson, M.K., et al., Prevention of falls in the elderly--a review. Osteoporos Int, 2013. 31 32 24(3): p. 747-62. 33 34 35 8. Akesson, K., et al., Capture the Fracture: a Best Practice Framework and global campaign 36 37 38 to break the fragility fracture cycle. Osteoporos Int, 2013. 24(8): p. 2135-52. 39 40 41 9. Lee, D.B., et al., National Bone Health Alliance: an innovative public-private partnership 42 43 improving America's bone health. Curr Osteoporos Rep, 2013. 11(4): p. 348-53. 44 45 46 10. Eisman, J.A., et al., Making the first fracture the last fracture: ASBMR task force report 47 48 on secondary fracture prevention. J Bone Miner Res, 2012. 27(10): p. 2039-46. 49 50 51 11. Ryg, J., et al., Hip fracture patients at risk of second hip fracture: a nationwide 52 53 54 population-based cohort study of 169,145 cases during 1977-2001. J Bone Miner Res, 2009. 55 56 24(7): p. 1299-307. 57 58 59 60 URL: http://mc.manuscriptcentral.com/eoop Email: [email protected] Page 91 of 111 Expert Opinion On Pharmacotherapy

1 2 3 12. Watts, N.B., et al., American Association of Clinical Endocrinologists Medical 4 5 6 Guidelines for Clinical Practice for the diagnosis and treatment of postmenopausal osteoporosis. 7 8 Endocr Pract, 2010. 16 Suppl 3: p. 1-37. 9 10 11 13. Delmas, P.D., et al., Severity of prevalent vertebral fractures and the risk of subsequent 12 13 vertebral and nonvertebral fractures: results from the MORE trial. Bone, 2003. 33(4): p. 522-532. 14 For Peer Review Only 15 16 17 14. Lindsay, R., et al., Risk of new vertebral fracture in the year following a fracture. JAMA, 18 19 2001. 285: p. 320-323. 20 21 22 15. Compston, J., et al., Diagnosis and management of osteoporosis in postmenopausal 23 24 women and older men in the UK: National Osteoporosis Guideline Group (NOGG) update 2013. 25 26 27 Maturitas, 2013. 75(4): p. 392-6. 28 29 30 16. Kanis, J.A., et al., European guidance for the diagnosis and management of osteoporosis 31 32 in postmenopausal women. Osteoporos Int, 2013. 24(1): p. 23-57. 33 34 35 17. Hans, D.B., et al., Joint Official Positions of the International Society for Clinical 36 37 38 Densitometry and International Osteoporosis Foundation on FRAX((R)) Executive Summary of 39 40 the 2010 Position Development Conference on Interpretation and Use of FRAX((R)) in Clinical 41 42 Practice. J.Clin.Densitom., 2011. 14(3): p. 171-180. 43 44 45 18. National Osteoporosis Foundation Clinician's Guide to Prevention and Treatment of 46 47 48 Osteoporosis; 2013, Version 3, Released February 25, 2014. 49 50 51 19. Nguyen, N.D., J.A. Eisman, and T.V. Nguyen, et al. Anti-hip fracture efficacy of 52 53 bisphosphonates: a Bayesian analysis of clinical trials. J.Bone Miner.Res., 2006. 21(2): p. 340- 54 55 56 349. 57 58 59 60 URL: http://mc.manuscriptcentral.com/eoop Email: [email protected] Expert Opinion On Pharmacotherapy Page 92 of 111

1 2 3 20. Boonen, S., et al., Effect of osteoporosis treatments on risk of non-vertebral fractures: 4 5 6 review and meta-analysis of intention-to-treat studies. Osteoporos Int, 2005. 16(10): p. 1291- 7 8 1298. 9 10 11 21. Shea, B., et al., Meta-analysis of calcium supplementation for the prevention of 12 13 postmenopausal osteoporosis. Endocrine Reviews, 2002. 23(4): p. 552-559. 14 For Peer Review Only 15 16 17 22. Guyatt, G.H., et al., Summary of meta-analyses of therapies for postmenopausal 18 19 osteoporosis and the relationship between bone density and fractures. Endocrinol Metab Clin 20 21 North Am, 2002. 31(3): p. 659-79, xii. 22 23 24 23. Seeman, E., Bone quality: the material and structural basis of bone strength. J Bone 25 26 27 Miner Metab, 2008. 26(1):1-8. 28 29 30 24. Donnelly, E., Methods for assessing bone quality: a review. Clin Orthop.Relat Res, 2011. 31 32 469(8): p. 2128-2138. 33 34 35 25. Silva, B.C., et al., Trabecular bone score: a noninvasive analytical method based upon the 36 37 38 DXA image. J Bone Miner Res, 2014. 29(3): p. 518-30. 39 40 41 26. Leslie, W.D., et al., Lumbar spine texture enhances 10-year fracture probability 42 43 assessment. Osteoporos Int, 2014. 25(9): p. 2271-7. 44 45 46 27. Silva, B.C., et al., Trabecular bone score (TBS)--a novel method to evaluate bone 47 48 microarchitectural texture in patients with primary hyperparathyroidism. J Clin Endocrinol 49 50 51 Metab, 2013. 98(5): p. 1963-70. 52 53 54 28. McCloskey, E.V., et al., Adjusting fracture probability by trabecular bone score. Calcif 55 56 Tissue Int, 2015. 96(6): p. 500-9. 57 58 59 60 URL: http://mc.manuscriptcentral.com/eoop Email: [email protected] Page 93 of 111 Expert Opinion On Pharmacotherapy

1 2 3 29. Hans, D., et al., Bone microarchitecture assessed by TBS predicts osteoporotic fractures 4 5 6 independent of bone density: the Manitoba study. J Bone Miner Res, 2011. 26(11): p. 2762-9. 7 8 9 30. Sattui, S.E. and K.G. Saag, Fracture mortality: associations with epidemiology and 10 11 osteoporosis treatment. Nat Rev Endocrinol, 2014. 10(10): p. 592-602. 12 13 14 31. Bliuc, D.,For et al., Mortality Peer risk associated Review with low-trauma Only osteoporotic fracture and 15 16 17 subsequent fracture in men and women. JAMA, 2009. 301(5): p. 513-21. 18 19 20 32. Bliuc, D., et al., Risk of subsequent fractures and mortality in elderly women and men 21 22 with fragility fractures with and without osteoporotic bone density: the Dubbo Osteoporosis 23 24 Epidemiology Study. J Bone Miner Res, 2015. 30(4): p. 637-46. 25 26 27 33. Krege, J.H., et al., Relationship Between Vertebral Fracture Burden, Height Loss, and 28 29 30 Pulmonary Function in Postmenopausal Women With Osteoporosis. J Clin Densitom, 2015. 31 32 33 34. Ahmed, L.A., et al., Progressively increasing fracture risk with advancing age after initial 34 35 incident fragility fracture: the Tromso study. J Bone Miner Res, 2013. 28(10): p. 2214-21. 36 37 38 35. Devogelaer, J.P., et al., Evidence-based guidelines for the prevention and treatment of 39 40 41 glucocorticoid-induced osteoporosis: a consensus document of the Belgian Bone Club. 42 43 Osteoporos Int, 2006. 17(1): p. 8-19. 44 45 46 36. Mazziotti, G., et al., Glucocorticoid-induced osteoporosis: an update. Trends Endocrinol 47 48 Metab, 2006. 17(4): p. 144-9. 49 50 51 37. Canalis, E., et al., Perspectives on glucocorticoid-induced osteoporosis. Bone, 2004. 52 53 54 34(4): p. 593-8. 55 56 57 58 59 60 URL: http://mc.manuscriptcentral.com/eoop Email: [email protected] Expert Opinion On Pharmacotherapy Page 94 of 111

1 2 3 38. Hansen, K.E., et al., Uncertainties in the prevention and treatment of glucocorticoid- 4 5 6 induced osteoporosis. J Bone Miner Res, 2011. 26(9): p. 1989-1996. 7 8 9 39. Zuo, C., et al., Osteoblastogenesis regulation signals in bone remodeling. Osteoporos.Int, 10 11 2012. 23(6): p. 1653-1663. 12 13 14 40. Dallas,For S.L., M. Prideaux, Peer and L.F. Review Bonewald, The Osteocyte: Only An Endocrine Cell and 15 16 17 More. Endocr Rev, 2013. 34(5): p. 658-690. 18 19 20 41. Ke, H.Z., et al., Sclerostin and Dickkopf-1 as Therapeutic Targets in Bone Diseases. 21 22 Endocr.Rev., 2012. 33(5): p. 747-783. 23 24 25 42. Zangeneh, F., et al., Chronic Kidney Disease-Mineral and Bone Disorders (CKD-MBDs): 26 27 What the Endocrinologist Needs to Know. Endocr Pract, 2014. 20(5): p. 500-16. 28 29 30 31 43. Gennari, L., et al., Circulating sclerostin levels and bone turnover in type 1 and type 2 32 33 diabetes. J Clin Endocrinol Metab, 2012. 97(5): p. 1737-44. 34 35 36 44. Lewiecki, E.M., et al., Update on osteoporosis from the 2014 Santa Fe Bone symposium. 37 38 Endocr Res, 2015. 40(2): p. 106-19. 39 40 41 45. Drake, M.T., unveiling skeletal fragility in patients diagnosed with MGUS: no longer a 42 43 44 condition of undetermined significance? J Bone Miner Res, 2014. 29(12): p. 2529-33. 45 46 47 46. Lewiecki, E.M. and P.D. Miller, Skeletal effects of primary hyperparathyroidism: bone 48 49 mineral density and fracture risk. J Clin Densitom, 2013. 16(1): p. 28-32. 50 51 52 47. Vestergaard, P. and S. Thomsen, Medical treatment of primary, secondary, and tertiary 53 54 55 hyperparathyroidism. Curr Drug Safety, 2011. 6(2): p. 108-13. 56 57 58 59 60 URL: http://mc.manuscriptcentral.com/eoop Email: [email protected] Page 95 of 111 Expert Opinion On Pharmacotherapy

1 2 3 48. Bjorkman, M., A. Sorva, and R. Tilvis, Parathyroid hormone as a mortality predictor in 4 5 6 frail aged inpatients. Gerontology, 2009. 55(6): p. 601-606. 7 8 9 49. Parisien, M., et al., Bone disease in primary hyperparathyroidism. Endocrinol.Metab Clin 10 11 North Am., 1990. 19(1): p. 19-34. 12 13 14 50. Rejnmark,For L., et al., Peer Increased fracture Review risk in normocalcemic Only postmenopausal women 15 16 17 with high parathyroid hormone levels: a 16-year follow-up study. Calcif.Tissue Int., 2011. 88(3): 18 19 p. 238-245. 20 21 22 51. Cole, M.H., et al., Use of a short-form balance confidence scale to predict future 23 24 recurrent fallers in Parkinson's disease. Arch Phys Med Rehabil, 2015. 25 26 27 52. Chalhoub, D., et al., Risk of Nonspine Fractures in Older Adults with Sarcopenia, Low 28 29 30 Bone Mass, or Both. J Am Geriatr Soc, 2015. 31 32 33 53. Sternberg, S.A., et al., Frailty and osteoporosis in older women--a prospective study. 34 35 Osteoporos Int, 2014. 25(2): p. 763-8. 36 37 38 54. Cooper, C., et al., Frailty and sarcopenia: definitions and outcome parameters. 39 40 41 Osteoporos Int, 2012. 23(7): p. 1839-48. 42 43 44 55. Binkley, N., D. Krueger, and B. Buehring, What's in a name revisited: should 45 46 osteoporosis and sarcopenia be considered components of "dysmobility syndrome?". Osteoporos 47 48 Int, 2013. 24(12): p. 2955-9. 49 50 51 56. Bliuc, D., et al., The impact of nonhip nonvertebral fractures in elderly women and men. 52 53 54 J Clin Endocrinol Metab, 2014. 99(2): p. 415-23. 55 56 57 58 59 60 URL: http://mc.manuscriptcentral.com/eoop Email: [email protected] Expert Opinion On Pharmacotherapy Page 96 of 111

1 2 3 57. Huntjens, K.M., et al., Risk of subsequent fracture and mortality within 5 years after a 4 5 6 non-vertebral fracture. Osteoporos Int, 2010. 21(12): p. 2075-82. 7 8 9 58. Whyte, M.P., Hypophosphatasia. 2013: p. 337-360. 10 11 12 59. Rea, J.A., et al., Vertebral morphometry: a comparison of long-term precision of 13 14 morphometric ForX-ray absorptiometry Peer and morphometricReview radiography Only in normal and osteoporotic 15 16 17 subjects. Osteoporos Int, 2001. 12(2): p. 158-166. 18 19 20 60. El Maghraoui, A., et al., Systematic vertebral fracture assessment in asymptomatic 21 22 postmenopausal women. Bone, 2013. 52(1): p. 176-80. 23 24 25 61. Lewiecki, E.M., Bone densitometry and vertebral fracture assessment. Curr.Osteoporos 26 27 Rep., 2010. 8(3): p. 123-130. 28 29 30 31 62. Link, T.M., Radiology of Osteoporosis. Can Assoc Radiol J, 2015. 32 33 34 63. Bertoldo, F., et al., Prevalence of asymptomatic vertebral fractures in late-onset Pompe 35 36 disease. J Clin Endocrinol Metab, 2015. 100(2): p. 401-6. 37 38 39 64. Angeli, A., et al., High prevalence of asymptomatic vertebral fractures in post- 40 41 menopausal women receiving chronic glucocorticoid therapy: a cross-sectional outpatient study. 42 43 44 Bone, 2006. 39(2): p. 253-9. 45 46 47 65. Schousboe, J.T., et al., Prediction of Incident Major Osteoporotic and Hip Fractures by 48 49 Trabecular Bone Score (TBS) and Prevalent Radiographic Vertebral Fracture in Older Men. J 50 51 Bone Miner Res, 2015. 52 53 54 55 66. Rosen, H.N., et al., The Official Positions of the International Society for Clinical 56 57 Densitometry: vertebral fracture assessment. J Clin Densitom, 2013. 16(4): p. 482-8. 58 59 60 URL: http://mc.manuscriptcentral.com/eoop Email: [email protected] Page 97 of 111 Expert Opinion On Pharmacotherapy

1 2 3 67. Kaptoge, S., et al., Whom to treat? The contribution of vertebral X-rays to risk-based 4 5 6 algorithms for fracture prediction. Results from the European Prospective Osteoporosis Study. 7 8 Osteoporos Int, 2006. 17(9): p. 1369-81. 9 10 11 68. Kanis, J.A., et al., A meta-analysis of previous fracture and subsequent fracture risk. 12 13 Bone, 2004. 35(2): p. 375-382. 14 For Peer Review Only 15 16 17 69. Johnell, O., et al., Fracture risk following an osteoporotic fracture. Osteoporos Int, 2004. 18 19 15(3): p. 175-179. 20 21 22 70. Gluer, M.G., et al. Prospective identification of postmenopausal osteoporotic women at 23 24 high vertebral fracture risk by radiography, bone densitometry, quantitative ultrasound, and 25 26 27 laboratory findings: results from the PIOS study. J Clin Densitom, 2005. 8(4): p. 386-95. 28 29 30 71. Greenspan, S.L., et al., Instant vertebral assessment: a noninvasive dual X-ray 31 32 absorptiometry technique to avoid misclassification and clinical mismanagement of osteoporosis. 33 34 35 J Clin Densitom, 2001. 4(4): p. 373-80. 36 37 38 72. Schousboe, J.T., et al., Prediction models of prevalent radiographic vertebral fractures 39 40 among older women. J Clin Densitom, 2014. 17(3): p. 378-85. 41 42 43 73. Siminoski, K., et al., The accuracy of historical height loss for the detection of vertebral 44 45 fractures in postmenopausal women. Osteoporos Int, 2006. 17(2): p. 290-296. 46 47 48 74. Vokes, T., et al., Vertebral Fracture Assessment: The 2005 ISCD Official Positions. J 49 50 51 Clin Densitom, 2006. 9(1): p. 37-46. 52 53 54 75. Lentle, B., et al., Osteoporosis Canada 2010 guidelines for the assessment of fracture 55 56 risk. Can Assoc Radiol J, 2011. 62(4): p. 243-50. 57 58 59 60 URL: http://mc.manuscriptcentral.com/eoop Email: [email protected] Expert Opinion On Pharmacotherapy Page 98 of 111

1 2 3 76. Delmas, P.D., et al., Underdiagnosis of vertebral fractures is a worldwide problem: the 4 5 6 IMPACT study. J Bone Miner Res, 2005. 20(4): p. 557-63. 7 8 9 77. Fink, H.A., et al., What proportion of incident radiographic vertebral deformities is 10 11 clinically diagnosed and vice versa? J Bone Miner Res, 2005. 20(7): p. 1216-22. 12 13 14 78. Kim, N.,For et al., Underreporting Peer of Reviewvertebral fractures on routineOnly chest radiography. AJR 15 16 17 Am J Roentgenol, 2004. 182(2): p. 297-300. 18 19 20 79. Mujumdar SR, et al. Incidental vertebral fractures discovered with chest radiography in 21 22 the emergency department: prevalence, recognition, and osteoporosis management in a cohort of 23 24 elderly patients. Arch Int Med 2005; 165(8):905-909. 25 26 27 28 29 30 31 80. Siris, E.S., et al., Enhanced prediction of fracture risk combining vertebral fracture status 32 33 and BMD. Osteoporos Int, 2007. 18(6): p. 761-70. 34 35 36 81. Leidig-Bruckner, G., et al., Comparison of a semiquantitative and a quantitative method 37 38 for assessing vertebral fractures in osteoporosis. Osteoporos Int, 1994. 4(3): p. 154-61. 39 40 41 82. Genant HK, Jergas M. Assessment of prevalent and incident vertebral fractures in 42 43 44 osteoporosis research. Osteoporos Int. 2003;14 Suppl 3:S43-55. 45 46 47 83. Cauley, J.A., et al., Long-term risk of incident vertebral fractures. JAMA, 2007. 298(23): 48 49 p. 276-277 50 51 52 84. van Geel, T.A., et al., Timing of subsequent fractures after an initial fracture. Current 53 54 55 Osteoporos Reports, 2010. 8(3): p. 118-22. 56 57 58 59 60 URL: http://mc.manuscriptcentral.com/eoop Email: [email protected] Page 99 of 111 Expert Opinion On Pharmacotherapy

1 2 3 85. Schousboe JT, Fink HA, Lui LY, et al. Association between prior non-spine non-hip 4 5 6 fractures or prevalent radiographic vertebral deformities known to be at least 10 years old and 7 8 incident hip fracture. J Bone Miner Res 2006; 21(10): 1557e1564. 9 10 11 86. Kanis, J.A., et al., Interpretation and use of FRAX in clinical practice. Osteoporos Int, 12 13 2011. 22(9): p. 2395-2411. 14 For Peer Review Only 15 16 17 87. Kanis, J.A., et al., FRAX(R) and its applications to clinical practice. Bone, 2009. 44(5): 18 19 p. 734-743. 20 21 22 88. Lewiecki, E.M., Bone density measurement and assessment of fracture risk. Clin Obstet 23 24 Gynecol, 2013. 56(4): p. 667-76. 25 26 27 89. Kanis, J.A., et al., FRAX with and without bone mineral density. Calcif.Tissue Int, 2012. 28 29 30 90(1): p. 1-13. 31 32 33 90. Siris, E.S., et al., The clinical diagnosis of osteoporosis: a position statement from the 34 35 National Bone Health Alliance Working Group. Osteoporos Int, 2014. 25(5): p. 1439-43. 36 37 38 91. Canalis, E. and A. Giustina, Glucocorticoid-induced osteoporosis: Summary of a 39 40 41 workshop. Journal of Clinical Endocrinology and Metabolism, 2001. 86(12): p. 5681-5685. 42 43 44 92. van Staa, T.P., The pathogenesis, epidemiology and management of glucocorticoid- 45 46 induced osteoporosis. Calcif.Tissue Int, 2006. 79(3): p. 129-137. 47 48 49 93. Saag, K.G., Glucocorticoid-induced osteoporosis. Endocrinol Metab Clin North Am, 50 51 2003. 32(1): p. 135-57, vii. 52 53 54 55 94. Leib, E.S., et al., Official Positions for FRAX((R)) Clinical Regarding Glucocorticoids: 56 57 The impact of the Use of Glucocorticoids on the Estimate by FRAX((R)) of the 10 Year Risk of 58 59 60 URL: http://mc.manuscriptcentral.com/eoop Email: [email protected] Expert Opinion On Pharmacotherapy Page 100 of 111

1 2 3 Fracture From Joint Official Positions Development Conference of the International Society for 4 5 6 Clinical Densitometry and International Osteoporosis Foundation on FRAX((R)). 7 8 J.Clin.Densitom., 2011. 14(3): p. 212-219. 9 10 11 95. Levis, S. and G. Theodore, Summary of AHRQ's comparative effectiveness review of 12 13 treatment to prevent fractures in men and women with low bone density or osteoporosis: update 14 For Peer Review Only 15 16 of the 2007 report. J Manag.Care Pharm., 2012. 18(4 Suppl B): p. S1-15. 17 18 19 96. Reid, I.R., Short-term and long-term effects of osteoporosis therapies. Nat Rev 20 21 Endocrinol, 2015. 11(7): p. 418-28. 22 23 24 97. Crandall, C.J., et al., Comparative effectiveness of pharmacologic treatments to prevent 25 26 27 fractures: an updated systematic review. Ann Intern Med, 2014. 161(10): p. 711-23. 28 29 30 98. Reginster, J.Y., et al., Efficacy and safety of currently marketed anti-osteoporosis 31 32 medications. Best Pract Res Clin Endocrinol Metab, 2014. 28(6): p. 809-34. 33 34 35 99. Litwic, A., C. Cooper, and E. Dennison, Osteoporosis therapies in 2014. Panminerva 36 37 38 Med, 2014. 56(4): p. 273-83. 39 40 41 101. Miller, P.D., et al., Once-monthly oral ibandronate compared with weekly oral 42 43 alendronate in postmenopausal osteoporosis: results from the head-to-head MOTION study. 44 45 Current Medical Research and Opinion, 2008. 24(1): p. 207-213. 46 47 48 102. Bonnick, S., et al., Comparison of weekly treatment of postmenopausal osteoporosis with 49 50 51 alendronate versus risedronate over two years. J Clin Endocrinol Metab, 2006. 91(7): p. 2631-7. 52 53 54 103. Miller, P.D., Bone strength and surrogate markers: the first, second, and third fiddle. J 55 56 Bone Miner Res, 2012. 27(8): p. 1623-6. 57 58 59 60 URL: http://mc.manuscriptcentral.com/eoop Email: [email protected] Page 101 of 111 Expert Opinion On Pharmacotherapy

1 2 3 104. Russell, R.G., Pharmacological diversity among drugs that inhibit bone resorption. Curr 4 5 6 Opin Pharmacol, 2015. 22: p. 115-30. 7 8 9 105. Russell, R.G.G. and M.J. Rogers, Bisphosphonates: From the laboratory to the clinic and 10 11 back again. Bone, 1999. 25(1): p. 97-106. 12 13 14 106. Bonnick,For S.L. and PeerL. Shulman, Monitoring Review osteoporosis therapy:Only bone mineral density, 15 16 17 bone turnover markers, or both? Am J Med, 2006. 119(4 Suppl 1): p. S25-31. 18 19 20 107. Miller, P.D., Monitoring osteoporosis therapies. Curr Osteoporos Rep, 2007. 5(1): p. 38- 21 22 43. 23 24 25 108. Wasnich, R.D. and P.D. Miller, Antifracture efficacy of antiresorptive agents are related 26 27 to changes in bone density. Journal of Clinical Endocrinology and Metabolism, 2000. 85(1): p. 28 29 30 231-236. 31 32 33 109. Hochberg, M.C., et al., Changes in bone density and turnover explain the reductions in 34 35 incidence of nonvertebral fractures that occur during treatment with antiresorptive agents. J Clin 36 37 38 Endocrinol.Metab, 2002. 87(4): p. 1586-1592. 39 40 41 110. Austin, M., et al., Relationship between bone mineral density changes with denosumab 42 43 treatment and risk reduction for vertebral and nonvertebral fractures. J.Bone Miner.Res., 2012. 44 45 27(3): p. 687-693. 46 47 48 111. Delmas, P.D., et al., Efficacy of raloxifene on vertebral fracture risk reduction in 49 50 51 postmenopausal women with osteoporosis: Four-year results from a randomized clinical trial. 52 53 Journal of Clinical Endocrinology and Metabolism, 2002. 87(8): p. 3609-3617. 54 55 56 57 58 59 60 URL: http://mc.manuscriptcentral.com/eoop Email: [email protected] Expert Opinion On Pharmacotherapy Page 102 of 111

1 2 3 112. Vestergaard, P., L. Mosekilde, and B. Langdahl, Fracture prevention in postmenopausal 4 5 6 women. BMJ Clin Evid, 2011. 2011. 7 8 9 113. Harris, S.T., et al., Risk of fracture in women treated with monthly oral ibandronate or 10 11 weekly bisphosphonates: the eValuation of IBandronate Efficacy (VIBE) database fracture 12 13 study. Bone, 2009. 44(5): p. 758-65. 14 For Peer Review Only 15 16 17 114. Harris, S.T., W.A. Blumentals, and P.D. Miller, Ibandronate and the risk of non-vertebral 18 19 and clinical fractures in women with postmenopausal osteoporosis: results of a meta-analysis of 20 21 phase III studies. Curr.Med Res Opin., 2008. 24(1): p. 237-245. 22 23 24 115. Miller, P.D., Non-vertebral fracture risk reduction with oral bisphosphonates: challenges 25 26 27 with interpreting clinical trial data. Curr Med Res Opin, 2008. 24(1): p. 107-19. 28 29 30 116. Zebaze, R.M., et al., Differing effects of denosumab and alendronate on cortical and 31 32 trabecular bone. Bone, 2014. 59: p. 173-9. 33 34 35 117. Bilezikian, J.P., Efficacy of bisphosphonates in reducing fracture risk in postmenopausal 36 37 38 osteoporosis. Am.J Med, 2009. 122(2 Suppl): p. S14-S21. 39 40 41 118. Neer, R.M., et al., Effect of parathyroid hormone (1-34) on fractures and bone mineral 42 43 density in postmenopausal women with osteoporosis. N Engl J Med, 2001. 344: p. 1434-1441. 44 45 46 119. Eriksen, E.F., et al., Literature review: The effects of teriparatide therapy at the hip in 47 48 patients with osteoporosis. Bone, 2014. 67: p. 246-56. 49 50 51 120. Black, D.M., et al., Once-yearly zoledronic acid for treatment of postmenopausal 52 53 54 osteoporosis. N.Engl.J.Med., 2007. 356(18): p. 1809-1822. 55 56 57 58 59 60 URL: http://mc.manuscriptcentral.com/eoop Email: [email protected] Page 103 of 111 Expert Opinion On Pharmacotherapy

1 2 3 121. Austin, M., et al., Relationship between bone mineral density changes with denosumab 4 5 6 treatment and risk reduction for vertebral and nonvertebral fractures. J Bone Miner Res, 2012. 7 8 27(3): p. 687-93. 9 10 11 122. Bours, S.P., et al., Contributors to secondary osteoporosis and metabolic bone diseases in 12 13 patients presenting with a clinical fracture. J.Clin.Endocrinol.Metab, 2011. 96(5): p. 1360-1367. 14 For Peer Review Only 15 16 17 123. van Geel, T.A., et al., Timing of subsequent fractures after an initial fracture. Curr 18 19 Osteoporos Rep, 2010. 8(3): p. 118-22. 20 21 22 123. Kanis, J.A., et al., Excess mortality after hospitalisation for vertebral fracture. Osteoporos 23 24 Int, 2004. 15(2): p. 108-112. 25 26 27 124. Lindsay, R., et al., Increased risk of new vertebral fracture within 1 year of an incident 28 29 30 vertebral fracture. Osteoporos Int, 2000. 11 (Suppl 2): p. S112. 31 32 33 125. Civitelli, R., R. Armamento-Villareal, and N. Napoli, Bone turnover markers: 34 35 understanding their value in clinical trials and clinical practice. Osteoporos Int, 2009. 20(6): p. 36 37 38 843-851. 39 40 41 126. Glover, S.J., et al., Establishing a reference range for bone turnover markers in young, 42 43 healthy women. Bone, 2008. 42(4): p. 623-630. 44 45 46 127. Bauer, D., et al., National Bone Health Alliance Bone Turnover Marker Project: current 47 48 practices and the need for US harmonization, standardization, and common reference ranges. 49 50 51 Osteoporos.Int, 2012. 23(10): p. 2425-2433. 52 53 54 128. Watts, N.B., et al., Risedronate prevents new vertebral fractures in postmenopausal 55 56 women at high risk. J Clin Endocrinol Metab, 2003. 88(2): p. 542-9. 57 58 59 60 URL: http://mc.manuscriptcentral.com/eoop Email: [email protected] Expert Opinion On Pharmacotherapy Page 104 of 111

1 2 3 129. Rogers, M.J., et al., Cellular and molecular mechanisms of action of bisphosphonates. 4 5 6 Cancer., 2000. 88(12:Suppl): p. Suppl-78. 7 8 9 130. Fleisch, H., et al. Introduction to bisphosphonates. History and functional mechanisms. 10 11 Orthopade, 2007. 36(2): p. 103-4, 106-9. 12 13 14 131. Fleisch,For H.A., Bisphosphonates: Peer preclinicalReview aspects and useOnly in osteoporosis. Ann Med, 15 16 17 1997. 29(1): p. 55-62. 18 19 20 132. Miller, P.D., et al., Effects of intravenous ibandronate injection on renal function in 21 22 women with postmenopausal osteoporosis at high risk for renal disease--the DIVINE study. 23 24 Bone, 2011. 49(6): p. 1317-22. 25 26 27 133. Black, D.M., et al., The effect of 3 versus 6 years of zoledronic acid treatment of 28 29 30 osteoporosis: a randomized extension to the HORIZON-Pivotal Fracture Trial (PFT). J Bone 31 32 Miner Res, 2011. 33 34 35 134. Black, D.M., et al., Effects of continuing or stopping alendronate after 5 years of 36 37 38 treatment: the Fracture Intervention Trial Long-term Extension (FLEX): a randomized trial. 39 40 JAMA; 2006: 296(24): p. 2927-38. 41 42 43 135. Body, J.J., et al., A Study of the Biological Receptor Activator of Nuclear Factor- 44 45 {kappa}B Ligand Inhibitor, Denosumab, in Patients with Multiple Myeloma or Bone Metastases 46 47 48 from Breast Cancer. Clin Cancer Res, 2006. 12(4): p. 1221-1228. 49 50 51 136. Cummings, S.R., et al., Denosumab for prevention of fractures in postmenopausal 52 53 women with osteoporosis. N Engl J Med, 2009. 361(8): p. 756-765. 54 55 56 57 58 59 60 URL: http://mc.manuscriptcentral.com/eoop Email: [email protected] Page 105 of 111 Expert Opinion On Pharmacotherapy

1 2 3 137. Papapoulos, S., et al., Five years of denosumab exposure in women with postmenopausal 4 5 6 osteoporosis: results from the first two years of the FREEDOM extension. J Bone Miner Res, 7 8 2012. 27(3): p. 694-701. 9 10 11 138. McClung, M.R., et al., Effect of denosumab on bone mineral density and biochemical 12 13 markers of bone turnover: 8-year results of a phase 2 clinical trial. Osteoporos Int, 2013. 24(1): 14 For Peer Review Only 15 16 p. 227-35. 17 18 19 139. Miller, P.D., Denosumab: anti-RANKL antibody. Curr Osteoporos Rep., 2009. 7(1): p. 20 21 18-22. 22 23 24 140. Miller, P.D., et al., Effect of denosumab on bone density and turnover in postmenopausal 25 26 27 women with low bone mass after long-term continued, discontinued, and restarting of therapy: a 28 29 randomized blinded phase 2 clinical trial. Bone, 2008. 43(2): p. 222-9. 30 31 32 141. Bone, H.G., et al., Effects of denosumab treatment and discontinuation on bone mineral 33 34 35 density and bone turnover markers in postmenopausal women with low bone mass. J Clin 36 37 Endocrinol Metab, 2011. 96(4): p. 972-80. 38 39 40 142. Peterson, M.C., et al., The pharmacokinetics of denosumab (AMG 162) following 41 42 various multiple subcutaneous dosing regimens in postmenopausal women with low bone mass. 43 44 45 J Bone Miner Res, 2005. 20(Suppl 1): p. S293. 46 47 48 143. Jamal, S.A., et al., Effects of denosumab on fracture and bone mineral density by level of 49 50 kidney function. J Bone Miner Res, 2011. 26(8): p. 1829-35. 51 52 53 144. Jamal, S.A., S.L. West, and P.D. Miller, Bone and Kidney Disease: Diagnostic and 54 55 56 Therapeutic Implications. Curr.Rheumatol.Rep., 2012. 57 58 59 60 URL: http://mc.manuscriptcentral.com/eoop Email: [email protected] Expert Opinion On Pharmacotherapy Page 106 of 111

1 2 3 145. Fang, Y., et al., Early chronic kidney disease-mineral bone disorder stimulates vascular 4 5 6 calcification. Kidney Int, 2014. 85(1): p. 142-150. 7 8 9 146. Reid, I., et al. Effects of denosumab on bone histology and histomorphometry: the 10 11 FREEDOM and STAND studies. J Bone Miner Res, 2009. 24. 12 13 14 147 Cannata-Andia,For J.B., Peer P. Roman-Garcia, Review and K. Hruska, TheOnly connections between 15 16 17 vascular calcification and bone health. Nephrol Dial Transplant, 2011. 26(11): p. 3429-36. 18 19 20 148. Hruska, K.A., et al., The pathogenesis of vascular calcification in the chronic kidney 21 22 disease mineral bone disorder: the links between bone and the vasculature. Semin Nephrol, 2009. 23 24 29(2): p. 156-65. 25 26 27 149. Samelson, E.J., et al., RANKL inhibition with denosumab does not influence 3-year 28 29 30 progression of aortic calcification or incidence of adverse cardiovascular events in 31 32 postmenopausal women with osteoporosis and high cardiovascular risk.. J Bone Miner Res, 33 34 35 2014. 29(2):450-7.. 36 37 38 150. Block GA, Bone HG, Fang L, Lee E, Padhi D. A single-dose study of denosumab in 39 40 patients with various degrees of renal impairment J Bone Miner Res. 2012 ;27(7):1471-9 41 42 43 151. Orwoll, E.S., et al., The effect of teriparatide [human parathyroid hormone (1-34)] 44 45 therapy on bone density in men with osteoporosis. J Bone Miner Res, 2003. 18(1): p. 9-17. 46 47 48 152. Gluer, C.C., et al., Comparative effects of teriparatide and risedronate in glucocorticoid- 49 50 51 induced osteoporosis in men: 18-month results of the Euro GIOPs trial. J Bone Miner Res, 2013. 52 53 28(6): p. 1355-68. 54 55 56 57 58 59 60 URL: http://mc.manuscriptcentral.com/eoop Email: [email protected] Page 107 of 111 Expert Opinion On Pharmacotherapy

1 2 3 153. Saag, K.G., et al., Teriparatide or alendronate in glucocorticoid-induced osteoporosis. N 4 5 6 Engl J Med, 2007. 357(20): p. 2028-2039. 7 8 9 154. Harper, K.D., et al., Comments on Initial experience with teriparatide in the United 10 11 States. Curr Med Res Opin, 2006. 22(10): p. 1927. 12 13 14 155. Harper,For K.D., et al., Peer Osteosarcoma Review and teriparatide? J Bone Only Miner Res, 2007. 22(2): p. 15 16 17 334. 18 19 20 156. Andrews, E.B., et al., The US postmarketing surveillance study of adult osteosarcoma 21 22 and teriparatide: study design and findings from the first 7 years. J Bone Miner Res, 2012. 23 24 27(12): p. 2429-37. 25 26 27 157. Miller, P.D., Safety of parathyroid hormone for the treatment of osteoporosis. Curr 28 29 30 Osteoporos Rep., 2008. 6(1): p. 12-16. 31 32 33 158. Muschitz, C., et al., Antiresorptives overlapping ongoing teriparatide treatment result in 34 35 additional increases in bone mineral density. J Bone Miner Res, 2013. 28(1): p. 196-205. 36 37 38 159. Eastell, R., et al., Development of an algorithm for using PINP to monitor treatment of 39 40 41 patients with teriparatide. Curr Med Res Opin, 2006. 22(1): p. 61-6. 42 43 44 160. Dempster, D.W., et al., Anabolic actions of parathyroid hormone on bone. Endocr.Rev., 45 46 1993. 14: p. 690-709. 47 48 49 161. Tsujimoto, M., et al., PINP as an aid for monitoring patients treated with teriparatide. Bone, 50 51 2011. 48(4): p. 798-803. 52 53 54 55 56 57 58 59 60 URL: http://mc.manuscriptcentral.com/eoop Email: [email protected] Expert Opinion On Pharmacotherapy Page 108 of 111

1 2 3 162. Cosman, F., et al., Effects of teriparatide in postmenopausal women with osteoporosis on 4 5 6 prior alendronate or raloxifene: differences between stopping and continuing the antiresorptive 7 8 agent. J Clin Endocrinol Metab, 2009. 94(10): p. 3772-3780. 9 10 11 163. Cosman, F., et al., Effects of intravenous zoledronic acid plus subcutaneous teriparatide 12 13 [rhPTH(1-34)] in postmenopausal osteoporosis. J Bone Miner Res, 2011. 26(3): p. 503-511. 14 For Peer Review Only 15 16 17 164. Cosman, F., Anabolic and antiresorptive therapy for osteoporosis: combination and 18 19 sequential approaches. Curr Osteoporos Rep, 2014. 12(4): p. 385-95. 20 21 22 165. Cosman, F., et al., Daily and cyclic parathyroid hormone in women receiving 23 24 alendronate. N.Engl.J Med, 2005. 353(6): p. 566-575. 25 26 27 166. Cosman, F., et al., Effects of intravenous zoledronic acid plus subcutaneous teriparatide 28 29 30 [(1-34)rhPTH] in postmenopausal osteoporosis. J Bone Miner Res, 2010. 31 32 33 167. Leder, B., et al., The effects of combined denosumab and teriparatide administration on 34 35 bone mineral density in postmenopausal women: the DATA (Denosumab And Teriparatide 36 37 38 Administration) study. J Bone Miner Res, 2012. 27(Suppl 1): p. S31. 39 40 41 168. Hattersley, G., et al., Bone Anabolic Efficacy and Safety of BA058, a Novel Analog of 42 43 hPTHrP: Results from a Phase 2 Clinical Trial in Postmenopausal Women with Osteoporosis. 44 45 Endocr Rev, 2012. 33(03_MeetingAbstracts): p. OR08-1. 46 47 48 169. Seeman E, Martin TJ. Co-administration of antiresorptive and anabolic agents: a missed 49 50 51 opportunity. J Bone Miner Res. 2015 ;30(5):753-64. 52 53 54 170. McClung, M.R. and A. Grauer, Romosozumab in postmenopausal women with 55 56 osteopenia. N Engl J Med, 2014. 370(17): p. 1664-5. 57 58 59 60 URL: http://mc.manuscriptcentral.com/eoop Email: [email protected] Page 109 of 111 Expert Opinion On Pharmacotherapy

1 2 3 171. Bonewald, L.F., The amazing osteocyte. J Bone Miner Res, 2011. 26(2): p. 229-38. 4 5 6 172. Rodan, S.B. and L.T. Duong, Cathepsin K – A new molecular target for osteoporosis. 7 8 9 IBMS BoneKEy, 2008. 5(1): p. 16-24. 10 11 12 173. Costa, A.G., et al., Cathepsin K: its skeletal actions and role as a therapeutic target in 13 14 osteoporosis. Nat.Rev.Rheumatol.,For Peer 2011. Review7(8): p. 447-456. Only 15 16 17 174 . Sims NA, Martin TJ. Coupling Signals between the Osteoclast and Osteoblast: How are 18 19 20 Messages Transmitted between These Temporary Visitors to the Bone Surface? Front 21 22 Endocrinol (Lausanne). 2015;6:41. doi: 10.3389/fendo.2015.00041. eCollection 2015. Review 23 24 25 175. Adami, S., et al., Effect of one year treatment with the cathepsin-K inhibitor, balicatib, on 26 27 bone mineral density (BMD) in postmenopausal women with osteopenia/osteoporosis. J Bone 28 29 30 Miner Res, 2006. 21(Suppl 1): p. S24. 31 32 33 176. Langdahl, B., et al., Odanacatib in the treatment of postmenopausal women with low 34 35 bone mineral density: 5 years of continued therapy in a phase 2 study. J Bone Miner Res, 2012. 36 37 38 Epub. 39 40 41 177. Eastell, R., et al., Safety and efficacy of the cathepsin K inhibitor ONO-5334 in 42 43 postmenopausal osteoporosis: the OCEAN study. J Bone Miner Res, 2011. 26(6): p. 1303-1312. 44 45 46 178. Eisman, J.A., et al., Odanacatib in the treatment of postmenopausal women with low 47 48 bone mineral density: three-year continued therapy and resolution of effect. J Bone Miner Res, 49 50 51 2011. 26(2): p. 242-51. 52 53 54 References of Considerable Importance 55 56 57 58 59 60 URL: http://mc.manuscriptcentral.com/eoop Email: [email protected] Expert Opinion On Pharmacotherapy Page 110 of 111

1 2 3 1. Reference #5: This data from the USA shows the declining rates of osteoporosis medication use even 4 5 6 after hospitalization for a hip fracture. 7 8 2. Reference #8: The international movement Fracture Liaison Service (FLS), which is aimed at 9 10 developing pathways for patients admitted to various care stings with a fracture to receive 11 12 13 osteoporosis evaluation and management. 14 For Peer Review Only 15 3. Reference #16: The European guidelines for the diagnosis and management of osteoporosis in 16 17 postmenopausal women. 18 19 4. Reference 23: Understanding the issues surrounding bone quality which explains a large proportion 20 21 22 of the fracture risk independent of bone density 23 24 5. Reference #54: A perspective on the definition of frailty and sarcopenia, and strategies to manage 25 26 this age related phenomena which lead to high risk for falls and fractures. 27 28 29 6. Reference: #66: The ISCD Official Position Development statements on the detection and 30 31 importance of vertebral compression fractures. 32 33 7. Reference #86: The clinical application of FRAX™ in clinical practice 34 35 36 8. Reference #90: A novel approach for ways to broaden the diagnosis of osteoporosis from The 37 38 National Bone Health Alliance. 39 40 9. Reference # 123: The importance of the excessive high risk for a 2 nd fracture following the 1 st 41 42 fracture. 43 44 45 10. Reference # 144: The importance of understanding the spectrum of bone diseases in chronic kidney 46 47 disease and how to discriminate among them. 48 49 11. Reference # 171: The importance of the osteocyte in bone biology 50 51 52 53 54 55 56 57 58 59 60 URL: http://mc.manuscriptcentral.com/eoop Email: [email protected] Page 111 of 111 Expert Opinion On Pharmacotherapy

1 2 3 4 5 6 7 8 9 10 11 12 13 14 For Peer Review Only 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 URL: http://mc.manuscriptcentral.com/eoop Email: [email protected]