Managing Osteoporosis: Screening, Treatment, and More

This Clinical Resource gives subscribers additional insight related to the Recommendations published in July 2017 ~ Resource #330702 Managing Osteoporosis: Screening, Treatment, and More Osteoporosis is characterized by low bone mineral density and destruction of bone tissue leading to an increased risk for fractures. 23 The bones most commonly affected by osteoporosis include the hip, spine, and wrist. 23 Osteoporosis affects millions of people worldwide, with over 50 million men and women in the U.S. having osteoporosis or low bone mineral density. 23 About one out of every two people in the U.S. older than 50 years are at risk for an osteoporotic fracture. 23 The charts below provide an overview of risk factors, guidance on who should receive screening tests, and information about medications to treat osteoporosis. Screening and Treatment Candidates Certain patients are at an increased risk of osteoporosis. It is important to identify high-risk patients in order to appropriately screen for, diagnose, and treat osteoporosis. The chart below provides guidance on which patients should be screened for and offered treatment for osteoporosis. Abbreviations: BMD = bone mineral density; DXA = Dual-energy x-ray absorptiometry Clinical Question When should a DXA or BMD study be offered? Continued Suggested Approach Pertinent Information Recommend a DXA to check BMD and screen for osteoporosis in the following patients at high risk: 4,15 Men or women with a history of low-trauma fracture Men age 70 and older Men age 50 to 69 with risk factors (see risk factors below) Women age 65 and older Postmenopausal women under age 65, especially women: o Who went through natural or surgical menopause before age 45 o Who are thin, smoke, or have a family history of fracture o With a fracture risk of 9.3% or greater per the Fracture Risk Assessment Tool (FRAX, [available at: https://www.sheffield.ac.uk/frax/tool.jsp]) Other patients may also be good candidates for a DXA screening, especially those with multiple risk factors. 4 Examples of risk factors include: 4 o Alcoholism o Chronic meds that may increase fracture risk (e.g., glucocorticoids, leuprolide, aromatase inhibitors) o Immobility/Inactivity

(Clinical Resource #330702: Page 2 of 10) Clinical Question Screening for osteoporosis, continued Suggested Approach Pertinent Information o Lifetime low calcium intake o Organ transplant o Poor health o Radiographic osteopenia (DXA T-score between -1 and -2.5) o Repeated falls o Vertebral deformity o Vision impairment Some experts believe it is not necessary to check a DXA in patients currently receiving osteoporosis treatment. 23 Women receiving osteoporosis treatment may have reduced fractures regardless of impact on BMD. 23 There is no evidence to support monitoring BMD in men receiving osteoporosis treatment. 23 Others recommend continuing to check a DXA during treatment until BMD has stabilized. 28 Check a DXA every two to three years after osteoporosis meds are stopped (three to five years after bisphosphonates [Canadian guidelines]. 28,32,40 Indications for checking DXA more frequently may include a new fracture or starting a long-term corticosteroid (i.e., >2.5 mg/day for three or more months). 32,39 Consider restarting an osteoporosis medication if: 32 o DXA T-score drops to -2.5 or below (i.e., osteoporosis). o New risk factors develop (e.g., a new fracture, starting long-term corticosteroid). 39 Who should be offered treatment for osteoporosis? Postmenopausal women, and men age 50 and older, with a T-score of -2.5 or lower (i.e., osteoporosis). 2,15,28 Postmenopausal women, and men age 50 and older, with a previous hip or spine facture. 2,15 Patients with a T-score between -1 and -2.5 (i.e., osteopenia) with the following risks per the FRAX tool: 2,28 o 10-year hip fracture risk of 3% or higher o 10-year risk of major osteoporotic fracture of 20% or higher Consider treatment for patients with low-trauma or fragility fracture. 2,4,23 Continue to the next section for a review of Medications for Osteoporosis

(Clinical Resource #330702: Page 3 of 10) Medications for Osteoporosis There are many considerations when selecting a medication to prevent or treat osteoporosis. Ensure all patients get adequate calcium and vitamin D. Though many women take estrogen during menopause, especially those that experience menopause prematurely, estrogen is not indicated solely for prevention or treatment of osteoporosis. 4 Treating 10,000 women 50 to 79 years of age with estrogen/progestin for one year prevents six spine and six hip fractures. However, there will be eight more cases of breast cancer, nine more strokes, and 21 more thromboembolic events [Evidence level B; lower quality RCT]. 13 For patients with low fracture risk, adequate calcium and vitamin D, and estrogen if appropriate, may be all that is needed for osteoporosis prevention. 2,4 Use the chart below to help individualize pharmacotherapy choice based on efficacy, safety, cost, and convenience. All numbers needed to treat (NNT) are in comparison to placebo. These medications haven t been directly compared. Abbreviations: GI = gastrointestinal; RANKL = receptor activator of nuclear factor kappa-b ligand; SERM = selective estrogen receptor modifier Class/Cost f (Medication[s]) Oral Bisphosphonates (alendronate [Binosto (U.S.), Fosamax, generics, etc], ibandronate [Boniva (U.S.), generics], risedronate [Actonel, Atelvia (U.S.), Actonel DR (Canada), generics, etc]) (Examples of annual costs for some generic bisphosphonates [weekly dosing]: Alendronate: ~$100 [U.S.]; ~$115 [Canada] Risedronate: ~$1,330 [U.S.]; ~$140 [Canada]) NNT to prevent one fracture over 3 yrs c Consider for Avoid in patients Comments Vertebral fracture: 1 Alendronate: 15 (16 over 2 years for men 21 ) Ibandronate: 21 Risedronate: 20 Hip fracture: 1 Alendronate: 91 Risedronate: 91 Most patients first-line 2,3 Prevention of postmenopausal osteoporosis or corticosteroid-induced osteoporosis 4,39 Treatment of postmenopausal osteoporosis, corticosteroid-induced osteoporosis, or osteoporosis in men 4,23,39 Who cannot remain upright for at least 30 minutes 2 With esophageal or swallowing disorder 2 Unable or unwilling to follow dosing instructions 2 With hypocalcemia 2 With renal insufficiency (e.g., CrCl <30 ml/min) 2,4 Dosing options: daily, weekly, or monthly (see footnote a for exceptions) GI side effects: esophagitis, dysphagia, abdominal pain, diarrhea, upset stomach, heartburn 2,4 May cause musculoskeletal pain 4 Associated rarely with jaw osteonecrosis and atypical thigh fracture 4,32 o Jaw osteonecrosis may occur in up to 0.04% of patients treated with oral bisphosphonates 25 Consider stopping after 5 years [Evidence level C; expert opinion] 23 Consider longer therapy if high-risk (e.g., femoral neck T-score <-2.5 or previous vertebral fracture and femoral neck T-score -2 or lower) 7,23,28,29,32 Doses may be safely held during hospital admissions as drug accumulates in bone and activity continues even after discontinuation 34

(Clinical Resource #330702: Page 4 of 10) Class/Cost f (Medication[s]) Intravenous (IV) Bisphosphonates (zoledronic acid [Reclast, Aclasta (Canada)], ibandronate [Boniva; U.S.]) (Example of annual cost for zoledronic acid: ~$300 [U.S.]; ~$360 [Canada]) NNT to prevent one fracture over 3 yrs c Consider for Avoid in patients Comments Vertebral fracture: 1 14 Patient unable to take With hypocalcemia 2 Zoledronic acid: once a year for oral bisphosphonates With renal treatment, once every 2 years for Hip fracture: 1 91 due to gastrointestinal insufficiency (e.g., prevention (single dose for prevention in (zoledronic acid only) issues 2,23,28 CrCl <30 ml/min) 2 Canada) 10,11 Patient unwilling to Ibandronate given once every 3 months follow oral for treatment (postmenopausal women) 20 bisphosphonate dosing Associated rarely with jaw osteonecrosis instructions 2,23,28 and atypical thigh fracture 4,32 When adherence is a o Osteonecrosis may occur in up to 12% concern with oral of patients treated with IV bisphosphonates 23,28 bisphosphonates 25 Patient with Consider stopping after 3 to 5 years corticosteroid-induced [Evidence level C; expert opinion]. 7,23,28 osteoporosis who is not May continue for up to 6 years if high appropriate for oral risk (e.g., femoral neck T-score bisphosphonates 39 <-2.5 or previous vertebral fracture and femoral neck T-score -2 or lower). 7,23,28,29,33 Acute renal failure reported 2 Acute flu-like reaction 4,20 May cause musculoskeletal pain 4,20 Doses may be safely held during hospital admissions. Drug accumulates in bone and activity continues even after discontinuation 34

(Clinical Resource #330702: Page 5 of 10) Class/Cost f (Medication[s]) Conjugated estrogen/serm Conjugated estrogen/bazedoxifene (Duavee [U.S.], Duavive [Canada]) (~$1,900 per year U.S.; ~$1,200 per year Canada) SERM Raloxifene (Evista, generics) (~$1,200 per year U.S.; ~$180 per year Canada) NNT to prevent one fracture over 3 yrs c Consider for Avoid in patients Comments No primary outcome fracture data available from randomized controlled trials 23 Vertebral fracture: 12 29 (16 to 46; NNT decreases as risk increases) Prevention of postmenopausal osteoporosis in women less than 75 years old, especially in women who also require treatment for vasomotor menopausal symptoms 24 Prevention and treatment in: 2 postmenopausal women at high risk of breast cancer 2 postmenopausal women who cannot use a bisphosphonate 2 women in their 50s or 60s with concerns about long-term bisphosphonate safety. 2,19 postmenopausal women at high risk of breast cancer when hip fracture risk is not significant 28 postmenopausal women with corticosteroidinduced osteoporosis unable to take oral/iv bisphosphonates, parathyroid hormone analogs, or denosumab 39 With known or history of breast cancer or thromboembolism 24,35 With hepatic or renal impairment 24,35 With a deficiency of protein C, S, or antithrombin 24,35 With hot flashes 2 With history of venous thromboembolism 2 In whom hip fracture is the primary concern Do not take with a progestin, additional estrogen, or an additional SERM 24,35 Canadian Duavive not currently approved for an osteoporosis indication 35 Doses may be held during admissions due to increased risk of thromboembolism associated with immobility 24,25 Analgesic effect 2 Reduces the risk of breast cancer 2 o Treating 125 women for three years with raloxifene may prevent one case of breast cancer 26 Doses may be held during admissions due to increased risk of thromboembolism with immobility 37,38 Women in their 50s or 60s in general have a higher risk of vertebral vs hip fracture 19

(Clinical Resource #330702: Page 6 of 10) Class/Cost f (Medication[s]) Calcitonin nasal spray (U.S. only) (Generics only) (~$900 per year) Parathyroid Hormone Analogs Abaloparatide (Tymlos [U.S.]) Teriparatide (Forteo) (Abaloparatide: ~$19,500 per year [U.S.] Teriparatide: ~$36,000 per year [U.S.]; ~$12,500 per year [Canada]) Continued NNT to prevent one fracture over 3 yrs c Consider for Avoid in patients Comments Vertebral fracture: 6 12 (in patients with prior vertebral fracture) Vertebral fracture: Abaloparatide: d,22 28 Teriparatide: b,14 11 Nonvertebral fracture: Abaloparatide: b,36 50 Teriparatide: b,14,33 33 So far, have not been shown to specifically reduce hip fractures. 33,36 Treatment in postmenopausal women: 3,e who cannot use a bisphosphonate 2 with bone pain from vertebral compression fractures 2 Treatment in postmenopausal women: 2,4,22,28,39 with high fracture risk (e.g., corticosteroid induced osteoporosis, previous osteoporotic fracture, multiple risk factors, very low BMD) those who failed or cannot use other agents Teriparatide may also be considered: with primary or hypogonadal osteoporosis (men) 4 with corticosteroidinduced osteoporosis 31 after considering oral/iv bisphosphonates 4,39 In whom hip fracture is the primary concern Less than 5 years postmenopausal (not proven effective) 16 Abaloparatide: With pre-existing hypercalcemia or an underlying hypercalcemic disorder, (e.g., primary hyperparathyroidism) Teriparatide: With metabolic bone disease 2 With Paget s disease 4 With previous skeletal irradiation 4 With elevated alkaline phosphatase of unknown etiology 4 With severe renal impairment 2 Side effects include nausea, flushing, and runny nose 4 Not a first-line drug for osteoporosis. 16,23 o Does not have strong fracture efficacy and it has less effect on BMD than other osteoporosis meds 16 o Clinical significance of its relief of vertebral fracture pain unclear 18 No data available on missed doses and impact on prevention of osteoporosis. o Hospitalized patients may need to use home meds to avoid missed doses if not on formulary Daily subcutaneous injection 2,22 Abaloparatide: if patients experience orthostatic hypotension they should sit or lie down after each dose 22 Side effects may include abdominal pain (abaloparatide), dizziness, fatigue (abaloparatide), headache, hypercalciuria (abaloparatide), leg cramps (teriparatide), and nausea 2,22 Abaloparatide: monitor urine calcium in patients with previous hypercalciuria or if suspect kidney stones 22 Use for max of 2 years due to dosedependent risk of osteosarcoma in rats 2,14,17,22,28 o 2-yr treatment course may be followed by bisphosphonate to maintain BMD 2 Abaloparatide: based on a small study (n=31) no dosage adjustment needed with renal impairment. 22 However,

(Clinical Resource #330702: Page 7 of 10) Class/Cost f (Medication[s]) Parathyroid Hormone Analogs, continued RANKL inhibitor Denosumab (Prolia) (~$2,100 per year U.S.; ~$800 per year in Canada) NNT to prevent one Consider for Avoid in patients Comments fracture over 3 yrs c Vertebral fracture: 5 21 Hip fracture: 5 200 Treatment in patients with high fracture risk (e.g., previous fracture, multiple risk factors): 2,9 with postmenopausal osteoporosis, especially those who have failed or can t/won t take bisphosphonates, such as those with renal insufficiency 2,4,9,23,28 with prostate cancer, receiving androgen deprivation therapy for prostate cancer 8 with breast cancer, receiving an aromatase inhibitor 8 with corticosteroidinduced osteoporosis unable to take oral or IV bisphosphonate or parathyroid hormone analogs 39 With stage 5 kidney disease or patients on dialysis due to high risk of hypocalcemia 28 With hypocalcemia 2 patients with severe renal impairment may be at higher risk for adverse effects. Teriparatide: caution with moderate renal impairment 2 Patients will likely need to continue to use home meds when hospitalized, due to significant cost, as these meds will likely not be on formulary. If doses are missed, resume doses as soon as able. Do not try to catch up on missed doses. 17 Subcutaneous injection given every 6 months, by healthcare professional (U.S.) or patients after training (Canada) 8,9 Dermatologic reactions and cellulitis reported 2 Consider stopping after 5 years [Evidence level C; expert opinion]. 23 Reduction in fracture risk may be maintained for up to two years after discontinuation of therapy. 30 o However BMD may rapidly decline with discontinuation, so many experts recommend starting another osteoporosis med prior to stopping (e.g., bisphosphonate) 28 Potential for jaw osteonecrosis and atypical fractures 8,9 o Jaw osteonecrosis may occur in up to 1.7% of patients treated with denosumab. 27 If doses are missed due to hospitalization, administer dose as soon as able and schedule next dose 6 months following administered dose 8,9

(Clinical Resource #330702: Page 8 of 10) a. Alendronate does not have monthly dosing. Ibandronate does not have weekly dosing. b. Over 19 months. 14 c. All numbers needed to treat (NNT) are in comparison to placebo. These medications haven t been directly compared to one another. d. Over 18 months. 22,36 e. Though approved for use, calcitonin nasal spray is no longer widely used for osteoporosis and therefore not considered in the most recent 2017 guidelines. 23 f. U.S. cost information is wholesale acquisition cost (WAC). Users of this resource are cautioned to use their own professional judgment and consult any other necessary or appropriate sources prior to making clinical judgments based on the content of this document. Our editors have researched the information with input from experts, government agencies, and national organizations. Information and internet links in this article were current as of the date of publication.

(Clinical Resource #330702: Page 9 of 10) Levels of Evidence In accordance with the trend towards Evidence-Based Medicine, we are citing the LEVEL OF EVIDENCE for the statements we publish. Level Definition A High-quality randomized controlled trial (RCT) High-quality meta-analysis (quantitative systematic review) B Nonrandomized clinical trial Nonquantitative systematic review Lower quality RCT Clinical cohort study Case-control study Historical control Epidemiologic study C Consensus Expert opinion D Anecdotal evidence In vitro or animal study Adapted from Siwek J, et al. How to write an evidence-based clinical review article. Am Fam Physician 2002;65:251-8. Project Leader in preparation of this clinical resource (330702): Beth Bryant, Pharm.D., BCPS, Assistant Editor References 1. Ringe JD, Doherty JG. Absolute risk reduction in osteoporosis: assessing treatment efficacy by number needed to treat. Rheumatol Int 2010;30:863-9. 2. Silverman S, Christiansen C. Individualizing osteoporosis therapy. Osteoporos Int 2012;23:797-809. 3. Maclaughlin EJ, Sleeper RB, McNatty D, Raehl CL. Management of age-related osteoporosis and prevention of associated fractures. Ther Clin Risk Manag 2006;2:281-95. 4. Florence R, Allen S, Benedict L, et al. Institute for Clinical Systems Improvement (ICSI): diagnosis and treatment of osteoporosis. Guideline summary. Revised July 2013. https://guideline.gov/summaries/summary/47543/dia gnosis-and-treatment-of-osteoporosis. (Accessed May 30, 2017). 5. Cummings SR, San Martin J, McClung MR, et al. Denosumab for prevention of fractures in postmenopausal women with osteoporosis. N Engl J Med 2009;361:756-65. 6. Chesnut CH, Silverman S, Andriano K, et al. A randomized trial of nasal spray salmon calcitonin in postmenopausal women with established osteoporosis: the prevent recurrence of osteoporotic fractures study. Am J Med 2000;109:267-76. 7. Black DM, Bauer DC, Schwartz AV, et al. Continuing bisphosphonate treatment for osteoporosis--for whom and for how long? N Engl J Med 2012;366:2051-3. 8. Product information for Prolia. Amgen Inc. Thousand Oaks, CA 91320. January 2017. 9. Product monograph for Prolia. Amgen Canada Inc. Mississauga, ON L5N 0A4. April 2017. 10. Product information for Reclast. Novartis Pharmaceuticals Corporation. East Hanover, NJ 07936. April 2016. 11. Product monograph for Aclasta. Novartis Pharmaceuticals Canada Inc. Dorval, QC H9S 1A9. April 2017. 12. Ettinger B, Black DM, Mitlak BH, et al. Reduction of vertebral fracture risk in postmenopausal women with osteoporosis treated with raloxifene: results from a 3-year randomized clinical trial. JAMA 1999;282:637-45. 13. Nelson HD, Walker M, Zakher B, Mitchell J. Menopausal hormone therapy for the primary prevention of chronic conditions: a systematic review to update the U.S. Preventive Services Task Force recommendations. Ann Intern Med 2012;157:104-13. 14. Product information for Forteo. Lilly USA, LLC. Indianapolis, IN 46285. October 2016. 15. Watts NB, Adler RA, Bilezikian JP, et al. Osteoporosis in men: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 2012;97:1802-22. 16. Management of osteoporosis in postmenopausal women: 2010 position statement of the North American Menopause Society. Menopause 2010;17:25-54. 17. Product monograph for Forteo. Eli Lilly Canada Inc. Toronto, ON M1N 2E8. February 2010. 18. Bandolier. Calcitonin for pain relief following acute osteoporotic vertebral fractures. http://www.bandolier.org.uk/booth/painpag/chronrev/ muscskel/cp104.html. (Accessed May 29, 2017). 19. Skugor M. Osteoporosis. Cleveland Clinic. Center for Continuing Education. http://www.clevelandclinicmeded.com/medicalpubs/di seasemanagement/endocrinology/osteoporosisdisease/. (Accessed May 30, 2017). 20. Product information for Boniva injection. Genentech USA, Inc. South San Francisco, CA 94080. December 2016. 21. Orwoll E, Ettinger M, Weiss S, et al. Alendronate for the treatment of osteoporosis in men. N Engl J Med 2000;343:604-10. 22. Product information for Tymlos. Radius Health Inc. Waltham, MA 02451. April 2017. 23. Qaseem A, Forciea MA, McLean RM, Denberg TD. Treatment of low bone density or osteoporosis to prevent fractures in men and women: a clinical practice guideline update from the American College of Physicians. Ann Intern Med 2017;166:818-39. 24. Product information for Duavee. Wyeth Pharmaceuticals Inc. A subsidiary of Pfizer Inc. Philadelphia, PA 19101. September 2015. 25. Kumar V, Sinha RK. Bisphosphonate related osteonecrosis of the jaw: an update. J Maxillofac Oral Surg 2014;13:386-93.

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