Osteoporosis is a common systemic skeletal

Annals of Internal Medicine In the Clinic Osteoporosis Osteoporosis is a common systemic skeletal disorder resulting in bone fragility and increased fracture risk. However, management of osteoporosis and fracture prevention strategies are often not addressed by primary care clinicians, even in older patients with recent fractures. Evidence-based screening strategies will improve identification of patients who are most likely to benefit from drug treatment to prevent fracture. In addition, careful consideration of when pharmacotherapy should be started and choice of medication and duration of treatment will maximize the benefits of fracture prevention while minimizing potential harms of long-term drug exposure. Screening and Prevention Diagnosis Treatment for Fracture Prevention Practice Improvement CME/MOC activity available at Annals.org. Physician Writers Kristine E. Ensrud, MD, MPH Carolyn J. Crandall, MD, MS From the University of Minnesota and Veterans Affairs Health Care System, Minneapolis, Minnesota; and the University of California, Los Angeles, California. doi:10.7326/aitc201708010 CME Objective: To review current evidence for screening, prevention, diagnosis, treatment for fracture prevention, and practice improvement of osteoporosis. Funding Source: American College of Physicians. Acknowledgment: The authors thank E. Michael Lewiecki, author of the previous version of this In the Clinic. With the assistance of additional physician writers, the editors of Annals of Internal Medicine develop In the Clinic using MKSAP and other resources of the American College of Physicians. In the Clinic does not necessarily represent official ACP clinical policy. For ACP clinical guidelines, please go to https://www.acponline.org/clinical_information/guidelines/. Disclosures: Dr. Ensrud, ACP Contributing Author, reports personal fees from from Merck Sharpe & Dohme, outside the submitted work; Dr. Crandall, ACP Contributing Author, has disclosed no conflicts of interest. Disclosures can also be viewed at www.acponline.org /authors/icmje/conflictofinterestforms.do?msnum=m17-1218. 2017 American College of Physicians

1. Wright NC, Looker AC, Saag KG, et al. The recent prevalence of osteoporosis and low bone mass in the United States based on bone mineral density at the femoral neck or lumbar spine. J Bone Miner Res. 2014;29:2520-6. [PMID: 24771492] 2. U.S. Preventive Services Task Force. Screening for osteoporosis: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med. 2011;154:356-64. [PMID: 21242341] 3. National Osteoporosis Foundation. 2014 clinician's guide to prevention and treatment of osteoporosis. Accessed at www.nof.org/news/nofs-clinicians -guide-published-by-osteoporosis-international/ on 16 June 2017. 4. International Society for Clinical Densitometry. 2015 ISCD Official Positions Adult. Accessed at www.iscd.org/official -positions/2015-iscd-official-positions-adult/ on 15 August 2013. 5. Looker AC, Frenk SM. Percentage of adults aged 65 and over with osteoporosis or low bone mass at the femur neck or lumbar spine: United States, 2005-2010. Acceesed at www.cdc.gov/nchs/data /hestat/osteoporsis/ osteoporosis2005_2010.htm on 18 April 2017. 6. National Committee for Quality Assurance. Osteoporosis testing and management in older women. Accessed at www.ncqa.org /report-cards/health-plans /state-of-health-carequality/2016-table-of -contents/osteoporosis on 5May2017. 7. Doherty DA, Sanders KM, Kotowicz MA, Prince RL. Lifetime and five-year age-specific risks of first and subsequent osteoporotic fractures in postmenopausal women. Osteoporos Int. 2001;12: 16-2. [PMID: 11305078] 8. Camacho PM, Petak SM, Binkley N, et al. American Association of Clinical Endocrinologists and American College of Endocrinology clinical practice guidelines for the diagnosis and treatment of postmenopausal osteoporosis 2016. Endocr Pract. 2016;22:1-42. [PMID: 27662240] 9. Cadarette SM, McIsaac WJ, Hawker GA, et al. The validity of decision rules for selecting women with primary osteoporosis for bone mineral density testing. Osteoporos Int. 2004;15:361-6. [PMID: 14730421] Osteoporosis is a systemic skeletal disease characterized by low bone mass and microarchitectural deterioration in bone tissue, leading to enhanced bone fragility and increased fracture risk. The operational definition of osteoporosis is based on bone mineral density (BMD) measurement. An estimated 10.3% of noninstitutionalized adults aged 50 years or older in the United States had osteoporosis in 2010 (1). Hip and Screening and Prevention Who should be screened? All women aged 65 years or older should be screened for osteoporosis by BMD measurement at the hip and lumbar spine using dualenergy x-ray absorptiometry (DXA). This recommendation is universally endorsed by the U.S. Preventive Services Task Force (USPSTF) (2) and other professional societies (3, 4). Despite a prevalence of osteoporosis in this patient population of nearly 25% (5), recent data (6) suggest that 1 in 4 women aged 65 85 years has never had BMD testing. The risk assessment strategy to select younger postmenopausal women for osteoporosis screening is uncertain. Despite rapid rates of bone loss at the lumbar spine during the menopausal transition, the absolute fracture risk for any given BMD is much lower in younger postmenopausal women than in older women. In particular, the absolute 5-year probability of hip fracture is less than 1.0% until age 70 79 years, when it begins to increase exponentially (7). Data on the benefits and harms of drug treatment beginning at age 50 64 years and continuing over the next 3 decades of life are unavailable. Use of drug treatment in younger women leaves them with fewer options for pharmacotherapy in their 70s, when the risk clinical vertebral fractures are the most devastating consequences of osteoporosis and are associated with increased morbidity and mortality. Drug treatment has been found to reduce risk for subsequent clinical fractures among postmenopausal women with existing vertebral fractures or osteoporosis (as defined by BMD) and among adults aged 50 years or older with recent hip fracture. for hip fracture begins to increase. Some guidelines (3, 4, 8) encourage BMD measurement for women in this age group who have risk factors for fracture. However, there is no consensus regarding all the specific risk factors that should be considered in this decision. Another strategy is to use the Osteoporosis Self-Assessment Tool (OST) (see the Box), a simple calculator that uses age and weight and is designed to identify individuals who are more likely to have low BMD. Studies (9, 10) have suggested that an OST score less than 2isanappropriatecutofftoselect younger postmenopausal women for BMD testing. In 2011, the USPSTF (2) recommended selecting younger postmenopausal women for BMD measurement who have a 10-year fracture probability, as calculated by the Fracture Risk Assessment Tool (FRAX) (11), that is the same as or greater than that of a 65-year-old white woman without additional risk factors (i.e., 10-year probability of major osteoporotic fracture [hip, clinical vertebral, distal forearm, or humerus] 9.3% when estimated without BMD). Comparisons of the OST and USPSTF approaches have reported superior combined sensitivity and specificity, but the OST has better discrimination (10, 12). Thus, use of an OST cutoff less 2017 American College of Physicians ITC18 In the Clinic Annals of Internal Medicine 1 August 2017

Osteoporosis Self-assessment Tool Score = [weight (kg) age (years)] 0.2 than 2 is a reasonable strategy to identify younger postmenopausal women for BMD testing if it is agreed that drug treatment will be initiated for a BMD T-score of 2.5. Osteoporosis screening in older men has been proposed because it is an accepted strategy in older women. However, it is less common in men; the prevalence of BMD-defined osteoporosis among men aged 65 years or older is 5.6% (5). Data on the efficacy of pharmacotherapy in preventing fractures in men are limited; randomized trials in osteoporotic men have only evaluated radiographic vertebral fracture as an end point. Some guidelines (3, 13) recommend BMD testing in all men aged 70 years or older and in those aged 50 69 years with risk factors. Other research has suggested using the OST to identify men for screening (14). The USPSTF (2) made no recommendation about osteoporosis screening in men, citing insufficient evidence, but commented that those who are most likely to benefit from screening have a 10-year FRAX probability of fracture equal to or greater than that of a 65-year-old white woman without additional risk factors. A study (15) that compared proposed strategies for selecting men aged 70 years or older for osteoporosis screening reported that the OST (cutoff <2) performed slightly better than the more complex FRAX strategy; use of either tool substantially reduced the proportion of men referred for BMD measurement compared with universal screening. Future research on osteoporosis risk assessment tools and randomized trials with clinical fracture end points are needed to clarify whether targeted screening strategies or universal screening are warranted in this patient population. How often should older adults be screened, and when should screening stop? Studies indicate that the baseline BMD T-score is important in determining how often older adults without osteoporosis at the initial assessment should be tested. Those with lower BMD at baseline should have a shorter rescreening interval. A study (16) that estimated the cumulative incidence of osteoporosis in older communitydwelling women without osteoporosis at initial assessment reported that fewer than 10% became osteoporotic during follow-up if rescreening intervals were 15 years for those with normal BMD (T-score 1.0) or mild osteopenia (T-score < 1.0 and > 1.5), 5 years for those with moderate osteopenia (T-score < 1.5 and > 2.0), and 1 year for those with advanced osteopenia (T-score < 2.0 and > 2.5). Asimilarstudyincommunitydwelling older men without osteoporosis at initial assessment reported that only 0.2% of those with normal BMD or mild osteopenia transitioned to osteoporosis during follow-up; the time for 10% of men to transition to osteoporosis was 8.5 years among those with moderate osteopenia and 2.7 years among those with advanced osteopenia (17). The age at which to stop or decrease BMD testing to screen for osteoporosis has not been examined. Older women with higher BMD T-scores (> 1.5) have a very low risk for disabling fracture before their estimated time to death, and they may benefit less from rescreening. In contrast, older women with lower BMD T-scores (< 2.0 and > 2.5) have a high risk for disabling fracture before their estimated time to death, so they may bene- FRAX Clinical Risk Factors* Age Sex Weight Height Previous fracture Parental history of hip fracture Smoking status Glucocorticoid use Rheumatoid arthritis Secondary osteoporosis 3 units of alcohol per day Femoral neck BMD (g/cm 2 ) BMD = bone mineral density. * Calculator freely available at www.shef.ac.uk/frax. The quantity of alcohol that constitutes 1 unit varies slightly by country. For FRAX, 1 unit of alcohol is equivalent to 9 10 oz of beer, 4 oz of wine, 1 oz of spirits, or 2 oz of apéritif. 10. Leslie WD, Lix LM, Johansson H, Oden A, et al; Manitoba Bone Density Program. Selection of women aged 50-64 yr for bone density measurement. J Clin Densitom. 2013;16: 570-8. [PMID: 23452870] 11. Centre for Metabolic Bone Diseases. FRAX WHO fracture risk assessment tool. Accessed at www.shef.ac.uk/frax/ on 15 June 2017. 12. Crandall CJ, Larson J, Gourlay ML, et al. Osteoporosis screening in postmenopausal women 50 to 64 years old: comparison of US Preventive Services Task Force strategy and two traditional strategies in the Women's Health Initiative. J Bone Miner Res. 2014; 29:1661-6. [PMID: 24431262] 13. Watts NB, Adler RA, Bilezikian JP, et al; Endocrine Society. Osteoporosis in men: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2012;97: 1802-22. [PMID: 22675062] 14. Adler RA, Tran MT, Petkov VI. Performance of the Osteoporosis Selfassessment Screening Tool for osteoporosis in American men. Mayo Clin Proc. 2003;78: 723-7. [PMID: 12934782] 1August2017 AnnalsofInternalMedicine IntheClinic ITC19 2017 American College of Physicians

15. Diem SJ, Peters KW, Gourlay ML, et al. Screening for osteoporosis in older men: operating characteristics of proposed strategies for selecting men for BMD testing. J Gen Intern Med [Forthcoming]. 16. Gourlay ML, Fine JP, Preisser JS, et al; Study of Osteoporotic Fractures Research Group. Bonedensity testing interval and transition to osteoporosis in older women. NEnglJMed.2012; 366:225-33. [PMID: 22256806] 17. Gourlay ML, Overman RA, Fine JP, et al; Osteoporotic Fractures in Men (MrOS) Research Group. Time to osteoporosis and major fracture in older men: The MrOS Study. Am J Prev Med. 2016; 50:727-36. [PMID: 26821835] 18. ClinRisk. QFracture-2016 risk calculator. Accessed at www.qfracture.org/ on 1June2016. 19. Garvan Institute of Medical Research. Bone fracture risk calculator. garvan org au/bone-fracturerisk. Accessed at www.garvan.org.au/bone -fracture-risk on 1 June 2016. 20. Kanis JA, Hans D, Cooper C, et al; Task Force of the FRAX Initiative. Interpretation and use of FRAX in clinical practice. Osteoporos Int. 2011;22:2395-411. [PMID: 21779818] 21. Collins GS, Michaëlsson K. Fracture risk assessment: state of the art, methodologically unsound, or poorly reported? Curr Osteoporos Rep. 2012;10:199-207. [PMID: 22688862] 22. van den Bergh JP, van Geel TA, Lems WF, Geusens PP. Assessment of individual fracture risk: FRAX and beyond. Curr Osteoporos Rep. 2010;8:131-7. [PMID: 20563901] 23. Rubin KH, Friis- Holmberg T, Hermann AP, Abrahamsen B, Brixen K. Risk assessment tools to identify women with increased risk of osteoporotic fracture: complexity or simplicity? A systematic review. J Bone Miner Res. 2013;28:1701-17. [PMID: 23592255] 24. Ensrud KE, Lui LY, Taylor BC, et al; Study of Osteoporotic Fractures Research Group. A comparison of prediction models for fractures in older women: is more better? Arch Intern Med. 2009; 169:2087-94. [PMID: 20008691] fit more from rescreening. The age to stop screening may be lower in men than in women because of the higher competing risk for death. How should a patient's absolute risk be assessed? Because clinical factors contribute to fracture risk beyond that reflected by BMD, researchers have developed fracture risk assessment tools (11, 18, 19) to estimate apatient'sabsolutelong-termrisk for fracture. Of note, the World Health Organization (WHO) does not endorse the use of any specific instrument. FRAX (the tool most commonly endorsed in the United States for use in clinical decision making) is a computer-based algorithm that uses selected clinical risk factors (see the Box)with or without femoral neck BMD to estimate 10-year probability of hip and major osteoporotic fracture (11). FRAX has several strengths (20). Country-specific models are available that take into account countrywide fracture and mortality rates. Performance has been evaluated in several studies, and the algorithm is readily revised and updated. It also has several limitations (21, 22). Most important, there are no data from randomized trials demonstrating the benefit of pharmacotherapy for clinical fracture prevention in patients who are enrolled based on FRAX intervention thresholds recommended by such organizations as the National Osteoporosis Foundation (NOF) (3) for use in clinical decision making regarding whether to initiate drug treatment. FRAX is not transparent information used to derive the equations is not publicly available. Other limitations are that it includes only femoral neck BMD and underestimates fracture probability among patients whose spine BMD is markedly lower than femoral neck measurements. It does not account for the dose response relationship that exists for some clinical risk factors. For example, prior fracture is a FRAX clinical risk factor, but the algorithm does not consider recency, number, severity, or site of prior fractures, all of which affect subsequent risk. By design, fall history or propensity was not included as a clinical risk factor because the developers noted that markers of fall propensity identify a fracture risk that probably is not amenable to treatment with medications affecting bone metabolism. Hence, the tool may underestimate fracture risk in a patient with ahigherfallpropensity.finally,it should only be used to estimate fracture probability in treatmentnaive patients. A systematic review (23) of studies in postmenopausal women concluded that no fracture risk assessment tool is optimal. The evidence (23, 24) suggests that simple tools often perform as well as more complex ones. Suboptimal performance of existing tools has been reported in specific patient populations, including younger postmenopausal women (25) and older men (26, 27). This indicates that predicting fracture risk in these patient groups requires assessment of factors not incorporated into available strategies. The benefit of including fracture risk assessment tools into shared decision making is also uncertain. Current evidence (28) suggests that a decision aid incorporating FRAX probability may improve patient knowledge, but no effect on rates of treatment initiation or adherence was demonstrated. Further research to improve identification of patients at higher absolute risk for fracture is needed, with special attention to simple models that fit into the time constraints and competing demands of primary care practice. 2017 American College of Physicians ITC20 In the Clinic Annals of Internal Medicine 1 August 2017

What lifestyle measures are recommended for prevention? Lifestyle measures for fracture prevention include maintaining a healthy body weight (body mass index >20 kg/m 2 ) and adequate dietary protein intake (i.e., 0.8 g/kg of body weight per day). Patients should be counseled to avoid cigarette smoking and excessive alcohol intake. Physical activity is widely recommended to improve skeletal health, but randomized trials have not been conducted to identify the type, frequency, or duration necessary to prevent fractures. Guidelines (3, 8) endorse lifelong physical activity (both weight-bearing exercise and muscle-strengthening exercise) for osteoporosis prevention. Frequency and intensity of activity are not specified in guidelines. Nonetheless, a common clinical practice is to recommend both 30 minutes of walking per day and gentle resistance exercises. The vast majority of fractures result from falls, but only 10% 15% of falls in older adults result in fractures. The pathogenesis of falls in older adults is complex. Several factors are associated with increased risk, including age-related deficits in visual, proprioceptive, and vestibular systems; decreased lower extremity performance; medical conditions and comorbidity burden; use of selected medications and polypharmacy; and environmental factors (29). Guidelines (3, 8) recommend evaluation of risk factors for falls in all osteoporotic patients. Although minimizing use of medications associated with increased fall risk is appropriate, the extent to which other risk factors can be mitigated by home safety evaluation and fall prevention programs is controversial. Most trials of home-based exercise or fall prevention programs have not robustly decreased fall risk (30). A systematic review of trials (31) concluded that exercise or physical therapy interventions modestly reduced falls in communitydwelling older adults but noted that evidence for efficacy in preventing fall-related fractures was scant and inconclusive. The USPSTF (32) recommends individualized decision making and advocates exercise or physical therapy and vitamin D supplementation (800 IU/d) to prevent falls in community-dwelling older adults at increased risk. A reasonable strategy is to request physical therapy evaluation and intervention (e.g., gait assessment, balance training, and lower extremity strengthening programs) in older patients with deconditioning, reduced mobility, or balance or gait abnormalities. What is the recommended intake of calcium and vitamin D? The recommended dietary allowance (RDA) is calculated to meet the intake requirements of more than 97% of the U.S. population. For women, the RDA for calcium is 1000 mg/d for ages 19 50 years and increases to 1200 mg/d above age 50 years; for men, the RDA is 1000 mg/d for ages 19 70 years and increases to 1200 mg/d above age 70 years (33). Intake above 2500 mg/d should be avoided. Preferred sources of calcium are calcium-rich foods and beverages (34). The RDA for vitamin D is 600 IU/d for men and women aged 19 70 years and increases to 800 IU/d for those older than 70 years (33). These allowances were calculated assuming minimal or no sun exposure. The RDA for vitamin D corresponds to a serum 25-hydroxyvitamin D (25-[OH]D) level of 20 ng/ml. Because few foods in nature contain it, vitamin D in the U.S. diet is primarily provided by fortified foods. 25. Crandall CJ, Larson JC, Watts NB, et al. Comparison of fracture risk prediction by the US Preventive Services Task Force strategy and two alternative strategies in women 50-64 years old in the Women's Health Initiative. J Clin Endocrinol Metab. 2014;99:4514-22. [PMID: 25322268] 26. Ensrud KE, Taylor BC, Peters KW, et al; Osteoporotic Fractures in Men Study Group. Implications of expanding indications for drug treatment to prevent fracture in older men in United States: cross sectional and longitudinal analysis of prospective cohort study. BMJ. 2014;349: g4120. [PMID: 24994809] 27. Ettinger B, Ensrud KE, Blackwell T, et al; Osteoporotic Fracture in Men (MrOS) Study Research Group. Performance of FRAX in a cohort of community-dwelling, ambulatory older men: the Osteoporotic Fractures in Men (MrOS) study. Osteoporos Int. 2013;24:1185-93. [PMID: 23179575] 28. Montori VM, Shah ND, Pencille LJ, et al. Use of a decision aid to improve treatment decisions in osteoporosis: the osteoporosis choice randomized trial. Am J Med. 2011;124:549-56. [PMID: 21605732] 29. Ensrud KE. Epidemiology of fracture risk with advancing age. J Gerontol ABiolSciMedSci.2013; 68:1236-42. [PMID: 23833201] 30. Hill KD, Hunter SW, Batchelor FA, Cavalheri V, Burton E. Individualized home-based exercise programs for older people to reduce falls and improve physical performance: A systematic review and metaanalysis. Maturitas. 2015;82:72-84. [PMID: 25989701] 31. Michael YL, Whitlock EP, Lin JS, et al; US Preventive Services Task Force. Primary care-relevant interventions to prevent falling in older adults: a systematic evidence review for the U.S. Preventive Services Task Force. Ann Intern Med. 2010;153:815-25. [PMID: 21173416] 32. Moyer VA; U.S. Preventive Services Task Force. Prevention of falls in community-dwelling older adults: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med. 2012;157:197-204. [PMID: 22868837] 1August2017 AnnalsofInternalMedicine IntheClinic ITC21 2017 American College of Physicians

Screening and Prevention... Women aged 65 years or older should be screened for osteoporosis with DXA hip and spine BMD measurements. Use of an OST cutoff less than 2 is a reasonable strategy to identify younger postmenopausal women (aged 50 64 years) for BMD testing if there is agreement that drug treatment will be initiated for a BMD T-score 2.5. Data are insufficient to endorse a specific screening strategy in older men, but universal screening of men aged 70 years or older may be premature. The initial BMD T-score is the major determinant of the screening interval among older adults without osteoporosis at the initial assessment. No optimal fracture risk assessment tool is available, and simple tools often perform as well as more complex ones. Adequate exercise and intake of protein, calcium, and vitamin D are recommended for bone health. Potentially reversible risk factors for falls with particular attention to polypharmacy should be addressed in patients with osteoporosis. CLINICAL BOTTOM LINE 33. Institute of Medicine. Dietary reference intakes for calcium and vitamin D. Washington, DC: National Academies Pr; 2011. 34. Bauer DC. Clinical practice. Calcium supplements and fracture prevention. N Engl J Med. 2013;369:1537-43. [PMID: 24131178] Diagnosis How should osteoporosis be diagnosed? The diagnosis of osteoporosis in adults aged 50 years or older can be in patients with a history of hip or clinical vertebral fracture not due to excessive trauma, those with existing vertebral fractures identified on the basis of a spinal imaging study alone (radiographic vertebral fractures), and those with a BMD at or below the cutoff value (i.e., 2.5 SDs below that of a young white woman). BMD should be measured at the hip and its subregions and the lumbar spine (posterior anterior view of the L1 L4 vertebrae) using DXA. Measurement of BMD at the hip is preferred for diagnosing osteoporosis because it is a strong predictor of risk for nonvertebral fracture, including hip fracture. Measurements at the total hip and femoral neck subregion (but not those at Ward's area or greater trochanter subregions) should be used to make the diagnosis. Of note, spine BMD may increase with aging because of calcium deposition related to degenerative joint disease and abdominal aortic calcification. BMD results on DXA are reported as T-scores and Z scores (see the Box). The T-score should be reported in postmenopausal women and in men aged 50 years or older. It compares the patient's BMD with the average BMD in the young adult reference population and is the SD below or above the mean BMD for young adults. The reference group of young adults for calculation of total hip and femoral neck BMD T-scores in both men and women and individuals of all racial/ethnic groups should be non-hispanic white women aged 20 29 years from NHANES III (Third National Health and Nutrition Examination Survey) (4). Because there is no internationally recommended reference group for lumbar spine measurements, the reference group for calculation of lumbar spine BMD T-scores should be the DXA manufacturer-specific reference database of young white women. BMD within 1 SD of this reference group is classified as normal BMD, 1.0 2.5 SDs below that of a young white woman is considered to be osteopenia or low bone mass, and 2.5 SDs below that of a young white woman is defined as osteoporosis. BMD Z scores should be reported in premenopausal women and in 2017 American College of Physicians ITC22 In the Clinic Annals of Internal Medicine 1 August 2017

men younger than 50 years. The Z score provides a comparison of the patient's BMD with average age-, sex-, and race-matched BMD and is the number of SDs below or above mean BMD for people of the same age, sex, and race. When should clinicians consider laboratory testing to assess for underlying secondary causes or to determine whether consultation is necessary? The clinical utility of laboratory testing to identify secondary causes of osteoporosis is unclear, but some organizations (3, 8, 13) recommend ordering laboratory tests in patients with osteoporosis or high fracture risk or patients in whom a specific secondary, treatable cause of osteoporosis is being considered. Most studies that evaluated the utility of laboratory evaluation for secondary causes of osteoporosis had small sample sizes or were based on tertiary care patient populations (35, 36). Thus, results may not be generalizable to patients seen in the primary care practice setting. A large study of community-dwelling postmenopausal women (37) found that the prevalence of each specific laboratory test abnormality was similar among women with and without osteoporosis, except that low thyroidstimulating hormone levels were slightly more common among women with osteoporosis. Similarly, in a large study of communitydwelling older men (38), most had more than 1 laboratory test abnormality, regardless of whether they had osteoporosis; only vitamin D insufficiency (but not vitamin D deficiency) and high alkaline phosphatase levels were more common in men with osteoporosis than in those without. Measurement of 25-(OH)D levels is widely recommended in osteoporotic patients. However, there is no evidence that vitamin D supplementation to achieve a target serum level (e.g., 30 ng/ ml) is superior to a more conservative approach (e.g., supplementation if needed to reach the RDA of 600 800 IU/d) in reducing risk for falls or fractures. The clinical utility of this measurement is likely to be greatest in patients with problems absorbing or metabolizing vitamin D. Patients with specific presumed secondary causes of osteoporosis should be referred to subspecialists for further evaluation and management. Those with suspected celiac disease or inflammatory bowel syndrome should be referred to a gastroenterologist. Patients with probable Cushing syndrome, hyperthyroidism, hyperparathyroidism, or hyperprolactinemia should be referred to an endocrinologist. Patients with suspected Paget disease of bone or autoimmune disease should be referred to a rheumatologist, those with possible systemic mastocytosis should be referred to an allergist/immunologist, and those with multiple myeloma or other types of cancer should be referred to a hematologist/oncologist. Diagnosis... The diagnosis of osteoporosis in adults aged 50 years or older should be made in patients with a history of hip or clinical vertebral fracture not due to excessive trauma; those with existing radiographic vertebral fractures; and those with a BMD T-score at the femoral neck, total hip, or lumbar spine 2.5, calculated using a young white woman as a reference database. Current evidence is insufficient to support routine laboratory testing in patients with osteoporosis to identify possible secondary causes. Referral to a subspecialist is indicated in patients with complex diagnostic issues. CLINICAL BOTTOM LINE Classification of Bone Mineral Density by Dual-Energy X-Ray Absorptiometry In postmenopausal women and men aged 50 years or older, apply the WHO diagnostic criteria: Normal: T-score 1.0 Low bone mass (osteopenia): T-score < 1.0 and > 2.5 Osteoporosis: T-score 2.5 In premenopausal women and men younger than 50 years, do not apply the WHO diagnostic criteria: Z scores, not T-scores, are preferred Z score 2.0 is defined as below the expected range for age Z score > 2.0 is within the expected range for age WHO = World Health Organization. 35. Romagnoli E, Del Fiacco R, Russo S, et al. Secondary osteoporosis in men and women: clinical challenge of an unresolved issue. J Rheumatol. 2011;38:1671-9. [PMID: 21632675] 36. Ryan CS, Petkov VI, Adler RA. Osteoporosis in men: the value of laboratory testing. Osteoporos Int. 2011;22:1845-53. [PMID: 20936403] 37. Jamal SA, Leiter RE, Bayoumi AM, Bauer DC, Cummings SR. Clinical utility of laboratory testing in women with osteoporosis. Osteoporos Int. 2005;16:534-40. [PMID: 15340801] 38. Fink HA, Litwack-Harrison S, Taylor BC, et al; Osteoporotic Fractures in Men (MrOS) Study Group. Clinical utility of routine laboratory testing to identify possible secondary causes in older men with osteoporosis: the Osteoporotic Fractures in Men (MrOS) Study. Osteoporos Int. 2016;27: 331-8. [PMID: 26458388] 1August2017 AnnalsofInternalMedicine IntheClinic ITC23 2017 American College of Physicians

39. Watts NB, Geusens P, Barton IP, Felsenberg D. Relationship between changes in BMD and nonvertebral fracture incidence associated with risedronate: reduction in risk of nonvertebral fracture is not related to change in BMD. J Bone Miner Res. 2005;20: 2097-104. [PMID: 16294263] 40. Cummings SR, Karpf DB, Harris F, et al. Improvement in spine bone density and reduction in risk of vertebral fractures during treatment with antiresorptive drugs. Am JMed.2002;112:281-9. [PMID: 11893367] 41. Chen P, Miller PD, Delmas PD, Misurski DA, Krege JH. Change in lumbar spine BMD and vertebral fracture risk reduction in teriparatidetreated postmenopausal women with osteoporosis. J Bone Miner Res. 2006;21:1785-90. [PMID: 17002571] 42. U.S. Department of Health and Human Services. Bone health and osteporosis: a report of the Surgeon General. 2004. Rockville, MD, U.S. Department of Health and Human Services, Office of the Surgeon General. 43. Chung M, Lee J, Terasawa T, Lau J, Trikalinos TA. Vitamin D with or without calcium supplementation for prevention of cancer and fractures: an updated metaanalysis for the U.S. Preventive Services Task Force. Ann Intern Med. 2011;155:827-38. [PMID: 22184690] Treatment for Fracture Prevention What are the goals of treatment? The primary goal of osteoporosis treatment is to reduce the risk for clinical fractures, especially those of the hip and vertebrae. Change in BMD during drug treatment is far less important than the treatment effect on subsequent fracture risk. Most reduction of fracture risk with drug treatment is not explained by its effect on BMD (39 41). Even if BMD declines during pharmacotherapy, whether the patient would have had a much greater BMD decline without treatment is uncertain. Clinicians should emphasize to patients that the goal of treatment is to prevent disabling fractures. However, because drug treatment does not always achieve this goal, asinglefractureduringtreatment is not necessarily evidence of treatment failure, but it does indicate a higher risk for future fractures. Patients who have fractures while receiving drug treatment should be assessed for adherence, evaluated for underlying medical conditions (e.g., secondary causes), and assessed for fall propensity with consideration of preventive measures. In patients who have had multiple fractures or fractures with severe clinical consequences during treatment, clinicians may consider starting an alternate therapy or referring to a subspecialist. Clinicians should also review medication lists to determine whether those with adverse effects on bone metabolism can be decreased or discontinued. Medications reported to be associated with osteoporosis and higher fracture risk include long-term heparin, antiepileptic drugs, cyclosporine, tacrolimus, such chemotherapeutic agents as aromatase inhibitors, glucocorticoids, gonadotropinreleasing hormone agonists, thiazolidinediones, excessive doses of L-thyroxine, proton-pump inhibitors, selective serotonin reuptake inhibitors, parenteral nutrition, depo-medroxyprogesterone contraception, methotrexate, and aluminum antacids (42). Which patients should take calcium and vitamin D supplementation? Clinicians should follow the Institute of Medicine's 2011 recommendations regarding calcium and vitamin D intake (33). They should encourage patients to obtain these nutrients through dietary sources and recommend supplementation only in patients who do not meet intake levels. Calcium supplements include calcium carbonate and calcium citrate; determination of the dose required to meet daily requirements should be based on the elemental calcium content (34). Vitamin D 3 supplements are available in several doses, and many multivitamins contain 400 IU of vitamin D 3.Excessivecalciumintake can result in nephrolithiasis, so patients should not assume that more is better and exceed recommended doses (33). Asystematicreviewoftrialsof combined calcium and vitamin D supplementation (43) reported a reduction in fracture risk with supplementation, but effects were smaller and not significant among community-dwelling older adults than among institutionalized elderly persons. Thus, combined calcium and vitamin D supplementation at prudent doses should be recommended in older institutionalized patients and communitydwelling older adults with inadequate dietary intake. Which patients are candidates for drug treatment? Among postmenopausal women with osteoporosis (defined as a BMD T-score 2.5 or existing 2017 American College of Physicians ITC24 In the Clinic Annals of Internal Medicine 1 August 2017

radiographic vertebral fractures), treatment with alendronate, risedronate, zoledronic acid, or denosumab reduces risk for clinical fractures, including those of the hip and vertebrae. Several drug treatments lower risk for new radiographic vertebral fractures. Among men and women aged 50 years or older with recent lowtrauma hip fracture, treatment with zoledronic acid reduces the risk for clinical fractures. Although alendronate, risedronate, or zoledronic acid decrease risk for new radiographic vertebral fracture in men with osteoporosis, the efficacy of drug treatment in preventing clinical or nonvertebral fractures in men is uncertain. Some U.S. guidelines (3, 8, 13) endorse the use of specific FRAX intervention thresholds (10-year absolute probability of hip fracture 3% or 10-year absolute probability of major osteoporotic fracture 20%) to aid clinicians in deciding whether to recommend drug treatment in adults aged 50 years or older with osteopenia. These guidelines recommend initiation of drug treatment in adults with osteopenia who have a 10-year fracture probability at or above either NOF-endorsed FRAX intervention thresholds. In addition, the National Bone Health Alliance (NBHA) (44) has proposed changes in the diagnostic criteria for osteoporosis and recommends that adults aged 50 years or older be diagnosed with osteoporosis regardless of BMD if they have a FRAX score at or above either of the NOF FRAX intervention thresholds. Adoption of NOF or NBHA guidelines greatly expands the proportion of older adults identified as having an indication for drug treatment (26, 45). In the United States, it has been estimated that 4.3% of men and 15.4% of women aged 50 years or older have osteoporosis according to BMD criteria. With use of the expanded NBHA definition, the prevalence of osteoporosis increases 3.7-fold in men and almost 2-fold in women (45). Although basing a treatment decision on a patient's absolute risk for fracture is tempting, whether pharmacotherapy reduces risk for clinical fractures among adults without osteoporosis is unproven. Systematic reviews of bisphosphonate trials in postmenopausal women have not reported significantly reduced risk for nonvertebral fractures among women without osteoporosis (defined as BMD T-score 2.5) or existing vertebral fractures (46, 47). Pivotal trials of alendronate, risedronate, and denosumab found that treatment did not reduce risk for clinical fractures in postmenopausal women who did not meet these criteria (48 50). Thus, adoption of the guidelines labels a substantial proportion of older adults with a problem that might not benefit from pharmacologic therapy. It also increases demands on the health care system to identify and treat the excess patients meeting the expanded criteria (51). The American College of Physicians (ACP) (52) recommends that clinicians use shared decision making to decide whether to initiate drug treatment in osteopenic women aged 65 years or older who are at high risk for fracture (weak recommendation, low-quality evidence). ACP notes that clinicians can use their judgment for assessing fracture risk by an evaluation of risk factor status or application of an assessment tool. Randomized trials are needed to determine whether drug treatment is efficacious in preventing clinical fractures among middle-aged and older adults with osteopenia who have a higher estimated fracture risk. These data would inform treatment guidelines for this patient population. 44. Siris ES, Adler R, Bilezikian J, et al. The clinical diagnosis of osteoporosis: a position statement from the National Bone Health Alliance Working Group. Osteoporos Int. 2014;25: 1439-43. [PMID: 24577348] 45. Wright NC, Saag KG, Dawson-Hughes B, Khosla S, Siris ES. The impact of the new National Bone Health Alliance (NBHA) diagnostic criteria on the prevalence of osteoporosis in the USA. Osteoporos Int. 2017;28: 1225-1232. [PMID: 27966104] 46. MacLean C, Newberry S, Maglione M, et al. Systematic review: comparative effectiveness of treatments to prevent fractures in men and women with low bone density or osteoporosis. Ann Intern Med. 2008; 148:197-213. [PMID: 18087050] 47. Wells GA, Cranney A, Peterson J, et al. Alendronate for the primary and secondary prevention of osteoporotic fractures in postmenopausal women. Cochrane Database Syst Rev. 2008: CD001155. [PMID: 18253985] 48. Cummings SR, Black DM, Thompson DE, et al. Effect of alendronate on risk of fracture in women with low bone density but without vertebral fractures: results from the Fracture Intervention Trial. JAMA. 1998;280: 2077-82. [PMID: 9875874] 49. McClung MR, Geusens P, Miller PD, et al; Hip Intervention Program Study Group. Effect of risedronate on the risk of hip fracture in elderly women. Hip Intervention Program Study Group. N Engl J Med. 2001;344: 333-40. [PMID: 11172164] 50. McClung MR, Boonen S, TörringO,etal.Effectof denosumab treatment on the risk of fractures in subgroups of women with postmenopausal osteoporosis. J Bone Miner Res. 2012;27: 211-8. [PMID: 21976367] 51. Schousboe JT, Ensrud KE. Diagnostic criteria for osteoporosis should not be expanded. Lancet Diabetes Endocrinol. 2015;3:236-8. [PMID: 25797770] 1August2017 AnnalsofInternalMedicine IntheClinic ITC25 2017 American College of Physicians

How is a specific pharmacologic agent chosen for patients who are candidates for drug treatment? Bisphosphonates (Table) are the first-line agents for treatment of osteoporosis. All are now available in generic form. Ibandronate is rarely prescribed because there is no evidence from randomized trials that it reduces risk for nonvertebral fractures. Bisphosphonates are not recommended for patients with severe renal impairment. Thus, assessment of renal function is appropriate before treatment is begun, and creatinine clearance (CrCl) in patients prescribed bisphosphonates should exceed 35 ml/min/1.73 m 2. Oral bisphosphonates should be taken with a glass of water on an empty stomach to maximize absorption. These drugs are contraindicated in cases of esophageal stricture, achalasia, or Barrett esophagus; however, they are often tolerated in patients with a remote history of peptic ulcer disease or those with gastroesophageal reflux controlled with medications. Common adverse effects of oral bisphosphonates include upper gastrointestinal tract irritation and musculoskeletal problems. Risk for gastrointestinal irritation is minimized by adherence to dosing instructions. Common adverse effects of zoledronic acid include flu-like symptoms or bone pain typically with the initial dose and musculoskeletal symptoms. Rare but serious adverse effects of oral and intravenous bisphosphonates include osteonecrosis of the jaw (exposed bone in the maxillofacial region that does not heal within 8 weeks) and atypical femoral fractures (low-trauma subtrochanteric or femoral shaft fractures). Denosumab, the first biologic therapy approved to treat postmenopausal osteoporosis, reduces risk for vertebral and nonvertebral fractures, including hip fractures. It is administered twice yearly by subcutaneous injection. Common adverse effects include eczema, nausea, and injection site reactions. Rare but serious adverse effects include osteonecrosis of the jaw and atypical femoral fractures. Candidates for denosumab include patients with contraindications or intolerance to oral or intravenous bisphosphonates or those with severe renal impairment (e.g., CrCl <30 35 ml/min/1.73 m 2 ). Hypocalcemia must be corrected before denosumab is started, so serum calcium level should be checked in advance. In patients predisposed to hypocalcemia and disturbances of mineral metabolism (e.g., patients with CrCl <30 35 ml/min/1.73 m 2 ), checking serum calcium, phosphorus, and magnesium levels is recommended within 2 weeks of denosumab injection. Raloxifene, a selective estrogen receptor modulator, reduces risk for vertebral fractures in postmenopausal women with osteoporosis but has no effect on risk for nonvertebral fractures. Thus, it is not a first-line agent for postmenopausal osteoporosis. Longterm use of raloxifene decreases risk for breast cancer among women at higher risk for this condition but increases the risk for venous thromboembolic events. Use of estrogen therapy or combined hormone therapy (estrogen plus progestin) is not recommended or approved by the U.S. Food and Drug Administration (FDA) for treatment of postmenopausal osteoporosis. Although use of estrogen plus progestin or estrogen alone is moderately beneficial in reducing the risk for fractures, these benefits do not outweigh the harms in most postmenopausal women (53). Treatment with teriparatide, an anabolic agent, reduces risk for vertebral and nonvertebral fractures among women with postmenopausal osteoporosis but has not been found to reduce the risk for hip fracture. It is administered by daily subcutaneous injection. Because its efficacy and safety have not been evaluated beyond 2 years of treatment, the FDA recommends limiting the treatment period to a maximum of 2 years during a lifetime. Common adverse effects of teriparatide include nausea, arthralgia, leg cramps, hypercalcemia, and hypercalcuria. Rare adverse effects include hyperuricemia and hypotension. In light of results of long-term studies of teriparatide in rodents, it has a black box warning about risk for osteosarcoma. Candidates for teriparatide treatment include patients with contraindications to oral and intravenous bisphosphonates, those who have had a major osteoporotic fracture while receiving oral bisphosphonates, and treatment-naive persons with very low BMD T-scores ( 3.5). Abaloparatide, a human parathyroid hormone peptide analogue that is administered by daily subcutaneous injection, was recently approved by the FDA for treatment of postmenopausal women with osteoporosis who are at high risk for fracture. The efficacy and safety profiles and treatment period of abaloparatide are similar to those of teriparatide. Combination pharmacotherapy for osteoporosis is not recommended. The antifracture efficacy of combination medication regimens has not been adequately evaluated in randomized clinical trials, and safety has not been assessed. ACP (52) recommends that clinicians offer drug treatment with alendronate, risedronate, zoledronic acid, or denosumab to 2017 American College of Physicians ITC26 In the Clinic Annals of Internal Medicine 1 August 2017

Table. Pharmacologic Agents for Treatment of Osteoporosis Medication Method/Dosage Fracture Risk Reduction Side Effects/Risks Bisphosphonates* Alendronate Oral, 70 mg weekly Vertebral, nonvertebral, hip Ibandronate Oral, 150 mg monthly; Vertebral Intravenous, 3 mg every 3mo Risedronate Oral, 35 mg weekly or Vertebral, 150 mg monthly nonvertebral, hip Zoledronic Acid Intravenous, 5 mg annually Vertebral, nonvertebral, hip Oral alendronate, ibandronate, and risendronate. Common: upper gastrointestinal irritation, musculoskeletal complaints; uncommon: esophageal ulcer, bone pain; rare: ONJ, atypical femur fractures Intravenous ibandronate and zoledronic acid. Common: bone pain with first dose zoledronic acid), musculoskeletal symptoms; uncommon: hypocalcemia; rare: ONJ, atypical femur fractures RANKL inhibitor Denosumab Subcutaneous, 60 mg every 6 mo Vertebral, nonvertebral, hip Common: eczema, nausea, injection site reactions; rare: ONJ, atypical femur fractures SERMs Raloxifene Oral, 60 mg daily Vertebral Common: leg cramps, hot flashes; uncommon: uterine polyps, deep venous thrombosis Parathyroid hormone and related peptide analogues Teriparatide Subcutaneous, 20 mcg daily Approved for 2 y of use Subcutaneous, 80 mcg daily Approved for 2 y of use Vertebral, nonvertebral Common: nausea, arthralgia, leg cramps, hypercalcemia, hypercalcuria; uncommon: hyperuricemia, hypotension Common: dizziness, headache, nausea, palpitations, hypercalcemia, hypercalcuria Abaloparatide Vertebral, nonvertebral ONJ = osteonecrosis of the jaw; SERM = selective estrogen receptor modulator. * Approved by the U.S. Food and Drug Administration (FDA) for treatment of postmenopausal osteoporosis; all except ibandronate are approved for treatment of osteoporosis in men. All bisphosphonates are available in generic form. FDA approved for treatment of postmenopausal osteoporosis and osteoporosis in men. FDA approved for treatment of postmenopausal osteoporosis; available in generic form. FDA approved for treatment of postmenopausal women with osteoporosis at high risk for fracture; teriparatide also approved for increasing bone mass in men with osteoporosis at high risk for fracture. women with osteoporosis to reduce the risk for hip and vertebral fractures. It recommends against use of estrogen therapy, combined hormone therapy, or raloxifene in this group. Among men with osteoporosis, ACP recommends that clinicians offer treatment with bisphosphonates to reduce the risk for vertebral fractures. Should patients receiving drug treatment be monitored with serial BMD or bone turnover marker measurements? To monitor response to drug treatment, some organizations (3, 8, 13) recommend spine and hip DXA BMD measurements every 1 2 years until findings stabilize. However, there are no data from randomized trials demonstrating that this improves fracture risk prediction. Among postmenopausal women losing BMD in trials of alendronate (54) and raloxifene (55), those who were receiving drug treatment had a lower risk for new radiographic vertebral fractures than those in the placebo group. Analysis of data from a large alendronate trial (56) found that when BMD is measured annually, the observed response to bisphosphonate therapy may not reflect the true response because the within-person (measurement-related) variation in treatment effects on BMD is large compared with the smaller between-person (treatment-related) variation. Failure to recognize the large within-person BMD measurement variation may lead clinicians to make inappropriate decisions about continuing or changing medication. Because of the large background withinperson variation, monitoring BMD is also likely to be a suboptimal method of detecting nonadherence to treatment. Furthermore, there are no randomized trial data demonstrating improvements in treatment adherence with serial BMD monitoring. ACP (52) recommends against BMD monitoring during the 5-year drug treatment period for osteoporosis in postmenopausal women. Some organizations (3, 8, 13) also advocate obtaining bone 1August2017 AnnalsofInternalMedicine IntheClinic ITC27 2017 American College of Physicians

52. Qaseem A, Forciea MA, McLean RM, Denberg TD; Clinical Guidelines Committee of the American College of Physicians. 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;166:818-839. [PMID: 28492856] 53. Moyer VA; U.S. Preventive Services Task Force. Menopausal hormone therapy for the primary prevention of chronic conditions: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med. 2013;158:47-54. [PMID: 23090711] 54. Chapurlat RD, Palermo L, Ramsay P, Cummings SR. Risk of fracture among women who lose bone density during treatment with alendronate. The Fracture Intervention Trial. Osteoporos Int. 2005;16:842-8. [PMID: 15580479] 55. Sarkar S, Mitlak BH, Wong M, et al. Relationships between bone mineral density and incident vertebral fracture risk with raloxifene therapy. J Bone Miner Res. 2002;17:1-10. [PMID: 11771654] 56. Bell KJ, Hayen A, Macaskill P, et al. Value of routine monitoring of bone mineral density after starting bisphosphonate treatment: secondary analysis of trial data. BMJ. 2009;338: b2266. [PMID: 19549996] 57. Schousboe JT, Bauer DC. Clinical use of bone turnover markers to monitor pharmacologic fracture prevention therapy. Curr Osteoporos Rep. 2012;10:56-63. [PMID: 22286411] 58. Boudreau DM, Yu O, Balasubramanian A, et al. A survey of women's awareness of and reasons for lack of postfracture osteoporotic care. J Am Geriatr Soc. 2017. [PMID: 28422273] 59. Khan AA, Morrison A, Kendler DL, et al; International Task Force on Osteonecrosis of the Jaw. Case-based review of osteonecrosis of the jaw (ONJ) and application of the international recommendations for management from the International Task Force on ONJ. JClinDensitom.2017; 20:8-24. [PMID: 27956123] turnover markers (BTMs) before and 3 6 months after starting antiresorptive therapy to monitor treatment efficacy and patient adherence. However, evidence is insufficient to support this practice (57). At present, BTM measurement in the primary care setting is limited by high withinpatient variability, biologic variability, and poor standardization of most assays. Although evidence from randomized trials suggests that reductions in BTMs after initiation of antiresorptive therapy are associated with subsequent decreases in fracture, the optimal level of reduction in a specific BTM that identifies a responder to treatment has not been established. Similarly, measurement of these markers has been recommended as a method to detect nonadherence and improve adherence to pharmacotherapy. However, whether this strategy is superior to practical methods of achieving this goal (e.g., simply asking patients in a nonjudgmental manner if they are having problems taking treatment and reviewing pharmacy records) remains unclear. How long should patients be treated, and when should clinicians consider instituting a drug holiday? The ideal duration of antiresorptive treatment is controversial, especially because of the recognition that osteonecrosis of the jaw and atypical femoral fractures, although rare, are serious potential harms of longer-term treatment with potent agents (bisphosphonates and denosumab). Concerns of many women regarding these adverse effects may contribute to the reluctance to receive drug treatment, even among those who have had a major osteoporotic fracture (58). The association of bisphosphonate use with osteonecrosis of the jaw was first reported in patients with metastatic cancer who were treated with high-dose intravenous bisphosphonates for hypercalcemia of malignancy. Although the frequency of this disorder in oncology patients receiving high-dose bisphosphonates or denosumab has been reported to be 1% 15% (59), estimates of its incidence in patients with osteoporosis receiving smaller doses of bisphosphonates or denosumab treatment are substantially lower, ranging from about 0.001% 0.01% (60). Risk factors in patients treated with potent antiresorptive agents include poor oral hygiene, concomitant use of systemic glucocorticoids or chemotherapy, smoking, diabetes, and a recent history of invasive dental procedures. Atypical femoral fractures (61) usually occur with little or no antecedent trauma, may be preceded by thigh or groin pain, and may occur bilaterally. They are rare in the general population and have a markedly lower incidence than hip fractures. In studies that examined the association of antiresorptive treatment (primarily bisphosphonates) with rates of these fractures, incidence ranged from 1 out of 100 000 persons to 5 out of 10 000 persons among bisphosphonate users (62). Ameta-analysisofstudies(63)reported a 1.7-fold increase in risk for these fractures with bisphosphonate use, but the studies were heterogeneous. The pooled adjusted relative risk was 11.1 based on the case control studies versus 1.5 based on the cohort studies. Evidence has found that increasing duration of bisphosphonate use is associated with increasing incidence of atypical femoral fractures. In an analysis of 188 814 patients receiving bisphosphonates, the age-adjusted incidence rates increased from 1.8 per 100 000 persons per year with a 2-year exposure to 113 per 100 000 persons per year with an 8- to 10-year exposure (64). Thus, although the benefits of potent antiresorptive treatment 2017 American College of Physicians ITC28 In the Clinic Annals of Internal Medicine 1 August 2017

likely outweigh the risk for rare atypical femoral fractures early in treatment, this benefit is less clear for long-term users (65). Bisphosphonates have a long half-life in bone. Thus, unlike most drugs, stopping them does not result in cessation of action. Two randomized trials have evaluated the benefits of stopping versus discontinuing bisphosphonate treatment on fracture risk. Among older women who had received alendronate treatment for 5 years, those randomly assigned to alendronate versus those assigned to placebo for an additional 5 years had a similar rate of nonvertebral fracture and new radiographic fracture but a lower rate of clinical vertebral fracture (66). Among women assigned to placebo for an additional 5 years, older age and lower hip BMD T-score ( 2.5) at the time of alendronate discontinuation were associated with a higher risk for clinical fractures after discontinuation (67). Among older women who had received zoledronic acid infusions annually for 3 years, those randomly assigned to annual zoledronic acid infusions versus those assigned to annual placebo infusions for an additional 3 years had similar rates of nonvertebral fracture and clinical vertebral fracture but a lower rate of new radiographic vertebral fracture (68). These findings suggest that reduction in fracture risk may persist years after discontinuation of bisphosphonate treatment and that there is no clear benefit of long-term use for prevention of nonvertebral fractures. Because of concerns about a higher risk for atypical femoral fractures with long-term bisphosphonate treatment, some organizations have suggested a drug holiday (e.g., temporary discontinuation for up to 5 years, followed by reassessment) in certain patients, although evidence is insufficient to make recommendations regarding the exact timing and duration. A task force of the American Society for Bone and Mineral Research (60) recommended that clinicians consider a drug holiday in postmenopausal women after 5 or more years of oral bisphosphonate therapy (or 3 years of intravenous bisphosphonate therapy) if the patients satisfy the following 3 criteria: 1) they have had no hip, spine, or multiple other osteoporotic fractures before or during the initial treatment period; 2) hip BMD T-score is > 2.5 after the initial treatment period; and 3) they are not at high fracture risk. The task force also suggested that patients on a drug holiday be reassessed every 2 3 years. No guidelines have specifically addressed the role of a drug holiday for patients treated with medications other than bisphosphonates. Treatment with denosumab, raloxifene, or teriparatide results in BMD gains that rapidly wane after discontinuation of treatment. Use of an antiresorptive agent is recommended after discontinuation of teriparatide due to the ensuing rapid bone loss. Although the risk for atypical femoral fractures may increase with longer duration of denosumab treatment, stopping results in accelerated bone loss. In addition, rebound fractures after discontinuation have recently been reported (69, 70). Some experts believe that recipients of denosumab should not have a drug holiday and recommend initiation of an alternative medication after discontinuation. ACP (52) recommends that women with osteoporosis be treated with pharmacologic therapy (i.e., alendronate, risedronate, zoledronic acid, or denosumab) for 5 years (weak recommendation, low-quality evidence). This 60. Adler RA, El-Hajj Fuleihan G, Bauer DC, et al. Managing osteoporosis in patients on longterm bisphosphonate treatment: report of a task force of the American Society for Bone and Mineral Research. J Bone Miner Res. 2016;31:16-35. [PMID: 26350171] 61. Shane E, Burr D, Abrahamsen B, et al. Atypical subtrochanteric and diaphyseal femoral fractures: second report of a task force of the American Society for Bone and Mineral Research. J Bone Miner Res. 2014;29:1-23. [PMID: 23712442] 62. Black DM, Rosen CJ. Clinical Practice. Postmenopausal Osteoporosis. N Engl J Med. 2016; 374:254-62. [PMID: 26789873] 63. Gedmintas L, Solomon DH, Kim SC. Bisphosphonates and risk of subtrochanteric, femoral shaft, and atypical femur fracture: a systematic review and meta-analysis. J Bone Miner Res. 2013; 28:1729-37. [PMID: 23408697] 64. Dell RM, Adams AL, Greene DF, et al. Incidence of atypical nontraumatic diaphyseal fractures of the femur. J Bone Miner Res. 2012; 27:2544-50. [PMID: 22836783] 65. Ott SM. Long-term bisphosphonates: primum non nocere. Menopause. 2016;23:1159-1161. [PMID: 27676636] 66. Black DM, Schwartz AV, Ensrud KE, et al; FLEX Research Group. Effects of continuing or stopping alendronate after 5 years of treatment: the Fracture Intervention Trial Long-term Extension (FLEX): a randomized trial. JAMA. 2006;296: 2927-38. [PMID: 17190893] 67. Bauer DC, Schwartz A, Palermo L, et al. Fracture prediction after discontinuation of 4 to 5 years of alendronate therapy: the FLEX study. JAMA Intern Med. 2014;174: 1126-34. [PMID: 24798675] 68. Black DM, Reid IR, Boonen S, et al. The effect of 3 versus 6 years of zoledronic acid treatment of osteoporosis: a randomized extension to the HORIZON-Pivotal Fracture Trial (PFT). J Bone Miner Res. 2012; 27:243-54. [PMID: 22161728] 1August2017 AnnalsofInternalMedicine IntheClinic ITC29 2017 American College of Physicians

recommendation is based on the treatment duration of up to 5 years in randomized trials. ACP also acknowledges that continuing treatment after 5 years may benefit some patients. Prescribing oral bisphosphonates for 5 years (or intravenous bisphosphonates for 3 years) should be effective in preventing fractures and minimizing potential harms of long-term exposure. This strategy should also result in a decline in initiation of bisphosphonates in younger postmenopausal women and an increase in bisphosphonate initiation among older women who have a higher absolute fracture risk (71). It is increasingly important that clinicians counsel patients with osteoporosis to alleviate fears about taking these medications for 5 years, because the reduction in risk for disabling fractures outweighs the risk for short-term potential harms of treatment, and the potential risks for long-term harms of treatment are avoided with this strategy. When should consultation be considered? Referral to an osteoporosis specialist should be considered if there is uncertainty regarding whether a patient will benefit from pharmacotherapy for fracture prevention, when to resume medication after a drug holiday, or which medication should be used after a drug holiday. Consultation may also be warranted in patients with intolerance to standard drug treatments or those in whom treatment failure is suspected. Consultation with orthopedic or physical medicine and rehabilitation specialists is often required for management of patients presenting with an acute fracture. 69. Anastasilakis AD, Yavropoulou MP, Makras P, et al. Increased osteoclastogenesis in patients with vertebral fractures following discontinuation of denosumab treatment. Eur J Endocrinol. 2017;176:677-683. [PMID: 28283537] 70. Aubry-Rozier B, Gonzalez- Rodriguez E, Stoll D, Lamy O. Severe spontaneous vertebral fractures after denosumab discontinuation: three case reports. Osteoporos Int. 2016;27:1923-5. [PMID: 26510845] 71. Lee DR, Ettinger B, Chandra M, Hui RL, Lo JC. Changing Patterns in Oral Bisphosphonate Initiation in Women between 2004 and 2012 [Letter]. J Am Geriatr Soc. 2017;65:656-658. [PMID: 28152162] Treatment for Fracture Prevention... Reducing risk for clinical fractures is the primary goal of treatment. Among postmenopausal women with osteoporosis, treatment with alendronate, risedronate, zoledronic acid, or denosumab reduces risk for clinical fractures and new radiographic vertebral fractures. Bisphosphonates lower risk for new radiographic vertebral fractures in osteoporotic men. Treatment with zoledronic acid decreases risk for clinical fractures among patients with recent hip fracture. Calcium and vitamin D supplementation at prudent doses should be recommended in older adults with inadequate dietary intake. Evidence does not support routine use of serial BMD or BTM measurements after initiation of drug treatment to monitor response or adherence with therapy. A treatment period of 5 years with oral bisphosphonates (3 years for intravenous bisphosphonates) is a reasonable strategy for many patients. Patients with osteoporosis should be counseled not to be fearful of receiving bisphosphonates for 3 5 years, because the reduction in risk for disabling fractures outweighs the risk for short-term harms of treatment, and the potential risks for long-term harms of treatment are avoided with this approach. Practice Improvement What measures do U.S. stakeholders use to evaluate quality of care? The Healthcare Effectiveness Data and Information Set includes 2 measures in the domain of osteoporosis in women aged 65 85 CLINICAL BOTTOM LINE years: osteoporosis testing and osteoporosis management in women who had a fracture. In 2015 (6), the proportion of women aged 65 85 years who had ever undergone BMD measurement for osteoporosis was 2017 American College of Physicians ITC30 Annals of Internal Medicine 1 August 2017

73.8% for HMOs and 79.3% for PPOs. Among women aged 65 85 years who had had a fracture, the proportion of women in the 6 months after the fracture who either had BMD measurement or received a prescription for drug treatment to prevent fracture was 40.7% for HMOs and 32.8% for PPOs. Management of patients after fracture is problematic and must be addressed by a concerted effort of health care systems, primary care physicians, specialists, and patients. A recent survey (58) of postmenopausal women who had had osteoporotic fractures reported that 93% had contact with their primary care physician during the 6 months after fracture; 73% indicated that their primary care physician knew about the fracture, but 63% and 55% reported that management of osteoporosis and fracture prevention, respectively, were not discussed at these visits. In the Clinic Tool Kit Osteoporosis Clinical Guidelines www.annals.org/aim/article/2625385/treatment-low -bone-density-osteoporosis-prevent-fractures-men -women-clinical Recent guideline from the American College of Physicians on treatment of low bone density or osteoporosis to prevent fractures. www.annals.org/aim/article/746858/screening -osteoporosis-u-s-preventive-services-task-force -recommendation-statement www.uspreventiveservicestaskforce.org/page /Document/UpdateSummaryFinal/osteoporosis -screening 2011 U.S. Preventive Services Task Force guidelines on screening for osteoporosis and recommendations for screening in postmenopausal women. www.aace.com/files/postmenopausal-guidelines.pdf Clinical practice guideline for the diagnosis and treatment of postmenopausal osteoporosis from the American Association of Clinical Endocrinologists. Patient Information www.niams.nih.gov/health_info/bone/osteoporosis /osteoporosis_hoh.asp Patient handout from the National Institutes of Health. www.acog.org/patients/faqs/osteoporosis Information from the American College of Obstetrics and Gynecology. www.mayoclinic.org/diseases-conditions/osteoporosis /manage/ptc-20207963 Self-management information from the Mayo Clinic. www.nof.org/patients/ Information from the National Osteoporosis Foundation. www.medlineplus.gov/osteoporosis.html Information from Medline Plus. IntheClinic 1August2017 AnnalsofInternalMedicine ITC31 2017 American College of Physicians

WHAT YOU SHOULD KNOW ABOUT OSTEOPOROSIS In the Clinic Annals of Internal Medicine What Is Osteoporosis? Osteoporosis is a disease that reduces the density of bones, which can cause them to weaken. Weak bones can easily break. These breaks, sometimes called fractures, can be painful and may make it hard to take care of yourself. The risk for osteoporosis increases with age. Who Should Be Screened? All women aged 65 years or older. Women younger than 65 years may need screening if they have certain risk factors, including low weight, smoking cigarettes, and history of bone fractures. Talk to your doctor about other risks you may have. How Is It Diagnosed? Your doctor can check for bone loss using a test called a DXA scan. This test takes pictures of your bones. If your DXA results are below a certain number, your doctor may diagnose you with osteoporosis and you may need treatment. How Is It Treated? There are medicines for osteoporosis called bisphosphonates that help prevent fractures. They are usually taken for at least 5 years. After 5 years, you may have another DXA scan and your treatment may change. How Can It Be Prevented? Keep a healthy body weight. Eat enough protein. Avoid drinking heavily. Don't smoke. Exercise regularly. Eat foods with calcium and vitamin D. These include dairy, tofu, leafy greens, and fatty fish like salmon. Questions for My Doctor How do I know if I am at risk for osteoporosis? Should I take calcium or vitamin D supplements? I was diagnosed with osteoporosis. Can I still do the things I like to do? Should I make changes to my diet? What can I do to prevent falls? What side effects does the medicine have? How much will the medicine cost? Will my osteoporosis ever go away? What happens if I stop taking the medicine? For More Information National Osteoporosis Foundation www.nof.org American College of physicians www.acponline.org/patient_ed/rheumatology Medline Plus www.nlm.nih.gov/medlineplus/osteoporosis.html Patient Information