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
Authors: Amir Qaseem, Mary Ann Forciea, Robert M. McLean, Thomas D. Denberg
Journal: Annals of Internal Medicine (2017)

Clinical Guidelines6 June 2017Treatment of Low Bone Density or Osteoporosis to Prevent Fractures in Men and Women: A Clinical Practice Guideline Update From the American College of PhysiciansFREEAmir Qaseem, MD, PhD, MHA, Mary Ann Forciea, MD, Robert M. McLean, MD, and Thomas D. Denberg, MD, PhD, for the Clinical Guidelines Committee of the American College of Physicians*Amir Qaseem, MD, PhD, MHAFrom the American College of Physicians and University of Pennsylvania Health System, Philadelphia, Pennsylvania, and Yale School of Medicine, New Haven, Connecticut., Mary Ann Forciea, MDFrom the American College of Physicians and University of Pennsylvania Health System, Philadelphia, Pennsylvania, and Yale School of Medicine, New Haven, Connecticut., Robert M. McLean, MDFrom the American College of Physicians and University of Pennsylvania Health System, Philadelphia, Pennsylvania, and Yale School of Medicine, New Haven, Connecticut., and Thomas D. Denberg, MD, PhDFrom the American College of Physicians and University of Pennsylvania Health System, Philadelphia, Pennsylvania, and Yale School of Medicine, New Haven, Connecticut., for the Clinical Guidelines Committee of the American College of Physicians*Author, Article, and Disclosure Informationhttps://doi.org/10.7326/M15-1361 SectionsSupplemental MaterialAboutVisual AbstractAbstractPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail AbstractThis article has been corrected. The original version (PDF) is appended to this article as a Supplement.AbstractDescription:This guideline updates the 2008 American College of Physicians (ACP) recommendations on treatment of low bone density and osteoporosis to prevent fractures in men and women. This guideline is endorsed by the American Academy of Family Physicians.Methods:The ACP Clinical Guidelines Committee based these recommendations on a systematic review of randomized controlled trials; systematic reviews; large observational studies (for adverse events); and case reports (for rare events) that were published between 2 January 2005 and 3 June 2011. The review was updated to July 2016 by using a machine-learning method, and a limited update to October 2016 was done. Clinical outcomes evaluated were fractures and adverse events. This guideline focuses on the comparative benefits and risks of short- and long-term pharmacologic treatments for low bone density, including pharmaceutical prescriptions, calcium, vitamin D, and estrogen. Evidence was graded according to the GRADE (Grading of Recommendations Assessment, Development and Evaluation) system.Target Audience and Patient Population:The target audience for this guideline includes all clinicians. The target patient population includes men and women with low bone density and osteoporosis.Recommendation 1:ACP recommends that clinicians offer pharmacologic treatment with alendronate, risedronate, zoledronic acid, or denosumab to reduce the risk for hip and vertebral fractures in women who have known osteoporosis. (Grade: strong recommendation; high-quality evidence)Recommendation 2:ACP recommends that clinicians treat osteoporotic women with pharmacologic therapy for 5 years. (Grade: weak recommendation; low-quality evidence)Recommendation 3:ACP recommends that clinicians offer pharmacologic treatment with bisphosphonates to reduce the risk for vertebral fracture in men who have clinically recognized osteoporosis. (Grade: weak recommendation; low-quality evidence)Recommendation 4:ACP recommends against bone density monitoring during the 5-year pharmacologic treatment period for osteoporosis in women. (Grade: weak recommendation; low-quality evidence)Recommendation 5:ACP recommends against using menopausal estrogen therapy or menopausal estrogen plus progestogen therapy or raloxifene for the treatment of osteoporosis in women. (Grade: strong recommendation; moderate-quality evidence)Recommendation 6:ACP recommends that clinicians should make the decision whether to treat osteopenic women 65 years of age or older who are at a high risk for fracture based on a discussion of patient preferences, fracture risk profile, and benefits, harms, and costs of medications. (Grade: weak recommendation; low-quality evidence)Osteoporosis is a systemic skeletal disease characterized by decreasing bone mass and microarchitectural deterioration of bone tissue that leads to an increased risk for bone fragility and fracture ( 1). Although osteoporosis can be present in any bone, the hip, spine, and wrist are most likely to be affected. Osteoporosis is found in an estimated 200 million people worldwide ( 2), and an estimated 54 million men and women in the United States have osteoporosis or low bone density ( 3). Approximately 50% of Americans older than 50 years are at risk for osteoporotic fracture ( 4). The economic impact of osteoporosis on the health care system is estimated to be $25.3 billion per year by 2025 ( 3).Risk factors for osteoporotic fracture include (but are not limited to) increasing age, female sex, postmenopause for women, hypogonadism or premature ovarian failure, low body weight, history of parental hip fracture, ethnic background (white persons are at higher risk than black persons), previous clinical or morphometric vertebral fracture, previous fracture due to minimal trauma (that is, previous osteoporotic fracture), rheumatoid arthritis, current smoking, alcohol intake (3 or more drinks daily), low bone mineral density (BMD), vitamin D deficiency, low calcium intake, hyperkyphosis, falling, and immobilization ( 5). Another risk factor for osteoporotic fracture is long-term use of certain medications, the most commonly implicated being glucocorticoids, anticoagulants, anticonvulsants, aromatase inhibitors, cancer chemotherapeutic drugs, and gonadotropin-releasing hormone agonists ( 5).Osteoporosis can be diagnosed by the occurrence of fragility fracture. In patients without fragility fracture, osteoporosis is often diagnosed by low BMD. Dual-energy x-ray absorptiometry (DXA) is the current gold standard test for diagnosing osteoporosis in people without an osteoporotic fracture. Results of DXA are scored as SDs from a young, healthy norm (usually female) and reported as T scores. For example, a T score of –2 indicates a BMD that is 2 SDs below the comparative norm. The international reference standard for the description of osteoporosis in postmenopausal women and in men aged 50 years or older is a femoral neck BMD of 2.5 SD or more below the young female adult mean ( 2). Low BMD as measured by DXA is an imperfect predictor of fracture risk, identifying less than one half of the people who go on to have an osteoporotic fracture.Bone density can also be classified according to the Z score, the number of SD above or below the expected BMD for the patient's age and sex. A Z score of –2.0 or lower is defined as either "low BMD for chronological age" or "below the expected range for age," and those above –2.0 are "within the expected range for age" ( 6). Risk scores that combine clinical risk factors with BMD testing results, such as FRAX (the World Health Organization Fracture Risk Assessment Tool), can be used to predict fracture risk among people with low bone density.Pharmacologic treatments for osteoporosis include bisphosphonates (alendronate, risedronate, ibandronate, zoledronic acid), peptide hormones (teriparatide [the 1,3,4 amino acid fragment of parathyroid hormone] and calcitonin), estrogen (in the form of menopausal hormone therapy) for postmenopausal women, and selective estrogen receptor modulators (SERMs) (raloxifene for postmenopausal women). Most of the treatments aim to prevent bone resorption. Denosumab (a new biologic agent), dietary and supplemental calcium, and vitamin D are also used for treatment. Bazedoxifene, a SERM, has recently been approved by the U.S. Food and Drug Administration (FDA) with conjugated estrogen for prevention of osteoporosis.Guideline Focus and Target PopulationThis updated guideline presents additional available evidence on treatments, including new medications and biologic agents, to prevent fractures in men and women with low bone density or osteoporosis since publication of the ACP 2008 guideline, and replaces the 2008 guideline ( 7). Several therapies included in the 2008 guideline have been excluded from the update, including calcitonin, which is no longer widely used for osteoporosis treatment, and both etidronate and pamidronate, neither of which are FDA-approved for the prevention of fractures or treatment of osteoporosis. One new biologic, denosumab, a human monoclonal antibody approved by the FDA for treatment of osteoporosis, has been added since publication of the 2008 guideline. Different medications for the treatment of osteoporosis may affect various parts of the skeletal system differently. The target audience for this guideline includes all clinicians and the target patient population includes men and women with low bone density and osteoporosis. These recommendations are based on a systematic evidence review sponsored by the Agency for Healthcare Research and Quality (AHRQ) ( 6, 8). This guideline is endorsed by the American Academy of Family Physicians.MethodsSystematic Review of the EvidenceThe evidence review was conducted by AHRQ's Southern California Evidence-based Practice Center–RAND Corporation. Appendix 1 summarizes the methods for the evidence review, and additional details can be found in the reports ( 6, 8).Reviewers searched databases from 2 January 2005 to 3 June 2011. A machine-learning method was used to update the searches, once in 2014 and then specifically on bisphosphonates, calcium, vitamin D, and estrogen through 12 July 2016 ( 9). Appendix 2 shows the search methodology for the update. Reviewers also did a limited search on the recently FDA-approved drug bazedoxifene from 1 January 2013 to 26 October 2016. Evidence tables for studies identified in the 2016 update search are found in Appendix Tables 1 and 2.Appendix Table 1. Evidence Table for New Randomized, Controlled Trials Identified in the UpdateAppendix Table 2. Evidence Table for Post hoc and Subgroup Analyses and Follow-up Studies Identified in the UpdateGrading the Evidence and Developing RecommendationsThis guideline was developed by ACP's Clinical Guidelines Committee (CGC) according to ACP's guideline development process, details of which can be found in ACP's methods paper ( 10). The CGC used the evidence tables in the accompanying systematic review ( 8), full report ( 6), and update when reporting the evidence and graded the recommendations by using the GRADE (Grading of Recommendations, Assessment, Development and Evaluation) methodology ( Table 1).Table 1. The American College of Physicians Guideline Grading System*Peer ReviewThe AHRQ systematic review was peer-reviewed and posted on the AHRQ Web site for public comments. The 2014 evidence review was also peer-reviewed through the journal. The guideline was peer-reviewed through the journal and posted online for comments from ACP Regents and ACP Governors, who represent physician members at the national and international level.Comparative Benefits of Treatment Versus Placebo for Reducing Fractures in Patients With OsteoporosisBisphosphonatesHigh-quality evidence showed that bisphosphonates, including alendronate ( 11–42- 43–45), risedronate ( 34–36, 42, 46–77- 78), and zoledronic acid ( 79–85), reduce vertebral, nonvertebral, and hip fractures compared with placebo in postmenopausal osteoporotic women. High-quality evidence also showed that ibandronate reduces the risk for radiographic vertebral fractures, although evidence is insufficient to determine the effect of ibandronate on hip fractures ( 38, 86–94). Moderate-quality evidence showed that zoledronic acid reduces radiographic vertebral fractures in osteoporotic men ( 95).DenosumabHigh-quality evidence showed that treatment with denosumab reduces radiographic vertebral, nonvertebral, and hip fractures compared with placebo in postmenopausal osteoporotic women ( 96–108). One Japanese trial and its 1-year open-label extension study included postmenopausal osteoporotic women with prevalent radiographic vertebral fractures and showed that denosumab protected against radiographic vertebral fractures ( 101, 109).TeriparatideHigh-quality evidence showed that treatment with teriparatide reduces radiographic vertebral and nonvertebral fractures compared with placebo in postmenopausal osteoporotic women ( 34, 110–120).SERMsHigh-quality evidence showed that raloxifene reduces vertebral fractures in osteoporotic women; however, it did not statistically significantly decrease the risk for nonvertebral or hip fractures compared with placebo ( 34, 121–127).Bazedoxifene is FDA-approved in combination with conjugated estrogens for the prevention of osteoporosis (20 mg, with 0.45 mg conjugated estrogen). The systematic review did not find any randomized controlled trials (RCTs) with this combination that had primary fracture outcomes.Estrogen Therapy for Postmenopausal WomenModerate-quality evidence showed no difference in reduced fracture with estrogen treatment in postmenopausal women with established osteoporosis ( 40, 41, 123, 128–130). This differs from the 2008 guideline, which reported high-quality evidence that estrogen therapy was associated with reduced risk for vertebral, nonvertebral, and hip fractures in postmenopausal women ( 7, 131). Studies included in the 2008 guideline focused on postmenopausal women or those with low bone density as opposed to the newer data, which focused on postmenopausal women with established osteoporosis.Calcium or Vitamin DModerate-quality evidence showed that the overall effect of calcium or vitamin D alone on fracture risk is uncertain. Studies showed no difference between calcium alone and placebo for reduced vertebral and nonvertebral fracture risk ( 132–157), although adherence was low. Data on the efficacy of vitamin D alone for reducing fracture risk are mixed, and the overall effect is uncertain ( 34, 129, 134–139, 142–144, 146, 148, 149, 152, 158–189- 190–209).Physical ActivityEvidence is insufficient to conclusively show the effect of physical activity on fracture risk ( 210–218). There are no studies that evaluated the comparative effectiveness of physical activity with that of other interventions.Comparative Benefits of Treatment Within and Among Classes for Reducing Fractures in Patients With OsteoporosisEvidence is insufficient to determine the comparative effectiveness of pharmacologic therapy or the superiority of one medication over another, within the same class or among classes, for prevention of fractures ( 21, 29, 40–42, 123, 129, 130, 139, 149, 156, 175, 199, 201, 208, 219–234). Network meta-analyses addressing the lack of head-to-head comparisons between the drugs mostly show no statistically significant differences among the various therapies ( 235–239).Benefits of Treatment for Fracture Risk Reduction in Individuals With Different Fracture RisksBone Mineral DensityModerate-quality evidence from post hoc analysis of 1 RCT showed that low femoral neck BMD did not predict the effect of alendronate on clinical vertebral or nonvertebral fracture risk ( 240).FRAX Risk AssessmentModerate-quality evidence from post hoc analysis of 1 RCT showed no significant interaction between fracture risk as assessed by FRAX and the efficacy of raloxifene for reducing the relative risk for vertebral fractures in women older than 75 years ( 241).Prior Fractures (Prevention vs. Treatment)Evidence is insufficient for prevalent fractures to predict the efficacy of alendronate or raloxifene treatment in reducing risk for fractures in postmenopausal women, because studies reported conflicting results ( 240, 242–244). Moderate-quality evidence from post hoc analysis of 1 RCT showed that postmenopausal women with prevalent vertebral fractures benefited more from teriparatide treatment than those without prevalent fractures ( 245).AgeHigh-quality evidence showed that bisphosphonates and teriparatide are at least as effective for older patients as they are for younger patients ( 246–249).SexEvidence is insufficient regarding the effectiveness of therapies to prevent fractures or treat osteoporosis in men, because few relevant studies have been published ( 28, 50–52, 82, 90, 136, 157, 166). Two RCTs evaluated vitamin D treatment in men and women and reported on fractures ( 136, 166). One study showed that calcium plus vitamin D3 reduced the risk for fracture among elderly women but not elderly men ( 136). The other study showed no difference in fracture reduction for elderly men treated with intramuscular injection of ergocalciferol, whereas women had increased risk for wrist fractures ( 166).Race/EthnicityHigh-quality evidence from post hoc analysis of 2 RCTs showed that compared with placebo, raloxifene decreases the relative risk for vertebral fracture but not nonvertebral or hip fracture among Asian women ( 250), consistent with findings from U.S. studies.Glucocorticoid TreatmentModerate-quality evidence showed that alendronate, risedronate, and teriparatide reduced fracture risk in patients taking glucocorticoids ( 30, 219).Renal InsufficiencyEvidence is insufficient from trials assessing the effect of renal function on the efficacy of alendronate, raloxifene, and teriparatide in preventing fractures in osteoporotic women ( 251–254).Harms of Pharmacologic Treatment for Reducing FracturesBisphosphonatesLow-quality evidence showed that bisphosphonates are associated with atypical subtrochanteric fractures, and the FDA has issued a warning for these drugs ( 255). Evidence suggests that this adverse event may be related to treatment duration, because the rate of atypical fractures for women taking bisphosphonates for less than 2 years was 1.78 per 100 000 and increased to over 100 per 100 000 in women taking the drugs for 8 years or more ( 256).Low-quality evidence also showed that bisphosphonates are associated with osteonecrosis of the jaw, although this side effect is rare ( 257–282).The 2008 guideline reported that bisphosphonates may be associated with atrial fibrillation; however, most new evidence suggests that there is no increased risk ( 126, 283–288). A recent post hoc double-blind extension of the HORIZON-PFT trial found no difference in atrial fibrillation with 9 years versus 6 years of treatment with zoledronic acid in osteoporotic postmenopausal women, although women treated for 9 years had a higher incidence of any arrhythmia (14.1% vs. 4.2%; P = 0.02) ( 85). One study showed that bisphosphonates were associated with increased risk for incident acute myocardial infarction (hazard ratio [HR], 1.38 [95% CI, 1.08 to 1.77], after cardiovascular disease risk factors were controlled for) after a median 3.6 years of follow-up ( 289). A population-based cohort study also showed that bisphosphonates were associated with increased risk for cardiovascular events, including atrial fibrillation (adjusted HR, 1.55 [CI, 1.04 to 2.39]) and congestive heart failure (adjusted HR, 1.65 [CI, 1.36 to 1.99]) ( 290). In contrast, a recent meta-analysis concluded that there is no significant association between oral or intravenous bisphosphonate use and total cardiovascular events, stroke, myocardial infarction, or cardiovascular death ( 287).High-quality evidence showed that bisphosphonates are associated with mild upper gastrointestinal symptoms ( 83, 291–303), and a network meta-analysis did not show statistically significant differences between the various bisphosphonates for gastrointestinal symptoms ( 304).High-quality evidence showed that zoledronic acid is associated with hypocalcemia (odds ratio [OR], 7.22 [CI, 1.81 to 42.7]) ( 81, 305). High-quality evidence also showed that zoledronic acid is associated with influenza-like symptoms (OR, 6.39 [CI, 5.76 to 7.09]) ( 79, 81, 82, 306–308). A recent secondary analysis of a double-blind RCT showed an increased incidence of uveitis (1.1% [CI, 0.5% to 2.1%]) and episcleritis (0.1% [CI, 0.0% to 0.7%]) in women treated with zoledronic acid ( 309).Ibandronate is associated with myalgias, cramps, and limb pain (OR, 2.25 [CI, 1.57 to 3.29]) ( 92, 310), and zoledronic acid is associated with adverse effects including atrial fibrillation (OR, 1.45 [CI, 1.14 to 1.86]) ( 81), arthritis and arthralgias (OR, 2.82 [CI, 2.32 to 3.45]), headaches (OR, 3.18 [CI, 2.57 to 3.97]), and uveitis (OR, 12.1 [CI, 1.78 to 516]).Evidence is insufficient to associate bisphosphonates with increased cancer risk, because studies report conflicting results ( 292, 311–326).DenosumabHigh-quality evidence showed that denosumab is associated with mild upper gastrointestinal symptoms (OR, 1.74 [CI, 1.29 to 2.38]) ( 43, 327). Moderate-quality evidence showed that denosumab is associated with increased risk for infection (risk ratio [RR], 1.26 [CI, 1.01 to 1.57]) ( 328). One small RCT reported a slight increase in bacterial cellulitis with patients treated with denosumab compared with placebo (1.3% vs. 0.6%), but no increase in serious infection (1.1% vs. 1.5%) ( 109). Denosumab has also been associated with rash/eczema (OR, 1.96 [CI, 1.46 to 2.66]) ( 43, 96, 97). A post hoc analysis of the open-label extension of FREEDOM (Fracture Reduction Evaluation of Denosumab in Osteoporosis every 6 Months) confirmed 2 events of atypical femoral fracture and 8 events of osteonecrosis of the jaw through 8 years of denosumab therapy ( 100).TeriparatideHigh-quality evidence showed that teriparatide is associated with mild upper gastrointestinal symptoms (OR, 3.26 [CI, 2.82 to 3.78]) ( 113, 117, 329, 330), headache (OR, 1.46 [CI, 1.27 to 1.69]) ( 113, 117, 331), and hypercalcemia (OR, 12.9 [CI, 10.5 to 16]) ( 116, 117, 331, 332). Other adverse effects include renal side effects (OR, 2.36 [CI, 2.01 to 2.77]) and hypercalciuria (OR, 2.44 [CI, 2.08 to 2.86]) ( 254). There were no incident cases of osteosarcoma associated with use of this medication in the first 4 years of the voluntary Forteo Patient Registry safety study ( 333), and in a postmarketing case series study encompassing 9 years of osteosarcoma cases, no patient reported use of teriparatide before diagnosis of osteosarcoma ( 334).SERMsHigh-quality evidence showed that raloxifene is associated with hot flashes (OR, 1.58 [CI, 1.35 to 1.84]) ( 122, 123, 335–340) and thromboembolic events (OR, 1.63 [CI, 1.36 to 1.98]) ( 122, 336, 341–346). Raloxifene is also associated with pulmonary embolism (OR, 1.82 [CI, 1.16 to 2.92) ( 122, 341, 345, 347) and cerebrovascular death (OR, 1.56 [CI, 1.04 to 2.39]) ( 122, 341, 342, 348–350). A study comparing postmarketing surveillance of raloxifene in younger women (aged <75 y) versus older women (aged ≥75 y) showed no difference in overall adverse effects from raloxifene ( 351).Estrogen Therapy for Postmenopausal WomenHigh-quality evidence from the Women's Health Initiative showed that menopausal hormone therapy was associated with increased risk for cerebrovascular accidents and venous thromboembolic events ( 7, 352). One subsequent assessment of the trial showed that the higher incidence of breast cancer decreased after therapy was discontinued ( 353). Another study showed that estrogen plus progestin therapy was associated with more invasive breast cancer, more node-positive tumors, and more deaths due to breast cancer than placebo ( 354).Calcium and Vitamin DAlthough previous data suggested an association between calcium supplementation and increased risk for myocardial infarction, moderate-quality evidence shows no association ( 355). One study showed increased risk for hypercalciuria with vitamin D supplementation ( 356).Monitoring of Patients With OsteoporosisThere is no evidence from RCTs regarding how often to monitor BMD during osteoporosis treatment. Moderate-quality evidence suggests that most women do not need regular monitoring ( 357–368). Data from 1 study ( 365) showed that only 10% of women with normal or mildly osteopenic DXA scores (T score > –1.49) develop osteoporosis within 15 years; 10% of women with moderate osteopenia (T score, –1.50 to –1.99) develop osteoporosis within 5 years; and 10% of women with advanced osteopenia (T score, –2.0 to –2.49) develop osteoporosis within 1 year. Another study showed no improvement in prediction of hip or major fractures in women who had BMD measured 4 years after baseline ( 357). Overall data from several studies ( 358–363) showed that women treated with bisphosphonates, raloxifene, and teriparatide benefited from reduced fractures with treatment even if BMD did not increase.Duration of Pharmacologic TherapyLow-quality evidence showed that the appropriate duration of treatment is uncertain, although high-risk patients may benefit from more than 5 years of treatment ( 240, 242, 369–371). One study showed no cumulative difference in the risk for nonvertebral fractures in women continuing alendronate therapy for 5 versus 10 years (18.9% vs. 19%) ( 240). Post hoc analysis of this study showed that women with femoral neck T scores of –2.5 or worse without baseline prevalent vertebral fracture had reduced fracture risk by continuing alendronate therapy for 10 years versus stopping after 5 years compared with placebo (11.1% to 5.3%) ( 242). Another study on zoledronic acid showed no difference for clinical vertebral fractures, hip fractures, nonvertebral fractures, or all clinical fractures in women who continued to receive the drug for 3 versus 6 years ( 369).The Figure provides a summary of the recommendations and clinical considerations.Figure. Summary of the American College of Physicians guideline on the treatment of low bone density or osteoporosis to prevent fractures in men and women.BMD = bone mineral density; DXA = dual-energy x-ray absorptiometry; FRAX = World Health Organization Fracture Risk Assessment Tool; GI = gastrointestinal. Download figure Download PowerPoint Future ResearchMost of the evidence for treating osteoporotic men is based on trials that included women, and further research is needed on the treatment of men. Studies directly addressing the efficacy of pharmacologic treatments for reducing fractures in patients with osteopenia are also needed.RecommendationsRecommendation 1: ACP recommends that clinicians offer pharmacologic treatment with alendronate, risedronate, zoledronic acid, or denosumab to reduce the risk for hip and vertebral fractures in women who have known osteoporosis. (Grade: strong recommendation; high-quality evidence)High-quality evidence showed that pharmacologic treatment in postmenopausal women who have osteoporosis (T scores ≤ –2.5 or those who have experienced fragility fractures) is beneficial for preventing further bone loss and reducing the risk for initial or subsequent fractures. Some bisphosphonates (alendronate, risedronate, and zoledronic acid) and the newer biologic agent denosumab reduce radiographic vertebral as well as clinical, nonvertebral, and hip fractures.Both bisphosphonates and denosumab are associated with mild gastrointestinal symptoms. Denosumab is also associated with increased risk for infection and rash or eczema. Bisphosphonates are associated with atypical subtrochanteric fractures and osteonecrosis of the jaw. Although there is no association between bisphosphonates and atrial fibrillation, some studies have reported increased cardiovascular events. Zoledronic acid is associated with hypocalcemia, influenza-like symptoms, arthritis and arthralgias, headache, and uveitis.When prescribing bisphosphonates, clinicians should discuss the importance of adherence. Factors associated with poor adherence include side effects and the inconvenience of taking medications, absence of symptoms for underlying disease, comorbid conditions, age, and socioeconomic status.Although evidence showed that raloxifene and ibandronate reduce radiographic vertebral fractures, and teriparatide reduces vertebral and nonvertebral fractures, studies have shown no benefit for these drugs to reduce all fracture types; therefore, they are not recommended as a first-line pharmacologic treatment. Raloxifene is associated with serious harms, such as thromboembolism. Calcitonin, which is no longer widely used for osteoporosis treatment, was not considered in this guideline.Calcium and vitamin D may be added as dietary supplements to osteoporosis treatment regimens, although the effectiveness of these regimens on fracture prevention is unclear. The majority of trials with bisphosphonate therapy gave women calcium supplements and many also gave vitamin D; therefore, supplementation with these agents may be considered. However, dosages should be carefully considered, because excess dosing has been associated with hypercalcemia ( 221, 372–377). Moderate-quality evidence showed no association between calcium supplementation and increased risk for myocardial infarction ( 355), but a large trial demonstrated an increase in kidney stones ( 137).Recommendation 2: ACP recommends that clinicians treat osteoporotic women with pharmacologic therapy for 5 years. (Grade: weak recommendation; low-quality evidence)Although the direct evidence is insufficient to determine the appropriate duration of pharmacologic therapy, most studies that evaluated the benefit of treatment continued therapy for up to 5 years. Continuing treatment after the initial 5 years may be beneficial for some patients and may be appropriate after reassessing the risks and benefits of continuing therapy. Post hoc analysis from an RCT (242) suggested that patients treated with alendronate without preexisting fractures and a BMD