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Clinical Guidelines |

Pharmacologic Treatment of Low Bone Density or Osteoporosis to Prevent Fractures: A Clinical Practice Guideline from the American College of Physicians FREE

Amir Qaseem, MD, PhD, MHA; Vincenza Snow, MD; Paul Shekelle, MD, PhD; Robert Hopkins Jr., MD; Mary Ann Forciea, MD; Douglas K. Owens, MD, MS, Clinical Efficacy Assessment Subcommittee of the American College of Physicians
[+] Article and Author Information

This paper, written by Amir Qaseem, MD, PhD, MHA; Vincenza Snow, MD; Paul Shekelle, MD, PhD; Robert Hopkins Jr., MD; Mary Ann Forciea, MD; and Douglas K. Owens, MD, MS, was developed for the Clinical Efficacy Assessment Subcommittee of the American College of Physicians (ACP): Douglas K. Owens, MD, MS (Chair); Donald E. Casey Jr., MD, MPH, MBA; Paul Dallas, MD; Thomas D. Denberg, MD, PhD; Mary Ann Forciea, MD; Lakshmi Halasyamani, MD; Robert H. Hopkins Jr., MD; William Rodriguez-Cintron, MD; and Paul Shekelle, MD, PhD. Approved by the ACP Board of Regents on 12 May 2008.

See related article in 5 February 2008 issue (volume 148, pages 197-213).


From the American College of Physicians and University of Pennsylvania, Philadelphia, Pennsylvania; Veterans Affairs Greater Los Angeles Healthcare System and RAND, Santa Monica, California; University of Arkansas, Little Rock, Arkansas; and Veterans Affairs Palo Alto Health Care System and Stanford University, Stanford, California.


Note: Clinical practice guidelines are “guides” only and may not apply to all patients and all clinical situations. Thus, they are not intended to override clinicians' judgment. All ACP clinical practice guidelines are considered automatically withdrawn or invalid 5 years after publication, or once an update has been issued.

Disclaimer: The authors of this article are responsible for its contents, including any clinical or treatment recommendations. No statement in this article should be construed as an official position of the Agency for Healthcare Research and Quality or the U.S. Department of Health and Human Services.

Grant Support: Financial support for the development of this guideline comes exclusively from the American College of Physicians' operating budget.

Potential Financial Conflicts of Interest:Employment: R. Hopkins (University of Arkansas). Consultancies: D.K. Owens (GE Healthcare). Grants received: V. Snow (Novo Nordisk, United Healthcare Foundation, Centers for Disease Control and Prevention, Atlantic Philanthropies). Any conflict of interest of the Guideline Development Committee group members was declared, discussed, and resolved.

Requests for Single Reprints: Amir Qaseem, MD, PhD, MHA, American College of Physicians, 190 N. Independence Mall West, Philadelphia, PA 19106; e-mail, aqaseem@acponline.org.

Current Author Addresses: Drs. Qaseem and Snow: 190 N. Independence Mall West, Philadelphia, PA 19106.

Dr. Shekelle: 1776 Main Street, Santa Monica, CA 90401.

Dr. Hopkins: 4301 West Markham Street, Little Rock, AR 72205.

Dr. Forciea: 3615 Chestnut Street, Philadelphia, PA 19104.

Dr. Owens: 117 Encina Commons, Stanford, CA 94305.


Ann Intern Med. 2008;149(6):404-415. doi:10.7326/0003-4819-149-6-200809160-00007
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Description: The American College of Physicians (ACP) developed this guideline to present the available evidence on various pharmacologic treatments to prevent fractures in men and women with low bone density or osteoporosis.

Methods: Published literature on this topic was identified by using MEDLINE (1966 to December 2006), the ACP Journal Club database, the Cochrane Central Register of Controlled Trials (no date limits), the Cochrane Database of Systematic Reviews (no date limits), Web sites of the United Kingdom National Institute of Health and Clinical Excellence (no date limits), and the United Kingdom Health Technology Assessment Program (January 1998 to December 2006). Searches were limited to English-language publications and human studies. Keywords for search included terms for osteoporosis, osteopenia, low bone density, and the drugs listed in the key questions. This guideline grades the evidence and recommendations according to the ACP's clinical practice guidelines grading system.

Recommendation 1: ACP recommends that clinicians offer pharmacologic treatment to men and women who have known osteoporosis and to those who have experienced fragility fractures (Grade: strong recommendation; high-quality evidence).

Recommendation 2: ACP recommends that clinicians consider pharmacologic treatment for men and women who are at risk for developing osteoporosis (Grade: weak recommendation; moderate-quality evidence).

Recommendation 3: ACP recommends that clinicians choose among pharmacologic treatment options for osteoporosis in men and women on the basis of an assessment of risk and benefits in individual patients (Grade: strong recommendation; moderate-quality evidence).

Recommendation 4: ACP recommends further research to evaluate treatment of osteoporosis in men and women.

The National Institutes of Health's consensus conference (1) defined osteoporosis as “a skeletal disorder characterized by compromised bone strength predisposing to an increased risk for fracture. Bone strength reflects the integration of two main features: bone density and bone quality.…Bone quality refers to architecture, turnover, damage accumulation (e.g., microfractures), and mineralization.” Although osteoporosis can affect any bone, the hip, spine, and wrist are most likely to be affected. Osteoporosis affects an estimated 44 million Americans or 55% of people 50 years of age or older. Another 34 million Americans are estimated to have low bone mass, meaning that they are at an increased risk for osteoporosis.

Osteoporosis can be diagnosed by the occurrence of fragility fracture. In patients without fragility fracture, osteoporosis is often diagnosed by low bone density. Dual x-ray absorptiometry (DXA) is the current gold standard test for diagnosing osteoporosis in people without an osteoporotic fracture. Dual x-ray absorptiometry results are scored as standard deviations (SDs) from a young healthy norm (usually female) and reported as T-scores. For example, a T-score of −2 indicates a bone mineral density that is 2 SDs below the comparative norm. The international reference standard for the description of osteoporosis in postmenopausal women and in men age 50 years or older is a femoral neck bone mineral density of 2.5 SD or more below the young female adult mean (2). Low bone density, as measured by DXA, is an imperfect predictor of fracture risk, identifying fewer than half the people who go on to have an osteoporotic fracture. Screening guidelines for women are well established (3), and the American College of Physicians (ACP) recently published guidelines on screening for men (4).

This guideline presents the available evidence on various pharmacologic treatments to prevent fractures in men and women with low bone density or osteoporosis. Medications used to treat osteoporosis may affect different parts of the skeletal system differently, and efficacy for vertebral fractures does not necessarily imply efficacy for nonvertebral fractures. The target audience for this guideline is all clinicians and the target patient population is all adult men and women with low bone density or osteoporosis. These recommendations are based on the systematic evidence review by MacLean and colleagues (5) and the Agency for Healthcare Research and Quality–sponsored Southern California Evidence-Based Practice Center evidence report (6).

The drugs currently approved for prevention of osteoporosis include alendronate, ibandronate, risedronate, zoledronic acid, estrogen, and raloxifene. The drugs currently approved for treatment of osteoporosis include alendronate, ibandronate, risedronate, calcitonin, teriparatide, zoledronic acid (in postmenopausal women), and raloxifene. Testosterone, pamidronate, and etidronate are not approved by the U.S. Food and Drug Administration for the treatment or prevention of osteoporosis.

The literature search done by MacLean and colleagues for the systematic review (5) included studies from MEDLINE (1966 to December 2006), the ACP Journal Club database, the Cochrane Central Register of Controlled Trials (no date limits), the Cochrane Database of Systematic Reviews (no date limits), Web sites of the United Kingdom National Institute of Health and Clinical Excellence (no date limits), and the United Kingdom Health Technology Assessment Program (January 1998 to December 2006). The reviewers limited their search to English-language publications and human studies. They derived evidence for comparative benefits of various treatments exclusively from randomized, controlled trials, whereas they included evidence from other types of studies for short- and long-term harms.

Two physicians independently abstracted data about study populations, interventions, follow-up, and outcome ascertainment by using a structured form. For each group within a randomized trial, a statistician extracted the sample size and number of persons reporting fractures. Two reviewers, under the supervision of the statistician, independently abstracted information about adverse events. The statistician or the principal investigator resolved disagreements.

This guideline is based on an evaluation of 76 randomized, controlled trials, 4 of which were identified in the updated search, and 24 meta-analyses that were included in the efficacy analyses. The analyses of adverse events included 491 articles, representing 417 randomized trials, 25 other controlled clinical trials, 11 open-label trials, 31 large observational studies, and 9 case reports of osteonecrosis among bisphosphonate users. MacLean and colleagues' background article (5) includes details about the methods used for the systematic evidence review.

The ACP rates the evidence and recommendations by using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) system with minor modifications (Table 1). In addition, the evidence reviewers used predefined criteria to assess the quality of systematic reviews and randomized trials, based on internal and external validity assessments detailed in the Quality of Reporting of Meta-Analyses (QUOROM) statement (7).

Table Jump PlaceholderTable 1.  The American College of Physicians' Guideline Grading System

The objective of this guideline is to synthesize the evidence for the following questions:

  1. What are the comparative benefits in fracture reduction among and also within the following treatments for low bone density: bisphosphonates, specifically alendronate, risedronate, etidronate, ibandronate, pamidronate, and zoledronic acid; calcitonin; estrogen for women; teriparatide; selective estrogen receptor modulators (SERMs), specifically raloxifene and tamoxifen; testosterone for men; vitamins and minerals, specifically vitamin D and calcium; and the combination of calcium plus vitamin D?

  2. How does fracture reduction resulting from treatments vary among individuals with different risks for fracture as determined by bone mineral density (borderline, low, or severe), previous fractures (prevention vs. treatment), age, sex, glucocorticoid use, and other factors (such as community-dwelling vs. institutionalized or vitamin D–deficient vs. not)?

  3. What are the short- and long-term harms (adverse effects) of these therapies, and do these vary by specific subpopulations?

Evidence from 24 meta-analyses (830) and 35 additional randomized trials published after the meta-analyses (3165) described the effect of 9 of the 14 agents (alendronate, etidronate, risedronate, calcitonin, estrogen, teriparatide, raloxifene, calcium, and vitamin D) on fracture incidence. For 4 agents (ibandronate, pamidronate, zoledronic acid, and tamoxifen), the reviewers found no meta-analyses and instead gathered the evidence from 14 randomized trials (6679). No studies were found that reported fracture rates for testosterone. Three randomized trials (35, 8081) and 1 meta-analysis (82) evaluated the combination of calcium plus vitamin D on fractures.

Bisphosphonates

Good-quality evidence showed that alendronate, etidronate, ibandronate, and risedronate prevent vertebral fractures. In addition, evidence from good-quality studies demonstrated that both alendronate and risedronate prevent nonvertebral and hip fractures. Two large randomized trials showed that zoledronic acid prevents vertebral and nonvertebral fractures in high-risk populations and reduces the risk for hip fracture (67, 74). Ibandronate has not been shown to reduce nonvertebral fractures (68). Of the 6 fairly small trials that looked at vertebral fractures, 1 demonstrated a statistically significant reduction in fractures with pamidronate relative to placebo (0.14 [95% CI, 0.03 to 0.72]) (73). However, after these data were pooled, the pooled risk estimate for fractures for pamidronate relative to placebo was not significant (0.52 [CI, 0.21 to 1.24]) (6).

Calcitonin

Fair-quality evidence shows that calcitonin reduces vertebral fractures (8384). Good-quality evidence indicates that calcitonin does not reduce nonvertebral fractures (13, 16).

Estrogen

Good-quality evidence shows that estrogen reduces the incidence of vertebral (29, 85), nonvertebral (86), and hip fractures (85).

Teriparatide

Good-quality evidence shows that teriparatide prevents vertebral fractures. The evidence related to teriparatide preventing nonvertebral fractures is mixed; 1 large randomized trial showed a reduction in nonvertebral fractures (34) but 2 small trials did not (8788).

SERMs

Good-quality evidence shows that raloxifene prevents vertebral fractures, but that tamoxifen has no effect on vertebral fractures (8991). In addition, both raloxifene and tamoxifen had no effect on hip fractures (91). Tamoxifen is not approved by the U.S. Food and Drug Administration for the treatment or prevention of osteoporosis.

Testosterone

No studies reported fracture rates for testosterone.

Calcium and Vitamin D

In the studies evaluated by MacLean and colleagues (5), the evidence for the effect of calcium alone on reduction of fractures is complex. Most studies of pharmacologic agents for osteoporosis include calcium and vitamin D as part of the treatment regimen. Evidence from 1 meta-analysis (27) and several randomized trials (35, 48, 51, 92) showed no significant difference between calcium and placebo in preventing vertebral, nonvertebral, and hip fractures in postmenopausal women. However, nonadherence to therapy may influence this result, and 1 trial with a prespecified analysis of adherent patients found a reduction in fracture risk (48). A recent meta-analysis (82) concluded that the relative risk (RR) for fracture with calcium alone was 0.90 (CI, 0.80 to 1.00), but it did not include a modestly large trial with negative results (35).

MacLean and colleagues (5) included 5 systematic reviews that evaluated vitamin D. Four meta-analyses (8, 21, 24, 28) found that standard vitamin D (D2, D3, or 25-hydroxyvitamin [25(OH)]D) did not have any effect on risk for vertebral, nonvertebral, or hip fractures; a fifth (35) showed a statistically significant reduction in the pooled risk for nonvertebral and hip fractures for vitamin D2 or D3. In addition, MacLean and colleagues identified 3 meta-analyses (21, 2324) that showed that vitamin D analogues [1,25(OH)D and 1(OH)D] significantly reduced the risk for vertebral, nonvertebral, and hip fractures. A meta-analysis published after MacLean and colleagues' review concluded that vitamin D and calcium reduced fractures by 13% (RR, 0.87 [CI, 0.77 to 0.97]) (82).

In summary, for evaluating the comparative benefits of drugs versus placebo in fracture reduction, good-quality evidence shows that alendronate, etidronate, ibandronate, risedronate, calcitonin, teriparatide, and raloxifene prevent vertebral fractures. The reviewers also found good-quality evidence that alendronate and risedronate prevent nonvertebral and hip fractures. No clear evidence demonstrates the appropriate duration of treatment with bisphosphonates; however, bisphosphonate trials ranged from 3 months to 60 months. Good evidence shows that estrogen reduced the incidence of vertebral, nonvertebral, and hip fractures. The effect of calcium alone is less certain. Systematic reviews of the effectiveness of vitamin D and calcium have reached different conclusions, with the most recent systematic review (82) finding a modest reduction in fracture risk.

Evidence from 9 randomized trials comparing different bisphosphonates (41, 93100), 1 study comparing different SERMs (101), and 16 studies with head-to-head comparisons of agents from different classes (3132, 35, 37, 42, 50, 64, 98, 100, 102108) evaluated intermediate outcomes, such as bone mineral density and changes in markers of bone turnover. These studies were too short to detect clinically important differences in fracture incidence. The 2 head-to-head trials that compared fracture incidence outcomes (risedronate vs. etidronate [97] and raloxifene vs. alendronate [107]) were underpowered and showed no statistically significant differences.

In summary, evidence is insufficient to determine whether one bisphosphonate is superior to another, with the exception that ibandronate did not reduce nonvertebral fractures in a relatively large trial (68). Little evidence comparing drugs from different classes is available.

Low-Risk Populations

We defined “low risk” as a 10-year risk for osteoporotic fracture (vertebral, nonvertebral, or hip) of up to 2% and a lifetime risk of up to 21%. The reviewers gathered evidence from 4 meta-analyses (1415, 28, 107). Summary estimates for alendronate showed a statistically nonsignificant reduction in the risk for vertebral fracture (RR, 0.45 [CI, 0.06 to 3.15]) and nonvertebral fracture (RR, 0.79 [CI, 0.28 to 2.24]) (15). Estrogen did not reduce the risk for vertebral fracture (28) but reduced nonvertebral fractures (28, 109). However, raloxifene and vitamin D did reduce the risk for vertebral fractures (raloxifene RR, 0.53 [CI, 0.35 to 0.79]; vitamin D RR, 0.86 [CI, 0.72 to 1.02]) (28). Evidence from 2 randomized trials did not show any difference between raloxifene and tamoxifen for reducing fractures (63, 101).

Special Populations
Men

Studies showed that risedronate decreased the risk for hip fractures (RR, 0.25 [CI, 0.08 to 0.78]) (56), calcitonin decreased the risk for vertebral fractures (RR, 0.09 [CI, 0.01 to 0.96]) (61), and teriparatide decreased the risk for total fractures (RR, 0.16 [CI, 0.01 to 0.96]) and possibly the risk for vertebral fractures (odds ratio [OR], 0.44 [CI, 0.18 to 1.09]) (44). Evidence is insufficient to evaluate the effect of calcium alone in men (35).

Populations at Increased Risk for Falls

Populations studied included patients with stroke and hemiplegia, Alzheimer disease, a recent hip fracture, or Parkinson disease. Zoledronic acid reduced the risk for vertebral fractures (hazard ratio, 0.54 [CI, 0.32 to 0.92]) and nonvertebral fractures (hazard ratio, 0.73 [CI, 0.55 to 0.98]) in patients with a recent hip fracture (74). In patients with Alzheimer disease, risedronate reduced the risk for nonvertebral fracture (RR, 0.29 [CI, 0.15 to 0.57]) (53) and hip fracture (RR, 0.29 [CI, 0.13 to 0.66]) (58). Risedronate also reduced the risk for hip fracture in patients with stroke (RR, 0.22 [CI, 0.05 to 0.88]) and hemiparesis (RR, 0.25 [CI, 0.08 to 0.78]) (5556). In patients with Parkinson disease, alendronate (RR, 0.30 [CI, 0.12 to 0.78]) reduced the risk for hip fracture (57). Vitamin D also reduced the risk for hip fracture in patients with stroke and hemiparesis (RR, 0.12 [CI, 0.02 to 0.90]).

Populations with Renal Insufficiency

One trial (110) showed that alendronate reduced the risk for fractures to a similar degree in patients with and those without reduced renal function.

Populations with Long-Term Glucocorticoid Use

Evidence from 3 studies included in a systematic review (111) showed a possible reduction in vertebral fracture rate with bisphosphonate treatment (112114). Six additional trials have been published since this systematic review. Three of these randomized trials (115117) showed that bisphosphonates reduced the fracture rate. Results from 2 studies also showed that risedronate treatment led to a statistically significant reduction in the absolute risk (11%) and RR (70%) of incident radiographic vertebral fractures after 1 year (117) and in vertebral fractures (116). In another trial (115), alendronate was associated with a reduction in the risk for incident radiographic vertebral fractures. However, 3 additional trials showed no significant effect on fracture risk for etidronate (32, 53), from calcium (32), between calcium and a combination of etidronate and calcium (32), or between calcium and pamidronate (103).

To summarize the overall fracture reduction benefits of drug treatments in special populations in different risk groups, a SERM (raloxifene) and vitamin D both reduced the risk for vertebral fracture in low-risk patients. Far fewer men than women have been included in these trials, resulting in less evidence about the effectiveness of treatment in men. In men, risedronate decreased hip fractures and calcitonin decreased vertebral fractures. Teriparatide decreased total fractures and possibly vertebral fractures. In patients with a previous hip fracture, zoledronic acid reduced the risk for vertebral and nonvertebral fractures. Risedronate reduced the hip and nonvertebral fracture risk among patients with Alzheimer disease. Bisphosphonates (risedronate and alendronate) also reduced the clinical and radiographic fracture rate in patients receiving glucocorticoids.

Bisphosphonates

The most common adverse effects of bisphosphonates are gastrointestinal. Trials reported esophageal ulcerations from all bisphosphonates except zoledronic acid. One trial of etidronate versus placebo showed a statistically significant increase in esophageal ulceration (OR, 1.33 [CI, 1.05 to 1.68]) (118). Mild upper gastrointestinal events (acid reflux, esophageal irritation, nausea, vomiting, and heartburn) were more common with etidronate in a pooled analysis (OR, 1.33 [CI, 1.21 to 1.46]) (32, 42, 5354, 64, 112, 118128) and with pamidronate (OR, 3.14 [CI, 1.93 to 5.21]) (75, 79, 129133). Pooled analysis showed no difference in occurrence of mild upper gastrointestinal events between alendronate, ibandronate, risedronate, or zoledronic acid and placebo. However, pooled analysis of head-to-head trials showed a higher risk for mild upper gastrointestinal events with alendronate than with etidronate (OR, 5.89 [CI, 1.61 to 32.7]), calcitonin (OR, 3.42 [CI, 1.79 to 7.00]), or estrogen (OR, 1.57 [CI, 1.00 to 2.46]). The pooled estimate from 3 studies showed that etidronate users were at increased risk for perforations, ulcerations, and gastrointestinal bleeding events (OR, 1.32 [CI, 1.04 to 1.67]) (59, 118, 134), whereas the pooled estimate from 2 studies showed that ibandronate had a lower risk for serious gastrointestinal adverse events (OR, 0.33 [CI, 0.14 to 0.74]) (68, 135). Case reports and case series have documented increased osteonecrosis of the jaw in patients receiving bisphosphonates, but the most cases of osteonecrosis have occurred in patients with cancer who received high doses of intravenous bisphosphonates (136). However, we could not calculate the risk for this event from the available studies. Some studies showed a link between atrial fibrillation and either zoledronic acid or alendronate (5, 137).

Calcitonin

Evidence from randomized trials showed no clinically important serious adverse events associated with the use of calcitonin.

Estrogen

Estrogen was associated with an increased risk for thromboembolic events versus placebo in pooled results from 4 studies (OR, 1.36 [CI, 1.01 to 1.86]) (37, 85, 138139). In addition, pooled results for estrogen–progestin also showed a higher risk for thromboembolic events versus placebo (OR, 2.27 [CI, 1.72 to 3.02]) (52, 140141). Pooled odds of stroke were increased with estrogen (OR, 1.28 [CI, 1.05 to 1.57]) (83, 138139) and combined estrogen–progestin (OR, 1.28 [CI, 1.05 to 1.57]) relative to placebo (52, 140). Women who received estrogen had a lower pooled risk for breast cancer than those who received placebo (OR, 0.79 [CI, 0.66 to 0.93]) (83, 138, 142144). However, pooled analysis showed that women who received an estrogen–progestin combination had an increased risk for breast cancer (OR, 1.28 [CI, 1.03 to 1.60]) (52, 131, 140). One study showed a lower risk for colon cancer among women who received an estrogen–progestin combination (OR, 0.64 [CI, 0.43 to 0.95]) (85).

Teriparatide

Evidence from randomized trials showed no clinically important serious adverse events associated with the use of teriparatide.

SERMs

Raloxifene increased the pooled risk for pulmonary embolism (OR, 6.26 [CI, 1.55 to 54.80]) (145146). In addition, pooled results showed that raloxifene increased the risk for thromboembolic events (OR, 2.08 [CI, 1.47 to 3.02) (145, 147152) and mild cardiac events, including chest pain, palpitations, tachycardia, and vasodilatation (OR, 1.53 [CI, 1.01 to 2.35]) (147, 149, 152155).

Testosterone

No trials of testosterone reported adverse events; however, testosterone has well-known side effects.

Calcium and Vitamin D

Evidence from randomized trials showed no clinically important serious adverse events associated with the use of calcium and vitamin D.

To summarize the adverse effects of drugs, estrogen increased the risk for stroke and thromboembolic events; estrogen–progestin increased the risk for stroke and breast cancer; and raloxifene increased the risk for pulmonary embolism, thromboembolic events, and mild cardiac events. Etidronate was associated with increased risk for esophageal ulcerations and, in addition to mild upper gastrointestinal events, increased the risk for perforations, ulcerations, and bleeding events. Alendronate was associated with a higher risk for mild upper gastrointestinal events than were etidronate, calcitonin, and estrogen.

Good evidence shows that bisphosphonates (alendronate, etidronate, and risedronate) reduce the risk for vertebral, nonvertebral, and hip fractures. Ibandronate reduces vertebral fractures. No clear evidence indicates the appropriate duration of treatment with bisphosphonates; however, bisphosphonate trials ranged from 3 months to 60 months. Estrogen reduces the risk for vertebral, nonvertebral, and hip fractures. Whereas evidence for fracture risk reduction from calcium alone is less clear, it is stronger for vitamin D and calcium in combination (82). Evidence showed a statistically significant reduction in the risk for vertebral fractures from vitamin D analogues [1,25(OH)D and 1(OH)D] but mixed results for nonvertebral and hip fractures.

Oral bisphosphonates increase the risk for such gastrointestinal adverse events as acid reflux. However, pooled analyses showed no differences in occurrence of mild upper gastrointestinal events among alendronate, ibandronate, risedronate, or zoledronic acid versus placebo; however, pooled analyses of 18 trials of etidronate versus placebo indicated an increased risk for mild gastrointestinal events. The evidence linking zoledronic acid infusion with atrial fibrillation is contradictory. Raloxifene increased the pooled risk for pulmonary embolism and thromboembolic events. Estrogen was linked to an increased risk for cerebrovascular and thromboembolic events.

Recommendation 1: ACP recommends that clinicians offer pharmacologic treatment to men and women who have known osteoporosis and to those who have experienced fragility fractures (Grade: strong recommendation; high-quality evidence).

Good evidence supports the treatment of patients who have osteoporosis to prevent further loss of bone and to reduce the risk for initial or subsequent fracture. Randomized, controlled trials offer good evidence that, compared with placebo, alendronate, ibandronate, risedronate, calcitonin, teriparatide, and raloxifene prevent vertebral fractures. Evidence is also good that teriparatide prevents nonvertebral fractures compared with placebo and that risedronate and alendronate prevent both nonvertebral and hip fractures compared with placebo. Estrogen has been shown to be associated with reduced vertebral, nonvertebral, and hip fractures. The evidence on use of calcium with or without vitamin D is mixed, and the effectiveness is modest. Because most trials of other pharmacologic therapy included their use, we recommend adding calcium and vitamin D to osteoporosis treatment regimens. Evidence is insufficient to determine the appropriate duration of therapy.

Recommendation 2: ACP recommends that clinicians consider pharmacologic treatment for men and women who are at risk for developing osteoporosis (Grade: weak recommendation; moderate-quality evidence).

Evidence supports the treatment of selected patients who are at risk for osteoporosis but who do not have a T-score on DXA less than −2.5. Evidence supporting preventive treatment is stronger for patients who are at moderate risk for osteoporosis, which includes patients who have a T-score from −1.5 to −2.5, are receiving glucocorticoids, or are older than 62 years of age.

Factors that increase the risk for osteoporosis in men include age (>70 years), low body weight (body mass index <20 to 25 kg/m2), weight loss (>10% [compared with the usual young or adult weight or weight loss in recent years]), physical inactivity (no physical activities performed regularly, such as walking, climbing stairs, carrying weights, housework, or gardening), corticosteroid use, and androgen deprivation therapy (4). Risk factors for women include lower body weight, the single best predictor of low bone mineral density; smoking; weight loss; family history; decreased physical activity; alcohol or caffeine use; and low calcium and vitamin D intake (3). In certain circumstances, a single risk factor (for example, androgen deprivation therapy in men) is enough for clinicians to consider pharmacologic treatment.

Research groups are developing calculators, such as the World Health Organization's Fracture Risk Assessment Tool (available at http://www.shef.ac.uk/FRAX/), to predict the risk for osteoporotic fracture. Such tools will help guide both clinician and patient decisions.

Recommendation 3: ACP recommends that clinicians choose among pharmacologic treatment options for osteoporosis in men and women on the basis of an assessment of the risk and benefits to individual patients (Grade: strong recommendation; moderate-quality evidence).

We recommend that the choice of therapy for patients who are candidates for pharmacologic treatment be guided by judgment of the risks, benefits, and adverse effects of drug options for each individual patient. Table 2 summarizes the benefits and harms of pharmacologic agents for fracture risk. Because good-quality evidence shows that bisphosphonates reduce the risk for vertebral, nonvertebral, and hip fractures, they are reasonable options to consider as first-line therapy, particularly for patients who have a high risk for hip fracture. Evidence from head-to-head trials is insufficient to demonstrate the superiority of one bisphosphonate over another. Alendronate and risedronate have been studied more than other bisphosphonates (Table 2). Ibandronate has not been shown to reduce nonvertebral or hip fractures, which may be an important consideration for some patients. In a recent trial, zoledronic acid administered to patients with a recent hip fracture reduced subsequent fracture and improved survival (74). Of the other agents available for treatment of osteoporosis, estrogen has efficacy for vertebral, nonvertebral, and hip fractures but is associated with other serious risks; calcitonin has not been demonstrated to reduce nonvertebral and hip fractures; and calcium and vitamin D are part of the treatment regimen in most studies of pharmacologic agents for osteoporosis.

Table Jump PlaceholderTable 2.  Summary of Evidence about Drugs and Fracture Risk

Gastrointestinal events are the most common adverse effects associated with bisphosphonate therapy. No evidence was found that bisphosphonates, calcium, vitamin D, calcitonin, or teriparatide differ regarding risk for serious cardiac events. Etidronate is associated with an increased risk for esophageal ulcers, bleeding events, and mild upper gastrointestinal events (acid reflux, esophageal irritation, nausea, vomiting, and heartburn). Raloxifene is associated with a higher risk for pulmonary embolism, thromboembolic events, and mild cardiac events (including chest pain, palpitations, tachycardia, and vasodilatation). Estrogen is associated with a greater risk for stroke, and the estrogen–progestin combination is associated with a greater probability of stroke and higher odds of breast cancer. In trials, perforations, ulcerations, and bleeding events occurred with all of the bisphosphonates except zoledronic acid.

Recommendation 4: ACP recommends further research to evaluate treatment of osteoporosis in men and women.

Current evidence is mostly concentrated on postmenopausal women; more research on other patient populations, including men, is needed. Comparative effectiveness data on preventing fractures from head-to-head studies with sufficient power to detect differences would be helpful. The association between bisphosphonates and osteonecrosis of the jaw also needs to be studied. Finally, further research is needed on prevention strategies in both men and women and on the appropriate duration of treatment for osteoporosis.

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Johnell O, Scheele WH, Lu Y, Reginster JY, Need AG, Seeman E.  Additive effects of raloxifene and alendronate on bone density and biochemical markers of bone remodeling in postmenopausal women with osteoporosis. J Clin Endocrinol Metab. 2002; 87:985-92. PubMed
 
Rubin MR, Lee KH, McMahon DJ, Silverberg SJ.  Raloxifene lowers serum calcium and markers of bone turnover in postmenopausal women with primary hyperparathyroidism. J Clin Endocrinol Metab. 2003; 88:1174-8. PubMed
 

Figures

Tables

Table Jump PlaceholderTable 1.  The American College of Physicians' Guideline Grading System
Table Jump PlaceholderTable 2.  Summary of Evidence about Drugs and Fracture Risk

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Woo SB, Hellstein JW, Kalmar JR.  Narrative [corrected] review: bisphosphonates and osteonecrosis of the jaws. Ann Intern Med. 2006; 144:753-61. PubMed
 
Heckbert SR, Li G, Cummings SR, Smith NL, Psaty BM.  Use of alendronate and risk of incident atrial fibrillation in women. Arch Intern Med. 2008; 168:826-31. PubMed
 
Cherry N, Gilmour K, Hannaford P, Heagerty A, Khan MA, Kitchener H, et al. ESPRIT team.  Oestrogen therapy for prevention of reinfarction in postmenopausal women: a randomised placebo controlled trial. Lancet. 2002; 360:2001-8. PubMed
 
Mosekilde L, Beck-Nielsen H, Sørensen OH, Nielsen SP, Charles P, Vestergaard P. et al.  Hormonal replacement therapy reduces forearm fracture incidence in recent postmenopausal women—results of the Danish Osteoporosis Prevention Study. Maturitas. 2000; 36:181-93. PubMed
 
Hulley S, Grady D, Bush T, Furberg C, Herrington D, Riggs B. et al.  Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. Heart and Estrogen/progestin Replacement Study (HERS) Research Group. JAMA. 1998; 280:605-13. PubMed
 
Recker RR, Davies KM, Dowd RM, Heaney RP.  The effect of low-dose continuous estrogen and progesterone therapy with calcium and vitamin D on bone in elderly women. A randomized, controlled trial. Ann Intern Med. 1999; 130:897-904. PubMed
 
Cummings SR, Schwartz AV, Black DM.  Alendronate and atrial fibrillation [Letter]. N Engl J Med. 2007; 356:1895-6. PubMed
 
Notelovitz M, John VA, Good WR.  Effectiveness of Alora estradiol matrix transdermal delivery system in improving lumbar bone mineral density in healthy, postmenopausal women. Menopause. 2002; 9:343-53. PubMed
 
Stefanick ML, Anderson GL, Margolis KL, Hendrix SL, Rodabough RJ, Paskett ED, et al. WHI Investigators.  Effects of conjugated equine estrogens on breast cancer and mammography screening in postmenopausal women with hysterectomy. JAMA. 2006; 295:1647-57. PubMed
 
Grady D, Ettinger B, Moscarelli E, Plouffe L Jr, Sarkar S, Ciaccia A, et al. Multiple Outcomes of Raloxifene Evaluation Investigators.  Safety and adverse effects associated with raloxifene: multiple outcomes of raloxifene evaluation. Obstet Gynecol. 2004; 104:837-44. PubMed
 
Smith MR, Fallon MA, Lee H, Finkelstein JS.  Raloxifene to prevent gonadotropin-releasing hormone agonist-induced bone loss in men with prostate cancer: a randomized controlled trial. J Clin Endocrinol Metab. 2004; 89:3841-6. PubMed
 
Johnston CC Jr, Bjarnason NH, Cohen FJ, Shah A, Lindsay R, Mitlak BH. et al.  Long-term effects of raloxifene on bone mineral density, bone turnover, and serum lipid levels in early postmenopausal women: three-year data from 2 double-blind, randomized, placebo-controlled trials. Arch Intern Med. 2000; 160:3444-50. PubMed
 
Jolly EE, Bjarnason NH, Neven P, Plouffe L Jr, Johnston CC Jr, Watts SD. et al.  Prevention of osteoporosis and uterine effects in postmenopausal women taking raloxifene for 5 years. Menopause. 2003; 10:337-44. PubMed
 
Kung AW, Chao HT, Huang KE, Need AG, Taechakraichana N, Loh FH. et al.  Efficacy and safety of raloxifene 60 milligrams/day in postmenopausal Asian women. J Clin Endocrinol Metab. 2003; 88:3130-6. PubMed
 
Meunier PJ, Vignot E, Garnero P, Confavreux E, Paris E, Liu-Leage S. et al.  Treatment of postmenopausal women with osteoporosis or low bone density with raloxifene. Raloxifene Study Group. Osteoporos Int. 1999; 10:330-6. PubMed
 
Michalská D, Stepan JJ, Basson BR, Pavo I.  The effect of raloxifene after discontinuation of long-term alendronate treatment of postmenopausal osteoporosis. J Clin Endocrinol Metab. 2006; 91:870-7. PubMed
 
Zheng S, Wu Y, Zhang Z, Yang X, Hui Y, Zhang Y. et al.  Effects of raloxifene hydrochloride on bone mineral density, bone metabolism and serum lipids in postmenopausal women: a randomized clinical trial in Beijing. Chin Med J (Engl). 2003; 116:1127-33. PubMed
 
Draper MW, Flowers DE, Huster WJ, Neild JA, Harper KD, Arnaud C.  A controlled trial of raloxifene (LY139481) HCl: impact on bone turnover and serum lipid profile in healthy postmenopausal women. J Bone Miner Res. 1996; 11:835-42. PubMed
 
Johnell O, Scheele WH, Lu Y, Reginster JY, Need AG, Seeman E.  Additive effects of raloxifene and alendronate on bone density and biochemical markers of bone remodeling in postmenopausal women with osteoporosis. J Clin Endocrinol Metab. 2002; 87:985-92. PubMed
 
Rubin MR, Lee KH, McMahon DJ, Silverberg SJ.  Raloxifene lowers serum calcium and markers of bone turnover in postmenopausal women with primary hyperparathyroidism. J Clin Endocrinol Metab. 2003; 88:1174-8. PubMed
 

Letters

NOTE:
Citing articles are presented as examples only. In non-demo SCM6 implementation, integration with CrossRef’s "Cited By" API will populate this tab (http://www.crossref.org/citedby.html).

Comments

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Don't Forget About Denosumab
Posted on September 16, 2008
Daniel G. Arkfeld
USC Keck School of Medicine
Conflict of Interest: None Declared

It was with great interest that i read "Pharmacologic Treatment of Low Bone Density or Osteoporosis to Prevent Fractures: A Clinical Practice Guideline from the American College of Physicians" by Qaseem et al and am in agreement with most of their findings. However, I found it suprising that denosumab, which targets RankL, was not mentioned in the article. Since the phase 3 data that has been released, there are apparent benefits of this agent. In addition to being favorable for the treatment of osteopenia and osteoporosis, it has demonstrated benefit in erosions of RA patients. As a rheumatologist I am excited to have this agent hopefully in the very near future. Perhaps it's use with methotrexate or other DMARD's will allow the successful management of patients with varying types of arthritis that have concomitant osteoporosis. The future of osteoporosis is evolving at a fast pace and future guidelines will need to incorporate newer agents such as denosumab.

Conflict of Interest:

None declared

Osteoporosis treatment guidelines: too interventionist?
Posted on October 11, 2008
Pablo Alonso-Coello
Iberoamerican Cochrane Center, Hospital Santpau, Barcelona
Conflict of Interest: None Declared

We have reviewed with great interest the ACP guidelines on the treatment of low bone density or osteoporosis to prevent fractures (1). Strengths of these guidelines include their rigorous methods, using the GRADE approach (2) , and being based on an extensive systematic review. We are worried that adherence to these guidelines may not yield the balance of benefits and costs the authors may have judged as favorable when they made strong treatment recommendations and formulate here a few questions to clarify this issue.

The panel strongly recommended that clinicians offer pharmacological treatment to everyone with densitometric osteoporosis as well as those who have experienced fragility fractures. They point, however, that "osteoporosis affects an estimated of 55% of people 50 years or older in America(1)." Do they really mean that half of Americans over 55 should be offered medications? Consider first the group of patients with previous fragility fractures. This is the highest risk group and, arguably, a strong recommendation to offer medication to reduce the risk of fractures seems compelling.

As the authors acknowledge, bone mineral density (BMD) is not a good fracture predictor (3) and many at-risk patients may not choose to take the medication once informed about their fracture risk and the benefits (fracture risk reduction), risks, burden and cost of therapy. Offering treatment to a 50-year-old woman with just densitometric osteoporosis will require treating women with a 10-year risk of any fragility fracture of less than 9% (4). The risk for hip fracture, the most morbid fragility fracture, would be under 3%.

Also, the efficacy of osteoporosis treatment programs is lower than expected due to poor patient adherence to these programs, adherence that could be improved in at-risk patients who commit to treatment understanding their risk and the potential for risk reduction with medications.

According to the GRADE approach, a weak recommendation indicates an expectation that different patient preferences and circumstances will lead to different optimal management approaches(2). Shouldn't the panel have formulated a weak (GRADE 2) recommendation for medication for women with densitometric osteoporosis?

Why did the panel decided to set "high risk of fracture" thresholds (e.g., 3% for a 50-year-old woman) at levels well below those used for cardiovascular disease? This choice suggests that the panel believes the implications of a fragility fracture to be much greater in magnitude and patient importance than a cardiovascular event, since high-risk thresholds for the latter are usually stated as 20-30% at 10 years.

Recommendation 2 suggests treating women with osteopenia (T-score from -1.5 to -2.5) or those that are older than 62. This recommendation is appropriately weak, but did the panel intend to recommend treatment of individuals at low risk of fractures that belong to this population? Why not recommend that physicians and patients consider the risk of fractures resulting from risk factors apart from BMD using models like the one recently developed by the World Health Organization3? Why not recommend that clinicians and patients share information about this baseline risk and consider the burdens, side effects, and costs of medications vis-à-vis the expected reduction in this baseline risk? This exercise may lead to decisions that are sensitive to both risk and patient preferences.

Drafting guidelines requires rigor, judgment, consensus, and expertise. In addition to these features of the present guideline, the panel may want to consider making more explicit the values and preferences they used to arrive at these recommendations. Answering the questions we formulate in this letter may facilitate this process.

References

1. Qaseem A, Snow V, Shekelle P, Hopkins R Jr, Forciea MA, Owens DK; Clinical Efficacy Assessment Subcommittee of the American College of Physicians. Pharmacologic treatment of low bone density or osteoporosis to prevent fractures: a clinical practice guideline from the American College of Physicians. Ann Intern Med 2008; 149(6):404-15.

2. Guyatt GH, Oxman AD, Vist GE, Kunz R, Falck-Ytter Y, Alonso-Coello P, Schünemann HJ; GRADE Working Group. GRADE: an emerging consensus on rating quality of evidence and strength of recommendations. BMJ 2008; 336(7650):924-6.

3. FRAX - WHO Fracture Risk Assessment Tool. http://www.shef.ac.uk/FRAX/

Conflict of Interest:

None declared

Comment on Guidelines
Posted on November 3, 2008
Jonas Hines
Public Citizen
Conflict of Interest: None Declared

The new Guidelines on the Pharmacologic Treatment of Low Bone Density or Osteoporosis to Prevent Fractures state that "evidence supports the treatment of selected patients who are at risk for osteoporosis" but remain vague about which patients should be selected, and include patients without fractures who have a bone mineral density (BMD) better than -2.5. Although no specific pharmacologic treatment is suggested for these patients, the Guidelines later state that bisphosphonates "are reasonable options to consider as first-line therapy." Without clarification, these Guidelines risk recommending treatment for patients that may not benefit from bisphosphonates.

Three meta-analyses from the Cochrane Database, published after the date of the Guidelines' literature review, contribute to this uncertainty about the efficacy of bisphosphonates. Although effective when used for secondary prevention of fractures* in postmenopausal women, when used for primary prevention,* risedronate and etidronate did not reduce the risk of any type of fracture and alendronate reduced the risk of vertebral fractures only.1,2,3 The evidence for fracture risk reduction for these 3 bisphosphonates is presented in the Table.

Additionally, an important unanswered question remains whether or not to pharmacologically treat women with low bone density in the immediate postmenopausal period. These women have a low ten-year risk of fracture but significant long-term risk. Studies with alendronate (up to 10 years)4 and risedronate (up to 7 years)5 have shown decreased fracture risk compared to placebo for the first 3 to 4 years; thereafter, the fracture rates remained stable. If BMD T-score was better than -2.0, those taking alendronate for ten years had 50% more nonvertebral fractures than those taking it for 5 years followed by 5 years of placebo, but this was not statistically significant (RR 1.5, CI 0.86-2.6).5 Hence, there is a critical need to further explore the long-term effects and safety profile of bisphosphonates before strong recommendations for early or prolonged treatment can be made, particularly because these drugs have a half-life of greater than ten years.

Lastly, Table 2 of the Guidelines states in error that zoledronic acid is approved by the Food and Drug Administration for the prevention of osteoporosis; it is approved only for the treatment of osteoporosis.6

Author's Response to Dr. Alonso-Coello et al.
Posted on January 8, 2009
Amir Qaseem
American College of Physicians
Conflict of Interest: None Declared

We thank Drs. Alonso-Coello, Lopez, Pencille, and Montori for their comments regarding the American College of Physicians' recent guideline (1) on pharmacologic treatment of osteoporosis. FRAX may be a useful instrument for estimating an individual patient's risk of fracture, and we noted in our guideline that physicians may utilize models such as FRAX to help guide their decisions. However, currently there is a lack of evidence from randomized controlled trials showing the benefits of treatment in patients who were selected based on their scores from FRAX. Almost all trials demonstrating benefit of treatment enrolled patients on the basis of BMD-determined osteoporosis, as defined by T-score, and /or the presence of existing fragility fractures. For example, Liberman and colleagues (2) enrolled post-menopausal women solely on the basis of a BMD score of -2.5 or less. This trial showed that treatment with alendronate was associated with a 48 percent reduction in the proportion of women with new vertebral fractures (3.2 percent vs. 6.2 percent in the placebo group; P = 0.03), a decreased progression of vertebral deformities (33 percent vs. 41 percent in the placebo group; P = 0.028), and a reduced loss of height (P = 0.005) and was well tolerated.

Similarly, Reid and colleagues (3) showed benefits of zoledronic acid in the study population that included women with bone mineral density at the lumbar spine of at least 2.0 SD below the mean value for young adults (a T-score lower than -2.0). Thus, our guideline statements define the populations to be considered for treatment to be consistent with the enrollment criteria in the clinical trials that reported benefits. We await evidence from clinical trials showing the benefits of using the FRAX score to make decisions on treatment.

References

1. Qaseem A, Snow V, Shekelle P, Hopkins R Jr, Forciea MA, Owens DK; Pharmacologic treatment of low bone density or osteoporosis to prevent fractures: A Clinical Practice Guideline from the American College of Physicians. Annals of Internal Medicine 2008; 149(6):404-15.

2. Liberman UA, Weiss SR, Broll J, et al. Effect of oral alendronate on bone mineral density and the incidence of fractures in postmenopausal osteoporosis. The Alendronate Phase III Osteoporosis Treatment Study Group. N Engl J Med 1995;333(22):1437-43.

3. Reid IR, Brown JP, Burckhardt P, et al. Intravenous zoledronic acid in postmenopausal women wiht low bone mineral density. N Engl J Med 2002;346(9):653-61.

Conflict of Interest:

None declared

Ibandronate and non-vertebral fractures
Posted on February 4, 2009
Jonathan D. Adachi
St. Joseph's Healthcare - McMaster University
Conflict of Interest: None Declared

To the editor:

The review articles published in the Annals describing the comparative efficacy of treatments for osteoporosis are of great interest to clinicians treating individuals at risk for fractures (1, 2). As is often the case, new relevant articles which might alter treatment decisions are constantly being published. One such example is the use of ibandronate. We have recently published new data showing reduction of non-vertebral fractures with ibandronate treatment in postmenopausal women.

In a meta-analysis, Harris et al (3) examined the marketed doses of ibandronate, 150 mg once-monthly oral and 3 mg quarterly intravenous (IV) injection. This meta-analysis assessed whether these doses reduced fracture risk relative to placebo. They found that ibandronate at higher doses, including both the marketed 150 mg once-monthly oral and 3 mg quarterly IV injection regimens, provided significant non-vertebral and clinical fracture efficacy.

Cranney et al (4) conducted an analysis to assess the effect of higher versus lower doses of ibandronate on non-vertebral fractures. After adjusting for clinical fracture, age, and bone mineral density, they found that the treatment effect was dose-dependent, with higher doses of ibandronate significantly reducing the risk of non-vertebral fractures more efficaciously compared with lower doses. This study was unique in that it demonstrated efficacy against an active comparator previously found to be effective in preventing vertebral fractures rather than placebo.

A study utilizing administrative databases confirmed non-vertebral fracture benefit in "real world" clinical practice (5). These three recently published analyses add new evidence of non-vertebral efficacy for ibandronate in treatment of postmenopausal osteoporosis.

References

1. MacLean C, Newberry S, Maglione M, McMahon M, Ranganath V, Suttorp 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]

2. Qaseem A, Snow V, Shekelle P, Hopkins R Jr, Forciea MA, Owens DK. Clinical Efficacy Assessment Subcommittee of the American College of Physicians. Pharmacologic treatment of low bone density or osteoporosis to prevent fractures: a clinical practice guideline from the American College of Physicians. Ann Intern Med. 2008;149:404-15. [PMID: 18794560]

3. Harris ST, Blumentals WA, Miller PD. Ibandronate and the risk of nonvertebral and clinical fractures in women with postmenopausal osteoporosis: results of a metaanalysis of phase III studies. Curr Med Res Opin. 2008;24:237"“45. [PMID: 18047776]

4. Cranney A, Wells GA, Yetsir E, Adami S, Cooper C, Delmas PD, et al. Ibandronate for the prevention of nonvertebral fractures: a pooled analysis of individual patient data. Osteoporos Int. 2009 20:291-7. Epub 2008 Jul 29 [PMID: 18663402]

5. Harris ST, Reginster J-Y, Harley C, Blumentals WA, Poston SA, Barr CE, et al. Risk of fracture in women treated with monthly oral ibandronate or weekly bisphosphonates: The eValuation of IBandronate Efficacy (VIBE) database fracture study. Bone. 2009, doi:10.1016/j.bone.2009.01.002

Conflict of Interest:

Consultant/Speaker: Amgen, Astra Zeneca, Eli Lilly, Glaxo Smith Kline, Merck, Novartis, Nycomed,Pfizer, Procter & Gamble, Roche, Sanofi Aventis, Servier, Wyeth Clinical Trials: Amgen, Eli Lilly, Glaxo Smith Kline, Merck, Novartis, Pfizer, Procter & Gamble, Sanofi Aventis, Roche, Wyeth

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Summary for Patients

Drug Treatment for Low Bone Density or Osteoporosis to Prevent Fractures: A Clinical Practice Guideline from the American College of Physicians

The summary below is from the full report titled “Pharmacologic Treatment of Low Bone Density or Osteoporosis to Prevent Fractures: A Clinical Practice Guideline from the American College of Physicians.” It is in the 16 September 2008 issue of Annals of Internal Medicine (volume 149, pages 404-415). The authors are A. Qaseem, V. Snow, P. Shekelle, R. Hopkins Jr., M.A. Forciea, and D.K. Owens, for the Clinical Efficacy Assessment Subcommittee of the American College of Physicians.

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