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A m e r i c a n C o l l e g e o f P h y s i c i a n s G U I D E L I N E S
Pharmacologic Treatment of Low Bone Density or Osteoporosis to
Prevent Fractures: A Clinical Practice Guideline from the American
College of Physicians
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, for the Clinical Efficacy Assessment Subcommittee of the American College of Physicians*
Description: The American College of Physicians (ACP) developed
Recommendation 1: ACP recommends that clinicians offer phar-
this guideline to present the available evidence on various pharma- macologic treatment to men and women who have known osteo- cologic treatments to prevent fractures in men and women with porosis and to those who have experienced fragility fractures (Grade: strong recommendation; high-quality evidence). Methods: Published literature on this topic was identified by using
Recommendation 2: ACP recommends that clinicians consider
MEDLINE (1966 to December 2006), the ACP Journal Club data- pharmacologic treatment for men and women who are at risk for base, the Cochrane Central Register of Controlled Trials (no date developing osteoporosis (Grade: weak recommendation; moderate- limits), the Cochrane Database of Systematic Reviews (no date limits), Web sites of the United Kingdom National Institute of Recommendation 3: ACP recommends that clinicians choose
Health and Clinical Excellence (no date limits), and the United among pharmacologic treatment options for osteoporosis in men Kingdom Health Technology Assessment Program (January 1998 to and women on the basis of an assessment of risk and benefits in December 2006). Searches were limited to English-language publi- individual patients (Grade: strong recommendation; moderate- cations and human studies. Keywords for search included terms for osteoporosis, osteopenia, low bone density, and the drugs listed inthe key questions. This guideline grades the evidence and recom- Recommendation 4: ACP recommends further research to evalu-
mendations according to the ACP’s clinical practice guidelines grad- ate treatment of osteoporosis in men and women. Ann Intern Med. 2008;149:404-415.
www.annals.org
For author affiliations, see end of text.
See related article in 5 February 2008 issue (volume 148, pages 197-213).
TheNationalInstitutesofHealth’sconsensusconference 50 years of age or older. Another 34 million Americans are
(1) defined osteoporosis as “a skeletal disorder charac- estimated to have low bone mass, meaning that they are at terized by compromised bone strength predisposing to an increased risk for fracture. Bone strength reflects the inte- Osteoporosis can be diagnosed by the occurrence of fra- gration of two main features: bone density and bone quality.
gility fracture. In patients without fragility fracture, osteopo- . . . Bone quality refers to architecture, turnover, damage rosis is often diagnosed by low bone density. Dual x-ray ab- accumulation (e.g., microfractures), and mineralization.” sorptiometry (DXA) is the current gold standard test for Although osteoporosis can affect any bone, the hip, spine, diagnosing osteoporosis in people without an osteoporotic and wrist are most likely to be affected. Osteoporosis af- fracture. Dual x-ray absorptiometry results are scored as stan- fects an estimated 44 million Americans or 55% of people dard deviations (SDs) from a young healthy norm (usuallyfemale) and reported as T-scores. For example, a T-score of Ϫ2 indicates a bone mineral density that is 2 SDs below thecomparative 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 Summary for Patients. . . . . . . . . . . . . . . . . . . . . . . I-46 density of 2.5 SD or more below the young female adult Web-Only
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 * 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.
404 2008 American College of Physicians
Treatment of Low Bone Density or Osteoporosis to Prevent Fractures Clinical Guidelines the American College of Physicians (ACP) recently published Table 1. The American College of Physicians’ Guideline
guidelines on screening for men (4).
Grading System*
This guideline presents the available evidence on vari- ous pharmacologic treatments to prevent fractures in men Quality of Evidence
Strength of Recommendation
and women with low bone density or osteoporosis. Medi-cations used to treat osteoporosis may affect different parts Benefits Clearly
Benefits Finely
of the skeletal system differently, and efficacy for vertebral Outweigh Risks
Balanced with
and Burden OR
Risks and Burden
fractures does not necessarily imply efficacy for nonverte- Risks and Burden
bral fractures. The target audience for this guideline is all Clearly Outweigh
Benefits
clinicians and the target patient population is all adult menand women with low bone density or osteoporosis. These recommendations are based on the systematic evidence re- view by MacLean and colleagues (5) and the Agency forHealthcare Research and Quality–sponsored Southern Cal- ifornia Evidence-Based Practice Center evidence report (6).
The drugs currently approved for prevention of osteo- porosis include alendronate, ibandronate, risedronate, * Adopted from the classification developed by the Grading of Recommendations,Assessment, Development, and Evaluation (GRADE) workgroup.
zoledronic acid, estrogen, and raloxifene. The drugs cur-rently approved for treatment of osteoporosis include alen- necrosis among bisphosphonate users. MacLean and col- dronate, ibandronate, risedronate, calcitonin, teriparatide, leagues’ background article (5) includes details about the zoledronic acid (in postmenopausal women), and ralox- methods used for the systematic evidence review.
ifene. Testosterone, pamidronate, and etidronate are not The ACP rates the evidence and recommendations by approved by the U.S. Food and Drug Administration for using the Grading of Recommendations, Assessment, De- the treatment or prevention of osteoporosis.
velopment, and Evaluation (GRADE) system with minor
modifications (Table 1). In addition, the evidence review-
ers used predefined criteria to assess the quality of system- atic reviews and randomized trials, based on internal and The literature search done by MacLean and colleagues external validity assessments detailed in the Quality of Re- for the systematic review (5) included studies from MEDLINE porting of Meta-Analyses (QUOROM) statement (7).
(1966 to December 2006), the ACP Journal Club database, The objective of this guideline is to synthesize the ev- the Cochrane Central Register of Controlled Trials (no date limits), the Cochrane Database of Systematic Reviews 1. What are the comparative benefits in fracture reduc- (no date limits), Web sites of the United Kingdom Na- tion among and also within the following treatments for tional Institute of Health and Clinical Excellence (no date low bone density: bisphosphonates, specifically alendro- limits), and the United Kingdom Health Technology As- nate, risedronate, etidronate, ibandronate, pamidronate, sessment Program (January 1998 to December 2006). The and zoledronic acid; calcitonin; estrogen for women; teripa- reviewers limited their search to English-language publica- ratide; selective estrogen receptor modulators (SERMs), spe- tions and human studies. They derived evidence for com- cifically raloxifene and tamoxifen; testosterone for men; vita- parative benefits of various treatments exclusively from ran- mins and minerals, specifically vitamin D and calcium; and domized, controlled trials, whereas they included evidence the combination of calcium plus vitamin D? from other types of studies for short- and long-term harms.
2. How does fracture reduction resulting from treat- Two physicians independently abstracted data about ments vary among individuals with different risks for frac- study populations, interventions, follow-up, and outcome ture as determined by bone mineral density (borderline, ascertainment by using a structured form. For each group low, or severe), previous fractures (prevention vs. treat- within a randomized trial, a statistician extracted the sam- ment), age, sex, glucocorticoid use, and other factors (such ple size and number of persons reporting fractures. Two as community-dwelling vs. institutionalized or vitamin reviewers, under the supervision of the statistician, indepen- dently abstracted information about adverse events. The stat- 3. What are the short- and long-term harms (adverse istician or the principal investigator resolved disagreements.
effects) of these therapies, and do these vary by specific This guideline is based on an evaluation of 76 ran- domized, controlled trials, 4 of which were identified inthe updated search, and 24 meta-analyses that were in-cluded in the efficacy analyses. The analyses of adverse COMPARATIVE BENEFITS OF DRUGS VERSUS PLACEBO IN
events included 491 articles, representing 417 randomized FRACTURE REDUCTION
trials, 25 other controlled clinical trials, 11 open-label trials, Evidence from 24 meta-analyses (8 –30) and 35 addi- 31 large observational studies, and 9 case reports of osteo- tional randomized trials published after the meta-analyses www.annals.org
16 September 2008 Annals of Internal Medicine Volume 149 • Number 6 405
Clinical Guidelines Treatment of Low Bone Density or Osteoporosis to Prevent Fractures (31– 65) described the effect of 9 of the 14 agents (alen- tion of fractures is complex. Most studies of pharmacologic dronate, etidronate, risedronate, calcitonin, estrogen, agents for osteoporosis include calcium and vitamin D as teriparatide, raloxifene, calcium, and vitamin D) on frac- part of the treatment regimen. Evidence from 1 meta- ture incidence. For 4 agents (ibandronate, pamidronate, analysis (27) and several randomized trials (35, 48, 51, 92) zoledronic acid, and tamoxifen), the reviewers found no showed no significant difference between calcium and pla- meta-analyses and instead gathered the evidence from 14 cebo in preventing vertebral, nonvertebral, and hip frac- randomized trials (66 –79). No studies were found that tures in postmenopausal women. However, nonadherence reported fracture rates for testosterone. Three randomized to therapy may influence this result, and 1 trial with a trials (35, 80, 81) and 1 meta-analysis (82) evaluated the prespecified analysis of adherent patients found a reduction combination of calcium plus vitamin D on fractures.
in fracture risk (48). A recent meta-analysis (82) concluded Bisphosphonates
that the relative risk (RR) for fracture with calcium alone Good-quality evidence showed that alendronate, etidro- was 0.90 (CI, 0.80 to 1.00), but it did not include a mod- nate, ibandronate, and risedronate prevent vertebral frac- estly large trial with negative results (35).
tures. In addition, evidence from good-quality studies MacLean and colleagues (5) included 5 systematic re- demonstrated that both alendronate and risedronate pre- views that evaluated vitamin D. Four meta-analyses (8, 21, vent nonvertebral and hip fractures. Two large randomized 24, 28) found that standard vitamin D (D2, D3, or 25- trials showed that zoledronic acid prevents vertebral and hydroxyvitamin [25(OH)]D) did not have any effect on nonvertebral fractures in high-risk populations and reduces risk for vertebral, nonvertebral, or hip fractures; a fifth (35) the risk for hip fracture (67, 74). Ibandronate has not been showed a statistically significant reduction in the pooled shown to reduce nonvertebral fractures (68). Of the 6 fairly risk for nonvertebral and hip fractures for vitamin D2 or small trials that looked at vertebral fractures, 1 demon- D3. In addition, MacLean and colleagues identified 3 strated a statistically significant reduction in fractures with meta-analyses (21, 23, 24) that showed that vitamin D pamidronate relative to placebo (0.14 [95% CI, 0.03 to analogues [1,25(OH)D and 1(OH)D] significantly re- 0.72]) (73). However, after these data were pooled, the duced the risk for vertebral, nonvertebral, and hip frac- pooled risk estimate for fractures for pamidronate relative tures. A meta-analysis published after MacLean and col- to placebo was not significant (0.52 [CI, 0.21 to 1.24]) (6).
leagues’ review concluded that vitamin D and calciumreduced fractures by 13% (RR, 0.87 [CI, 0.77 to 0.97]) Calcitonin
Fair-quality evidence shows that calcitonin reduces In summary, for evaluating the comparative benefits of vertebral fractures (83, 84). Good-quality evidence indi- drugs versus placebo in fracture reduction, good-quality cates that calcitonin does not reduce nonvertebral fractures evidence shows that alendronate, etidronate, ibandronate, risedronate, calcitonin, teriparatide, and raloxifene prevent Estrogen
vertebral fractures. The reviewers also found good-quality Good-quality evidence shows that estrogen reduces the evidence that alendronate and risedronate prevent nonver- incidence of vertebral (29, 85), nonvertebral (86), and hip tebral and hip fractures. No clear evidence demonstrates the appropriate duration of treatment with bisphospho-nates; however, bisphosphonate trials ranged from 3 Teriparatide
months to 60 months. Good evidence shows that estrogen Good-quality evidence shows that teriparatide pre- reduced the incidence of vertebral, nonvertebral, and hip vents vertebral fractures. The evidence related to teri- fractures. The effect of calcium alone is less certain. Sys- paratide preventing nonvertebral fractures is mixed; 1 large tematic reviews of the effectiveness of vitamin D and cal- randomized trial showed a reduction in nonvertebral frac- cium have reached different conclusions, with the most tures (34) but 2 small trials did not (87, 88).
recent systematic review (82) finding a modest reduction in Good-quality evidence shows that raloxifene prevents vertebral fractures, but that tamoxifen has no effect onvertebral fractures (89 –91). In addition, both raloxifene COMPARATIVE BENEFITS OF DRUGS WITHIN AND
and tamoxifen had no effect on hip fractures (91). Tamox- AMONG CLASSES IN FRACTURE REDUCTION
ifen is not approved by the U.S. Food and Drug Admin- Evidence from 9 randomized trials comparing differ- istration for the treatment or prevention of osteoporosis.
ent bisphosphonates (41, 93–100), 1 study comparing dif- Testosterone
ferent SERMs (101), and 16 studies with head-to-head No studies reported fracture rates for testosterone.
comparisons of agents from different classes (31, 32, 35,37, 42, 50, 64, 98, 100, 102–108) evaluated intermediate Calcium and Vitamin D
outcomes, such as bone mineral density and changes in In the studies evaluated by MacLean and colleagues markers of bone turnover. These studies were too short to (5), the evidence for the effect of calcium alone on reduc- detect clinically important differences in fracture incidence.
406 16 September 2008 Annals of Internal Medicine Volume 149 • Number 6
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Treatment of Low Bone Density or Osteoporosis to Prevent Fractures Clinical Guidelines The 2 head-to-head trials that compared fracture incidence also reduced the risk for hip fracture in patients with stroke outcomes (risedronate vs. etidronate [97] and raloxifene vs.
and hemiparesis (RR, 0.12 [CI, 0.02 to 0.90]).
alendronate [107]) were underpowered and showed no statis-tically significant differences.
Populations with Renal Insufficiency
In summary, evidence is insufficient to determine One trial (110) showed that alendronate reduced the whether one bisphosphonate is superior to another, with risk for fractures to a similar degree in patients with and the exception that ibandronate did not reduce nonvertebral those without reduced renal function.
fractures in a relatively large trial (68). Little evidence com-paring drugs from different classes is available.
Populations with Long-Term Glucocorticoid Use
Evidence from 3 studies included in a systematic re- BENEFITS OF DRUGS IN DIFFERENT RISK GROUPS FOR
view (111) showed a possible reduction in vertebral frac- FRACTURE REDUCTION
ture rate with bisphosphonate treatment (112–114). Six Low-Risk Populations
additional trials have been published since this systematic We defined “low risk” as a 10-year risk for osteopo- review. Three of these randomized trials (115–117) rotic fracture (vertebral, nonvertebral, or hip) of up to 2% showed that bisphosphonates reduced the fracture rate. Re- and a lifetime risk of up to 21%. The reviewers gathered sults from 2 studies also showed that risedronate treatment evidence from 4 meta-analyses (14, 15, 28, 107). Summary led to a statistically significant reduction in the absolute estimates for alendronate showed a statistically nonsignifi- risk (11%) and RR (70%) of incident radiographic verte- cant reduction in the risk for vertebral fracture (RR, 0.45 bral fractures after 1 year (117) and in vertebral fractures [CI, 0.06 to 3.15]) and nonvertebral fracture (RR, 0.79 (116). In another trial (115), alendronate was associated [CI, 0.28 to 2.24]) (15). Estrogen did not reduce the risk with a reduction in the risk for incident radiographic ver- for vertebral fracture (28) but reduced nonvertebral frac- tebral fractures. However, 3 additional trials showed no tures (28, 109). However, raloxifene and vitamin D did significant effect on fracture risk for etidronate (32, 53), reduce the risk for vertebral fractures (raloxifene RR, 0.53 from calcium (32), between calcium and a combination of [CI, 0.35 to 0.79]; vitamin D RR, 0.86 [CI, 0.72 to 1.02]) etidronate and calcium (32), or between calcium and pam- (28). Evidence from 2 randomized trials did not show any difference between raloxifene and tamoxifen for reducing To summarize the overall fracture reduction benefits of drug treatments in special populations in different riskgroups, a SERM (raloxifene) and vitamin D both reduced Special Populations
the risk for vertebral fracture in low-risk patients. Far fewer men than women have been included in these trials, result- Studies showed that risedronate decreased the risk for ing in less evidence about the effectiveness of treatment in hip fractures (RR, 0.25 [CI, 0.08 to 0.78]) (56), calcitonin men. In men, risedronate decreased hip fractures and cal- decreased the risk for vertebral fractures (RR, 0.09 [CI, citonin decreased vertebral fractures. Teriparatide de- 0.01 to 0.96]) (61), and teriparatide decreased the risk for creased total fractures and possibly vertebral fractures. In total fractures (RR, 0.16 [CI, 0.01 to 0.96]) and possibly patients with a previous hip fracture, zoledronic acid re- the risk for vertebral fractures (odds ratio [OR], 0.44 [CI, duced the risk for vertebral and nonvertebral fractures.
0.18 to 1.09]) (44). Evidence is insufficient to evaluate the Risedronate reduced the hip and nonvertebral fracture risk effect of calcium alone in men (35).
among patients with Alzheimer disease. Bisphosphonates(risedronate and alendronate) also reduced the clinical andradiographic fracture rate in patients receiving glucocorti- Populations at Increased Risk for Falls
Populations studied included patients with stroke and hemiplegia, Alzheimer disease, a recent hip fracture, or Par-kinson disease. Zoledronic acid reduced the risk for verte- ADVERSE EFFECTS OF DRUGS
bral fractures (hazard ratio, 0.54 [CI, 0.32 to 0.92]) and Bisphosphonates
nonvertebral fractures (hazard ratio, 0.73 [CI, 0.55 to The most common adverse effects of bisphosphonates 0.98]) in patients with a recent hip fracture (74). In pa- are gastrointestinal. Trials reported esophageal ulcerations tients with Alzheimer disease, risedronate reduced the risk from all bisphosphonates except zoledronic acid. One trial for nonvertebral fracture (RR, 0.29 [CI, 0.15 to 0.57]) of etidronate versus placebo showed a statistically signifi- (53) and hip fracture (RR, 0.29 [CI, 0.13 to 0.66]) (58).
cant increase in esophageal ulceration (OR, 1.33 [CI, 1.05 Risedronate also reduced the risk for hip fracture in pa- to 1.68]) (118). Mild upper gastrointestinal events (acid tients with stroke (RR, 0.22 [CI, 0.05 to 0.88]) and hemi- reflux, esophageal irritation, nausea, vomiting, and heart- paresis (RR, 0.25 [CI, 0.08 to 0.78]) (55, 56). In patients burn) were more common with etidronate in a pooled with Parkinson disease, alendronate (RR, 0.30 [CI, 0.12 to analysis (OR, 1.33 [CI, 1.21 to 1.46]) (32, 42, 53, 54, 64, 0.78]) reduced the risk for hip fracture (57). Vitamin D 112, 118 –128) and with pamidronate (OR, 3.14 [CI, 1.93 www.annals.org
16 September 2008 Annals of Internal Medicine Volume 149 • Number 6 407
Clinical Guidelines Treatment of Low Bone Density or Osteoporosis to Prevent Fractures to 5.21]) (75, 79, 129 –133). Pooled analysis showed no the risk for thromboembolic events (OR, 2.08 [CI, 1.47 to difference in occurrence of mild upper gastrointestinal 3.02) (145, 147–152) and mild cardiac events, including events between alendronate, ibandronate, risedronate, or chest pain, palpitations, tachycardia, and vasodilatation zoledronic acid and placebo. However, pooled analysis of (OR, 1.53 [CI, 1.01 to 2.35]) (147, 149, 152–155).
head-to-head trials showed a higher risk for mild upper Testosterone
gastrointestinal events with alendronate than with etidr- No trials of testosterone reported adverse events; how- onate (OR, 5.89 [CI, 1.61 to 32.7]), calcitonin (OR, 3.42 ever, testosterone has well-known side effects.
[CI, 1.79 to 7.00]), or estrogen (OR, 1.57 [CI, 1.00 to2.46]). The pooled estimate from 3 studies showed that Calcium and Vitamin D
etidronate users were at increased risk for perforations, ul- Evidence from randomized trials showed no clinically cerations, and gastrointestinal bleeding events (OR, 1.32 important serious adverse events associated with the use of [CI, 1.04 to 1.67]) (59, 118, 134), whereas the pooled estimate from 2 studies showed that ibandronate had a To summarize the adverse effects of drugs, estrogen lower risk for serious gastrointestinal adverse events (OR, increased the risk for stroke and thromboembolic events; 0.33 [CI, 0.14 to 0.74]) (68, 135). Case reports and case estrogen–progestin increased the risk for stroke and breast series have documented increased osteonecrosis of the jaw cancer; and raloxifene increased the risk for pulmonary in patients receiving bisphosphonates, but the most cases of embolism, thromboembolic events, and mild cardiac osteonecrosis have occurred in patients with cancer who events. Etidronate was associated with increased risk for received high doses of intravenous bisphosphonates (136).
esophageal ulcerations and, in addition to mild upper gas- However, we could not calculate the risk for this event trointestinal events, increased the risk for perforations, ul- from the available studies. Some studies showed a link be- cerations, and bleeding events. Alendronate was associated tween atrial fibrillation and either zoledronic acid or alen- with a higher risk for mild upper gastrointestinal events than were etidronate, calcitonin, and estrogen.
Calcitonin
Evidence from randomized trials showed no clinically important serious adverse events associated with the use of Good evidence shows that bisphosphonates (alendro- nate, etidronate, and risedronate) reduce the risk for verte-bral, nonvertebral, and hip fractures. Ibandronate reduces Estrogen
vertebral fractures. No clear evidence indicates the appro- Estrogen was associated with an increased risk for priate duration of treatment with bisphosphonates; how- thromboembolic events versus placebo in pooled results ever, bisphosphonate trials ranged from 3 months to 60 from 4 studies (OR, 1.36 [CI, 1.01 to 1.86]) (37, 85, 138, months. Estrogen reduces the risk for vertebral, nonverte- 139). In addition, pooled results for estrogen–progestin bral, and hip fractures. Whereas evidence for fracture risk also showed a higher risk for thromboembolic events versus reduction from calcium alone is less clear, it is stronger for placebo (OR, 2.27 [CI, 1.72 to 3.02]) (52, 140, 141).
vitamin D and calcium in combination (82). Evidence Pooled odds of stroke were increased with estrogen (OR, showed a statistically significant reduction in the risk for 1.28 [CI, 1.05 to 1.57]) (83, 138, 139) and combined vertebral fractures from vitamin D analogues [1,25(OH)D estrogen–progestin (OR, 1.28 [CI, 1.05 to 1.57]) relative and 1(OH)D] but mixed results for nonvertebral and hip to placebo (52, 140). Women who received estrogen had a lower pooled risk for breast cancer than those who received Oral bisphosphonates increase the risk for such gastro- placebo (OR, 0.79 [CI, 0.66 to 0.93]) (83, 138, 142–144).
intestinal adverse events as acid reflux. However, pooled However, pooled analysis showed that women who re- analyses showed no differences in occurrence of mild upper ceived an estrogen–progestin combination had an in- gastrointestinal events among alendronate, ibandronate, creased risk for breast cancer (OR, 1.28 [CI, 1.03 to 1.60]) risedronate, or zoledronic acid versus placebo; however, (52, 131, 140). One study showed a lower risk for colon pooled analyses of 18 trials of etidronate versus placebo cancer among women who received an estrogen–progestin indicated an increased risk for mild gastrointestinal events.
combination (OR, 0.64 [CI, 0.43 to 0.95]) (85).
The evidence linking zoledronic acid infusion with atrial Teriparatide
fibrillation is contradictory. Raloxifene increased the Evidence from randomized trials showed no clinically pooled risk for pulmonary embolism and thromboembolic important serious adverse events associated with the use of events. Estrogen was linked to an increased risk for cere- brovascular and thromboembolic events.
Raloxifene increased the pooled risk for pulmonary RECOMMENDATIONS
embolism (OR, 6.26 [CI, 1.55 to 54.80]) (145, 146). In Recommendation 1: ACP recommends that clinicians offer addition, pooled results showed that raloxifene increased pharmacologic treatment to men and women who have known 408 16 September 2008 Annals of Internal Medicine Volume 149 • Number 6
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Treatment of Low Bone Density or Osteoporosis to Prevent Fractures Clinical Guidelines osteoporosis and to those who have experienced fragility fractures rosis in men and women on the basis of an assessment of the (Grade: strong recommendation; high-quality evidence). risk and benefits to individual patients (Grade: strong rec- Good evidence supports the treatment of patients ommendation; moderate-quality evidence). who have osteoporosis to prevent further loss of bone We recommend that the choice of therapy for pa- and to reduce the risk for initial or subsequent fracture.
tients who are candidates for pharmacologic treatment Randomized, controlled trials offer good evidence that, be guided by judgment of the risks, benefits, and adverse compared with placebo, alendronate, ibandronate, effects of drug options for each individual patient. Ta-
risedronate, calcitonin, teriparatide, and raloxifene pre- ble 2 summarizes the benefits and harms of pharmaco-
vent vertebral fractures. Evidence is also good that logic agents for fracture risk. Because good-quality evi- teriparatide prevents nonvertebral fractures compared dence shows that bisphosphonates reduce the risk for with placebo and that risedronate and alendronate pre- vertebral, nonvertebral, and hip fractures, they are rea- vent both nonvertebral and hip fractures compared with sonable options to consider as first-line therapy, partic- placebo. Estrogen has been shown to be associated with ularly for patients who have a high risk for hip fracture.
reduced vertebral, nonvertebral, and hip fractures. The Evidence from head-to-head trials is insufficient to dem- evidence on use of calcium with or without vitamin D ismixed, and the effectiveness is modest. Because most onstrate the superiority of one bisphosphonate over an- trials of other pharmacologic therapy included their use, other. Alendronate and risedronate have been studied we recommend adding calcium and vitamin D to osteo- more than other bisphosphonates (Table 2). Ibandr-
porosis treatment regimens. Evidence is insufficient to deter- onate has not been shown to reduce nonvertebral or hip mine the appropriate duration of therapy.
fractures, which may be an important consideration forsome patients. In a recent trial, zoledronic acid admin- Recommendation 2: ACP recommends that clinicians istered to patients with a recent hip fracture reduced consider pharmacologic treatment for men and women who subsequent fracture and improved survival (74). Of the are at risk for developing osteoporosis (Grade: weak recom- other agents available for treatment of osteoporosis, es- mendation; moderate-quality evidence). trogen has efficacy for vertebral, nonvertebral, and hip Evidence supports the treatment of selected patients fractures but is associated with other serious risks; cal- who are at risk for osteoporosis but who do not have a citonin has not been demonstrated to reduce nonverte- T-score on DXA less than Ϫ2.5. Evidence supporting pre- bral and hip fractures; and calcium and vitamin D are ventive treatment is stronger for patients who are at mod- part of the treatment regimen in most studies of phar- erate risk for osteoporosis, which includes patients who have a T-score from Ϫ1.5 to Ϫ2.5, are receiving glucocor- Gastrointestinal events are the most common ad- ticoids, or are older than 62 years of age.
verse effects associated with bisphosphonate therapy. No Factors that increase the risk for osteoporosis in evidence was found that bisphosphonates, calcium, vita- men include age (Ͼ70 years), low body weight (body min D, calcitonin, or teriparatide differ regarding risk mass index Ͻ20 to 25 kg/m2), weight loss (Ͼ10% for serious cardiac events. Etidronate is associated with [compared with the usual young or adult weight or an increased risk for esophageal ulcers, bleeding events, weight loss in recent years]), physical inactivity (no and mild upper gastrointestinal events (acid reflux, physical activities performed regularly, such as walking, esophageal irritation, nausea, vomiting, and heartburn).
climbing stairs, carrying weights, housework, or garden- Raloxifene is associated with a higher risk for pulmonary ing), corticosteroid use, and androgen deprivation ther-apy (4). Risk factors for women include lower body embolism, thromboembolic events, and mild cardiac weight, the single best predictor of low bone mineral events (including chest pain, palpitations, tachycardia, density; smoking; weight loss; family history; decreased and vasodilatation). Estrogen is associated with a greater physical activity; alcohol or caffeine use; and low cal- risk for stroke, and the estrogen–progestin combination cium and vitamin D intake (3). In certain circum- is associated with a greater probability of stroke and stances, a single risk factor (for example, androgen de- higher odds of breast cancer. In trials, perforations, ul- privation therapy in men) is enough for clinicians to cerations, and bleeding events occurred with all of the bisphosphonates except zoledronic acid.
Research groups are developing calculators, such as the World Health Organization’s Fracture Risk AssessmentTool (available at www.shef.ac.uk/FRAX/), to predict the Recommendation 4: ACP recommends further research to risk for osteoporotic fracture. Such tools will help guide evaluate treatment of osteoporosis in men and women. both clinician and patient decisions.
Current evidence is mostly concentrated on post- menopausal women; more research on other patient pop- Recommendation 3: ACP recommends that clinicians ulations, including men, is needed. Comparative effective- choose among pharmacologic treatment options for osteopo- ness data on preventing fractures from head-to-head www.annals.org
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Clinical Guidelines Treatment of Low Bone Density or Osteoporosis to Prevent Fractures Table 2. Summary of Evidence about Drugs and Fracture Risk
Effect on Risk and Level of Evidence
Adverse Effects
FDA Approval
Vertebral Fracture
Nonvertebral
Hip Fracture
Fracture
Bisphosphonates
ulcerations,perforations, andbleeding events Calcitonin
Estrogen
events;cerebrovascularaccident, stroke,and breast cancer(when combinedwith progestin);gynecologicproblems(endometrialbleeding); breastabnormalities (pain,tenderness, andfibrocytosis) Teriparatide
Testosterone
Calcium and
vitamin D
2 ϭ decreased; 7 ϭ no effect; FDA ϭ U.S. Food and Drug Administration; GI ϭ gastrointestinal; SERM ϭ selective estrogen receptor modulator.
* Pooled estimate across fracture sites.
studies with sufficient power to detect differences would be further research is needed on prevention strategies in both helpful. The association between bisphosphonates and os- men and women and on the appropriate duration of treat- teonecrosis of the jaw also needs to be studied. Finally, 410 16 September 2008 Annals of Internal Medicine Volume 149 • Number 6
www.annals.org
Treatment of Low Bone Density or Osteoporosis to Prevent Fractures Clinical Guidelines From the American College of Physicians and University of Pennsylva- 8. Avenell A, Gillespie WJ, Gillespie LD, O’Connell DL. Vitamin D and vita-
nia, Philadelphia, Pennsylvania; Veterans Affairs Greater Los Angeles min D analogues for preventing fractures associated with involutional and post- Healthcare System and RAND, Santa Monica, California; University of menopausal osteoporosis. Cochrane Database Syst Rev. 2005:CD000227.
Arkansas, Little Rock, Arkansas; and Veterans Affairs Palo Alto Health Care System and Stanford University, Stanford, California.
9. Bischoff-Ferrari HA, Willett WC, Wong JB, Giovannucci E, Dietrich T,
Dawson-Hughes B. Fracture prevention with vitamin D supplementation: a
meta-analysis of randomized controlled trials. JAMA. 2005;293:2257-64.
Note: Clinical practice guidelines are “guides” only and may not apply to
all patients and all clinical situations. Thus, they are not intended to 10. Boonen S, Laan RF, Barton IP, Watts NB. Effect of osteoporosis treatments
override clinicians’ judgment. All ACP clinical practice guidelines are on risk of non-vertebral fractures: review and meta-analysis of intention-to-treat considered automatically withdrawn or invalid 5 years after publication, studies. Osteoporos Int. 2005;16:1291-8. [PMID: 15986101] 11. Cranney A, Welch V, Adachi JD, Homik J, Shea B, Suarez-Almazor ME,
et al. Calcitonin for the treatment and prevention of corticosteroid-induced os-
teoporosis. Cochrane Database Syst Rev. 2000:CD001983. [PMID: 10796457]
Disclaimer: The authors of this article are responsible for its contents,
12. Cranney A, Tugwell P, Adachi J, Weaver B, Zytaruk N, Papaioannou A,
including any clinical or treatment recommendations. No statement in et al. Osteoporosis Methodology Group and The Osteoporosis Research Advi-
this article should be construed as an official position of the Agency for sory Group. Meta-analyses of therapies for postmenopausal osteoporosis. III.
Healthcare Research and Quality or the U.S. Department of Health and Meta-analysis of risedronate for the treatment of postmenopausal osteoporosis.
Endocr Rev. 2002;23:517-23. [PMID: 12202466]
13. Cranney A, Tugwell P, Zytaruk N, Robinson V, Weaver B, Shea B, et al.
Grant Support: Financial support for the development of this guideline
Osteoporosis Methodology Group and The Osteoporosis Research Advisory
Group. Meta-analyses of therapies for postmenopausal osteoporosis. VI. Meta-
comes exclusively from the American College of Physicians’ operating analysis of calcitonin for the treatment of postmenopausal osteoporosis. Endocr Rev. 2002;23:540-51. [PMID: 12202469]
14. Cranney A, Adachi JD, Griffith L, Guyatt G, Krolicki N, Robinson VA,
Potential Financial Conflicts of Interest: Employment: R. Hopkins
et al. WITHDRAWN: Etidronate for treating and preventing postmenopausal
(University of Arkansas). Consultancies: D.K. Owens (GE Healthcare).
osteoporosis. Cochrane Database Syst Rev. 2006:CD003376. [PMID: Grants received: V. Snow (Novo Nordisk, United Healthcare Founda- tion, Centers for Disease Control and Prevention, Atlantic Philanthro- 15. Cranney A, Wells G, Willan A, Griffith L, Zytaruk N, Robinson V, et al.
pies). Any conflict of interest of the Guideline Development Committee Osteoporosis Methodology Group and The Osteoporosis Research Advisory
group members was declared, discussed, and resolved.
Group. Meta-analyses of therapies for postmenopausal osteoporosis. II. Meta-
analysis of alendronate for the treatment of postmenopausal women. Endocr Rev.
2002;23:508-16. [PMID: 12202465]
Requests for Single Reprints: Amir Qaseem, MD, PhD, MHA, Amer-
16. Kanis JA, McCloskey EV. Effect of calcitonin on vertebral and other frac-
ican College of Physicians, 190 N. Independence Mall West, Philadel- tures. QJM. 1999;92:143-9. [PMID: 10326073] phia, PA 19106; e-mail, [email protected].
17. Karpf DB, Shapiro DR, Seeman E, Ensrud KE, Johnston CC Jr, Adami S,
et al. Prevention of nonvertebral fractures by alendronate. A meta-analysis. Alen-
Current author addresses are available at www.annals.org.
dronate Osteoporosis Treatment Study Groups. JAMA. 1997;277:1159-64.
[PMID: 9087473]
18. Miller PD, Roux C, Boonen S, Barton IP, Dunlap LE, Burgio DE. Safety
and efficacy of risedronate in patients with age-related reduced renal function as
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