Amir Qaseem, MD, PhD, MHA; Vincenza Snow, MD; Paul Shekelle, MD, PhD; Robert Hopkins, MD; Mary Ann Forciea, MD; Douglas K. Owens, MD, MS; Clinical Efficacy Assessment Subcommittee of the American College of Physicians
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.
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.
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).
ACP recommends that clinicians consider pharmacologic treatment for men and women who are at risk for developing osteoporosis (Grade: weak recommendation; moderate-quality evidence).
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).
ACP recommends further research to evaluate treatment of osteoporosis in men and women.
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?
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)?
What are the short- and long-term harms (adverse effects) of these therapies, and do these vary by specific subpopulations?
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Daniel G. Arkfeld
USC Keck School of Medicine
September 16, 2008
Don't Forget About Denosumab
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.
Iberoamerican Cochrane Center, Hospital Santpau, Barcelona
October 11, 2008
Osteoporosis treatment guidelines: too interventionist?
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-Ã -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.
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, SchÃ¼nemann 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/
November 3, 2008
Comment on Guidelines
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
American College of Physicians
January 8, 2009
Author's Response to Dr. Alonso-Coello et al.
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.
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.
Jonathan D. Adachi
St. Joseph's Healthcare - McMaster University
February 4, 2009
Ibandronate and non-vertebral fractures
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.
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
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Qaseem A, Snow V, Shekelle P, Hopkins R, Forciea MA, Owens DK, et al. 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;149:404-415. doi: 10.7326/0003-4819-149-6-200809160-00007
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Published: Ann Intern Med. 2008;149(6):404-415.
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