When do bisphosphonates make the most sense?

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Applied Evidence

When do bisphosphonates make the most sense?

J Fam Pract. 2011 January;60(1):18-28

By

Tania Winzenberg, MBBS, FRACGP

Mmedsc, PHD

A Cochrane Musculoskeletal Group review

Should you prescribe bisphosphonates for postmenopausal patients for primary as well as secondary prevention of osteoporotic fractures? Here’s what the evidence tells us.

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References

1. National Osteoporosis Foundation. America’s bone health: the state of osteoporosis and low bone mass in our nation. Washington, DC: National Osteoporosis Foundation; 2002.

2. Burge R, Dawson-Hughes B, Solomon DH, et al. Incidence and economic burden of osteoporosis-related fractures in the United States, 2005-2025. J Bone Miner Res. 2007;22:465-475.

3. Wells GA, Cranney A, Peterson J, et al. Alendronate for the primary and secondary prevention of osteoporotic fractures in postmenopausal women. Cochrane Database Syst Rev. 2008;(1):CD001155.-

4. Wells G, Cranney A, Peterson J, et al. Risedronate for the primary and secondary prevention of osteoporotic fractures in postmenopausal women. Cochrane Database Syst Rev. 2008;(1):CD004523.-

5. Wang Q, Decai C. Ibandronate sodium for osteoporosis in post-menopausal women (Protocol). Cochrane Database Syst Rev. 2007;CD006514.-DOI:10.1002/14651858.

6. Albergaria BH, Gomes Silva BN, Atallah AN, et al. Intravenous zoledronate for postmenopausal osteoporosis (Protocol). Cochrane Database Syst Rev. 2010;(1):CD008332.-DOI:10.1002/14651858.

7. Anonymous. Australian Medicines Handbook. Adelaide, Australia: Australian Medicines Handbook Pty Ltd; 2007.

8. Silverman SL, Landesberg R. Osteonecrosis of the jaw and the role of bisphosphonates: a critical review. Am J Med. 2009;122 (suppl 2):S33-S45.

9. Reid IR. Osteonecrosis of the jaw: who gets it, and why? Bone. 2009;44:4-10.

10. Black DM, Schwartz AV, Ensrud KE, et al. Effects of continuing or stopping alendronate after 5 years of treatment: the Fracture Intervention Trial Long-term Extension (FLEX): a randomized trial. JAMA. 2006;296:2927-2938.

11. Cummings SR, Black DM, Thompson DE, et al. Effect of alendronate on risk of fracture in women with low bone density but without vertebral fractures: results from the Fracture Intervention Trial. JAMA. 1998;280:2077-2082.

12. Reginster J, Minne HW, Sorensen OH, et al. Randomized trial of the effects of risedronate on vertebral fractures in women with established postmenopausal osteoporosis. Vertebral Efficacy with Risedronate Therapy (VERT) Study Group. Osteoporos Int. 2000;11:83-91.

13. Mellstrom DD, Sorensen OH, Goemaere S, et al. Seven years of treatment with risedronate in women with postmenopausal osteoporosis. Calcif Tissue Int. 2004;75:462-468.

14. Cranney A, Wells GA, Yetisir E, et al. Ibandronate for the prevention of nonvertebral fractures: a pooled analysis of individual patient data. Osteoporos Int. 2009;20:291-297.

15. Chesnut IC, Skag A, Christiansen C, et al. Effects of oral ibandronate administered daily or intermittently on fracture risk in postmenopausal osteoporosis. J Bone Miner Res. 2004;19:1241-1249.

16. Delmas PD, Recker RR, Chesnut CH, et al. Daily and intermittent oral ibandronate normalize bone turnover and provide significant reduction in vertebral fracture risk: results from the BONE study. Osteoporosis Int. 2004;15:792-798.

17. Recker R, Stakkestad JA, Chesnut CH, et al. Insufficiently dosed intravenous ibandronate injections are associated with suboptimal antifracture efficacy in postmenopausal osteoporosis. Bone. 2004;34:890-899.

18. Adami S, Felsenberg D, Christiansen C, et al. Efficacy and safety of ibandronate given by intravenous injection once every 3 months. Bone. 2004;34:881-889.

19. Delmas PD, Adami S, Strugala C, et al. Intravenous ibandronate injections in postmenopausal women with osteoporosis. One-year results from the dosing intravenous administration study. Arthritis Rheum. 2006;54:1838-1846.

20. Epstein S, Delmas PD, Emkey R, et al. Oral ibandronate in the management of postmenopausal osteoporosis: review of upper gastrointestinal safety. Maturitas. 2006;54:1-10.

21. Ettinger MP, Felsenberg D, Harris ST, et al. Safety and tolerability of oral daily and intermittent ibandronate are not influenced by age. J Rheumatol. 2005;32:1968-1974.

22. Black DM, Delmas PD, Eastell R, et al. Once-yearly zoledronic acid for treatment of postmenopausal osteoporosis. N Engl J Med. 2007;356:1809-1822.

23. Lyles KW, Colon-Emeric CS, Magaziner JS, et al. Zoledronic acid and clinical fractures and mortality after hip fracture. N Engl J Med. 2007;357:1799-1809.

24. Shane E, Burr D, Ebeling PR, et al. Atypical subtrochanteric and diaphyseal femoral fractures: report of a task force of the American Society for Bone and Mineral Research. J Bone Miner Res. 2010;25:2267-2294.

25. US Food and Drug Administration. FDA Drug Safety Communication: Safety update for osteoporosis drugs, bisphosphonates, and atypical fractures. October 13, 2010. Available at: http://www.fda.gov/drugs/drugsafety/ucm229009.htm. Accessed December 7, 2010.

26. Seeman E, Compston J, Adachi J, et al. Non-compliance: the Achilles’ heel of anti-fracture efficacy. Osteoporos Int. 2007;18:711-719.

27. Cramer JA, Gold DT, Silverman SL, et al. A systematic review of persistence and compliance with bisphosphonates for osteoporosis. Osteoporos Int. 2007;18:1023-1031.

28. Adami S, Giannini S, Bianchi G, et al. Vitamin D status and response to treatment in post-menopausal osteoporosis. Osteoporos Int. 2009;20:239-244.

An estimated 10 million US residents, most of them women over the age of 50, suffer from osteoporosis, and another 33 million have low bone mass.¹ Together, they incur more than 2 million osteoporotic fractures annually.^1,2 In addition to the high cost of a single osteoporotic fracture in terms of morbidity, mortality, and health care spending, individuals who sustain one such fracture are at high risk for another. That risk can be greatly reduced with appropriate treatment.

FAST TRACK

There is little evidence to support the use of bisphosphonates for primary prevention, with the exception of alendronate.

Bisphosphonates, which act on osteoclasts to inhibit bone resorption, are first-line therapy for prevention of osteoporotic fractures. Four bisphosphonates—alendronate, ibandronate, risedronate, and zoledronic acid—are approved by the US Food and Drug Administration (FDA) for the treatment of postmenopausal osteoporosis.

While menopause itself increases a woman’s risk for osteoporotic fracture, questions remain about when to initiate preventive therapy, which patients are candidates for bisphosphonates, and whether bisphosphonates are effective for primary as well as secondary prevention. This overview from the Cochrane Musculoskeletal Group (CMSG) addresses those questions.

To help you provide optimal treatment for postmenopausal patients, we present the findings of recently conducted systematic reviews of 2 bisphosphonates—alendronate and risedronate—from the Cochrane Database of Systematic Reviews,^3,4 in context with the available evidence on the efficacy of ibandronate and zoledronic acid. Cochrane reviews of ibandronate and zoledronic acid are underway, but not yet completed.^5,6

How this series can help you

This is the second in a series of articles based on the findings of the Cochrane Musculoskeletal Group (CMSG), one of the largest review groups in the Cochrane Collaboration. The CMSG synthesizes the results of high-quality clinical trials to determine whether interventions for the prevention, treatment, and rehabilitation of musculoskeletal disorders are safe and effective. In this article and those that follow, CMSG’s aim is to bring its findings to the attention of family physicians in a context that is relevant to clinical practice.

Alendronate reduces vertebral fracture risk across the board

Wells et al identified 11 RCTs for the alendronate review (3 primary and 8 secondary prevention trials), representing a total of 12,068 women.³ (For definitions of what constituted a primary vs a secondary prevention trial, see the box.)

Doses of alendronate ranged from 1 to 20 mg daily, with most studies using doses of 5 or 10 mg. Treatment duration ranged from 1 to 4 years.

A look at the relative risk (RR) for primary and secondary prevention at different fracture sites (TABLE 1) highlights similarities and differences. The risk reduction for vertebral fractures was statistically significant—and about the same—for women being treated with alendronate for primary and secondary prevention (RR=0.55; 95% confidence interval [CI], 0.38-0.80; RR=0.55; 95% CI, 0.43-0.69, respectively). For all other (nonvertebral) fractures in patients being treated with alendronate, only the outcomes for secondary prevention were statistically significant.

Primary vs secondary trials: A look at the definitions

The Cochrane reviewers studied the effects of alendronate and risedronate^3,4 for both primary and secondary prevention of osteoporotic fractures in postmenopausal women, using the following definitions (with slight variations in definitions between trials):

Primary prevention. Randomized controlled trials were classified as primary prevention trials if the participants had baseline T-scores >–2.0 or a baseline prevalence of vertebral fracture <20%.

Secondary prevention. Studies were classified as secondary prevention trials if the women had baseline T-scores ≤–2.0 (ie, bone mineral density [BMD] ≥2 standard deviations below peak bone mass) or previous vertebral compression fractures. (In the ibandronate individual patient meta-analysis,¹⁴ secondary prevention was defined as lumbar spine T-score <–2.5 or baseline vertebral fracture prevalence >20% or mean age of participants >60 years.)

Age-based criterion. When data on T-scores and/or vertebral compression fractures were unavailable, age was the determinant: Trials were considered secondary prevention if the average age of the participants was >62 years, and primary prevention if the average age was ≤62.

Risedronate is effective only for secondary prevention

Seven RCTs, including 2 primary and 5 secondary prevention trials, were included in the Cochrane review of risedronate, representing a total of 14,049 women.⁴ Doses ranged from 2.5 to 5 mg daily, but also included cyclical dosing—for example, taking 5 mg/d for the first 2 weeks of every month. Treatment duration ranged from 2 to 3 years.

At doses of 5 mg/d, there were no statistically significant decreases in fracture risk at any site in the primary prevention trials (TABLE 1), although the quality of evidence assessed was low. For secondary prevention, however, the risk reduction for vertebral fracture was significant (RR=0.61; 95% CI, 0.50-0.76), as were the reductions in risk for nonvertebral and hip fractures.