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Benefits and Risks of Long-Term Alendronate

The FLEX study results help us determine for whom long-term alendronate therapy is beneficial.

Alendronate (and the related biphosphonates, risedronate and zoledronic acid), when taken for 3 to 5 years, increases bone density and reduces both vertebral and nonvertebral fracture rates in postmenopausal women. However, some experts have voiced concern that prolonged exposure to these drugs eventually might decrease bone strength by suppressing bone turnover (Journal Watch Apr 5 2005). This apprehension led researchers to ask whether a "holiday" from alendronate after 5 years of therapy might be reasonable.

In the Fracture Intervention Trial Long-term Extension (FLEX), a multi-institutional team began with 1099 women who previously had been randomized to alendronate therapy for a median of 5 years. These participants were randomized again to either daily alendronate (5–10 mg) or placebo for 5 additional years (Journal Watch Jan 9 2007). Women who took placebo showed declines in bone-mineral density (BMD) at the hip and spine during the next 5 years, as well as increased serum markers of bone turnover. In contrast, women who received alendronate did not have these findings.

Relative risk for symptomatic vertebral fractures in women taking alendronate (now for 10 consecutive years) was considerably lower than that in subjects taking alendronate for 5 years and then placebo for 5 years. However, no significant differences were noted in the rates of nonsymptomatic vertebral fractures or nonvertebral fractures. Subgroup analysis revealed that the greatest benefit from an additional 5 years of alendronate therapy was in women with baseline BMD T scores of –2.5 or lower or those who already had experienced vertebral fractures at the time of enrollment in the FLEX study.

No significant difference was seen between the alendronate and placebo groups in serious adverse events or discontinuations of drug because of suspected adverse events. In particular, not a single case of osteonecrosis of the jaw occurred — an adverse effect that got a lot of media attention but that has been seen primarily in patients with cancer who are treated with high-dose intravenous bisphosphonates, not in typical patients taking oral bisphosphonates (Journal Watch Jul 19 2007).

The FLEX study results help us determine for whom long-term alendronate therapy (as long as 10 years) is beneficial. For women with low T scores or previous fractures, continued alendronate therapy conferred benefits. For women with better BMD scores and no vertebral fractures at baseline, however, one could make a case for discontinuing alendronate after 5 years and monitoring BMD closely. The same could be true for women who are at low 5-year risk of hip fracture; based on a large, recently published observational study (Journal Watch Dec 11 2007); risk can be determined using a Web-based interactive calculator.

— Anthony L. Komaroff, MD

Published in Journal Watch General Medicine December 28, 2007

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