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Cumulative Alendronate Dose and the Long-Term Absolute Risk of Subtrochanteric and Diaphyseal Femur Fractures: A Register-Based National Cohort Analysis.
Abrahamsen, Bo; Eiken, Pia; Eastell, Richard
[Article] Journal of Clinical Endocrinology & Metabolism. 95(12):5258-5265, December 2010.

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Context: Bisphosphonates are the mainstay of anti-osteoporotic treatment and are commonly used for a longer duration than in the placebo-controlled trials. A link to development of atypical subtrochanteric or diaphyseal fragility fractures of the femur has been proposed, and these fractures are currently the subject of a U.S. Food and Drug Administration review.

Objective: Our objective was to examine the risk of subtrochanteric/diaphyseal femur fractures in long term users of alendronate.

Design: We conducted an age- and gender-matched cohort study using national healthcare data.

Patients: Patients were alendronate users, without previous hip fracture, who began treatment between January 1, 1996, and December 31, 2005 (n = 39,567) and untreated controls, (n = 158,268).

Main outcome measures: Subtrochanteric or diaphyseal femur fractures were evaluated.

Results: Subtrochanteric and diaphyseal fractures occurred at a rate of 13 per 10,000 patient-years in untreated women and 31 per 10,000 patient-years in women receiving alendronate [adjusted hazard ratio (HR) = 1.88; 95% confidence interval (CI) = 1.62-2.17]. Rates for men were six and 31 per 10,000 patient-years, respectively (HR = 3.98; 95% CI = 2.62-6.05). The HR for hip fracture was 1.37 (95% CI = 1.30-1.46)) in women and 2.47 (95% CI = 2.07-2.95) in men. Risks of subtrochanteric/diaphyseal fracture were similar in patients who had received 9 yr of treatment (highest quartile) and patients who had stopped therapy after the equivalent of 3 months of treatment (lowest quartile).

Conclusions: Alendronate-treated patients are at higher risk of hip and subtrochanteric/diaphyseal fracture than matched control subjects. However, large cumulative doses of alendronate were not associated with a greater absolute risk of subtrochanteric/diaphyseal fractures than small cumulative doses, suggesting that these fractures could be due to osteoporosis rather than to alendronate.