To evaluate the effect of alendronate on the occurrence rate of multiple symptomatic fractures and on the risk of multiple symptomatic fractures (likelihood of having more than one fracture diagnosed because of the symptoms the fractures caused over the study period) among women with osteoporosis.
Primary analysis of data from a randomized, placebo-controlled, double-blind trial.
Eleven community-based clinical research centers.
Subset of women enrolled in the Fracture Intervention Trial: aged 55 to 81 and having at least one morphometric vertebral fracture at baseline (n = 2,027) or having no vertebral fracture but meeting prevailing World Health Organization bone mineral density criteria for osteoporosis (T-score ≤−2.5 at the femoral neck) (n = 1,631).
All participants reporting calcium intake of 1,000 mg/day or less received a supplement of 500 mg calcium and 250 IU cholecalciferol. Participants were randomly assigned to placebo or alendronate sodium (5 mg/day for 2 years and 10 mg/day for the remainder of the study). Average total follow-up was 4.3 years.
Symptomatic fractures were diagnosed by personal physicians and confirmed by review of radiological data by an expert committee blinded to treatment assignments.
Eighty-six of 1,817 women receiving placebo experienced multiple symptomatic fractures during the follow-up period, compared with 51 of 1,841 receiving alendronate. Reduction of risk for multiple symptomatic fractures combined was 42% (relative risk (RR) = 0.58, 95% confidence interval (CI) = 0.41, 0.81) and for multiple symptomatic vertebral fractures was 84% (RR = 0.16, 95% CI = 0.05, 0.42). Cumulative incidence curves showed divergence after as little as 3 months of treatment, with a statistically significant (P = .044) reduction at 6 months for multiple symptomatic vertebral fractures. When all fractures over the follow-up period were included, the occurrence rates of all symptomatic fractures and symptomatic vertebral fractures were 34% and 63% lower, respectively, with alendronate than with placebo. These reductions were sustained during the follow-up period. All reductions in risk were consistent across predefined subgroups: age (<75 vs ≥75), morphometric vertebral fracture (present vs absent), prior clinical fracture since age 45 (yes vs no), and whether the subject had fallen in the 12 months before randomization.
These data demonstrate that treatment with alendronate reduces the risk of multiple symptomatic fractures during a treatment period averaging 4.3 years. The reductions were consistent across prespecified subgroups. This effect is evident early in treatment and is sustained. J Am Geriatr Soc 50:409–415, 2002.
Most studies examining the effectiveness of drugs in the reduction of symptomatic osteoporotic fractures have restricted their analyses to the first fracture event for each participant, excluding additional fractures that might have occurred during the remainder of the trial.1–4 However, the reporting of not just the first fracture but of all subsequent fractures is clinically revealing, because osteoporotic patients are increasingly experiencing multiple fracture events, as observed in clinical practice and reported by several clinical trials.5–22 However, when multiple fractures are reported, the analyses of additional fractures must be adjusted for the fact that sustaining first fractures increases the risk of subsequent fractures. For example, sustaining a first vertebral fracture quadruples an individual's risk of sustaining an additional vertebral fracture.5,23