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; for the Fracture Intervention Trial Research Group Context.-Alendronate sodium reduces fracture risk in postmenopausal women who have vertebral fractures, but its effects on fracture risk have not been studied for women without vertebral fractures. Objective.-To test the hypothesis that 4 years of alendronate would decrease the risk of clinical and vertebral fractures in women who have low bone mineral density (BMD) but no vertebral fractures. Design.-Randomized, blinded, placebo-controlled trial. Setting.-Eleven community-based clinical research centers. Subjects.-Women aged 54 to 81 years with a femoral neck BMD of 0.68 g/cm 2 or less (Hologic Inc, Waltham, Mass) but no vertebral fracture; 4432 were randomized to alendronate or placebo and 4272 (96%) completed outcome measurements at the final visit (an average of 4.2 years later). Intervention.-All participants reporting calcium intakes of 1000 mg/d or less received a supplement containing 500 mg of calcium and 250 IU of cholecalciferol. Subjects were randomly assigned to either placebo or 5 mg/d of alendronate sodium for 2 years followed by 10 mg/d for the remainder of the trial. Main Outcome Measures.-Clinical fractures confirmed by x-ray reports, new vertebral deformities detected by morphometric measurements on radiographs, and BMD measured by dual x-ray absorptiometry. Results.-Alendronate increased BMD at all sites studied (PϽ.001) and reduced clinical fractures from 312 in the placebo group to 272 in the intervention group, but not significantly so (14% reduction; relative hazard [RH], 0.86; 95% confidence interval [CI], 0.73-1.01). Alendronate reduced clinical fractures by 36% in women with baseline osteoporosis at the femoral neck (Ͼ2.5 SDs below the normal young adult mean; RH, 0.64; 95% CI, 0.50-0.82; treatment-control difference, 6.5%; number needed to treat [NNT], 15), but there was no significant reduction among those with higher BMD (RH, 1.08; 95% CI, 0.87-1.35). Alendronate decreased the risk of radiographic vertebral fractures by 44% overall (relative risk, 0.56; 95% CI, 0.39-0.80; treatment-control difference, 1.7%; NNT, 60). Alendronate did not increase the risk of gastrointestinal or other adverse effects. Conclusions.-In women with low BMD but without vertebral fractures, 4 years of alendronate safely increased BMD and decreased the risk of first vertebral deformity. Alendronate significantly reduced the risk of clinical fractures among women with osteoporosis but not among women with higher BMD.

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To examine the risk of mortality following all clinical fractures, we followed 6459 women age 55-81 years participating in the Fracture Intervention Trial for an average of 3.8 years. All fractures and deaths were confirmed by medical record or death certificate. Clinical fractures were fractures that came to medical attention. Fracture status was used as a time-dependent covariate in proportional hazards models. The 907 women who experienced a fracture were older, had lower bone mineral density and were more likely to report a positive fracture history. A total of 122 women died over the course of the study with 23 of these deaths occurring after a clinical fracture. The age-adjusted relative risk (95% confidence intervals) of dying following a clinical fracture was 2.15 (1.36, 3.42). This primarily reflected the higher mortality following a hip fracture, 6.68 (3.08, 14.52); and clinical vertebral fracture, 8.64 (4.45, 16.74). Results were similar after adjusting for treatment assignment, health status and specific common comorbidities. There was no increase in mortality following a forearm or other fracture (non-hip, non-wrist, nonvertebral fracture). In conclusion, clinical vertebral fractures and hip fractures are associated with a substantial increase in mortality among a group of relatively healthy older women.