In this study annual infusions of zoledronic acid (5 mg) for 3 years were evaluated to determine whether they reduced the risk of vertebral, hip, and other types of fracture. 3,889 postmenopausal women with osteoporosis (mean age 73 years) were randomly assigned to receive a single 15-minute infusion of zoledronic acid (5 mg) and 3,876 were assigned to receive placebo at baseline, at 12 months and at 24 months; the women were followed until 36 months. Primary end points were new vertebral fracture; secondary end points included bone mineral density, bone turnover markers (C-telopeptide of type I collagen, bone-specific alkaline phosphatase, N-terminal propeptide of type I collagen), safety. The 3-year incidence of morphometric vertebral fracture was 10.9% (310 women) in the placebo group vs 3.3% (92 women) in the zoledronic-acid group, a reduction of 70%. The incidence of hip fracture was 2.5% (88 women) in the placebo group and 1.4% (52 women) in the zoledronic-acid group, a 41% reduction. In the zoledronic-acid group, bone mineral density increased significantly at the total hip (6.02%), lumbar spine (6.71%), femoral neck (5.06%) as compared with the placebo group. All three biochemical markers of bone turnover decreased significantly in patients in the zoledronic-acid group as compared with those in the placebo group. A once-yearly infusion of zoledronic-acid during a 3-year period significantly reduced the risk of vertebral, hip, other fractures. The treatment had a favourable safety profile and was generally well tolerated.