Strontium ranelate is an orally active agent that stimulates new bone formation and decreases bone resorption. A recent phase 2 placebo-controlled study of postmenopausal women with osteoporosis indicated a reduction in vertebral fractures and increased bone mineral density (BMD). The present phase 3 trial, the Spinal Osteoporosis Therapeutic Intervention study, evaluated strontium ranelate, given orally in a dose of 2 g daily for 3 years, in women aged 50 years and older who had been postmenopausal for at least 5 years, had had at least 1 spinal fracture, and had a lumbar spine BMD of 0.84 g/cm2 or lower. A total of 1442 women were randomized to receive strontium ranelate or placebo and were included in an intention-to-treat analysis. All women received calcium and vitamin D supplements. BMD was estimated at 6-month intervals, and spinal radiographs were obtained each year. After 12 months, the risk of a new vertebral fracture was 49% lower in women given strontium ranelate (6.4% vs. 12.2%) for a relative risk of 0.51. Symptomatic fractures were decreased 52%. The reduction in risk of a new spinal fracture persisted throughout the 3-year study period. The risk of having more than 1 new vertebral fracture was 6.4% in the study group and 9.8% in placebo recipients. Fewer patients in the study group lost 1 cm or more in height (30.1% vs. 37.5%). Nonvertebral fractures were similarly frequent in the 2 groups. BMD in the lumbar spine increased by 12.7% in strontium-treated women. None of 14 bone biopsies disclosed osteomalacia or signs of a primary defect in mineralization. Compliance rates were 83% and 85% in the study and placebo groups, respectively. Diarrhea, the most common adverse gastrointestinal effect, tended to resolve after 3 months of treatment. Serum calcium levels were lower and serum phosphate levels higher in strontium-treated women. Strontium ranelate provides a rapid and lasting reduction in the risk of vertebral fractures in postmenopausal women with osteoporosis.