The objective of the study was to determine the efficacy and safety of tiludronate in the treatment of postmenopausal osteoporosis. Two placebo-controlled, randomized, double-masked, multicenter, cyclical, intermittent, dose-ranging studies including 1805 women with low vertebral bone mineral density and prevalent vertebral fractures and 488 women with low bone mineral density and no prevalent fracture were conducted. Patients were randomized to either tiludronate 50 mg/day, tiludronate 200 mg/day or placebo, given orally for the first 7 days of each month. A supplement of 500 mg elemental calcium was provided daily from day 8 to the end of the month. Both studies demonstrated no statistically or clinically relevant trends in the incidence of adverse effects across the three treatment groups. However, tiludronate administered at these two doses in a cyclic intermittent regimen was not effective in reducing the incidence of vertebral fractures or increasing spinal bone mineral density. Thus, tiludronate, administered at these doses in a cyclic intermittent regimen, cannot be considered an appropriate treatment of postmenopausal osteoporosis, notwithstanding a high safety profile.