This study was carried out to investigate the effectiveness and tolerability of cyclical etidronate therapy in the prevention of bone loss occurring in early postmenopausal women who are not undergoing hormone replacement therapy (HRT). A total of 109 Caucasian women aged 45-60 years were treated with etidronate 400 mg/day or placebo for 14 days followed by calcium supplementation 500 mg/day for 77 days. Ninety-one women completed the 2 years of the study. After 2 years, the estimated difference between the two groups as regards lumbar spine bone mineral density (BMD) was 2.53% (SEM 1.07%; p = 0.01); BMD of the hip and wrist were not significantly different between treatment groups. A clear reduction in bone turnover was obtained as evidenced by a significant decrease in serum alkaline phosphatase level and in urinary N-telopeptide/ creatinine ratio in the etidronate group; the difference between the two groups was -12% +/- 3.2% for serum alkaline phosphatase level (p = 0.019) and -22.9% +/- 13.7% for the urinary N-telopeptide/creatinine ratio (p = 0.047). There was no statistically significant difference between the two groups in terms of the serum osteocalcin levels and urinary hydroxyproline/ creatinine and calcium/creatinine ratios. Etidronate was generally well tolerated and its adverse event profile was similar to that of placebo. The results of this study indicate that cyclic etidronate therapy can prevent trabecular bone loss, with no deleterious effect on cortical bone, in the first 5 years of menopause and that it has a very high safety margin.