There is no established treatment for osteoporosis in men, a common and disabling condition the incidence of which is increasing rapidly. We conducted an open study to investigate the efficacy and mode of action of testosterone therapy in eugonadal men with osteoporotic vertebral crush fracture. Twenty-one men, aged 34-73 (mean 58), were treated with intramuscular testosterone esters (Sustanon 250) every 2 weeks for 6 months. Bone mineral density (BMD) measurement by dual-energy X-ray absorptiometry was performed at baseline and 6 months. We also measured biochemical markers of bone turnover, testosterone, estradiol, sex hormone binding globulin (SHBG), and gonadotrophins at baseline and after 3 and 6 months of treatment. Treatment was well tolerated, and side effects were uncommon. Lumbar spine BMD increased by 5% from 0.799 to 0.839 g/cm2 (p < 0.001). All bone markers decreased, indicating that treatment suppressed bone turnover. Although serum osteocalcin levels fell only slightly, there were large reductions in urinary deoxypyridinoline and N-telopeptide (p < 0.05), which were correlated with the increase in spinal BMD. Interpretation of the findings with other markers, such as bone-specific alkaline phosphatase and pyridinoline, was confounded by the wide scatter of values. Serum testosterone increased by 55%, while SHBG decreased by 20%, leading to a rise in free androgen of 90%. Serum estradiol also increased by 45%. The change in spine BMD was significantly correlated with a change in serum estradiol but not with a change in serum testosterone. We therefore conclude that testosterone is a promising treatment for men with idiopathic osteoporosis, acting to suppress bone resorption by a mechanism that may involve estrogen.