The effects of cyclical treatment with estrone sulfate (0.3, 0.625, or 1.25 mg), plus calcium carbonate, on spinal trabecular bone density were compared with placebo in 120 postmenopausal women in this 2-year, multicenter, double-blind study. While the placebo and 0.3-mg treatment groups lost bone density (-3.6% and -5.1%), the 0.625- and 1.25-mg treatment groups experienced no significant change from baseline at 24 months (-0.8% and +0.7%). The 1.25-mg treatment group was significantly different from the placebo group at 12, 18, and 24 months. Although the 0.625-mg treatment group was significantly different from the placebo group only at 18 months, the data suggest that 0.625 and 1.25 mg of estrone sulfate had different effects than placebo and 0.3 mg of estrone sulfate and, given with supplemental calcium, are effective doses for the prevention of spinal bone loss.