In a randomized double-masked placebo-controlled parallel-group trial 166 hysterectomized (+/- oophorectomy) perimenopausal and postmenopausal women aged 45-55 years with a follicle stimulating hormone level above 20 IU/l were treated with one daily dose of either 0.5 mg 17beta-estradiol (E2), 1 mg E2, 2 mg E2 or placebo for 2 years. Bone mineral density (BMD) and biochemical bone markers were determined. All three doses of E2 were significantly better than placebo with respect to change in BMD at the lumbar spine (L1-L4) (p<0.0001 for all pairwise comparisons) and hip (femoral neck, trochanter, Ward's triangle). The mean percentage change from baseline at the lumbar spine was -0.2%, 0.8% and 1.8% in the 0.5, 1 and 2 mg E2 groups respectively compared with -3.5% in the placebo group. Both 1 and 2 mg E2 were significantly better than placebo in increasing the BMD at the femoral neck (p<0.001), trochanter (p<0.01) and Ward's triangle (p<0.0001), while 0.5 mg E2 was significantly better than placebo at the femoral neck (p<0.001) and Ward's triangle (p<0.0001). The overall difference in mean percentage change in BMD at the femoral neck versus placebo (-0.2%) was 3.8% for 0.5 mg, 4.0% for 1 mg and 3.9% for 2 mg E2; the corresponding numbers for trochanter were 1.3%, 3.3% and 3.2%, respectively, and -2.2%,, 2.9, 2.9% and 4.0%, respectively, for Ward's triangle. More than half the women who received placebo presented with a decrease in BMD at the hip. The percentage of women in the 0.5 mg E2 group who maintained or increased BMD at the femoral neck, trochanter and Ward's triangle was 69%, 56% and 44%, respectively. For 1 mg E2 the numbers were 69%, 78% and 61% respectively, and for 2 mg E2 were 59%, 68% and 59% respectively. Osteocalcin, serum pyridinium crosslinks, urinary pyridinium cross-links and urinary hydroxyproline/creatinine decreased significantly (p<0.0001, p<0.05) in the 0.5, 1 and 2 mg E2 groups compared with the placebo group after 6 and 24 months of treatment.