Bone mass is maintained when low-dose ethinylestradiol is used in combination with the new progestogen drospirenone as an oral contraceptive, making a regimen of drospirenone combined with 17beta-estradiol an attractive option for hormone replacement therapy (HRT) in postmenopausal women. Drospirenone is a novel progestogen, more closely related to endogenous progesterone in its pharmacological properties than other progestogens available; in combination with estrogen, drospirenone can closely mimic the premenopausal hormonal balance. In a phase II/III double-blind, placebo-controlled, randomized trial, three different doses of drospirenone plus low-dose 17beta-estradiol were compared with placebo, in order to determine their effects on bone density. Of 240 healthy postmenopausal women aged 45-65 years who enrolled, 180 completed the 2-year prospective study. Treatment groups received 1 mg 17beta-estradiol combined with 1, 2 or 3 mg drospirenone daily or placebo. Bone mineral densities at the lumbar spine, hip and total body and markers of bone turnover were measured at 1, 3, 6, 12, 18 and 24 months. In the pooled HRT groups, the bone mineral density at the lumbar spine, hip and total body increased by 7%, 4% and 3%, respectively, compared with placebo (all p < 0.001). Markers of bone turnover in HRT groups all decreased accordingly (serum osteocalcin 52%, serum bone-specific alkaline phosphatase 36%, serum CrossLaps 67% and urinary CrossLaps 75% from baseline; all p < 0.001). The combination of 17beta-estradiol with drospirenone offers a safe and effective medication for decreasing bone turnover and preventing postmenopausal bone loss in postmenopausal women.