Effect of trimegestone alone or in combination with estradiol on bone mass and bone turnover in an adult rat model of osteopenia

The effects of trimegestone (1 mg/kg/day orally), a novel norpregnane progestin, and 17 beta-estradiol (10 micrograms/kg/day subcutaneously), alone and in combination, on bone mass and turnover were investigated using an experimental model of osteoporosis involving ovariectomized rats. An equivalent dose (1 mg/kg/day orally) or norethisterone was used as a reference progestin. Six-month-old rats were ovariectomized and left untreated for 2 months to allow the development of osteopenia. Treatment with a progestin, alone or in combination with estradiol, was then started and continued for 2 months. Bone was assessed by a combination of static and dynamic histomorphometric measurements, by densitometry and by the use of biochemical markers of bone turnover. Ovariectomy induced a pronounced uterine atrophy, which was reversed by estradiol. Trimegestone effectively counteracted the uterotropic effect of estradiol, whilst norethisterone showed a less pronounced antagonistic effect. A severe osteopenia was established in the initial 2 months after ovariectomy, and further bone loss occurred during the 2-month treatment period in animals not receiving estradiol. This effect was associated with a marked increase in both biochemical and dynamic histomorphometric markers of bone turnover, reflecting in an imbalance between resorption and formation. 17 beta-estradiol given alone prevented further bone loss, but neither trimegestone nor norethisterone alone had a beneficial effect on bone mass and turnover. When given in combination with 17 beta-estradiol, however, trimegestone significantly improved its effect on bone mass and turnover. This effect was more potent than that induced by combined 17 beta-estradiol and norethisterone therapy. We conclude that trimegestone, when combined with 17 beta-estradiol, is a more effective progestin than norethisterone in preventing bone loss in adult ovariectomized rats.