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

The effects of trimegestone (1 mg/kg/day orally), a novel norpregnane proge stin, and 17 beta -estradiol (10 mug/kg/day subcutaneously), alone and in c ombination, on bone mass and turnover were investigated using an experiment al model of osteoporosis involving ovariectomized rats. An equivalent dose (1 mg/kg/day orally) or norethisterone was used as a reference progestin. S ix-month-old vats were ovariectomized and left untreated for 2 months to al low the development of osteopenia. Treatment With a progestin, alone or in combination with estradiol, was then started and continued for 2 months. Bo ne was assessed by a combination of static and dynamic histomorphometric me asurement ltr, by densitometry and by the use of biochemical markers of bon e turnover. Ovariectomy induced a pronounced uterine atrophy, which was rev ersed by estradiol. Trimegestone effectively counteracted the uterotropic e ffect of estradiol, whilst norethisterone showed a less pronounced antagoni stic effect. A severe osteopenia was established in the initial 2 months af ter ovariectomy, and further bone loss occurred during the 2-month treatmen t period in animals not receiving estradiol. This effect was associated wit h a marked increase in both biochemical and dynamic histomorphometric marke rs of bone turnover, reflecting in an imbalance between resorption and form ation. 17 beta -estradiol given alone prevented further bone loss, but neit her trimegestone nor norethisterone alone had a beneficial effect on bone m ass and turnover. When given in combination with 17 beta -estradiol, howeve r, trimegestone significantly improved its effect on bone mass and turnover . This effect was more potent than that induced by combined 17 beta -estrad iol and norethisterone therapy. We conclude that trimegestone, when combine d with 17 beta -estradiol, is a more effective progestin than norethisteron e in preventing bone loss in adult ovariectomized rats.