PROGESTERONE ANTAGONIST RU-486 HAS BONE-SPARING EFFECTS IN OVARIECTOMIZED RATS

We demonstrated previously that progesterone prevents ovariectomy-induced bone loss. RU 486 is a synthetic steroid with antiprogesterone activities in reproductive tissue. We used 12-week-old rats to evaluate effects of RU 486 in sham-operated rats and to compare medroxyprogesterone (MPA), RU 486, and medroxyprogesterone plus RU 486 combined treatment in ovariectomized rats. Ovariectomized rats were treated with MPA (60 mg/kg intramuscularly), RU 486 (10 mg/kg/day subcutaneously every 4 days), both, or vehicle. Sham-operated rats were treated with similar doses of RU 486 or vehicle. After 4 weeks of treatment the rats were sacrificed and bone histomorphometry was performed on proximal tibial metaphysis. Trabecular bone volume was lower (33.9 +/- 1.5% vs. 46.3 +/- 1.4%) and bone turnover was higher in ovariectomized than in sham-operated rats. The fraction of trabecular bone in OVX rats treated with MPA, RU 486, or both were 41.6 +/- 2.5%, 44.8 +/- 2.8%, and 38.4 +/- 1.4%, respectively. Medroxyprogesterone treatment tended to preserve bone mass by inhibiting the increased resorption indices while maintaining higher formation rates seen in ovariectomized rats. The effects of RU 486 were similar to those of medroxyprogesterone, suggesting an agonist-like effect. Medroxyprogesterone effects were attenuated when it was combined with RU 486, suggesting that RU 486 acted as a partial antagonist in the presence of exogenous progesterone. Bone parameters were less affected in sham-operated RU 486-treated rats, and there was no significant change in bone volume (43.2 +/- 1.7%). Thus, RU 486 mimicked the effects of progesterone on trabecular bone in ovariectomized rats when given alone, but acted as a partial antagonist when administered together with progesterone.