RALOXIFENE (LY139481 HCL) PREVENTS BONE LOSS AND REDUCES SERUM-CHOLESTEROL WITHOUT CAUSING UTERINE HYPERTROPHY IN OVARIECTOMIZED RATS

There is a medical need for an agent with the positive effects of estr ogen on bone and the cardiovascular system, but without the negative e ffects on reproductive tissue. Raloxifene (Ly139481 HCl) is a benzothi ophene derivative that binds to the estrogen receptor and inhibits the effects of estrogen on the uterus. In an ovariectomized (OVX) rat mod el we investigated the effects of raloxifene on bone loss (induced by estrogen deficiency), serum lipids, and uterine tissue. After oral adm inistration of raloxifene for 5 wk (0.1-10 mg/kg per d) to OVX rats, b one mineral density in the distal femur and proximal tibia was signifi cantly greater than that observed in OVX controls (ED(50) of 0.03-0.3 mg/kg). Serum cholesterol was lower in the raloxifene-treated animals, which had a minimal effective dose of 0.1 mg/kg and an approximate or al ED(50) of 0.2 mg/kg. The effects of raloxifene on bone and serum ch olesterol were comparable to those of a 0.1-mg/kg per d oral dose of e thynyl estradiol. Raloxifene diverged dramatically from estrogen in it s lack of significant estrogenic effects on uterine tissue. Ethynyl es tradiol produced a marked elevation in a number of uterine histologic parameters (e.g., epithelial cell height, stromal eosinophilia). These data suggest that raloxifene has promise as an agent with beneficial bone and cardiovascular effects in the absence of significant uterine effects.