COMPARATIVE EFFECTS OF DROLOXIFENE, TAMOXIFEN, AND ESTROGEN ON BONE, SERUM-CHOLESTEROL, AND UTERINE HISTOLOGY IN THE OVARIECTOMIZED RAT MODEL

The purpose of this study was to compare the effects of droloxifene (D RO), tamoxifen (TAM), and 17 alpha-ethynyl estradiol (EE) on bone mine ral density, bone histomorphometry, total serum cholesterol, and uteri ne histology in the ovariectomized (ovx) rat model. Sprague-Dawley fem ale rats at five months of age were sham-operated and treated orally w ith vehicle (n = 8), or ovx (n = 56) and treated (p.o.) with either ve hicle, DRO at 0.1 or 1.0 mg/kg daily, TAM at 0.1 or 1 mg/kg daily, or EE at 3 or 30 mu g/kg daily for 4 weeks, The uterine wet weight and ut erine histologic parameters (cross-sectional tissue area, stromal thic kness, and luminal epithelial thickness) were determined. Femoral and lumbar vertebral bone mineral density was determined ex vivo using dua l energy x-ray absorptiometry. Static and dynamic cancellous bone hist omorphometry was performed on double-labeled, undecalcified longitudin al sections from proximal tibial metaphyses. Furthermore, the changes in total serum cholesterol and body weight gain were also determined, Compared to sham controls, ovx for four weeks significantly decreased uterine weight (-72%), uterine cross-sectional tissue area (-74%), str omal thickness (-52%), and luminal epithelial thickness (-53%), ovx ra ts treated with EE at 30 mu g/kg/day maintained these parameters at th e levels of sham controls, Uterine weight and uterine cross-sectional tissue area in 3 mu g/kg/day of EE treated ovx rats were higher than t hat of vehicle-treated ovx rats, In ovx rats treated with TAM at both 0.1 and 1 mg/kg/day, these parameters were significantly less than sha m controls but significantly higher than ovx controls, DRO at 0.1 mg/k g/day had no effects on all above parameters, Uterine weight and cross -sectional tissue area in 1 mg/kg/day of DRO treated ovx rats,vas slig htly but significantly higher than that in ovx controls, However, DRO at 1 mg/kg/day had no effects on uterine stromal thickness and luminal epithelial thickness compared to ovx controls. The ovx-induced decrea se in femoral and lumbar vertebral bone mineral density was prevented by treatment with EE at 30 mu g/kg/day, TAM at both 0.1 and 1 mg/kg/da y, or DRO at 1 mg/kg/day. Similarly, the decrease in bone mass and the increase in bone resorption and bone turnover in proximal tibial meta physes were prevented by treatment with EE at 30 mu g/kg/day or TAM at both 0.1 and 1 mg/kg/day, or DRO at 1 mg/kg/day. Total serum choleste rol decreased significantly in ovx rats treated with either EE, DRO, o r TAM at all dose levels compared to vehicle treated ovx controls (-32 % to -56%), The ovx-induced body weight gain was completely prevented by EE at 30 mu g/kg/day, and partially prevented by DRO at 1 mg/kg/day , TAM at both 0.1 and 1 mg doses caused a significant decrease in body weight compared to both sham and ovx controls. Our results indicated that DRO prevented ovx-induced bone loss and lowered total serum chole sterol with an ED(50) less than 1 mg/kg/day. The bone protective and c holesterol lowering effects of DRO were comparable to those observed w ith TAM and EE. However, DRO differed from TAM and EE in its lack of s ignificant estrogenic effects on uterine tissue at doses which were bo ne protective. These data suggest that DRO may be a significant altern ative to EE and TAM for prevention and treatment of postmenopausal ost eoporosis. (C) 1997 by Elsevier Science Inc.