Prevention of bone loss by EM-800 and raloxifene in the ovariectomized rat

Some undesirable effects are associated with chronic estrogen and progestin administration used to prevent bone loss in postmenopausal women, thus lea ding to poor compliance and the need for improved therapeutic and preventiv e agents. We have thus studied the ability of the new antiestrogen EM-800 ( SCH 57050) to prevent bone toss and lower serum cholesterol levels and comp ared its effects with those of raloxifene. Ovariectomized (OVX) female rats were treated by oral gavage for 37 weeks with increasing daily doses (0.01 , 0.03, 0.1, 0.3 or 1 mg/kg) of EM-800 or raloxifene. At 35 weeks after OVX , lumbar spine bone mineral density (BMD) was 19% lower than in intact anim als (P < 0.01), while the OVX animals given EM-800 or raloxifene had 90-93 and 85-90%, respectively, of the BMD values observed in intact rats. Simila r effects were observed on femoral BMD. Bone histomorphometry measurements were performed on proximal tibia. At the 0.01 mg/kg dose, EM-800 prevented the effect of OVX on TBV by 34% (P < 0.01), while raloxifene had no detecta ble effect. Treatment with 1 mg/kg EM-800 and raloxifene resulted in, respe ctively, 68% (P < 0.01) and 64% (P < 0.01) prevention of the OVX-induced de crease in TBV. In addition, the administration of 0.01 and 0.03 mg/kg EM-80 0 caused, respectively, 54% (P < 0.01) and 56% (P < 0.01) inhibitions of se rum cholesterol levels, while raloxifene administered at the same doses cau sed, respectively, 24% (P < 0.01) and 41% (P < 0.01) decreases of the value of the same parameter. At the highest doses used (0.1-1 mg/kg), both compo unds lowered serum cholesterol levels by approximately 65% (P < 0.01). No s timulatory effect of EM-800 was observed on the endometrial epithelial cell s at doses up to 1 mg/kg, while hypertrophy of uterine epithelium was obser ved with raloxifene. EM-800 and raloxifene achieve the same degree of effec tiveness on bone and serum cholesterol at higher doses, but EM-800 is at le ast three to ten times more potent than raloxifene at lower concentrations and has no stimulatory effect on uterine epithelium. The present data show the potent effect of EM-800 preventing bone loss and lower serum cholestero l levels without the negative effect on the endometrium, thus suggesting th e particular interest of this new fully tissue-specific selective estrogen receptor modulator. (C) 2000 Elsevier Science Ltd. All rights reserved.