THE BONE-SPECIFIC ESTROGEN CENTCHROMAN INHIBITS OSTEOCLASTIC BONE-RESORPTION IN-VITRO

There is considerable interest in identifying bone-specific estrogen-like compounds with beneficial activities on bone and the cardiovascular system, but lacking side effects on the reproductive system. Two such compounds are currently under clinical investigation - raloxifene (Lilly) and centchroman (Novo-Nordisk). There is evidence suggesting that 17 beta-estradiol can inhibit osteoclastic bone resorption although this is somewhat controversial. Therefore, we examined the effect of centchroman and raloxifene, as well as 17 beta-estradiol, in the in vitro bone slice assay, where the direct effect of compounds on osteoclast activity can be assessed, Centchroman (0.001 - 1 mu M) dose-dependently inhibited osteoclastic bone resorption up to 70% at 1 mu M (p = 0.007) with an IC50 = 0.1 mu M, while in contrast, raloxifene had no significant effect on bone resorption over the same dose range. 17 beta-estradiol (0.0001 - 1 mu M) had a modest but significant inhibitory effect on resorption (40%, p < 0.05) at 1 mu M, but no effect at lower physiological/therapeutic concentrations. Centchroman (1 mu M) inhibited osteoclast cytoplasmic spreading by 32%, while raloxifene and 17 beta-estradiol were without effect. These results show that centchroman at therapeutic concentrations (ED(50) similar to 1 mg/kg in animal models) is a potent inhibitor of osteoclastic bone resorption in vitro, suggesting that bone-specific estrogen-like molecules may have different mechanisms of action. (C) 1995 Academic Press, Inc.