The Bone-Specific Estrogen Centchroman Inhibits Osteoclastic Bone Resorption in Vitro

Abstract

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 17β-estradiol can inhibit osteoclastic bone resorption although this is somewhat controversial. Therefore, we examined the effect of centchroman and raloxifene, as well as 17β-estradiol, in the in vitro bone slice assay, where the direct effect of compounds on osteoclast activity can be assessed, Centchroman (0.001 - 1 μM) dose-dependently inhibited osteoclastic bone resorption up to 70% at 1 μM (p = 0.007) with an IC50 = 0.1 μM, while in contrast, raloxifene had no significant effect on bone resorption over the same dose range. 17β-estradiol (0.0001 - 1 μM) had a modest but significant inhibitory effect on resorption (40%, p < 0.05) at 1 μM, but no effect at lower physiological/therapeutic concentrations. Centchroman (1 μM) inhibited osteoclast cytoplasmic spreading by 32%, while raloxifene and 17β-estradiol were without effect. These results show that centchroman at therapeutic concentrations (ED50 ∼ 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.