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 microM) dose-dependently inhibited osteoclastic bone resorption up to 70% at 1 microM (p = 0.007) with an IC50 = 0.1 microM, while in contrast, raloxifene had no significant effect on bone resorption over the same dose range. 17 beta-estradiol (0.0001 - 1 microM) had a modest but significant inhibitory effect on resorption (40%, p < 0.05) at 1 microM, but no effect at lower physiological/therapeutic concentrations. Centchroman (1 microM) inhibited osteoclast cytoplasmic spreading by 32%, while raloxifene and 17 beta-estradiol were without effect. These results show that centchroman at therapeutic concentrations (ED50 approximately 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.
D000818:Animals; D000831:Animals, Newborn; D001862:Bone Resorption; D002116:Calcitonin / Q000494:pharmacology; D002478:Cells, Cultured; D002486:Centchroman / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004958:Estradiol / Q000494:pharmacology; D004965:Estrogen Antagonists / Q000494:pharmacology; D006801:Humans; D007700:Kinetics; D015394:Molecular Structure; D010010:Osteoclasts / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D010880:Piperidines / Q000494:pharmacology; D020849:Raloxifene Hydrochloride; D051381:Rats; D013329:Structure-Activity Relationship
D004965:Estrogen Antagonists; D010880:Piperidines; D002486:Centchroman; D020849:Raloxifene Hydrochloride; D004958:Estradiol; D002116:Calcitonin