Cytochrome P-450 inhibition blocks bone resorption in vitro and in vivo

Although the cyclooxygenase and lipoxygenase pathways of arachidonic acid metabolism have been shown to lead to osteoclastic resorption, the cytochrome P450 pathway has not been implicated. We investigated the effects of the cytochrome P450 pathway in IL-1β-induced calcium release from cultured mouse calvaria in vitro in the presence of clotrimazole, a cytochrome P450 inhibitor, or L-N(G)-arginine methyl ester, a nitric oxide synthase inhibitor. Clotrimazole inhibited calcium release in a dose- dependent manner; however, L-N(G)-arginine methyl ester did not inhibit resorption. These results suggest that cytochrome P450 may be another possible mediator of IL-1β-induced bone resorption in vitro. In the in vivo portion of the study, clotrimazole was administered in the gerbil model of adaptive bone modeling. Clotrimazole inhibited osteoclast surface; however, it did not reduce the osteoclast number, mean erosion surface per osteoclast, mineralization surface, or mineral-apposition rate. These results suggest that clotrimazole may inhibit the activation of osteoclasts and that cytochrome P450-dependent enzymes may be related to osteoclast activation in vivo.