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

Although the cyclooxygenase and lipoxygenase pathways of arachidonic acid m etabolism have been shown to lead to osteoclastic resorption, the cytochrom e P450 pathway has not been implicated. We investigated the effects of the cytochrome P450 pathway in IL-1 beta-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 inhibito r. Clotrimazole inhibited calcium release in a dose-dependent manner; howev er, L-N-G-arginine methyl ester did not inhibit resorption. These results s uggest that cytochrome P450 may be another possible mediator of IL-1 beta-i nduced bone resorption in vitro. In the in vivo portion of the study, clotr imazole was administered in the gerbil model of adaptive bone modeling. Clo trimazole inhibited osteoclast surface; however, it did not reduce the oste oclast number, mean erosion surface per osteoclast, mineralization surface, or mineral-apposition rate. These results suggest that clotrimazole may in hibit the activation of osteoclasts and that cytochrome P450-dependent enzy mes may be related to osteoclast activation in vivo.