Effect of bisphosphonates on prostaglandin synthesis by rat bone cells and mouse calvaria in culture

Bisphosphonates are potent inhibitors of bone resorption and also inhibit prostaglandin (PG) E2 synthesis in bone cells. Therefore we have investigated whether a correlation exists between inhibition of bone resorption and inhibition of PGE2 formation. Initially, bisphosphonates were tested for their effect on the release of [14C]PGE2 from rat calvaria cells labelled with [14C]arachidonic acid and stimulated by bradykinin, thrombin and mechanical manipulation. The effect on [14C]-PGE2 synthesis was not correlated with the known inhibitory activity of bisphosphonates on bone resorption. Mouse calvaria were then treated with epidermal growth factor (EGF) to induce PGE2 synthesis and bone resorption, with or without bisphosphonates. The bisphosphonates either decreased, had no effect or increased PGE2 production, but all inhibited the release of calcium. Finally, the bisphosphonates were given in vivo to mice before explantation of the calvaria. Some of the bisphosphonates decreased the production of PGE2, suggesting that these compounds may have such an effect in vivo. But again no relationship between the effect on PGE2 synthesis and bone resorption was found. Thus, these experiments show the inhibitory effect of bisphosphonates on bone resorption is unlikely to be explained only by their effect on PGE2 synthesis.