Novel insights into the molecular pharmacology of bisphosphonate drugs
Nitrogen-containing bisphophonates (N-BPs) are a blockbuster class of drugs for the treatment of common metabolic bone diseases. Recently, N-BPs have been shown to inhibit FPP synthase and/or isopentenyl diphosphate (IPP) isomerase (both enzymes in the mevalonate pathway), thereby preventing the synthesis of the isoprenoid lipids farnesyl diphosphate (FPP) and geranylgeranyl diphosphate (GGPP), which are vital substrates for protein prenylation. By preventing the synthesis of FPP and GGPP, N-BPs prevent the prenylation of small GTPases and inhibit osteoclast function. This study demonstrates conclusively that the major pharmacological target of N-BPs is FPP synthase. Furthermore, minor structural modifications to the N-BPs that govern n vivo potency have a marked effect on potency for inhibition of FPP synthase in vitro. Non-N-BPs, such as clodronate and etidronate, did not inhibit FPP synthase, consistent with other studies suggesting that the non-N-BPs and N-BPs act by different molecular mechanisms. Clinically, N-BPs have been shown to exhibit marked differences in efficacy between patients and may lie resident in the skeleton for many years. J774 macrophage-like cells resistant to the effects of N-BP (J774-RES) were generated to study the possible cellular mechanisms underlying clinical resistance to treatment. The J774-RES cells accumulated N-BP to a lesser extent than parental cells and also exhibited increased expression of the MCSF receptor, although further studies are required to clarify the exact mechanism of the resistance of J774-RES cells. Finally, N-BPs have been shown to induce the proliferation of the major subset (Vg9Vd2) of g,d-T cells in humans, attributed to an agnostic effect on the g,d-T cell receptor (TCR). The findings of this study indicate that the N-BPs act indirectly, by inhibiting FPP synthase and causing the accumulation of IPP, a known agonist of the g,d-TCR. Furthermore, this proliferative effect of N-BPs could be abrogated by statins, possibly indicating a means of preventing the acute-phase response, the major side effect to intravenously-administrated N-BPs.