Molecular Mechanisms of Action of Bisphosphonates: Current Status

Abstract

Purpose: Bisphosphonates are currently the most important class of antiresorptive agents used in the treatment of metabolic bone diseases, including tumor-associated osteolysis and hypercalcemia. These compounds have high affinity for calcium ions and therefore target bone mineral, where they are internalized by bone-resorbing osteoclasts and inhibit osteoclast function. Experimental Design: This article reviews the pharmacology of bisphosphonates and the relationship between chemical structure and antiresorptive potency. We also describe new insights into their intracellular molecular mechanisms of action, methods for assessing the effects of bisphosphonates on protein prenylation, and their potential as direct antitumor agents. Results: Nitrogen-containing bisphosphonates act intracellularly by inhibiting farnesyl diphosphate synthase, an enzyme of the mevalonate pathway, thereby preventing prenylation of small GTPase signaling proteins required for normal cellular function. Inhibition of farnesyl diphosphate synthase also seems to account for their antitumor effects observed in vitro and for the activation of g,y T cells, a feature of the acute-phase response to bisphosphonate treatment in humans. Bisphosphonates that lack a nitrogen in the chemical structure do not inhibit protein prenylation and have a different mode of action that seems to involve primarily the formation of cytotoxic metabolites in osteoclasts. Conclusions: Bisphosphonates are highly effective inhibitors of bone resorption that selectively affect osteoclasts in vivo but could also have direct effects on other cell types, such as tumor cells. After >30 years of clinical use, their molecular mechanisms of action on osteoclasts are finally becoming clear but their exact antitumor properties remain to be clarified.Bisphosphonates remain the most widely used and effective antiresorptive agents for the treatment of diseases in which there is an increase in the number or activity of osteoclasts, including tumor-associated osteolysis and hypercalcemia (1). This brief review summarizes our current understanding of the molecular mechanisms of action of bisphosphonates on osteoclasts and their potential to affect other cell types, such as tumor cells, via the same molecular mechanisms. General Properties of BisphosphonatesBisphosphonates are synthetic, nonhydrolyzable analogues of PP i (Fig. 1). The P-C-P structure of bisphosphonates imparts the ability to bind divalent metal ions, such as Ca 2+ (2). For this reason, bisphosphonates are rapidly cleared from the circulation (3, 4) and bind to bone mineral surfaces in vivo at sites of active bone remodeling, particularly areas undergoing osteoclastic resorption (5). The targeting of bisphosphonates to bone, localized release during osteoclastic bone resorption, and efficient uptake into osteoclasts by endocytosis explains why bisphosphonates seem to have a highly selective effect on osteoclasts (2). However, this does not exclude the possibility that small amounts of these drugs are internaliz...

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“…Organ distribution studies demonstrated that BPs are mainly localized in newly formed bones and internalized by the bone resorbing osteoclasts where they inhibit their activity [316]. Due to their high affinity for bone matrix, systemic availability of BPs is rather low with the exception of a transient raise of plasma levels in the post-administration period [317].…”

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“…Bisphosphonates are stable synthetic analogues of pyrophosphate with a P-C-P backbone which can reduce osteolytic bone resorption. Bisphosphonates such as zoledronic acid and ibandronate have been shown to significantly reduce skeletal related events (SREs) across a number of tumor sites including breast prostate, lung and kidney cancers, as well as multiple myeloma and they can even significantly ameliorate bone pain [180]. Denosumab a fully humanised monoclonal antibody (IgG2) that binds with high affinity and high specificity to RANKL inhibits osteoclast formation and bone resorption.…”

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“…However, Zoledronate treatment of patients are reported to induce toxic side effect characterised by osteonecrosis of the jaw while non N-BP did not produce this effect (Van den Wingaert, 2006;Diel et al, 2007). N-BPs, such as zoledronate, act on the mevalonate pathway, inhibiting the farnesyl diphosphate synthase (FPP) and thereby depleting the cells of the farnesyl (FPP) or geranylgeranyl (GGPP) diphosphate isoprenoids (Roelofs et al, 2006). Isoprenoids are required for translocation and anchorage of small G proteins like Rho or Ras to the plasma membrane assuring their ultimate involvement in signal transduction during several important normal and tumor cellular pathways.…”