Endocrine Abstracts (2007) 14 S22.1

Bisphosphonates: molecular mode of action and adverse effects

Michael J Rogers

University of Aberdeen, Aberdeen, United Kingdom.

Bisphosphonates are the mainstay of treatment for metabolic bone diseases such as post-menopausal osteoporosis and Paget’s disease. Enormous progress has been made over the last few years in understanding how these drugs act at the molecular level. After targeting bone and selective internalisation by osteoclasts, simple bisphosphonates are incorporated into cytotoxic, non-hydrolysable analogues of ATP. By contrast, the more potent nitrogen-containing bisphosphonates inhibit FPP synthase (an enzyme of the mevalonate pathway), which disrupts the synthesis of the isoprenoid lipids FPP and GGPP. These lipids are required for the carboxy-terminal modification (prenylation) of small GTP-binding proteins such as Ras, Rho, Rac and Rabs. Prenylated small GTPases act as molecular switches, regulating processes fundamental to osteoclast function, including membrane ruffling, vesicular trafficking, cytoskeletal organisation and cell survival. Inhibition of FPP synthase by bisphosphonates prevents the prenylation of small GTPases and causes the accumulation of the unprenylated (and, in some cases, inappropriately activated) forms of the proteins, thus disrupting osteoclast function and causing osteoclast apoptosis.

The most common adverse effect of intravenous bisphosphonate therapy is a brief, ‘flu-like acute-phase reaction. We have recently demonstrated that this effect appears to be due to inhibition of FPP synthase in peripheral blood mononuclear cells, which causes an accumulation of the upstream isoprenoid lipid IPP. The latter is known to stimulate the Vgamma9Vdelta2 subset of gamma,delta-T cells, causing the release of TNFalpha and IFNgamma and hence the rapid onset of ‘flu-like symptoms. Esophageal irritation by oral bisphosphonates may also be caused by inhibition of FPP synthase in GI epithelial cells, however the exact cause of recently-described, rare cases of osteonecrosis of the jaw remains unclear.

Thus, the ability of nitrogen-containing bisphosphonates to inhibit the mevalonate pathway explains their well-known, potent inhibitory effects on bone-destroying osteoclasts as well some of their adverse effects.

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