Searchable abstracts of presentations at key conferences in endocrinology
Endocrine Abstracts (2005) 10 S37

SFE2005 Special Interest Groups Endocrinology of bone diseases: recent clinical and basic developments (4 abstracts)

Understanding the molecular basis of adverse effects of bisphosphonate drugs in the treatment of bone diseases

MJ Rogers & K Thompson


University of Aberdeen, Aberdeen, United Kingdom.


Bisphosphonates are powerful inhibitors of bone resorption and have become blockbuster drugs in the treatment of metabolic bone diseases. Enormous progress has been made over the last few years in understanding exactly how bisphosphonate drugs act at the molecular level. After targeting bone and selective internalisation by osteoclasts, nitrogen-containing bisphosphonates potently inhibit FPP synthase. Inhibition of this enzyme disrupts the flux through the mevalonate pathway, the metabolic route required for the intracellular biosynthesis of the isoprenoid lipids that are required for the carboxy-terminal modification (prenylation) of small GTP-binding proteins such as Ras, Rho, Rac and Rabs. This modification is essential for the correct localisation of small GTPases to cell membranes. Prenylated small GTPases act as molecular switches, playing key roles in membrane ruffling, trafficking of vesicles, cytoskeletal organisation and cell survival. Inhibition of FPP synthase by bisphosphonates causes loss of synthesis of FPP and its metabolite GGPP, thereby preventing the prenylation of small GTPases. This results in the accumulation of the unprenylated forms of the proteins, thus disrupting osteoclast function and causing osteoclast apoptosis.

The most significant adverse effect of intravenous bisphosphonate therapy is a ‘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 metabolites IPP and DMAPP. The latter are known to stimulate the Vgamma9Vdelta2 subset of gamma,delta-T cells, causing the release of TNFalpha and IFNgamma. This likely induces release of IL6 and C reactive protein and causes the rapid onset of ‘flu-like symptoms. Hence, the ability of nitrogen-containing bisphosphonates to inhibit the mevalonate pathway explains their well-known, potent inhibitory effects on osteoclasts as well as their transient, adverse effects that have been described clinically.

Volume 10

196th Meeting of the Society for Endocrinology and Society for Endocrinology joint Endocrinology and Diabetes Day

Society for Endocrinology 

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