Nitrogen-containing bisphosphonates inhibit isopentenyl pyrophosphate isomerase farnesyl pyrophosphate synthase activity with relative potencies corresponding to their antiresorptive potencies in vitro and in vivo

Bisphosphonates, synthetic compounds which suppress bone resorption, are us ed in the treatment of skeletal disorders. Their mode of action and intrace llular targets have not yet been identified. Recent evidence suggested that enzymes of the mevalonate pathway are the potential targets. In this study , we examined the effect of four potent nitrogen (N)-containing bisphosphon ates, clodronate and NH2-olpadronate, an inactive analogue of olpadronate, on isopentenyl pyrophosphate isomerase/farnesyl pyrophosphate synthase, ger anylgeranyl pyrophosphate synthase, and protein geranylgeranyl transferase I activity. We found that all N-containing bisphosphonates inhibited isopen tenyl pyrophosphate isomerase/farnesyl pyrophosphate synthase activity dose dependently with relative potencies corresponding to their antiresorptive potencies in vitro and in vivo, whereas clodronate and NH2-olpadronate had no effect. Furthermore, none of the bisphosphonates tested affected geranyl geranyl pyrophosphate synthase or geranylgeranyl transferase I activity. Ou r study reveals for the first time the intracellular target of N-containing bisphosphonates and supports the view that all bisphosphonates do not shar e the same molecular mechanism of action. (C) 1999 Academic Press.