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Vol. 296, Issue 2, 235-242, February 2001
Department of Medicine and Therapeutics, University of Aberdeen
Medical School, Foresterhill, Aberdeen, United Kingdom (J.E.D., K.T.,
F.P.C., S.P.L., M.J.R.); Department of Chemistry, University of Utah,
Salt Lake City, Utah (C.D.P.); Maui Agricultural Research Center,
University of Hawaii, Kula, Hawaii (F.M.H.); and Procter & Gamble
Pharmaceuticals, Health Care Research Center, Mason, Ohio (F.H.E.)
It has long been known that small changes to the structure of the
R2 side chain of nitrogen-containing bisphosphonates can
dramatically affect their potency for inhibiting bone resorption in
vitro and in vivo, although the reason for these differences in
antiresorptive potency have not been explained at the level of a
pharmacological target. Recently, several nitrogen-containing
bisphosphonates were found to inhibit osteoclast-mediated bone
resorption in vitro by inhibiting farnesyl diphosphate synthase,
thereby preventing protein prenylation in osteoclasts. In this study,
we examined the potency of a wider range of nitrogen-containing
bisphosphonates, including the highly potent, heterocycle-containing
zoledronic acid and minodronate (YM-529). We found a clear correlation
between the ability to inhibit farnesyl diphosphate synthase in vitro, to inhibit protein prenylation in cell-free extracts and in purified osteoclasts in vitro, and to inhibit bone resorption in vivo. The
activity of recombinant human farnesyl diphosphate synthase was
inhibited at concentrations 
1 nM zoledronic acid or minodronate, the
order of potency (zoledronic acid 
minodronate > risedronate > ibandronate > incadronate > alendronate > pamidronate) closely matching the order of
antiresorptive potency. Furthermore, minor changes to the structure of
the R2 side chain of heterocycle-containing
bisphosphonates, giving rise to less potent inhibitors of bone
resorption in vivo, also caused a reduction in potency up to
~300-fold for inhibition of farnesyl diphosphate synthase in vitro.
These data indicate that farnesyl diphosphate synthase is the major
pharmacological target of these drugs in vivo, and that small changes
to the structure of the R2 side chain alter antiresorptive
potency by affecting the ability to inhibit farnesyl diphosphate synthase.
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