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Vol. 56, Issue 1, 131-140, July 1999
Bone Research Group, Department of Medicine and Therapeutics,
University of Aberdeen Medical School, Foresterhill, Aberdeen, United
Kingdom (H.L.B., J.C.F., M.J.R.); Department of Human Metabolism and
Clinical Biochemistry, University of Sheffield Medical School,
Sheffield, United Kingdom (J.C.F.); and Departments of Pharmaceutical
Chemistry (S.A.) and Pharmaceutics (J.M.), University of Kuopio,
Kuopio, Finland
Recently, advances have been made in understanding the molecular
mechanisms by which bisphosphonate drugs inhibit bone resorption. Studies with the macrophage-like cell line J774 have suggested that
alendronate, an amino-containing bisphosphonate, causes apoptosis by
preventing post-translational modification of GTP-binding proteins with
isoprenoid lipids. However, clodronate, a nonaminobisphosphonate, does
not inhibit protein isoprenylation but can be metabolized intracellularly to a cytotoxic, 
-
-methylene (AppCp-type)
analog of ATP. These observations raise the possibility that
bisphosphonates can be divided into two groups with distinct molecular
mechanisms of action depending on the nature of the R2 side
chain. We addressed this question by directly comparing the ability of
three aminobisphosphonates (alendronate, ibandronate, and
pamidronate) and three nonaminobisphosphonates (clodronate, etidronate,
and tiludronate) to inhibit protein isoprenylation and activate
caspase-3-like proteases or to be metabolized to AppCp-type nucleotides
by J774 cells. All three aminobisphosphonates inhibited protein
isoprenylation and activated caspase-3-like proteases. Apoptosis and
caspase activation after 24-h treatment with the aminobisphosphonates
could be prevented by addition of farnesol or geranylgeraniol,
confirming that these bisphosphonates inhibit the metabolic mevalonate
pathway. No AppCp-type metabolites of the aminobisphosphonates could be
detected by mass spectrometry. The three nonaminobisphosphonates did
not inhibit protein isoprenylation or cause activation of
caspase-3-like proteases, but were incorporated into AppCp-type
nucleotides. Taken together, these observations clearly demonstrate
that bisphosphonate drugs can be divided into two pharmacological
classes: the aminobisphosphonates, which act by inhibiting protein
isoprenylation, and the less potent nonaminobisphosphonates, which act
through the intracellular accumulation of AppCp-type metabolites.
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