Inhibition of bone resorption by alendronate and risedronate does not require osteoclast apoptosis.
Bisphosphonate inhibition of bone resorption was proposed to be due to osteoclast apoptosis. We tested this hypothesis for both the N-containing bisphosphonates alendronate and risedronate, which inhibit farnesyldiphosphate synthase and thus protein isoprenylation, and for clodronate and etidronate, which are metabolized to adenosine triphosphate (ATP) analogs. We found, in dose-response studies, that alendronate and risedronate inhibit bone resorption (in pit assays) at doses tenfold lower than those reducing osteoclast number. At an N-bisphosphonate dose that inhibited resorption and induced apoptosis, the antiapoptotic caspase inhibitor, Z-VAD-FMK, maintained osteoclast (Oc) number but did not prevent inhibition of resorption. Furthermore, when cells were treated with either alendronate alone or in combination with Z-VAD-FMK for 24 or 48 h, subsequent addition of geranylgeraniol, which restores geranylgeranylation, returned bone resorption to control levels. On the other hand, Z-VAD-FMK did block etidronate and clodronate inhibition of resorption. Moreover, in cells treated with etidronate, but not alendronate or risedronate, Z-VAD-FMK also prevented actin disruption, an early sign of osteoclast inhibition by bisphosphonates. These observations indicate that, whereas induction of apoptosis plays a major role in etidronate and clodronate inhibition of resorption, alendronate and risedronate suppression of bone resorption is independent of their effects on apoptosis.
Halasy-Nagy
J M
JM
Department of Bone Biology and Osteoporosis Research, Merck Research Laboratories, West Point, PA 19486, USA.
Rodan
G A
GA
Reszka
A A
AA
D000199:Actins / Q000378:metabolism; D019386:Alendronate / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001862:Bone Resorption / Q000517:prevention & control*; D003599:Cytoskeleton / Q000378:metabolism; D012968:Etidronic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology*; D051379:Mice; D010010:Osteoclasts / Q000166:cytology / Q000187:drug effects*; D000068296:Risedronic Acid
D000199:Actins; D000068296:Risedronic Acid; D012968:Etidronic Acid; D019386:Alendronate