title: Inhibition of bone resorption by alendronate and risedronate does not require osteoclast apoptosis.
abstract: 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.
authors.affiliation: Department of Bone Biology and Osteoporosis Research, Merck Research Laboratories, West Point, PA 19486, USA.
authors.forename: J M
authors.initials: JM
authors.lastname: Halasy-Nagy
authors.forename: G A
authors.initials: GA
authors.lastname: Rodan
authors.forename: A A
authors.initials: AA
authors.lastname: Reszka
mesh_terms: 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
chemical_list: D000199:Actins; D000068296:Risedronic Acid; D012968:Etidronic Acid; D019386:Alendronate