title: Inhibition of bone resorption by the cathepsin K inhibitor odanacatib is fully reversible.
abstract: The cathepsin K (CatK) inhibitor odanacatib (ODN) is currently being developed for the treatment of osteoporosis. In clinical trials, efficacy and resolution of effect of ODN treatment on bone turnover biomarkers and accrued bone mass have been demonstrated. Here, we examine the effects of continuing treatment and discontinuation of ODN versus alendronate (ALN) on osteoclast (OC) function. First, accessibility and reversible engagement of active CatK in intracellular vesicles and resorption lacunae of actively resorbing OCs were demonstrated by the selective and reversible CatK inhibitors, BODIPY-L-226 (IC50=39nM) and L-873,724 (IC50=0.5nM). Next, mature human OCs on bone slices were treated with vehicle, ODN, or ALN for 2days, followed by either continuing with the same treatment, or replacement of the inhibitors by vehicle for additional times as specified per experimental conditions. Maintaining OCs on ODN or ALN significantly reduced CTx-I release compared to vehicle controls. However, only the treatment of OCs with ODN resulted in the formation of small shallow discrete resorption pits, retention of intracellular vesicles enriched with CatK and other lysosomal enzymes, increase in 1-CTP release and number of TRAP(+) OCs. Upon discontinuation of ODN treatment, OCs rapidly resumed bone resorption activity, as demonstrated by a return of OC functional markers (CTx-I, 1-CTP), cell number and size, morphology and number of resorption pits, and vesicular secretion of CatK toward the respective vehicle levels. As expected, discontinuation of ALN did not reverse the treatment-related inhibition of OC activity in the time frame of the experiment. In summary, this study demonstrated rapid kinetics of inhibition and reversibility of the effects of ODN on OC bone resorption, that differentiated the cellular mechanism of CatK inhibition from that of the bisphosphate antiresorptive ALN.
authors.affiliation: Department of Bone Biology, Merck Research Laboratories, West Point, PA, USA. Electronic address: ya_zhuo@merck.com.
authors.forename: Y
authors.initials: Y
authors.lastname: Zhuo
authors.affiliation: Pharmascience, 6111 Avenue Royalmount, suite100, Montréal, QC H4P 2T4, Canada. Electronic address: jgauthie@pharmascience.com.
authors.forename: J-Y
authors.initials: JY
authors.lastname: Gauthier
authors.affiliation: Kaneq Pharma Inc., 110 Churchill, Baie d'Urfé, QC H9X 2Y6, Canada. Electronic address: cameron.black@kaneq.ca.
authors.forename: W C
authors.initials: WC
authors.lastname: Black
authors.affiliation: Inception Sciences Canada Inc., 887 Great Northern Way, Vancouver, BC V5T4T5, Canada. Electronic address: dpercival@inceptionsci.ca.
authors.forename: M D
authors.initials: MD
authors.lastname: Percival
authors.affiliation: Department of Bone Biology, Merck Research Laboratories, West Point, PA, USA. Electronic address: le_duong@merck.com.
authors.forename: L T
authors.initials: LT
authors.lastname: Duong
mesh_terms: D001713:Biphenyl Compounds / Q000494:pharmacology* / Q000627:therapeutic use*; D015153:Blotting, Western; D001862:Bone Resorption / Q000517:prevention & control*; D056657:Cathepsin K / Q000037:antagonists & inhibitors*; D002478:Cells, Cultured; D006801:Humans; D008855:Microscopy, Electron, Scanning; D010010:Osteoclasts / Q000187:drug effects* / Q000648:ultrastructure
chemical_list: D001713:Biphenyl Compounds; C527129:L-873724; D056657:Cathepsin K; C527128:odanacatib
keywords: Bone resorption; Cathepsin K inhibitor; Osteoclast; Resorption lacunae; Ruffled border