title: Odanacatib, effects of 16-month treatment and discontinuation of therapy on bone mass, turnover and strength in the ovariectomized rabbit model of osteopenia.
abstract: Odanacatib (ODN) a selective and reversible cathepsin K inhibitor, inhibits bone resorption, increases bone mass and reduces fracture risk in women with osteoporosis. A 16-month (~7-remodeling cycles) study was carried out in treatment mode to assess the effects of ODN versus ALN on bone mass, remodeling status and biomechanical properties of lumbar vertebrae (LV) and femur in ovariectomized (OVX) rabbits. This study also evaluated the impact of discontinuing ODN on these parameters. Rabbits at 7.5months post-OVX were dosed for 16-months with ODN (7.5μM·h0-24, in food) or ALN (0.2mg/kg/wk, s.c.) and compared to vehicle-treated OVX- (OVX+Veh) or Sham-operated animals. After 8months, treatment was discontinued in half of the ODN group. ODN treatment increased in vivo LV aBMD and trabecular (Tb) vBMD until reaching plateau at month 12 by 16% and 23% vs. baseline, respectively, comparable levels to that in Sham and significantly above OVX+Veh. LV BMD was also higher in ALN that plateaued around month 8 to levels below that in ODN or Sham. ODN treatment resulted in higher BMD, structure and improved biomechanical strength of LV and central femur (CF) to levels similar to Sham. ALN generally showed less robust efficacy compared to ODN. Neither ODN nor ALN influenced material properties at these bone sites following ODN or ALN treatment for 7 remodeling cycles in rabbits. ODN and ALN persistently reduced the bone resorption marker urinary helical peptide over study duration. While ALN reduced the bone formation marker BSAP, ODN treatment did not affect this marker. ODN also preserved histomorphometry-based bone formation indices in LV trabecular, CF endocortical and intracortical surfaces, at the levels of OVX+Veh. Discontinuation of ODN returned bone mass, structure and strength parameters to the comparable respective levels in OVX+Veh. Together, these data demonstrate efficacy and bone safety profile of ODN and suggests the potential long-term benefits of this agent over ALN with respect to accrued bone mass without long-term effects on bone formation.
authors.affiliation: Bone Biology, Merck Research Laboratories, Kenilworth, NJ, USA. Electronic address: le_duong@merck.com.
authors.forename: Le T
authors.initials: LT
authors.lastname: Duong
authors.affiliation: Informatics, Merck Research Laboratories, Kenilworth, NJ, USA.
authors.forename: Randy
authors.initials: R
authors.lastname: Crawford
authors.affiliation: Bone Biology, Merck Research Laboratories, Kenilworth, NJ, USA.
authors.forename: Kevin
authors.initials: K
authors.lastname: Scott
authors.affiliation: Imaging, Merck Research Laboratories, Kenilworth, NJ, USA.
authors.forename: Christopher T
authors.initials: CT
authors.lastname: Winkelmann
authors.affiliation: Molecular Biomarkers, Merck Research Laboratories, Kenilworth, NJ, USA.
authors.forename: Gouxin
authors.initials: G
authors.lastname: Wu
authors.affiliation: SALAR, Merck Research Laboratories, Kenilworth, NJ, USA.
authors.forename: Pete
authors.initials: P
authors.lastname: Szczerba
authors.affiliation: Bone Biology, Merck Research Laboratories, Kenilworth, NJ, USA.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Gentile
mesh_terms: D015502:Absorptiometry, Photon; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D001696:Biomechanical Phenomena; D001713:Biphenyl Compounds / Q000494:pharmacology / Q000627:therapeutic use*; D015519:Bone Density / Q000187:drug effects; D001851:Bone Diseases, Metabolic / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000503:physiopathology*; D016723:Bone Remodeling / Q000187:drug effects; D001842:Bone and Bones / Q000000981:diagnostic imaging / Q000187:drug effects / Q000473:pathology* / Q000503:physiopathology*; D000071556:Cancellous Bone / Q000000981:diagnostic imaging / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D000071538:Cortical Bone / Q000000981:diagnostic imaging / Q000473:pathology / Q000503:physiopathology; D004195:Disease Models, Animal; D005260:Female; D005269:Femur / Q000000981:diagnostic imaging / Q000473:pathology / Q000503:physiopathology; D008159:Lumbar Vertebrae / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D009929:Organ Size / Q000187:drug effects; D010052:Ovariectomy; D011817:Rabbits; D012044:Regression Analysis; D014057:Tomography, X-Ray Computed; D028761:Withholding Treatment
chemical_list: D015415:Biomarkers; D001713:Biphenyl Compounds; C527128:odanacatib
keywords: Alendronate; Bone remodeling; Bone strength; Cathepsin K inhibitor; Odanacatib; Osteoporosis