title: High-resolution peripheral quantitative computed tomography and finite element analysis of bone strength at the distal radius in ovariectomized adult rhesus monkey demonstrate efficacy of odanacatib and differentiation from alendronate.
abstract: Translational evaluation of disease progression and treatment response is critical to the development of therapies for osteoporosis. In this study, longitudinal in-vivo monitoring of odanacatib (ODN) treatment efficacy was compared to alendronate (ALN) in ovariectomized (OVX) non-human primates (NHPs) using high-resolution peripheral computed tomography (HR-pQCT). Treatment effects were evaluated using several determinants of bone strength, density and quality, including volumetric bone mineral density (vBMD), three-dimensional structure, finite element analysis (FEA) estimated peak force and biomechanical properties at the ultradistal (UD) radius at baseline, 3, 6, 9, 12, and 18 months of dosing in three treatment groups: vehicle (VEH), low ODN (2 mg/kg/day, L-ODN), and ALN (30 μg/kg/week). Biomechanical axial compression tests were performed at the end of the study. Bone strength estimates using FEA were validated by ex-vivo mechanical compression testing experiments. After 18months of dosing, L-ODN demonstrated significant increases from baseline in integral vBMD (13.5%), cortical thickness (24.4%), total bone volume fraction BV/TV (13.5%), FEA-estimated peak force (26.6%) and peak stress (17.1%), respectively. Increases from baseline for L-ODN at 18 months were significantly higher than that for ALN in DXA-based aBMD (7.6%), cortical thickness (22.9%), integral vBMD (12.2%), total BV/TV (10.1%), FEA peak force (17.7%) and FEA peak stress (11.5%), respectively. These results demonstrate a superior efficacy of ODN treatment compared to ALN at the UD radii in ovariectomized NHPs.
authors.affiliation: MerckSharp and Dohme Corp., Whitehouse Station, NJ, USA. antonio_cabal@merck.com
authors.forename: Antonio
authors.initials: A
authors.lastname: Cabal
authors.forename: Richa Y
authors.initials: RY
authors.lastname: Jayakar
authors.forename: Swanand
authors.initials: S
authors.lastname: Sardesai
authors.forename: Eual A
authors.initials: EA
authors.lastname: Phillips
authors.forename: John
authors.initials: J
authors.lastname: Szumiloski
authors.forename: Diane J
authors.initials: DJ
authors.lastname: Posavec
authors.forename: Parker D
authors.initials: PD
authors.lastname: Mathers
authors.forename: Alan T
authors.initials: AT
authors.lastname: Savitz
authors.forename: Boyd B
authors.initials: BB
authors.lastname: Scott
authors.forename: Christopher T
authors.initials: CT
authors.lastname: Winkelmann
authors.forename: Sherri
authors.initials: S
authors.lastname: Motzel
authors.forename: Lynn
authors.initials: L
authors.lastname: Cook
authors.forename: Richard
authors.initials: R
authors.lastname: Hargreaves
authors.forename: Jeffrey L
authors.initials: JL
authors.lastname: Evelhoch
authors.forename: Bernard J
authors.initials: BJ
authors.lastname: Dardzinski
authors.forename: Thomas N
authors.initials: TN
authors.lastname: Hangartner
authors.forename: Paul J
authors.initials: PJ
authors.lastname: McCracken
authors.forename: Le T
authors.initials: LT
authors.lastname: Duong
authors.forename: Donald S
authors.initials: DS
authors.lastname: Williams
mesh_terms: D019386:Alendronate / Q000627:therapeutic use*; D000818:Animals; D001713:Biphenyl Compounds / Q000627:therapeutic use*; D015519:Bone Density / Q000187:drug effects*; D050071:Bone Density Conservation Agents / Q000627:therapeutic use*; D020342:Finite Element Analysis; D008253:Macaca mulatta; D010052:Ovariectomy; D011884:Radius; D014057:Tomography, X-Ray Computed
chemical_list: D001713:Biphenyl Compounds; D050071:Bone Density Conservation Agents; C527128:odanacatib; D019386:Alendronate
keywords: Finite element analysis; HR-pQCT; Odanacatib