title: Evaluation of high-resolution peripheral quantitative computed tomography, finite element analysis and biomechanical testing in a pre-clinical model of osteoporosis: a study with odanacatib treatment in the ovariectomized adult rhesus monkey.
abstract: This study aimed to validate finite element analysis (FEA) estimation of strength, identify high-resolution peripheral quantitative computed tomography (HR-pQCT) measures correlating with strength, and evaluate the precision of HR-pQCT measurements to longitudinally monitor effects of osteoporosis treatment in ovariectomized (OVX) non-human primates (NHPs). HR-pQCT images were acquired in three groups of NHPs: Intact (n=10), OVX-odanacatib treated (OVX-ODN 30 mg/kg, n=10) and OVX-vehicle treated (OVX-Veh, n=10) at the ultradistal (UD) and distal 1/3 radii and tibia at 12, 16 and 20 months. FEA estimates of bone strength using the Pistoia criterion were validated by ex-vivo mechanical compression (r(2)=0.95) of the UD radius. Single linear regressions of FEA-determined ultimate stress showed high correlation with HR-pQCT derived parameters: integral vBMD (r(2)=0.86), bone volume fraction (r(2)=0.84) and cortical thickness (r(2)=0.79). Precision of HR-pQCT measurements, obtained from an excised radius and tibia, showed low variation (CV=0.005%-5.6%) and helped identify possible sources of error. Comparison of OVX-Veh and Intact groups showed decreases in bone parameters demonstrating trends consistent with bone loss. Comparison of OVX-ODN and OVX-Veh groups showed a treatment effect with increases in bone parameters: integral vBMD (477±27 vs. 364±22 mgHA/cm(3)) and cortical thickness (Ct.Th) (0.90±0.07 vs. 0.64±0.04 mm) at the UD radius, Ct.Th (2.15±0.28 vs. 1.56±0.08 mm) at the distal 1/3 radius. Axial compression peak stress calculated and obtained experimentally showed the OVX-ODN group was 33% stronger than the OVX-Veh group. We conclude that HR-pQCT and FEA serve as robust techniques to longitudinally monitor bone parameters and strength in NHP's.
authors.affiliation: Department of Imaging, Merck Research Laboratories, West Point, PA, USA.
authors.forename: Richa Y
authors.initials: RY
authors.lastname: Jayakar
authors.forename: Antonio
authors.initials: A
authors.lastname: Cabal
authors.forename: John
authors.initials: J
authors.lastname: Szumiloski
authors.forename: Swanand
authors.initials: S
authors.lastname: Sardesai
authors.forename: Eual A
authors.initials: EA
authors.lastname: Phillips
authors.forename: Andres
authors.initials: A
authors.lastname: Laib
authors.forename: Boyd B
authors.initials: BB
authors.lastname: Scott
authors.forename: Maureen
authors.initials: M
authors.lastname: Pickarski
authors.forename: Le T
authors.initials: LT
authors.lastname: Duong
authors.forename: Christopher T
authors.initials: CT
authors.lastname: Winkelmann
authors.forename: Paul J
authors.initials: PJ
authors.lastname: McCracken
authors.forename: Richard
authors.initials: R
authors.lastname: Hargreaves
authors.forename: Thomas N
authors.initials: TN
authors.lastname: Hangartner
authors.forename: Donald S
authors.initials: DS
authors.lastname: Williams
mesh_terms: D000818:Animals; D001696:Biomechanical Phenomena; D001713:Biphenyl Compounds / Q000627:therapeutic use*; D015519:Bone Density; D056657:Cathepsin K / Q000037:antagonists & inhibitors; D015853:Cysteine Proteinase Inhibitors / Q000627:therapeutic use; D004195:Disease Models, Animal; D005260:Female; D020342:Finite Element Analysis; D006801:Humans; D008253:Macaca mulatta; D010024:Osteoporosis / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000209:etiology / Q000503:physiopathology*; D010052:Ovariectomy; D055114:X-Ray Microtomography
chemical_list: D001713:Biphenyl Compounds; D015853:Cysteine Proteinase Inhibitors; D056657:Cathepsin K; C527128:odanacatib