Histological characterization of periprosthetic tissue responses for metal-on-metal hip replacement.

The histology of periprosthetic tissue from metal-on-metal (MOM) hip devices has been characterized using a variety of methods. The purpose of this study was to compare and evaluate the suitability of two previously developed aseptic lymphocyte-dominated vasculitis-associated lesions (ALVAL) scoring systems for periprosthetic hip tissue responses retrieved from MOM total hip replacement (THR) systems revised for loosening. Two ALVAL scoring systems (Campbell and Oxford) were used to perform histological analyses of soft tissues from 17 failed MOM THRs. The predominant reactions for this patient cohort were macrophage infiltration and necrosis, with less than half of the patients (41%) showing a significant lymphocytic response or a high ALVAL reaction (6%). Other morphological changes varied among patients and included hemosiderin accumulation, cartilage formation, and heterotopic ossification. Both scoring systems are useful for correlating macrophage and lymphocyte responses and for comparison with the other; however, given the diversity and variability of the current responses, the Oxford-ALVAL system is more suitable for scoring tissues from MOM THR patients revised for loosening. It is important that standardized methods of scoring MOM tissue responses be used consistently so multiple study results can be compared and a consensus can be generated.

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.

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.

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.

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.