Linking microarchitectural deterioration to altered tissue-level mechanical environments in ovariectomized mouse femora

Estrogen deficiency is a primary driver of osteoporotic bone fragility. While its morphometric characteristics are well-documented, the different tissue-level mechanical environments across femoral regions remain poorly characterized. This study employed an integrated experimental-computational approach, utilizing ex vivo femoral three-point bending data and high-resolution micro-computed tomography (microCT) images from a mouse model. We quantified morphometric parameters within distal metaphyseal cancellous, midshaft cortical, and proximal cortical volumes of interest. Specimen-specific, microCT-based finite element (FE) models were developed to replicate the experimental loading configuration and were validated against experimental displacement data. Local mechanical environments were analyzed using percentile-based metrics of maximum and minimum principal strains, and their relationships with structural parameters were assessed via linear regression. The estrogen-deficient group exhibited a lower quality of metaphyseal cancellous microarchitecture, marked by lower bone volume fraction, trabecular thickness, and trabecular number, alongside higher trabecular separation. In contrast, cortical bone displayed more modest but significant differences in area and moments of inertia. The validated FE models revealed that the ovariectomy (OVX) group had higher tissue-level strain magnitudes across all femoral regions. The most dramatic differences in strain levels were observed in the metaphyseal cancellous bone, where strains were primarily dictated by trabecular microarchitecture. Conversely, cortical bone strains remained governed by cross-sectional geometry. These findings demonstrate that estrogen deficiency is associated with a different distribution of mechanical loads at the tissue level, providing a mechanistic explanation for the higher bone fragility observed. Furthermore, this study highlights the utility of secondary FE analysis for extracting deep biomechanical insights from existing experimental datasets, offering a more nuanced understanding of how structural deficiency relates to mechanical failure in osteoporosis.