Bone microarchitecture and material properties decline differently across midlife for male and female F344 × BN F1 rats.

While bone mineral density (BMD) remains the clinical standard for assessing age-related fracture risk, accumulating evidence indicates that bone quality, including matrix properties and microarchitecture, contributes to fracture susceptibility in ways not captured by BMD alone. As matrix-targeted therapeutics emerge, preclinical models that exhibit translationally relevant bone quality changes are needed. Here, we evaluated the Fischer 344 × Brown Norway (F344×BN) F1 rat, a strain characterized by hybrid vigor and non-pathological aging, as a model for studying matrix-related mechanisms of skeletal aging. Femurs from male and female rats aged 7, 15, and 22 months were analyzed to quantify age- and sex-dependent changes in bone microarchitecture, fracture resistance, and matrix properties. Microcomputed tomography analyses revealed sexually dimorphic aging trajectories. From 7 to 22 months, females exhibited moderate declines in trabecular microarchitecture and no change in cortical porosity, whereas males showed pronounced trabecular deterioration and increased cortical porosity. Whole-bone flexural testing demonstrated age-related declines in material properties that were not attributable to changes in geometry, while females maintained geometry-scaled bone strength. Both sexes exhibited reduced bone toughness with age. Raman spectroscopy identified matrix-level alterations in males by 15 months, whereas systemic markers of bone turnover remained unchanged across age or sex. Together, these findings indicate that males exhibit combined tissue-scale and whole-bone deterioration by midlife, while females exhibit declining fracture resistance preceding substantial cortical bone loss or overt matrix deterioration. These results support the F344×BN F1 rat as a translational model for investigating matrix-driven skeletal aging.