Abstract
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. LAY SUMMARY: F344 x BN F1 hybrid rats provide a healthy, matrix-driven skeletal aging model. This strain exhibits distinct aging trajectories dependent on sex. Strength and toughness decrease in both sexes by midlife. Fracture resistance declines in females prior to substantial bone loss.