Sex-dependent alterations of the femoral geometry in a mouse model of Marfan syndrome.

Marfan syndrome (MFS), caused by mutations in the Fbn1 gene, is associated with skeletal fragility; yet, the geometric and mechanical consequences for long bones remain underexplored. We examined femoral geometry and rigidity in male and female Fbn1^C1041G/+ (MFS) and WT C57BL/6 J (littermate control) mice (n = 5/sex/genotype) at 6 mo of age using high-resolution micro-CT. Femur length, cortical and medullary areas, cross-sectional circularity, and derived rigidity indices (I MAX, I MIN) were quantified across 3 diaphyseal locations. Marfan syndrome mice had significantly longer femora than controls, with more circular cross-sections regardless of sex. Male MFS mice displayed endosteal expansion, reduced cortical bone (-18% to 30%), and lower bending rigidity, indicating weakened structural resistance. In contrast, female MFS mice maintained or exceeded control rigidity values despite geometric alterations. These findings reveal pronounced sex-dependent skeletal effects in MFS, suggesting that cortical bone loss and estimated mechanical weakening are male-biased features, potentially linked to hormonal influences and altered bone remodeling. Such differences may contribute to differential fracture risk and have implications for targeted interventions in connective tissue disorders.