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

ABSTRACT Marfan syndrome (MFS), caused by mutations in 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 wild-type C57BL/6J (littermate control) mice (n=5/sex/genotype) at 6 months of age using high-resolution micro-computed tomography. Femur length, cortical and medullary areas, cross-sectional circularity, and derived rigidity indices (IMAX, IMIN) were quantified across three diaphyseal locations. MFS mice had significantly longer femora than controls, with more circular cross-sections regardless of sex. Male MFS mice displayed endosteal expansion, reduced cortical bone (−18–30%), 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.