Sex Differences in Systemic Bone and Muscle Loss After Femur Fracture in Mice

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Abstract

It is likely that fracture initiates a period of bone loss throughout the body (systemic bone loss), which may permanently reduce skeletal strength, thereby increasing the risk of future fracture and osteoporosis. Additionally, fracture may also lead to greater muscle loss in males due to lower muscle fatigue resistance than females. However, sex differences in systemic loss of bone and muscle following a fracture have not been analyzed. This study compared the magnitude and time course of systemic bone and muscle loss after femur fracture in male and female mice. We hypothesized that both male and female mice would experience systemic bone and muscle loss following femur fracture, but that males would exhibit greater magnitudes of bone and muscle loss and a diminished recovery at later time points. Transverse femur fractures were created in 40 C57BL/6 mice (20 male and 20 female, 3 months old at the time of injury) and 40 mice had no surgical procedures. Longitudinal assessment of bone mineral density (BMD), bone mineral content (BMC), and gastrocnemius maximum muscle contraction force was performed prior to fracture and at 1, 2, 4, and 6 weeks post-fracture. Mice were euthanized 2 or 6 weeks after fracture and L5 vertebrae and femurs were analyzed with µCT. Quadriceps and gastrocnemius muscles were assessed histologically to determine muscle fiber diameter and fiber type. We found that whole-body BMD and BMC decreased at 2 weeks postinjury in both sexes, but that the magnitude of systemic bone loss was greater in males (-23.6% BMC in males, -16.9% BMC in females). Both sexes exhibited partial recovery of bone at later time points. Similarly, the maximum gastrocnemius contraction force decreased at 2 weeks post-injury (-38.7% in males, -42.5% in females) with a partial recovery afterwards for both sexes. Males and females exhibited comparable decreases in muscle mass in the fractured leg 2 weeks post-fracture. These findings indicate that males may have an increased risk of osteoporosis following fracture. These data provide valuable insight for identifying patients at high risk of refracture and inform therapeutic strategies for reducing future fracture risk.

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