Reduced bone formation in males and increased bone resorption in females drive bone loss in hemophilia A mice

Hemophilia A (HA), a rare X-linked recessive genetic disorder caused by insufficient blood clotting factor VIII, leaves affected individuals susceptible to spontaneous and traumatic hemorrhage. Although males generally exhibit severe symptoms, due to variable X inactivation, females can also be severely impacted. Osteoporosis is a disease of the skeleton predisposing patients to fragility fracture, a cause of significant morbidity and mortality and a common comorbidity in HA. Because the causes of osteoporosis in HA are unclear and in humans confounded by other traditional risk factors for bone loss, in this study, we phenotyped the skeletons of F8 total knockout (F8^TKO) mice, an animal model of severe HA. We found that trabecular bone accretion in the axial and appendicular skeletons of male F8^TKO mice lagged significantly between 2 and 6 months of age, with more modest cortical bone decline. By contrast, in female mice, diminished bone accretion was mostly limited to the cortical compartment. Interestingly, bone loss was associated with a decline in bone formation in male mice but increased bone resorption in female mice, a possible result of sex steroid insufficiency. In conclusion, our studies reveal a sexual dimorphism in the mechanism driving bone loss in male and female F8^TKO mice, preventing attainment of peak bone mass and strength. If validated in humans, therapies aimed at promoting bone formation in males but suppressing bone resorption in females may be indicated to facilitate attainment of peak mass in children with HA to reduce the risk for fracture later in life.