Comparison between dietary, parenteral, and genetic iron overload on bone health reveals secondary iron overload as a driver of cortical bone loss and fracture risk in mice

More than 18% of the global population suffers from osteoporosis and its associated fracture risk each year. Among the many factors implicated in osteoporosis development, high iron levels have been implicated in bone loss in mice and patients. Here, we performed a comparative analysis of the effect of iron overload induced via diet, injections, or genetic factors, on overall bone health and mechanical bone strength. We used female mice, given the higher risk of osteoporosis and associated fractures in women than in men. We show that dietary iron overload induced trabecular remodeling in the spine but not in the femur, with potentially pre-pathogenic structural changes. By contrast, iron injections caused severe bone deficits across all sites measured. Interestingly, the loss of cortical bone emerged as a common hallmark of secondary iron overload and was associated with decreased mechanical strength in mice. However, no bone anomalies were observed in mice with genetic iron overload, demonstrating that iron overload per se does not suffice to induce bone loss in genetic hemochromatosis. Collectively, our study shows that iron overload-induced by diet and injections, but not genetically, induces selective and specific bone deficits, which are associated with decreased bone mechanical strength in mice.