The Interplay Between Bone Biology and Iron Metabolism: Molecular Mechanisms and Clinical Implications.

The maintenance of bone homeostasis requires the coordinated activity of specialized cells (osteoblasts, osteoclasts and osteocytes), soluble factors and hormones with regulatory functions. Disruption of this tightly controlled balance contributes to several skeletal pathological conditions, among which osteoporosis is one of the most prevalent. Iron, an essential element for the basic cellular functions of both osteoblasts and osteoclasts, plays a pivotal role in preserving bone homeostasis and skeletal integrity. Both iron deficiency and iron overload impair bone remodeling through distinct but converging mechanisms. Iron deficiency compromises collagen synthesis, alters hypoxia-dependent signaling, and may affect vitamin D metabolism, collectively predisposing the individual to reduced bone mineral density and increased fracture risk. Conversely, excess iron enhances oxidative stress, promotes osteoclastogenesis, and suppresses osteoblast differentiation and function, thereby favoring bone loss, particularly in the aging population and postmenopausal individuals. Hepcidin, the master regulator of systemic iron availability, has emerged as a key modulator of bone turnover, whereas the bone-derived hormone fibroblast growth factor 23 (FGF23) links iron imbalance to phosphate homeostasis, vitamin D metabolism, and inflammation. Beyond metabolic bone diseases, dysregulated iron handling is increasingly recognized as a hallmark of osteosarcoma biology, influencing tumor growth, metabolic reprogramming, and an individual's susceptibility to ferroptosis. The emerging, albeit only preclinical, evidence of the roles of iron and ferroptosis in osteosarcoma is therefore also covered. This review summarizes the current understanding of the interactions between iron metabolism and bone biology and addresses how an imbalance in iron metabolism may lead to major skeletal disorders. Overall, iron homeostasis could represent a potential target for preventing and treating osteoporosis and for improving therapeutic strategies for osteosarcoma.