Iron and bones: effects of iron overload, deficiency and anemia treatments on bone

Iron is a vital trace element and exerts opposing effects on bone in both iron overload and iron deficiency situations. Remarkably, iron supplementation through intravenous infusion in patients with iron deficiency can also have detrimental effects on bone in special cases. The diverse mechanisms underlying these effects and their manifestations contribute to the complexity of this relationship. Iron overload impacts both bone resorption and formation, accelerating bone resorption while reducing bone formation. These effects primarily result from the direct action of reactive oxygen species (ROS), which influence the proliferation, differentiation, and activity of both osteoclasts and osteoblasts differently. This imbalance favors osteoclasts and inhibits the osteoblasts. Simultaneously, multiple pathways, including bone morphogenic proteins, RANK ligand, and others, contribute to these actions, leading to a reduction in bone mass and an increased susceptibility to fractures. In contrast, iron deficiency induces low bone turnover due to energy and co-factor deficiency, both of which require iron. Anemia increases the risk of fractures in both men and women. This effect occurs at various levels, reducing muscular performance and, on the bone-specific level, decreasing bone mineral density. Crucially, anemia increases the synthesis of the phosphaturic hormone iFGF23, which is subsequently inactivated by cleavage under physiological conditions. Thus, iFGF23 levels and phosphate excretion are not increased. However, in specific cases where anemia has to be managed with intravenous iron treatment, constituents-particularly maltoses-of the iron infusion suppress the cleavage of iFGF23. As a result, patients can experience severe phosphate wasting and, consequently, hypophosphatemic osteomalacia. This condition is often overlooked in clinical practice and is often caused by ferric carboxymaltose. Ending iron infusions or changing the agent, along with phosphate and vitamin D supplementation, can be effective in addressing this issue. Iron is a trace element that plays an important role in the human body and is crucial for maintaining the whole-body functions. However, both excess and insufficient levels of iron can have detrimental effects on bone. Iron overload overstimulates bone-resorbing cells, leading to increased bone breakdown. Moreover, iron overload inhibits the formation of bone-forming cells, thereby preventing the restoration of lost bone. These effects are driven by reactive oxygen species induced by iron overload. However, iron deficiency can also cause detrimental effects on bone and increase fracture susceptibility. Iron is needed not only as a cofactor for collagen formation but also for other anabolic processes within the cell, maintaining bone mass. Additionally, the resorption of damaged bone is hampered by the low activity of bone-resorbing cells caused by iron deficiency. Interestingly, anemia as a result of iron deficiency may be treated with iron infusions. Such infusions, however, can cause a severe form of osteomalacia due to increased phosphate excretion caused by iFGF23. iFGF23 is induced by iron deficiency, and its inactivation is disabled by intravenous iron infusions, such as e.g. ferric carboxymaltose. Graphical Abstract