Iron overload induced by ferric derisomaltose and ferric carboxymaltose both increase FGF-23 levels and lead to osteomalacia and bone loss in normal mice

Ferric carboxymaltose (FCM) and ferric derisomaltose (FDI) are key for treating iron deficiency anemia. However, FCM has been shown to raise serum fibroblast growth factor (FGF)-23 levels, causing hypophosphatemia and alterations in bone turnover in some patients. To date, it is unknown if FCM and FDI also affect bone mineralization. This study examined FDI and FCM effects on bone mineralization and FGF-23 in healthy mice, avoiding disease confounders. Male 12-week-old C57BL/6 J mice received single or weekly FDI, FCM, or placebo injections for 4 weeks.Repeated FDI and FCM injections affected body weight, blood counts, and caused significant liver iron accumulation and high serum iron. Both reduced most bone parameters by µCT; however, FCM showed falsely high bone density due to iron clusters in the bone marrow. Histology revealed greater bone volume loss with FCM than FDI (-36% FCM, p < 0.01; vs - 24% FDI, p < 0.05), predominantly from suppressed bone formation. Both iron formulations also led to a prominent increase in osteoid and FGF-23 (intact and C-terminal), raising the i:cFGF-23 ratio. A single dose led to similar, but milder effects than repeated dosing. In summary, repeated high doses of both, FDI and FCM, in healthy mice increased the i:cFGF-23 ratio and osteoid production, while reducing bone formation and volume.