High doses of ferric derisomaltose and ferric carboxymaltose both increase FGF-23 levels and lead to osteomalacia and bone loss in healthy male mice

Abstract Ferric carboxymaltose (FCM) and ferric derisomaltose (FDI) are key for treating anemia and iron deficiency. However, FCM has been shown to transiently raise serum fibroblast growth factor (FGF)-23 levels, causing hypophosphatemia and alterations in bone turnover in some patients. To date, detailed effects of FCM and FDI on bone mineralization are still missing.This study examined FDI and FCM effects on bone mineralization and FGF-23 in healthy mice, avoiding disease confounders. Male 12-week-old C57BL/6J 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 (-24% FDI, p < 0.05; -36% FCM, p < 0.01), likely 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. In summary, repeated high doses of FDI and FCM in healthy mice increased i:cFGF-23 ratio and osteoid, while reducing bone formation and volume. Repeated dosing had stronger effects on bone than single dosing.