Ferric carboxymaltose increases fracture risk in patients and reduces bone formation in mice with iron deficiency anemia

ABSTRACT: Modern IV iron formulations allow treatment of iron deficiency anemia (IDA) with 1 or 2 infusions. Ferric carboxymaltose (FCM) is a widely used IV iron, which causes hypophosphatemia in most of the patients. Osteomalacia and fractures are increasingly recognized after repeated infusions of FCM. It is unknown why ferric derisomaltose (FDI) rarely causes hypophosphatemia. In this study, we compare the effects of FCM and FDI on fracture risk and investigate potential underlying mechanisms explaining the different effects on bone and mineral metabolism. For this aim, fracture rate and osteomalacia were assessed in a cohort of 357 patients treated with either drug, who reported a significantly higher rate of incident osteomalacia or fracture after FCM. These findings were validated in >20 000 patients from the TriNetX database, where FCM treatment was independently associated with a higher fracture risk compared with FDI. The underlying mechanisms were investigated in a mouse model of IDA treated with FCM or FDI, an osteocyte model, and biochemically. FCM caused lower expression of collagen and ossification genes, associated with significantly higher bone iron concentrations than FDI. Electron microscopy showed iron-loaded vesicles in osteoblasts and early osteocytes. FCM but not FDI inhibited the binding of dentin matrix protein 1 to αVβ3-integrin on osteocytes. This is a potential mechanism for reduced bone formation and higher levels of intact fibroblast growth factor 23 after FCM. Our data report that IDA and FCM treatment can directly impair bone formation and increase fracture risk.