Ferric carboxymaltose increases fracture risk in patients and reduces bone formation in mice with iron deficiency anemia
Abstract
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.
Article Details
Authors (29)
Sonja A. Wagner
1Christian Doppler Laboratory for Iron and Phosphate Biology, Medical University of Innsbruck, Innsbruck, Austria
Marlene Panzer
1Christian Doppler Laboratory for Iron and Phosphate Biology, Medical University of Innsbruck, Innsbruck, Austria
Elke Pertler
Stefan Redl
Martina Saretto
2Department of Internal Medicine I, Medical University of Innsbruck, Innsbruck, Austria
Benedikt Schaefer
Lorenz M. Pammer
2Department of Internal Medicine I, Medical University of Innsbruck, Innsbruck, Austria
Laura Obholzer
2Department of Internal Medicine I, Medical University of Innsbruck, Innsbruck, Austria
Maria R. Troppmair
Michael W. Hess
Institute of Histology and Embryology, Medical University of Innsbruck
Willi Salvenmoser
5Institute of Zoology, Leopold-Franzens University of Innsbruck, Innsbruck, Austria
Gerald Degenhart
Marisa Grossgut
1Christian Doppler Laboratory for Iron and Phosphate Biology, Medical University of Innsbruck, Innsbruck, Austria
Heribert Talasz
7Institute of Medical Biochemistry, Protein Core Facility, Biocenter, Medical University of Innsbruck, Innsbruck, Austria
Klaus Faserl
Bettina Sarg
Institute of Medical Biochemistry, Protein Core Facility, Biocenter, Medical University of Innsbruck
Roland Haubner
8Department of Nuclear Medicine, Medical University of Innsbruck, Innsbruck, Austria
Markus A. Hartmann
91st Medical Department, Ludwig Boltzmann Institute of Osteology at Hanusch-Hospital of Oesterreichische Gesundheitskasse and Allgemeine Unfallversicherungsanstalt Trauma Centre Meidling, Hanusch Hospital, Vienna, Austria
Stéphane Blouin
91st Medical Department, Ludwig Boltzmann Institute of Osteology at Hanusch-Hospital of Oesterreichische Gesundheitskasse and Allgemeine Unfallversicherungsanstalt Trauma Centre Meidling, Hanusch Hospital, Vienna, Austria
Verena Petzer
Petra Gronich-Wondrak
2Department of Internal Medicine I, Medical University of Innsbruck, Innsbruck, Austria
Andreas Kronbichler
Claudia Manzl
12Institute of Neuropathology and Neuromolecular Pathology, Medical University of Innsbruck, Innsbruck, Austria
Bernhard Glodny
6University Clinic for Radiology, Core Facility MicroCT, Medical University of Innsbruck, Innsbruck, Austria
Herbert Tilg
Andre Franke
Myles Wolf
14Weill Department of Medicine, Weill Cornell Medical College, New York, NY
Michel V. Hadjihannas
13Institute of Clinical Molecular Biology, University Hospital Schleswig-Holstein, Christian Albrecht University Kiel, Kiel, Germany
Heinz Zoller