FERRIC CARBOXYMALTOSE INCREASES BONE FRACTURE RISK AND INHIBITS DMP1-MEDIATED αVβ3-INTEGRIN SIGNALIN

Sonja WAGNER¹, Bernhard GLODNY⁴, Heribert TALASZ³, Myles WOLF⁵, Herbert TILG², Heinz ZOLLER^1,2, Lorenz Michael PAMMER², Martina SARETTO^1,2, Elke PERTLER^1,2, Marlene PANZER^1,2, Benedikt SCHAEFER², Laura OBHOLZER², Klaus FASERL³, Bettina SARG³

¹Christian Doppler Laboratory for Iron and Phosphate Biology, Medical University of Innsbruck, Innsbruck, Austria
²Department of Internal Medicine I, Medical University of Innsbruck, Innsbruck, Austria
³Division of Medical Biochemistry, Protein Core Facility, Biocenter, Medical University of Innsbruck, Innsbruck, Austria
⁴Department of Neuroradiology, Medical University of Innsbruck, Innsbruck, Austria
⁵Division of Nephrology, Department of Medicine and Duke Clinical Research Institute, Duke University School of Medicine, Durham, United States

Objective: The intravenous iron formulation Ferric carboxymaltose (FCM) increases FGF23 and can cause hypophosphatemia. This study aims to identify the underlying mechanism and effects on bone.

Methods: The translational study includes retrospective data in FCM- or Ferric Derisomaltose (FDI)-treated patients. The experimental studies compared FCM, FDI, and low-molecular weight iron dextran (LMWID). Iron deficient animals were treated with intravenous irons. MC3T3-E1 cells were used for osteogenic differentiation. Receptor binding studies were conducted with dentin-matrix protein-1 (DMP1) and αVβ3-integrin. Intracellular signaling was analyzed with phospho-proteomics. Surface charge and phosphate binding of the irons were compared.

Results: In 289 intravenous iron-treated patients, FCM was associated with a significantly higher fracture risk than FDI, despite similar risks between groups prior to receiving intravenous iron. Bone marrow-free femora of FCM treated animals had significantly higher iron concentrations. Seven days post treatment, significantly more iron localized to the trabecular bone surface after FCM than after FDI or LMWID. Intact FGF23 plasma concentration was also significantly higher in FCM-treated animals. FCM had distinct phosphate-binding and pH-dependent charge properties. Only FCM inhibited DMP1 binding to αVβ3-integrin and MAP-Kinase signaling in cells. DMP1 is a known FGF23 inhibitor and important for bone turnover. Direct exposure to IV irons inhibited osteogenic differentiation, where intracellular iron was highest and collagen production was inhibited only after FCM.

Conclusion: The charge and affinity of FCM to phosphate correlates with inhibition of DMP1 binding and enhanced localization to trabecular bone. FCM treatment affects bone beyond hypophosphatemia and intact FGF23 induction.