Intravenous Iron-Induced Hypophosphatemia: An Emerging Syndrome

Abstract

Some, but not all, intravenous iron formulations have been recognized to induce renal phosphate wasting syndrome. Most commonly this has been reported following treatment of iron deficiency anemia (IDA) with ferric carboxymaltose (FCM). A search of PubMed identified relevant randomized controlled trials (RCTs), and case studies evaluating hypophosphatemia (HPP) resulting from intravenous iron treatment. While more recent larger comparative RCTs have confirmed that the majority of patients receiving FCM, especially those with normal renal function, may experience severe HPP, complete documentation is hampered by inconsistent reporting of serum phosphate in such trials. Similarly, while case series and RCTs have documented the persistence of HPP for several weeks or even months, the lack of studies lasting beyond 5-6 weeks has constrained full understanding of the duration of effect. Clinical trials have established that the mechanism involves the bone/metabolic axis with the elevation of intact fibroblast growth factor 23 playing the central role. Reports continue to accumulate of the clinical consequences of severe HPP which are, most commonly, bone abnormalities following repetitive dosing. Case reports and studies, however, have also shown that symptomatic hypophosphatemia can occur after a single FCM dose. The frequency of such events remains unknown, in part due to lack of awareness of hypophosphatemia coupled with the fact that the most common acute symptoms of HPP (fatigue and weakness) are the same for IDA and for many of the chronic diseases that cause IDA. Changes to US and European prescribing information for FCM should raise awareness of the potential for HPP and need to monitor patients at risk for it.

Keywords: Ferric carboxymaltose; Ferric derisomaltose; Ferumoxytol; Iron deficiency anemia; Iron treatment; Iron-induced hypophosphatemia; Osteomalacia.

Fig. 1

LS mean changes from baseline in biomarkers of mineral and bone homeostasis according to iron treatment. Red arrows indicate infusion of ferric carboxymaltose, 750 mg; blue arrows indicate infusion of iron isomaltoside, 1000 mg. *P < 0.05, **P < 0.01, ***P < 0.001 between-group comparisons from a mixed model for repeated measures analysis with treatment day, treatment-by-day, trial and stratum as fixed effects and baseline value and baseline value-by-day as covariates; safety analysis set. FCM, ferric carboxymaltose; FGF23, fibroblast growth factor 23; IIM, iron isomaltoside 1000/ferric derisomaltose; LS, least squares; SE, standard error. Reproduced with permission from JAMA. 2020;323(5):432–443. Copyright©(2020) American Medical Association. All rights reserved.

Fig. 2

Patient diagnosed with symptomatic hypophosphatemia and osteomalacia with bilateral symmetric pseudofractures (looser zones) in the femur necks. a Magnetic resonance imaging showing marked hyperintensities of both femoral necks on T1-weighted imaging using a turbo inversion recovery magnitude sequence. Hyperintensities mark horizontal hypointensities extending halfway across the femoral neck. b X-ray plain film radiograph fails to show the fracture lines. Reprinted from Gastroenterology, 152(6), Benedikt Schaefer, Bernhard Glodny, Heinz Zoller, Blood and Bone Loser, e5–e6, Copyright (2017), with permission from Elsevier