Severe FGF23-based hypophosphataemic osteomalacia due to ferric carboxymaltose administration

Abstract

Ferric carboxymaltose (FCM) is a novel iron formulation increasingly prescribed due to its effectiveness and fast infusion time. FCM administration can cause an asymptomatic hypophosphataemia secondary to fibroblast growth factor 23 (FGF23) dysregulation. In patients with chronic iron needs, however, a severe, long-lasting hypophosphataemia can lead to osteomalacia with associated bone pain. Lack of awareness of this complication results in delayed time to diagnosis and significant morbidity. We report a case of a patient with Crohn's disease and chronic iron-deficiency anaemia receiving multiple doses of FCM who developed severe hypophosphataemic osteomalacia with urinary phosphate loss and increased FGF23. FGF23 excess and osteomalacia resolved only months after FCM discontinuation and aggressive phosphate repletion. Potential mechanisms of FGF23 dysregulation are discussed, with the aim of raising awareness of this significant side effect for prescribers of chronic intravenous iron supplementation, and to help guide future studies to determine the safety of FCM in all patient populations.

Oral Iron Replacement Normalizes Fibroblast Growth Factor 23 in Iron-Deficient Patients With Autosomal Dominant Hypophosphatemic Rickets

“…When patients persist in iron deficiency, FGF23 gene expression would remain elevated and subsequent iron infusions could still induce additional spikes in circulating intact FGF23 and resulting hypophosphatemia. There are several reports describing such resulting hypophosphatemic osteomalacia after iron infusion, particularly with ferric polymaltose and ferric carboxymaltose …”

“…There are several reports describing such resulting hypophosphatemic osteomalacia after iron infusion, particularly with ferric polymaltose and ferric carboxymaltose. (24)(25)(26)(27) Thus, for safety reasons, we chose to focus on oral iron supplementation to avoid the risk of acutely worsening intact FGF23 and hypophosphatemia. Such an effect might be worse in a patient with ADHR, having a mutation that already impairs cleavage of the FGF23 produced from one allele, if iron infusions were to also impair the cleavage of FGF23 produced from the normal allele.…”

Incidence of hypophosphatemia in patients with inflammatory bowel disease treated with ferric carboxymaltose or iron isomaltoside

“…If hypophosphatemia is severe, potential complications include respiratory failure, rhabdomyolysis, haemolysis and left ventricular dysfunction . Additionally, an increasing number of published case reports have shown that prolonged hypophosphatemia can result in osteomalacia …”

“…6 There are numerous published case reports that document the risk of hypophosphatemia associated with ferric carboxymaltose treatment with potential severe complications. [7][8][9][10][11][12][13] Data from iron isomaltoside clinical trials suggest lower rates of hypophosphatemia with iron isomaltoside than have been observed in similarly designed trials of ferric carboxymaltose. [14][15][16][17][18][19][20][21] Phosphate is essential in human physiology.…”

“…26 Additionally, an increasing number of published case reports have shown that prolonged hypophosphatemia can result in osteomalacia. [9][10][11][12][27][28][29][30][31][32][33] The aim of this study was to investigate the rate of hypophosphatemia after infusion of a single dose of intravenous iron (1000 mg) in adults with IBD treated with either ferric carboxymaltose or iron isomaltoside.…”