Long-term iron polymaltose infusions associated with hypophosphataemic osteomalacia: a report of two cases and review of the literature

Abstract

Iron-induced hypophosphataemic osteomalacia remains under-recognized as a potential complication of parenteral iron therapy. We here report two cases of symptomatic hypophosphataemic osteomalacia with multiple insufficiency fractures in the context of chronic gastrointestinal blood loss, necessitating monthly iron polymaltose infusions over prolonged periods of time. Respective blood tests revealed severe hypophosphataemia [0.29 and 0.43; normal range (NR) 0.8-1.5 mmol/l] in the presence of normal serum calcium and 25-hydroxy vitamin D levels. Urinary fractional phosphate excretion was elevated (16% and 24%; NR < 5%) and the tubular maximum phosphate reabsorption was reduced, consistent with renal phosphate wasting. Serum fibroblast growth factor 23 (FGF23) obtained in one patient was significantly elevated at 285 pg/ml (NR < 54 pg/ml). Bone mineral density was significantly reduced and whole-body bone scans revealed metabolic bone disease and multiple insufficiency fractures consistent with osteomalacia. Cessation of iron infusions resulted in clinical and biochemical improvement within 2 months in one patient whereas the second patient required phosphate and calcitriol supplementation to improve symptomatically. Iron-induced hypophosphataemic osteomalacia is thought to be due to reduced degradation of FGF23, resulting in phosphaturia and reduced synthesis of 1,25-dihydroxy vitamin D. Monitoring of patients on long-term parenteral iron is recommended to avoid clinically serious adverse effects.

Hypophosphatemia, Severe Bone Pain, Gait Disturbance, and Fatigue Fractures After Iron Substitution in Inflammatory Bowel Disease: A Case Report

“…New iron formulations, such as iron isomaltoside or ferric carboxymaltose, have been introduced for selected patient populations with inflammatory bowel disease (IBD), chronic kidney disease, or cancer‐related anemia . Interestingly, the incidence of hypophosphatemia after iron infusion varies considerably, ranging from 2.1% to 86% . This suggests that the formulation of the drug may also affect FGF23 regulation .…”

Randomized trial of intravenous iron-induced hypophosphatemia

“…Coincident with increased utilization of intravenous iron, reports are accumulating of patients who developed severe hypophosphatemia with serious musculoskeletal complications following their administration, including osteomalacia, fragility fractures, and hypoxemia (3)(4)(5)(6)(7)(8)(9)(10)(11)(12). Although the molecular mechanism of hypophosphatemia is not fully understood, certain forms of intravenous iron may increase circulating concentrations of fibroblast growth factor 23 (FGF23) (13)(14)(15)(16).…”

“…While further studies are needed to investigate mechanisms of how these factors predispose to hypophosphatemia, clinicians should exercise special caution when prescribing ferric carboxymaltose to higher-risk patients. Hypophosphatemia was initially considered an uncommon, self-limited, and benign biochemical consequence of ferric carboxymaltose administration, but multiple cases with serious musculoskeletal complications have emerged (3)(4)(5)(6)(7)(8)(9)(10)(11)(12). Across these cases, the correct diagnosis of hypophosphatemia was delayed by a confluence of factors including lack of knowledge of the relationship between iron and phosphate homeostasis; low awareness of hypophosphatemia as an adverse effect of ferric carboxymaltose; failure to test serum phosphate; and misattribution of symptoms of hypophosphatemia to iron deficiency anemia or its underlying cause even when serum phosphate was measured.…”

Management of anemia in inflammatory bowel disease: a challenge in everyday clinical practice

“…There are known cases of symptomatic hypophosphatemia following intravenous iron administration such as fatigue or muscle weakness, and even osteomalacia or secondary bone fractures for long-term parenteral iron supplementation [ 31 , 32 ]. Symptomatic hypophosphatemia is more commonly associated with chronic iron use, low levels of ferritin and gastrointestinal disorders and malnutrition.…”