A recent review of the medical literature dating from 2009 to 2020 described the incidence, duration, risk factors, and mechanism of IV iron-inducing hypophosphatemia, as well as documented published cases since 2017.
The precise incidence of iron-induced hypophosphatemia is unclear because this laboratory parameter is not routinely measured in clinical trials, leading to underestimations of its occurrence. However, estimates place the incidence between 40% and 70%. One form of IV iron, ferric carboxymaltose (FCM), is more often associated with hypophosphatemia compared with other forms, although hypophosphatemia has also been reported with IV saccharated iron oxide and, to a lesser degree, with ferumoxytol and ferric derisomaltose. Severe hypophosphatemia (i.e., serum phosphate <2.0 mg/dL) and extreme hypophosphatemia (i.e., serum phosphate <1.3 mg/dL) has been reported in 50.8% and 10.0% of patients receiving FCM in one clinical trial, respectively.
Although the duration of iron-induced hypophosphatemia was initially thought to be brief (i.e., 2-3 weeks) and self-limiting, it now appears that this condition can persist for 6 months and up to 2 years, with patients—especially those receiving FCM—never reaching a normal serum phosphate level. Oral phosphate supplementation may be inadequate, with some patients experiencing a recurrence of symptoms once oral phosphate supplementation is stopped.
This recurrent or persistent hypophosphatemia is thought to be due to a persistent increase in fibroblast growth factor 23 (FGF23) and parathyroid hormone. The FGF23 gene directs the production of the protein FGF23, which is produced in osteocytes and osteoblasts and is required for phosphate homeostasis. FGF23 acts by decreasing the reabsorption of calcium and increasing the excretion of phosphate. Primary increases in FGF23 can lead to rickets or osteomalacia, whereas secondary increases in this growth factor occur in renal disease and are associated with adverse cardiovascular health. Administration of FCM is associated with significant increases in FGF23; this effect has not been seen with iron dextran or ferumoxytol.
Risk factors for iron-induced hypophosphatemia include use of FCM, low baseline serum phosphate levels, and a weight-adjusted iron dose. Hypophosphatemia can occur in patients with chronic kidney disease. Other risk factors for hypophosphatemia include abnormal uterine bleeding (as the etiology of iron-deficiency anemia), lower body weight, higher estimated glomerular filtration rate and hemoglobin, black race, and inflammatory bowel disease.
Symptoms of iron-induced hypophosphatemia may present as symptomatic musculoskeletal complaints, osteomalacia, evidence of fracture, weakness, tiredness, fatigue, shortness of breath, and respiratory failure. The diagnosis of hypophosphatemia is complicated since many of these symptoms mimic the symptoms of iron-deficiency anemia.
Pharmacists should be aware of this drug-laboratory interaction that can occur in patients receiving IV iron supplementation, especially FCM. It is important for pharmacists to have a high index of suspicion for the occurrence of hypophosphatemia. Pharmacists should educate other clinicians as well as patients that if severe hypophosphatemia develops, serum phosphate levels should be checked up to 1 to 2 months following cessation of therapy.
The content contained in this article is for informational purposes only. The content is not intended to be a substitute for professional advice. Reliance on any information provided in this article is solely at your own risk.
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Published September 16, 2021