Intravenous Iron Associated Hypophosphatemia: Much More Than a Laboratory Curiosity

It is overwhelmingly likely that anyone reading this Commentary and the manuscript it accompanies learned in their medical education that intravenous iron is dangerous. Much of this folklore was fomented by formulations that were associated with high rates of severe infusion reactions and are no longer available. Newer iron formulations that enable complete replacement doses of intravenous iron to be administered safely and rapidly at a single visit moved intravenous iron to the forefront of treatment of patients with iron deficiency. Six intravenous iron formulations are now approved by the United States Food and Drug Administration (FDA). Two of these, iron sucrose and ferric gluconate, are iron salts that require five to seven visits to deliver 1000 mg of elemental iron. In contrast, low molecular weight iron dextran, ferumoxytol, ferric derisomaltose, and ferric carboxymaltose (FCM) employ complex carbohydrate shells to bind elemental iron more tightly so that doses of 1000 mg or more can be administered at a single outpatient appointment. Randomized trials, observational studies and supportive meta-analyses demonstrate that all contemporary iron formulations correct iron deficiency and anemia with high efficacy. Rates of serious adverse events as low as one event per 200 000 infusions highlight the short-term safety of these formulations [1]. Beyond the immediate infusion, however, one major exception to this track record of safety is the high rate of significant and often protracted hypophosphatemia that occurs uniquely following administration of FCM. In this issue of the American Journal of Hematology, Magagnoli et al. [2] report the clinical significance of FCM-induced hypophosphatemia through a review of its associated adverse events. The authors add their voice to sound the alarms to warn physicians to be cognizant of this potentially serious outcome. FCM was approved in the United States in 2009 after a 2-year delay imposed by the FDA due to initial concerns of increased cardiovascular risk and hypophosphatemia. Subsequent trials allayed the cardiovascular concerns, and FCM was eventually approved based on a pair of Phase III pivotal clinical trials. The first confirmed that FCM was non-inferior (and superior) to iron sucrose in raising hemoglobin in 2584 patients with iron deficiency anemia and chronic kidney disease stages 3–5 who were not dialysis-dependent [3]. The second demonstrated superior effects of FCM on hemoglobin in 507 patients with iron deficiency anemia of varied causes who failed oral iron and were randomized to receive intravenous FCM or to continue oral iron; FCM was also superior to intravenous iron sucrose in a second cohort of 504 patients who enrolled in the trial based on having previously experienced adverse effects of oral iron [4]. Post-approval, FCM has been shown to be effective in treating iron deficiency in patients with heart failure, inflammatory bowel disease, pregnancy, and perioperatively [5]. While the pivotal trials were underway, a 2012 randomized physiological study investigated the mechanism of FCM-induced hypophosphatemia [6]. The study reported that iron deficiency itself drove astronomical increases in transcription of fibroblast growth factor 23 (FGF23), which is a bone-derived hormone that regulates systemic phosphate and vitamin D homeostasis [7]. Increased transcription was offset by post-translational cleavage of FGF23 so that circulating levels of the full-length, biologically active hormone and thus, serum phosphate, remained normal. Administration of FCM upsets this balance. Somehow, the carbohydrate shell of FCM is thought to interfere with cleavage of new transcribed and translated FGF23, leading to inappropriately increased circulating levels of full-length hormone, which induces renal phosphate wasting and hypophosphatemia within the first few weeks after FCM administration [6]. Regardless of the molecular mechanism of the acute increase in circulating concentrations of biologically active FGF23, a large and growing body of randomized clinical trial data and real-world evidence demonstrate that FCM causes hypophosphatemia (< 2.0 mg/dL) in 50%–75% of patients with normal kidney function [8-10]. Approximately 10% of patients who receive a single course of FM develop severe hypophosphatemia less than 1.0 mg/dL. Through its known physiological effects, FCM-induced increases in FGF23 activate a pathophysiological cascade that includes severe reductions in calcitriol levels, hypocalcemia and secondary hyperparathyroidism. Downstream of the FCM-induced increases in FGF23, secondary hyperparathyroidism prolongs the duration of hypophosphatemia even as FGF23 levels drift back towards normal over several weeks. This occurs because of the known effects of parathyroid hormone to also stimulate renal phosphate excretion, independently of FGF23. Randomized clinical trials demonstrate that the metabolic changes triggered by FCM culminate in changes in biomarkers of bone metabolism in patterns that are similar to changes observed in patients with osteomalacia due to other causes. These changes in bone biomarkers following a single course of FCM extend beyond the time to resolution of hypophosphatemia, suggesting that normalization of serum phosphate does not mark the end of potential adverse effects of FCM on bone [11]. Although clinical trials were not sufficiently large or long enough to investigate clinical outcomes of hypophosphatemia, Magagnoli et al. cite multiple reports of significant sequelae such as nephrolithiasis, osteomalacia, pathologic fracture, and bone deformities. These events are more common after multiple doses of FCM are administered and are especially concerning given the lack of effective treatments to correct hypophosphatemia. Indeed, most candidate treatments, such as oral or intravenous phosphate or calcitriol replacement, increase FGF23 levels anew and can prolong recovery [12]. Even in the absence of such severe sequelae, randomized double-blinded clinical trial data demonstrate that ferric derisomaltose improved fatigue in patients with iron deficiency due to inflammatory bowel disease significantly more rapidly than FCM despite identical effects of each iron formulation on correcting hemoglobin [10]. Onset of hypophosphatemia drove the differences in recovery of fatigue, indicating that the improvement in fatigue that all patients should have experienced based on receiving iron itself and their rising hemoglobin was undercut in the FCM group by concomitant development of hypophosphatemia. Alarmingly, Magagnoli et al. report that only 1% of serious adverse drug reactions due to FCM are reported to the FDA based on their estimate that as many as 39 300 cases of FCM-induced hypophosphatemia could occur annually in the United States alone. They reached this conclusion using SONAR, a systematic method for evaluating important adverse drug reactions that is predicated on comprehensive review of reports to FDA's Adverse Event Reporting System database, case reports, case series, randomized clinical trials, systematic reviews, and clinical reviews. Why has awareness remained so low? The mechanism of FCM-induced hypophosphatemia is complex, and it is not intuitive to expect intravenous iron to lower serum phosphate. As a result, most clinicians who administer intravenous iron were likely unaware of severe hypophosphatemia as a potential risk of FCM. Furthermore, many iron administering clinicians were likely unfamiliar with the clinical symptoms and signs of hypophosphatemia. Indeed, hematologists and gastroenterologists, who administer the majority of intravenous iron to patients with intact kidney function, rarely encounter, diagnose or manage hypophosphatemia in their day-to-day practice. In contrast, endocrinologists and nephrologists are the specialists who are most attuned to hypophosphatemia, but they rarely encounter FCM-induced hypophosphatemia for different reasons. Endocrinologists rarely administer intravenous iron at all, and nephrologists use it primarily in patients with end-stage kidney disease who are not at risk of hypophosphatemia due to their lack of kidney function, which is required for FGF23 to maximally induce its phosphate wasting effects. In the event of an unexpected adverse event like hypophosphatemia after treatment with intravenous iron, clinicians rely on the warning section of FDA labels. In the case of FCM-induced hypophosphatemia, however, the original label that warned of "transient decreases in laboratory blood phosphorus levels have been observed in 27% of patients in clinical trials" was lacking. Terming hypophosphatemia as transient underestimated the potential duration of this adverse effect that can last weeks to months, and the low rate of 27% underestimated the true frequency that is far higher. The latter is likely the consequence of the pivotal trials that informed the label being predominantly conducted in patients with chronic kidney disease who are partially protected from FGF23-mediated hypophosphatemia on account of their impaired kidney function. Yet another factor that conspired to obscure appreciation of FCM-induced hypophosphatemia is the non-specific symptoms of hypophosphatemia that can be easily confused with symptoms of iron deficiency anemia or its underlying cause for which patients are given FCM. The eye-opening report by Magagnoli et al. promotes a new paradigm that physicians using FCM in clinical practice should follow. The authors prudently point out that hypophosphatemia and its symptoms such as weakness and fatigue are often overlooked and can have potentially serious consequences. They recommend that serum phosphate levels should be routinely measured prior to each dose of FCM in all individuals. Second and subsequent infusions should be discontinued if hypophosphatemia is present. Since hypophosphatemia is difficult to treat, primary prevention of hypophosphatemia by using intravenous formulations other than FCM is preferred. Finally, to better understand the clinical significance of FCM-induced hypophosphatemia, clinicians should report all instances to the FDA. The authors declare no conflicts of interest. The authors have nothing to report.