Symptomatic Ferric Carboxymaltose-Induced Hypophosphataemia: A Case Series of 11 Patients.

All authors jointly discussed and decided to retrospectively identify and analyse patients who had experienced hypophosphataemia, with the aim of increasing awareness of this condition. All authors agreed to submit this manuscript as letter to editor. Over the past year, all authors had encountered one or more patients with hypophosphataemia. M.W. and H.K., together with the other authors, collected and analysed the patient characteristics and prepared the table. F.K. consulted the local Medical Ethics Review Committee and confirmed that this study did not fall under the scope of the Medical Research Involving Human Subjects Act (WMO). After M.W. and H.K. completed the first draft, F.K. critically reviewed and revised the manuscript. Subsequently, all authors reviewed the article and provided critical feedback. Finally, M.W., H.K. and F.K. prepared the final version of the manuscript and made it ready for submission.

The authors have nothing to report.

The authors declare no conflicts of interest.

Dear Editor, Intravenous iron therapy is widely used for the treatment of iron deficiency and iron deficiency anaemia, particularly in patients who do not tolerate oral iron or in whom rapid repletion is required. Among the available formulations, ferric carboxymaltose (FCM) is one of the most frequently administered due to its convenience, allowing the delivery of relatively high doses in a single session [ 1 ]. Although FCM is generally considered safe and effective, accumulating evidence indicates that it is consistently associated with a higher risk of hypophosphataemia compared with other intravenous iron preparations. FCM‐induced hypophosphataemia is now a well‐recognized adverse effect, consistently demonstrated in randomized clinical trials, observational studies and recent international expert consensus recommendations [ 1 , 2 , 3 , 4 , 5 ]. Nevertheless, severe symptomatic cases continue to occur in routine clinical practice and remain underrecognized, particularly when serum phosphate concentrations are not routinely monitored. This underscores the importance of recognizing hypophosphataemia not merely as a biochemical abnormality but as a clinically relevant condition with potential consequences for haematologic outcomes. Therefore, a better understanding of the clinical spectrum, risk factors and underlying pathophysiological mechanisms of FCM‐induced hypophosphataemia is essential to optimize patient safety, guide appropriate laboratory monitoring and support informed therapeutic decision‐making in haematological practice [ 6 , 7 ]. We report 11 female patients (aged 21–43 years) who developed severe hypophosphataemia following FCM administration (Table  1 ). Between January 2025 and April 2026, 678 patients received FCM at our institution. Eleven female patients (aged 21–43 years) with clinically significant symptomatic hypophosphataemia were retrospectively identified (Figure  1 ) and their clinical characteristics are summarized in Table  1 . Because serum phosphate was measured only in patients who developed symptoms suggestive of hypophosphataemia, asymptomatic or mildly symptomatic cases were likely missed. Therefore, this case series does not permit estimation of the true incidence of FCM‐induced hypophosphataemia (Figure  1 ). All patients had baseline iron deficiency or anaemia, with markedly low ferritin levels in most cases, consistent with significant iron depletion prior to treatment. Phosphate levels dropped rapidly, most commonly within 2–4 days after a single 1000 mg infusion, to critically low values (0.11–0.15 mmol/L), leading to hospitalization in the majority of patients. However, the time course was variable, with some patients presenting later (up to several weeks or even months), suggesting delayed recognition and diagnosis in some patients rather than delayed onset of hypophosphataemia. Levels were typically measured only after patients presented with symptoms suggestive of hypophosphataemia, including fatigue, muscle weakness or bone pain. Clinical characteristics of eleven patients with symptomatic hypophosphataemia following ferric carboxymaltose (1000 mg) infusion. Iron‐deficiency anaemia Constitutional eczema Ferrous fumarate 200 mg OD, omeprazole 20 mg OD Hb 6.9 mmol/L Ferritin < 1 µg/L 2 days Phosphate 0.11 mmol/L Phosphate IV Recovery in 10 days Vitamin D 35 mmol/L Referred to gastro‐enterologist Iron‐deficiency anaemia H. pylori eradication Hb 6.5 mmol/L Ferritin 4 µg/L 3 days Phosphate 0.24 mmol/L Phosphate IV Phosphate drink TID Alfacalcidol 1 ug OD Recovery in 3 days Iron‐deficiency anaemia (hypermenorrhoea) Hay fever Ferrous fumarate 200 mg TW Hb 7.2 mmol/L Ferritin 8 µg/L 3 days Phosphate 0.37 mmol/L Phosphate drink TID Alfacalcidol 0.5 ug OD Colecalciferol 5600IE OW Recovery in 4 days Iron‐deficiency anaemia (hypermenorrhoea) Vitamin D suppletion Hb 7.4 mmol/L Ferritin 10 µg/L 2 days Phosphate 0.30 mmol/L Phosphate IV Phosphate drink TID Alfacalcidol 1 ug OD Recovery in 5 days Vitamin D 85 mmol/L No known risk factors Hay fever Iron‐deficiency Ferrous fumarate 200 mg OD Hb 8.2 mmol/L Ferritin 15 mmol/L 2 weeks Phosphate 0.15 mmol/L Phosphate IV Phosphate drink TID Alfacalcidol 0.5 ug OD Re‐admissions Final recovery in 1 month Vitamin D 63 mmol/L No known risk factors Iron‐deficiency anaemia (hypermenorrhoea) Bowel infection Ferrous fumarate 200 mg OD Hb 8.3 mmol/L Ferrin 11 µg/L 2 days Phosphate 0.35 mmol/L Phosphate drink TID Alfacalcidol 0.5 ug OD Recovery in 6 days Chronic fatigue/cramps Hypophosphataemia 0.69 Non‐allergically non‐eosinophilic asthma Chronic migraine Fremanezumab Hb 8.5 mmol/L Ferrin 37 µg/L 2 to 3 days Phosphate 0.16 mmol/L Phosphate IV Alfacalcidol 0.75 ug OD Phosphate tablets Recovery within months Vitamin D 61 mmol/L Pre‐existent hypophosphataemia, possibly hereditary origin? Iron‐deficiency anaemia (blood loss from section) Intolerance of oral suppletion Endometriosis Irritable bowel syndrome Hb 7.6 mmol/L Ferritin 5 µg/L 10 days Phosphate 0.56 mmol/L Phosphate drink TID Alfacalcidol 0.25 ug OD Recovery in 18 days Vitamin D 66 mmol/L No known risk factors Hb 6.8 mmol/L Ferritin 4.9 µg/L 1 month Phosphate 0.49 mmol/L Multiple administrations of ferinject Secondary hyperparathyroidism after gastric bypass Iron‐deficiency anaemia (hypermenorrhoea) Hypophosphatemia due to ferinject Hb 8.0 mmol/L Ferritin 11 µg/L 3 days Phosphate 0.44 mmol/L Phosphate drink TID Alfacalcidol 0.25 ug OD Vitamin D 54 mmol/L Possibly hyperparathyroidism (PTH 10.9) Iron‐deficiency anaemia Sjogren's syndrome Fibromyalgia Ferrous fumarate 200 mg TW, omeprazole 20 mg OD Hb 7.4 mmol/L Ferritin 14 µg/L 2,5 months Phosphate 0.18 mmol/L Phosphate IV Phosphate drink TID Alfacalcidol 1.5 ug OD Recovery within months Vitamin D 72 mmol/L Colonoscopy without abnormalities Celiac disease excluded Note : Hb = haemoglobin: 7.5–10.0 mmol/L, ferritin: 22–291 µg/L, phosphate: 0.78–1.65 mmol/L, vitamin D: > 30 nmol/L  and  PTH: 1.8–7.8 pmol/L. Abbreviations: OD = once daily, IV = intravenously, TID = three times daily, TW = twice weekly, OW = once per week. Patient selection flowchart. Between January 2025 and April 2026, 164 patients received ferric carboxymaltose (FCM) at our institution. Eleven patients who developed clinically significant symptomatic hypophosphatemia following FCM administration were retrospectively identified and included in this case series. Serum phosphate concentrations were measured only in patients presenting with symptoms suggestive of hypophosphataemia; therefore, asymptomatic or mildly symptomatic cases may have remained undetected. Consequently, this case series should not be interpreted as reflecting the true incidence of FCM‐induced hypophosphatemia. Treatment consisted of supportive management with intravenous and/or oral phosphate supplementation combined with active vitamin D (alfacalcidol), often requiring repeated or prolonged therapy. While some patients recovered within days, others experienced a more protracted course lasting weeks to months, with one case requiring readmission, highlighting the heterogeneity in clinical severity and recovery. Although phosphate supplementation does not address the underlying FGF23‐mediated renal phosphate wasting and its clinical benefit remains debated, it was used in routine clinical practice according to the treating physician's judgement. Classical risk factors did not fully explain susceptibility [ 4 ]. Only two patients had vitamin D deficiency, while gastrointestinal comorbidities or malabsorption (e.g., prior gastric bypass surgery) were present in only 3 of the 11 patients. One patient had pre‐existing hypophosphataemia, and several used proton pump inhibitors, however these factors were not consistently observed across the cohort. Importantly, several cases occurred in otherwise healthy young women with iron deficiency due to hypermenorrhoea, highlighting that clinically significant hypophosphataemia may also occur in this commonly treated population [ 5 ]. Focusing on the pathophysiology, fibroblast growth factor‐23 (FGF23) is considered the principal mediator of FCM‐induced hypophosphataemia, although additional mechanisms are increasingly recognized [ 8 , 9 , 10 , 11 ]. Produced by osteocytes, FGF23 regulates phosphate homeostasis by increasing renal phosphate excretion and reducing 1,25‐dihydroxyvitamin D synthesis. FCM increases circulating biologically active FGF23 by inhibiting its cleavage, thereby promoting renal phosphate wasting and secondary hyperparathyroidism. In a haematological context, disturbances in phosphate homeostasis may also affect erythropoiesis and cellular energy metabolism, as phosphate is essential for adenosine triphosphate (ATP) production and red blood cell function [ 12 ]. Although FGF23 is widely regarded as the principal mediator of FCM‐induced hypophosphataemia, recent experimental evidence suggests that alterations in FGF23 alone do not fully explain the formulation‐specific differences between intravenous iron preparations. In particular, FCM and ferric derisomaltose have been shown to exert similar effects on intact and cleaved FGF23, yet differ in their propensity to induce hypophosphataemia, indicating that additional mechanisms regulating renal phosphate handling, including effects on the sodium‐phosphate cotransporter Npt2a, may contribute [ 10 , 13 ]. Because Npt2a is the major sodium‐phosphate cotransporter responsible for renal phosphate reabsorption, differential regulation of this transporter represents a plausible additional mechanism underlying the formulation‐specific differences in hypophosphataemia. Thus, the precise pathophysiology is likely multifactorial and remains incompletely understood. Supportive treatment in clinical practice may include phosphate supplementation and active vitamin D, although phosphate replacement alone does not correct the underlying FGF23‐mediated renal phosphate wasting and its clinical benefit remains debated. Consistent with these pathophysiological findings, Wagner et al. recently demonstrated that FCM increases fracture risk in patients with iron deficiency anaemia and reduces bone formation in mice, further supporting the clinical relevance of FCM‐induced hypophosphataemia for bone health [ 2 ]. Compared with FCM, ferric derisomaltose and several other intravenous iron formulations are associated with a substantially lower risk of hypophosphataemia [ 1 , 14 ]. These formulation‐specific differences are only partly explained by alterations in FGF23 and likely reflect additional mechanisms regulating renal phosphate handling, including effects on the sodium‐phosphate cotransporter Npt2a [ 10 , 13 ]. Ferric derisomaltose also permits administration of high‐dose iron in a single infusion, whereas iron sucrose generally requires multiple infusions to achieve equivalent iron replacement [ 1 , 10 , 14 ]. Compared with FCM, Ferric derisomaltose and several other intravenous iron formulations are associated with a substantially lower risk of hypophosphataemia. These formulation‐specific differences are only partly explained by alterations in FGF23 and likely reflect additional mechanisms regulating renal phosphate handling, including effects on the sodium‐phosphate cotransporter Npt2a. Ferric derisomaltose combines this lower risk of hypophosphataemia with the possibility of administering high‐dose iron in a single infusion. In contrast, iron sucrose generally requires multiple infusions to achieve equivalent iron replacement [ 3 ]. We were unable to perform detailed immunological or mechanistic analyses due to the retrospective nature of this cohort, which represents an important limitation. However, the consistent and in several cases severe phenotype observed across patients suggests that inter‐individual susceptibility may be influenced by underlying metabolic interactions. Taken together, our observations extend the current understanding of FCM‐associated hypophosphataemia by showing that not only iron deficiency itself, but also its rapid intravenous correction, may have clinically relevant systemic effects beyond mineral metabolism. We therefore advocate for phosphate monitoring following FCM administration in patients who develop symptoms such as muscle pain, weakness, confusion and/or bone pain, irrespective of classical risk factors. Although prospective studies have already established the temporal changes in FGF23 and phosphate metabolism following FCM administration, further studies are warranted to identify predictors of severe hypophosphataemia and to optimize prevention and monitoring strategies. Furthermore, our findings reinforce current evidence that clinicians should carefully consider the choice of intravenous iron formulation, particularly in patients at increased risk of hypophosphataemia or those requiring repeated iron administration.