Management of Hypophosphatemia after intravenous iron therapy

Contemporary intravenous iron formulations allow administration of high doses of elemental iron and enable correction of total iron deficit in one or two infusions. An important but underappreciated complication of certain formulations is hypophosphatemia caused by increased secretion of the phosphaturic hormone, fibroblast growth factor 23 (FGF23). B. Schaefer et al. summarizes the current understanding of the iron-phosphate axis as well as complications of intravenous iron-induced hypophosphatemia in a review article in the journal 'Bone'.

1. Iron therapy and hypophosphatemia

Iron deficiency is common and affects >15% of the world population. Poor gastrointestinal tolerability and limited uptake can render oral iron supplementation unfeasible or ineffective. The latest generation of iron formulations includes ferric carboxymaltose (FCM), ferric derisomaltose (FDI) (formerly known as iron isomaltoside) and ferrumoxytol. Despite their excellent short-term tolerability, hypophosphatemia has been reported in patients treated with FCM (highest), FDI and rarely after ferrumoxytol. While hypophosphatemia has previously been thought to be transient, it can persist for 6 months in about 5% of patients.

2. Mechanism of intravenous iron induced hypophosphatemia

Treatment with ferric carboxymaltose corrects iron deficiency within weeks but increases intact FGF23 within one day. The biochemical effects include increased urinary phosphate excretion, decreased calcitriol production, hypocalcemia and secondary hyperparathyroidism, which further increases urinary phosphate excretion leading to hypophosphatemia.

The decrease in calcitriol leads to mild hypocalcemia, which subsequently causes an increase in circulating parathyroid hormone (PTH) concentration. While the increase in PTH protects against severe hypocalcemia in the setting of reduced calcitriol levels, the phosphaturic effects of PTH further prolong hypophosphatemia beyond the period of FGF23 elevation.This sequence of biochemical changes can affect bone metabolism and ultimately result in osteomalacia.

3. Clinical manifestations of intravenous iron-induced hypophosphatemia

Authors performed a structured literature search to identify relevant publications with case reports of hypophosphatemia after FCM or FDI. They identified 77 patients (46 females) who developed hypophosphatemia following FCM treatment.

The mean age of the 77 patients (46 females) was 48.9 years. Mean hemoglobin was 9.6 (±2.3) g/dL (reference range females 12–16 g/dL, males 13–18 g/dL) and mean ferritin was 11.8 (±9.5) μg/L (reference range females 30–200 μg/L; males 30–300 μg/L) before FCM treatment, indicating severe iron deficiency.Most patients received more than one infusion (58%) with a mean cumulative iron dose of 7 g per patient. Mean lowest phosphate was 0.36 ± 0.14 mmol/L (1.05 ± 0.43 mg/dL) (reference range 0.8–1.5 mmol/L) and hypophosphatemia persisted for a mean of 31.2 weeks.

When patients were grouped by their underlying disease-causing iron deficiency, patients with gastrointestinal or gynecological blood loss were more often reported with symptomatic hypophosphatemia than patients with underlying kidney diseases.

A possible explanation for this observation is that patients with gastrointestinal or gynecological diseases typically present with severe iron deficiency which has been identified as a risk factor for hypophosphatemia after intravenous iron. Additional risk factors could be concomitant calcium malabsorption or vitamin D deficiency with secondary hyperparathyroidism in high-risk populations.

Specific symptoms were reported in 44 individual cases - general weakness, fatigue, bone, and muscle pain as well as osteomalacia with fractures were the most common manifestations.

4. Biochemical presentation of patients with intravenous iron induced hypophosphatemia

Prospective studies have shown that FCM-induced hypophosphatemia is triggered by an increase in intact FGF23 that also causes inhibition of vitamin D activation, hypocalcemia and secondary hyperparathyroidism.

5.Recommendations for diagnosis

• Measure serum phosphate in patients receiving multiple intravenous iron infusions, ongoing or worsening fatigue, bone pain or muscular weakness.

• Delay further intravenous iron doses and switch to iron formulations with lower hypophosphatemia risk in patients with hypophosphatemia.

• Assess fractional excretion of phosphate (FEPi) or TmP/GFR.

• If FEPi is high or TmP/GFR is low measure ionized calcium, total and bone-specific alkaline phosphatase, PTH, 25 (OH) vitamin D and 1,25 (OH)2 vitamin D.

• Patients with bone pain should undergo imaging studies.

6. Prevention and management of intravenous iron-induced hypophosphatemia

It is unknown if vitamin D supplementation before FCM administration reduces hypophosphatemia and fracture risk.

After diagnosis, treatment was started in the majority of patients including oral (n = 36) or intravenous (n = 20) phosphate, activated vitamin D (n = 21), vitamin D (n = 9) or calcium (n = 10). Treatment outcome was highly variable and inconsistently reported.

The rational treatment approaches would include mitigation of secondary hyperparathyroidism with activated vitamin D, which was successfully used in some patients.

High FGF23 could be directly inhibited with the therapeutic anti-FGF23 antibody burosumab which is not licensed for this indication. This treatment approach has been successfully used in one patient, and can be considered a contingency strategy in severe cases.

In conclusion, hypophosphatemia is a common medical problem after administration of FCM. The summary of symptoms and biochemical findings reported here represents a structured description of the potential clinical presentation of intravenous iron-induced hypophosphatemia and as such guides clinicians to recognize the complications and react accordingly.

Further reading:

Hypophosphatemia after intravenous iron therapy: Comprehensive review of clinical findings and recommendations for management

Benedikt Schaefer, Moritz Tobiasch, Sonja Wagner, Bernhard Glodny, Herbert Tilg, Myles Wolf, Heinz Zoller

Bone 154 (2022) 116202

https://doi.org/10.1016/j.bone.2021.116202