Secondary hyperparathyroidism with hypocalcaemia and hypophosphatemia due to concurrent use of denosumab and iron infusion

Letter to the Community

Fang Yi Lee

MPharm | Senior Community Services Pharmacist, Metro South Community and Oral Health | FangYi.Lee@health.qld.gov.au

[Pharmacy GRIT article no: 20241406]

To the AdPha Community,

This letter aims to bring awareness to the risk of hypophosphatemia, a well‐known consequence of intravenous iron infusion with a growing number of case reports.1 The incidence, severity, and duration of hypophosphatemia are highest after ferric carboxymaltose compared to other intravenous iron formulations.1 Hypocalcaemia is a recognised adverse event of denosumab, particularly in patients with chronic kidney disease.2

The interaction of denosumab and intravenous iron infusion causing severe hypophosphatemia and hypocalcaemia has been reported in multiple published case reports.2–4 Previously described cases occurred in patients with varying renal function and vitamin D levels, including the setting of normal renal function and vitamin D levels.3,4 Most patients were asymptomatic, but some patients still required urgent electrolyte replacement and calcitriol for the treatment of hyperparathyroidism.

The proposed mechanism of these severe electrolyte disturbances is that administration of iron infusion therapy causes renal wasting of phosphate by decreasing renal phosphate reabsorption and inhibiting renal conversion of 25-hydroxy-vitamin D to its active form.3 It then leads to impaired intestinal absorption of calcium and phosphate.3 Denosumab transiently reduces plasma calcium concentration, resulting in elevated parathyroid (PTH) levels by inhibiting osteoclastic bone resorption.3 This secondary hyperparathyroidism further decreases renal phosphate reabsorption, promoting phosphaturia.3 As iron infusion impairs activations of vitamin D production, the body would not be able to compensate for the hypocalcaemia induced by denosumab in patients who are also receiving an iron infusion.3 Hence co-administration of iron infusions and denosumab are expected to augment both the hypocalcaemia and hypophosphatemia. It is also important to correct hypomagnesemia as hypomagnesemia can impair PTH secretion and activation of PTH receptors.3  

Iron deficiency, impaired renal function, and osteoporosis are common and co-prevalent so the number of patients at risk for these complications could be significant.5 Physicians and pharmacists should be aware of the drug interaction between denosumab and iron infusion and monitor serum phosphate, calcium, and vitamin D concentrations in at-risk patients, including patients who are receiving repeated doses of specific intravenous iron formulations, patients with uncontrolled hyperparathyroidism and patients who have recently received denosumab or intravenous bisphosphonates. Physicians and pharmacists should ensure that patients who are on denosumab or intravenous bisphosphonates are receiving concurrent vitamin D.

Hypophosphatemia commonly occurs 1–2 weeks after intravenous iron and can persist for 6– 12 weeks, while hypocalcaemia can occur up to 6 months after denosumab.2 It is proposed that the highest risk for co‐administration of these drugs is within 2 weeks, but this risk may persist for up to 3 months.2 Therefore, it is recommended to avoid co-administration in close proximity,  with an interval of at least 3 months between denosumab and intravenous iron infusion in at-risk patients.2,3 However, it is also important not to delay denosumab for more than 4 weeks due to the risk of rebound fractures.3 If co-administrations cannot be avoided, weekly monitoring of serum calcium and phosphate post administration for up to 1 month and considering alternative intravenous iron infusions  associated with a lower risk of hypophosphatemia are recommended.

References

  1. Schaefer B, Tobiasch M, Wagner S, Glodny B, Tilg H, Wolf M, et al. Hypophosphatemia after intravenous iron therapy: comprehensive review of clinical findings and recommendations for management. Bone 2022; 154: 116202.
  2. Cohen A, Chacko B. Severe hypocalcaemia following denosumab and iron infusion. Nephrology (Carlton) 2022; 27: 781–2.
  3. Ye S, Grill V, Luo J, Nguyen HH. Concurrent Denosumab and Parenteral Iron Therapy Precipitating Severe Hypocalcemia and Hypophosphatemia. JCEM Case Rep 2024; 2: luae005.
  4. Tai R, Mouchaileh N, Ting C. Hypocalcaemia and hypophosphataemia following denosumab and IV ferric carboxymaltose in an older patient with normal renal function. J Pharm Pract Res 2022; 52: 49–52.
  5. Smyth B, Ong S. Severe hypocalcaemia and hypophosphataemia following intravenous iron and denosumab: a novel drug interaction. Intern Med J 2016; 46: 360–3.