An enigma of hypocalcaemia: unveiling the interaction between denosumab and intravenous iron when co-administered
Background: Denosumab is a human monoclonal antibody that works by binding to and inhibiting receptor activator of nuclear factor-κB ligand (RANKL), a protein crucial for osteoclast activity, thereby preventing osteoclast formation, function and survival, ultimately reducing bone resorption.1 In doi...
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| Main Authors: | , , |
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| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2025-07-01
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| Series: | Clinical Medicine |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S1470211825000776 |
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| Summary: | Background: Denosumab is a human monoclonal antibody that works by binding to and inhibiting receptor activator of nuclear factor-κB ligand (RANKL), a protein crucial for osteoclast activity, thereby preventing osteoclast formation, function and survival, ultimately reducing bone resorption.1 In doing so, it can cause hypocalcaemia, particularly in high-risk patients with chronic kidney disease (CKD), vitamin D deficiency or recent bisphosphonate therapy.2 Recent evidence suggests that intravenous iron therapy exacerbates this risk by inducing fibroblast growth factor 23 (FGF23)-mediated phosphate depletion and impaired calcium absorption.3 This case highlights a severe hypocalcaemia episode following denosumab and inrtravenous (IV) iron infusion, underscoring the importance of careful preparation before these infusions and proactive management. Case presentation: An 84-year-old woman with steroid-induced osteoporosis and polymyalgia rheumatica (PMR) was admitted with decompensated heart failure offloaded with IV diuretics. She also had progressive fatigue, muscle cramps and mild confusion. Laboratory investigations revealed severe hypocalcaemia adjusted calcium 1.78 mmol/L (2.2–2.6 mmol/L), profound hypophosphatemia 0.36 mmol/L (0.80–1.50 nmol/L), and markedly elevated parathyroid hormone 418 ng/L (15–68 ng/L), indicating secondary hyperparathyroidism. Vitamin D levels were insufficient at 52 nmol/L (50–220 nmol/L), and renal function showed CKD stage 3a. Investigating the cause of hypocalcaemia in records found a history of denosumab (60 mg s/c) 3.5 months previously and previous use of multiple bisphosphonates for osteoporosis.4 The patient was also under haematology for iron deficiency anaemia, receiving IV iron therapy at least twice a year, with the most recent one administered around the time of denosumab administration.5The patient was managed with IV calcium initially, followed by oral calcium supplementation, phosphate replacement and magnesium monitoring. Rapid loading was done with a high-dose of cholecalciferol (40,000 IU daily for 7 days).6 Close monitoring was implemented to assess electrolyte trends. Serum calcium and phosphate gradually improved over a week, and the patient was discharged with a structured long-term follow-up plan. Risk factors for hypocalcaemia: Denosumab-induced hypocalcaemia risk increases with CKD, vitamin D deficiency, high-dose denosumab and iron infusion within 1–4 weeks of denosumab.7 Loop diuretics, phosphate binders and acute illness further compound the risk.8Summary of mechanism and management of severe hypocalcaemia from denosumab and IV ironDenosumab suppresses osteoclast activity, reducing calcium release from bone, which normally triggers PTH and, thus, helps vitamin D-mediated compensation for correcting calcium.9 IV iron (especially ferric carboxymaltose) increases FGF23, causing phosphate loss and reduced calcitriol production, weakening this compensatory response.10 Combined use leads to severe refractory prolonged hypocalcaemia and hypophosphataemia. Preventive measures involve optimising calcium and vitamin D status before treatment, aiming for vitamin D level >100 nmol/L and starting oral calcium supplementation alongside. Avoiding close co-administration of denosumab and iron (separate by >4 weeks), preferring lower-risk iron (iron sucrose) and monitoring calcium, phosphate and magnesium levels for 4 weeks post-treatment are also recommended. Conclusion: Although no large trials specifically address this drug combination, the accumulating case series underscore a real safety signal.7 |
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| ISSN: | 1470-2118 |