Endocrine Abstracts

Introduction: Denosumab, a human monoclonal antibody that inhibits activation of osteoclasts provides sustained suppression of bone turnover in osteolytic bone disease. Denosumab has rarely been associated with late hypercalcaemia following therapeutic administration for bone tumours in children, bone metastases in adults and in children with Osteogenesis Imperfecta Type VI.

Case report: A male child of Indian origin was referred for advice to GOSH from a local hospital at 2.24 years for limping and hypercalcaemia (cCa: 3.32–3.91 mmol/l). Four months before presentation, 60 mg of denosumab were erroneously administered intramuscularly instead of a hepatitis immunization (not at either hospital involved). Following this, the child was reviewed at another hospital with an unremarkable clinical examination and serial bone profile testing which were normocalcaemic (cCa: 2.35 mmol/l). He was started on vitamin D supplements (6000 units OD). After presentation with the limp, calcium concentrations remained markedly elevated (cCa: 3.15 mmol/l), with an appropriately suppressed PTH (<0.7 pmol/l) while 25OH-vitamin D was markedly elevated (299 nmol/l). No signs of malignancy were noted on peripheral blood film and bone marrow aspirate was normal. Provisional diagnosis at this point was vitamin D intoxication. Second line investigations performed were negative for malignancy. Since hypercalcaemia was resistant to hyperhydration and frusemide, pamidronate (0.5 mg/kg iv) was used. Calcium concentrations returned to normal following the second dose (cCa: 2.47 mmol/l). 25OHD rapidly returned to normal while still hypercalcaemic. To elucidate the pathophysiology of hypercalcaemia, N-terminal telopeptide (NTX), as a marker of increased bone turnover, was elevated and 1,25(OH)₂D was low. PTHrP was undetectable. Lower leg x-rays showed dense metaphyseal bands (bilateral distal femurs, distal tibias and fibulas), indicating osteoclast inhibition that correlated with the time of denosumab administration.

Conclusions: There have been previously highlighted cases of rebound hypercalcaemia following cessation of Denosumab for therapeutic use. However, this is to our knowledge the first case of resolving late hypercalcaemia thought likely to be secondary to accidental administration of a toxic dose of Denosumab. This case suggests that this rare side effect is pharmacological and not a result of underlying conditions as previously noted.