Serious adverse effects of denosumab in adolescents treated for giant cell tumour of the bone: osteonecrosis of the jaw and rebound hypercalcaemia with acute kidney injury

Suma Uday; Louie Gaston; Robert Grimer; Jonathan Joffe; Wolfgang Hoegler

doi:10.1530/boneabs.6.LB4

Introduction: Giant cell tumour of the bone (GCTB) is a benign, locally aggressive tumour whose neoplastic stromal cells express receptor activator of nuclear factor kappa-B ligand (RANKL) and activate its receptor RANK on osteoclast-like giant cells. Denosumab (RANKL inhibitor) is an FDA/EMA approved treatment for GCTB in adults and ‘skeletally mature’ adolescents. Safety concerns include oversuppression of bone remodelling, with risk of osteonecrosis of the jaw [ONJ] and atypical femur fractures during treatment, and rebound hypercalcaemia after treatment cessation. To date, ONJ has never been reported in children or adolescents.

Case descriptions: Two adolescents with sacral GTCB received denosumab as per trial protocol (Table 1). Following 4 years of therapy (age 19 years), P1 developed ONJ after a dental extraction necessitating surgical debridement and sequestration of exposed jaw bone. P2 completed GCTB treatment without complications. Both patients presented unwell with hypercalcaemia and acute kidney injury 6–7 months after denosumab cessation. Other causes of hypercalcaemia were excluded. Since hypercalcaemia was unresponsive to hyperhydration, P1 received repeated doses of calcitonin. P2 received low dose pamidronate and despite prophylactic oral calcium developed symptomatic hypocalcaemia requiring intravenous calcium. Both patients received treatment for vitamin D deficiency.

Conclusion: Here, we report the first case of ONJ in an adolescent. Both adolescents were naïve to chemotherapy, radiotherapy, bisphosphonates, corticosteroids and metastases free; hence, denosumab therapy was confirmed as the cause of P1’s ONJ, and both patients’ rebound hypercalcaemia. Over-suppression of bone remodelling due to this potent, high-dose antiresorptive drug has to be weighed up against its effect on tumour shrinkage. These cases call for close monitoring for side-effects during and after therapy, for safety data to be collected in adolescents and consideration on weight-based dosing.

Table 1 Patient characteristics, treatment indication, duration, dosing information and hypercalcaemia management.
Patient 1 (P1)	Patient 2 (P2)
Age at diagnosis	14 years 9 months	14 years 2 months
Gender	Male	Female
Weight (Kg)	56.5	45.6
Location of GCTB	Sacrum	Sacrum
Denosumab indication	Tumour recurrence following surgery and embolization	Large tumour not amenable to surgery
Denosumab regimen	120 mg subcutaneously on day 1, 8,15, 28 and then 4 weekly	120 mg subcutaneously on day 1, 8,15, 28 and then 4 weekly
ClinicalTrials.gov Identifier:
NCT00680992
Individual dose (mg/kg)	2.1	2.6
Total number of doses	46	18 (12 pre-, and 6 post-operative)
Cumulative dose over treatment duration (total, and mg/kg)	5,520 mg	2,160 mg
98 mg/kg	47 mg/kg
Total treatment duration	3.6 years	1.3 years
Reason for treatment cessation	Osteonecrosis of the jaw (ONJ)	End of treatment
Rebound hypercalcaemia
Time from last denosumab dose	7 months	6 months
Calcium at presentation	3.1 mmol/l (nl 2.2–2.7)	3.4 mmol/l (nl 2.2–2.7)
Creatinine at presentation	180 μmol/l (nl 80–120)	137 μmol/l (nl 37–70)
Parathyroid hormone	0.4 pmol/l (nl 1.6–7.5)	< 3 ng/l (nl 11–29)
25 hydroxy-vitamin D	10.5 nmol/l (nl >50)	17 nmol/l (nl >50)
Treatment	Hyperhydration + calcitonin (400IU in 500 mls 0.9% NaCl over 6 hours)	Hyperhydration + pamidronate (0.6 mg/kg, over 8 hours, for 2 days)
Recurrent hypercalcaemia	Yes x2, requiring repeat calcitonin	No

Disclosure: The authors declared no competing interests.

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