Background: Hypercalcaemia is a risk following stem cell transplant (SCT) for all types of autosomal recessive osteopetrosis (ARO) due to restored osteoclast differentiation. This can be particularly severe in the osteoclast-poor (OP) form involving the tumour necrosis factor receptor superfamily 11A (TNFRSF11A) gene, encoding RANK. Denosumab, a monoclonal antibody blocking RANK activation, has been described for refractory post-SCT hypercalcaemia in two cases. Our case adds new information on dose, frequency and duration.
Presenting problem: A 2.3-year-old girl referred for investigation of short stature following craniosynostosis surgery. Investigation revealed underlying osteopetrosis due to TNFRSF11A gene compound heterozygous loss-of-function mutations (c. 414_427+7del and c.1664del). Maternal haploidentical SCT was undertaken aged 3.1 years. The anticipated hypercalcaemia following bone marrow engraftment developed on Day 18 (adjusted calcium 3.0 mmol/l RR 2.202.70) progressing despite a trial of hyper-hydration and diuretics.
Clinical management: Denosumab was initiated day 20 post-SCT (peak adjusted calcium 4.09 mmol/l): 0.13 mg/kg (1.2 mg; weight 9.2 kg) subcutaneously but achieved minimal improvement (4.09 to 3.65 mmol/l), so an additional larger denosumab dose (0.2 mg/kg) was administered 4 days later which normalised calcium (2.51 mmol/l). Recurrent, rapid onset, severe and symptomatic hypercalcaemia presented challenges to identify the ideal dosage regimen. Practical challenges included effective administration of small dose volume. Denosumab 0.25 mg/kg (2.4 mg) 4 weekly proved adequate, but larger doses (0.6 mg/kg) at 8 weekly intervals did not last longer and were associated with two emergency presentations with symptomatic hypercalcaemia at 7.5 and then 6.5 weeks post-dose. From 612 months post-SCT, denosumab 0.6 mg/kg 6 weekly has proven effective and is currently ongoing. Current status: otherwise good SCT function, markedly elevated bone mineral density (BMD) remains (L1L4 BMD 1.052 g/cm2, Z score +6.3) and two recent pathological fracture episodes (clavicle and proximal humerus).
Discussion: Hypercalcaemia post SCT for OP-ARO is an extremely rare but informative paradigm of osteoclast pathophysiology. The challenges in our case inform denosumab dose and duration in very young children for hypercalcemia post-SCT in osteopetrosis: effective regimen was denosumab 0.6 mg/kg (higher than previously reported, <0.3 mg/kg) 6 weekly ongoing 12 months post-SCT. We anticipate treatment duration of 1824 months will be needed, and the ideal approach to treatment withdrawal under consideration.
Disclosure: The authors declared no competing interests.