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Bone Abstracts (2019) 7 P71 | DOI: 10.1530/boneabs.7.P71

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Necessity of high dose and prolonged duration denosumab post stem cell transplant for TNFRSF11A osteoclast-poor autosomal recessive osteopetrosis

Tashunka Taylor-Miller1, Hemalatha Doss2, Heather Weerdenburg3, Sam Whiting3, Ponni Sivaprakasam2, Adam Gassass2, Sarah F Smithson4,5, Colin G Steward2 & Christine P Burren1,5

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1Department of Paediatric Endocrinology, Bristol Royal Hospital for Children, University Hospitals Bristol NHS Foundation Trust Bristol, Bristol, UK; 2Department of Blood and Marrow Transplantation, Bristol Royal Hospital for Children, University Hospitals Bristol NHS Foundation Trust Bristol, Bristol, UK; 3Department of Pharmacy, Bristol Royal Hospital for Children, University Hospitals Bristol NHS Foundation Trust Bristol, Bristol, UK; 4Department of Clinical Genetics, St Michaels Hospital, University Hospitals Bristol NHS Foundation Trust Bristol, Bristol, UK; 5Bristol Medical School: Translational Health Sciences, University of Bristol, Bristol, UK.


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 2.20–2.70) 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 6–12 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 (L1–L4 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 18–24 months will be needed, and the ideal approach to treatment withdrawal under consideration.

Disclosure: The authors declared no competing interests.

Volume 7

9th International Conference on Children's Bone Health

ICCBH 

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