Abstract
Osteogenesis imperfecta (OI) type VI, a recessively inherited form of OI caused by mutations in SERPINF1, is a severe form distinguished by osteomalacia on bone histomorphometry. We describe a boy with severe OI type VI who was initially treated with intravenous (IV) zoledronic acid (ZA) at 1.4 years of age; however, a year later he transitioned to denosumab 1 mg/kg sub-cutaneously every three months in an effort to decrease fracture rates. After two years on denosumab, he presented with symptomatic hypercalcemia due to the denosumab-induced, hyper-resorptive rebound phenomenon. Laboratory parameters at the time of the rebound were as follows: elevated serum ionized calcium (1.62 mmol/L, N 1.16–1.36), elevated serum creatinine due to hypercalcemia-induced muscle catabolism (83 µmol/L, N 9–55), and suppressed parathyroid hormone (PTH) (< 0.7 pmol/L, N 1.3–5.8). The hypercalcemia was responsive to low-dose IV pamidronate, with a rapid decline in serum ionized calcium, and otherwise normalization of the aforementioned parameters within 10 days. To benefit from the powerful, albeit short-term, anti-resorptive effect of denosumab without further rebound episodes, he was treated thereafter with denosumab 1 mg/kg alternating every three months with IV ZA 0.025 mg/kg. Five years later, he remained on dual alternating anti-resorptive therapy without further rebound episodes, and an overall improvement in his clinical status. This novel pharmacological approach of alternating short- and long-term anti-resorptive therapy every three months has not previously been described. Our report suggests this strategy may be an effective method for prevention of the rebound phenomenon in select children for whom denosumab may be beneficial.
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Funding
LMW is supported by a Tier 1 Clinical Research Chair in Pediatric Bone Disorders from the University of Ottawa and the Children’s Hospital of Eastern Ontario Research Institute. MER is supported by a Junior Clinical Research Chair in Genetic Skeletal Disorders from the University of Ottawa and the Children's Hospital of Eastern Ontario Research Institute.
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ES extracted the data from the medical chart, compiled the results, and prepared the first draft of the manuscript, with the assistance of LMW, NK, VK and MOM. LMW supervised the data extraction, the drafting of the case report, and edited all versions of the manuscript. LMW, MAP, HS, SC, and KS cared for the patient. FR carried out the bone histomorphometry, SW conducted the bone densitometry, and KK provided radiology expertise in interpretating imaging findings. All authors critically reviewed and endorsed the final submitted version.
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LMW has participated in clinical trials with ReveraGen, Ascendis, PTC, Catabasis, Novartis, Ultragenyx and Amgen, received unrestricted educational grants from Alexion, Ipsen and Ultragenyx, and received consulting fees from Santhera, Ipsen, Ultragenyx, PTC, Novartis, and Amgen (with funds to LMW's institution). MER has participated in clinical trials with Amgen (with funds to MER’s institution). SC has received research grant funding from Zimmer Biomet and ConMed Linvatec, consulting fees for assisting with surgical training from Stryker and Smith & Nephew, and has participated in a clinical trial with Ascendis Biopharma (with Funds to SC’s institution). KS has consulted for Medtronic and has received research grants from Meditronics, Ascendis and SpinoModulation (all funds to KS’s institution). FR has been a consultant to Sanofi and Ultragenyx, received research grants from MITACS and Mereo BioPharma and a study grant from Ultragenyx, Catabasis, PreciThera (all funds to FR’s institution). The other co-authors have no competing interests to declare.
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All procedures performed in this study that involved human participant were in accordance with the 1964 Helsinki Declaration and its later amendments. Written consent was obtained from the patient’s caregiver in line with the Children’s Hospital of Eastern Ontario Research Institute ethical requirements. Written consent was obtained from the patient’s caregiver in line with the Children’s Hospital of Eastern Ontario Research Institute ethical requirements.
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Supplementary file1 (PDF 1655 KB) Supplementary Figure. Serum phosphate levels pre- and post- hypercalcemia rebound event.
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Seale, E., Molina, M.O., Carsen, S. et al. Mitigating the Denosumab-Induced Rebound Phenomenon with Alternating Short- and Long-Acting Anti-resorptive Therapy in a Young Boy with Severe OI Type VI. Calcif Tissue Int 112, 613–620 (2023). https://doi.org/10.1007/s00223-023-01065-4
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DOI: https://doi.org/10.1007/s00223-023-01065-4