ESPEYB20 3. Bone, Growth Plate and Mineral Metabolism Novel Treatments for Rare Skeletal Disorders (3 abstracts)
3.1. Safety and efficacy of denosumab for fibrous dysplasia of bone
de Castro LF , Michel Z , Pan K , Taylor J , Szymczuk V , Paravastu S , Saboury B , Papadakis GZ , Li X , Milligan K , Boyce B , Paul SM , Collins MT & Boyce AM
N Engl J Med. 2023 Feb 23;388(8):766–768. doi: 10.1056/NEJMc2214862. PMID: 36812441. https://pubmed.ncbi.nlm.nih.gov/36812441/
In Brief: This phase 2 study investigated the effect of the RANKL inhibitor denosumab on fibrous dysplasia lesion activity, as well as the rebound in bone turnover after treatment discontinuation.
Commentary: Denosumab is a humanized monoclonal antibody that inhibits RANKL with potent but transient antiosteoclastic effects, and discontinuation of denosumab treatment is associated with a rebound in bone turnover. In this study, eight women received high dose denosumab for 6 months and were observed for a further 8 months after treatment discontinuation. The effect of denosumab on lesion activity was assessed by measuring reduction in serum levels of bone-formation and bone-resorption markers. In addition, combined positron-emission tomography–computed tomography (PET–CT), analysis of bone biopsies and assessment of pain score.
Denosumab therapy dramatically reduced in the serum levels of bone-formation marker procollagen type 1 N-terminal propeptide and bone-resorption marker C-terminal telopeptide. Consistently, there was a marked decrease in lesion activity assessed by PET-CT with uptake of 18F-sodium fluoride tracer. Participants also reported amelioration of complications associated with fibrous dysplasia, such as increased pulmonary function in a participant with severe thoracic fibrous dysplasia. Participants also reported reduced pain. One participant developed severe hypercalcemia 12 weeks after discontinuation of denosumab, and three additional participants had a rebound in bone turnover that was above the pretreatment level and was associated with mild-to-moderate asymptomatic hypercalcemia.
This is a small phase 2 study on selected patients with severe fibrous dysplasia that provides important information on the use of denosumab in this condition and strategies to manage rebound hypercalcemia. It confirms earlier reports that denosumab dramatically reduces bone formation and resorption markers and also demonstrates clinical benefits in selected patients with fibrous dysplasia. However, the risk of severe side-effects needs to be considered, e.g. osteonecrosis of the jaw with long-term treatment, as well as malignant hypercalcemia if treatment is interrupted or discontinued. Further studies are needed to determine the clinical situations in which the benefits justify the risks of denosumab treatment of fibrous dysplasia.
Volume 20
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ESPE Yearbook of Paediatric Endocrinology
ISSN 1662-4009 (Online)
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