Safety and Efficacy of Moderate-dose Denosumab in Fibrous Dysplasia: Observational Results From a Phase 2 Clinical Trial.

Xiaobai Li, Alison M Boyce, Babak Saboury, Vivian Szymczuk, Ibrahim I Elbashir, Ramzy Ahmed, Luis F de Castro, Kelly Milligan

Journal: The Journal of clinical endocrinology and metabolism 2025;110(9):2666-2673

PMID: 39673171

Full Text on Ovid Technologies, Inc. View on PubMed

Abstract

CONTEXT

Fibrous dysplasia (FD) is a rare skeletal mosaic disease associated with fractures and disability. A phase 2 trial of the RANKL inhibitor denosumab (NCT03571191) reported profound reductions in lesion activity and increased lesional mineralization after 6 months of high-dose treatment. Denosumab was well tolerated; however, discontinuation was associated with severe hypercalcemia.

OBJECTIVE

Investigate the safety and efficacy of moderate-dose denosumab (120 mg/3 months) compared to the standard high-dose regimen.

SETTING

Clinical research center.

PATIENTS

Adults with FD.

INTERVENTIONS

Eight adults received high-dose denosumab for 6 months (120 mg/month with loading doses on weeks 2 and 3) followed by an 8-month posttreatment observation. The protocol was amended to restart moderate-dose denosumab (120 mg/3 months) if clinically indicated.

MAIN OUTCOME MEASURES

Bone turnover markers, 18F-sodium fluoride positron emission tomography/computed tomography (18F-NaF PET/CT), lesion biopsies.

RESULTS

In 6 subjects who restarted moderate-dose treatment, changes in serum markers at the initial and final dose were comparable (procollagen type 1 N-terminal propeptide -82% and -91%, C-terminal telopeptide -86% and -86% for moderate- and high-dose, respectively). There was no difference in 18F-NaF PET/CT lesional activity or absolute change in avid lesion volume between moderate- and high-dose regimens. Sequential tissue histological analyses in 1 subject demonstrated progressive lesional mineralization and reduced cellularity with moderate-dose treatment. Bone turnover markers on moderate-dose treatment showed a sustained decline in 4 subjects; however, 2 severely affected subjects developed rebound between doses, with recurrent hypercalcemia in 1 subject.

CONCLUSION

Moderate-dose denosumab may provide clinical benefits comparable to the high-dose regimen in adults with FD while potentially lowering associated risks. However, discrepancies in the duration of efficacy are an important potential safety concern.

Published by Oxford University Press on behalf of the Endocrine Society 2024.

Address: Metabolic Bone Disorders Unit, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20892, USA.; Metabolic Bone Disorders Unit, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20892, USA.; School of Medicine, Eastern Virginia Medical School, Norfolk, VA 23507, USA.; Biostatistics and Clinical Epidemiology, Mark O. Hatfield Clinical Research Center, National Institutes of Health, Bethesda, MD 20892, USA.; Metabolic Bone Disorders Unit, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20892, USA.; Department of Radiology, University of Pennsylvania, Philadelphia, PA 19103, USA.; Institute of Nuclear Medicine, Radiology and Imaging Sciences, Bethesda, MD 20892, USA.

DOI: 10.1210/clinem/dgae867

Link outs

Subscription / membership required

Full Text Sources:

MeSH Terms: Humans, Denosumab, Female, Male, Adult, Middle Aged, Bone Density Conservation Agents, Fibrous Dysplasia of Bone, Treatment Outcome, Bone Remodeling, Dose-Response Relationship, Drug, Positron Emission Tomography Computed Tomography, Young Adult