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 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 (120mg/month with loading doses on weeks 2 and 3) followed by 8-months post-treatment observation. The protocol was amended to restart moderate-dose denosumab (120 mg/3 months) if clinically indicated.
Main outcome measures: Bone turnover markers, 18F-NaF PET/CT, lesion biopsies.
Results: In 6 subjects who restarted moderate-dose treatment, changes in serum markers at initial and final dose were comparable (P1NP -82% and -91%, CTX -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 sustained decline in 4 subjects, however 2 severely affected subjects developed rebound between doses, with recurrent hypercalcemia in 1 subject.
Conclusions: 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 duration of efficacy are an important potential safety concern.
Published by Oxford University Press on behalf of the Endocrine Society 2024.