Presentations

Abstract

Introduction:

Fibrous dysplasia (FD) is a rare disease in which normal bone and marrow are replaced with expansile fibro-osseous tissue, leading to fractures and disability. FD tissue demonstrates prominent osteoclastogenesis and increased expression of the pro-osteoclastic factor receptor activator of nuclear kappa-B ligand (RANKL). A phase 2 trial of the RANKL inhibitor denosumab (n=8 subjects) demonstrated profound reduction in FD lesion activity and increased lesional bone formation after 6 months of high-dose treatment (standard tumor regimen of 120mg/month with loading doses on weeks 2 and 3). Denosumab was well tolerated, however discontinuation was associated with severe hypercalcemia in 1 subject. These results demonstrated that denosumab can provide substantial clinical benefit in FD; however, dose-related side effects remain a concern. We performed a secondary analysis to evaluate the efficacy of a moderate-dose regimen (120 mg/3 months) in comparison to the standard high-dose regimen.

Methods:

Data was analyzed from a phase 2 clinical trial at the NIH (NCT03571191). 8 subjects (mean 31y, range 20-55) received high-dose denosumab (120mg/month with loading doses on weeks 2 and 3) for 6-months followed by an 8-month post-treatment observation period. Given the observed substantial clinical benefits, the protocol was amended to restart a moderate-dose regimen (120 mg/3 months) after the post-treatment observation period if clinically indicated. Serum bone turnover markers and radiographic 18F-NaF PET/CT scans were evaluated at the start of moderate-dose therapy and after 6- months in 6 subjects. Results: Changes in bone turnover markers were comparable on high vs moderate-dose denosumab (P1NP -82% and -92%, and CTX -86% and -82% for moderate and high-dose, respectively). Improvement in 18F-NaF PET/CT lesional activity were observed in all subjects on moderate-dose treatment. One subject experienced bone turnover rebound and mild hypercalcemia between 3-month doses, which necessitated discontinuation of denosumab. Of note, this subject had panostotic FD and the highest baseline bone turnover in the cohort.

Conclusions:

These findings demonstrate that moderate-dose denosumab may provide clinical benefits comparable to the high-dose regimen in adults with FD, while potentially lowering associated risks. However, patients with extensive FD and high baseline bone turnover may require more frequent dosing, indicating a need to individualize treatment regimens.