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

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.