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RANKL inhibition with denosumab improves fibrous dysplasia by decreasing lesional cell proliferation and increasing osteogenesis

BACKGROUND: Fibrous dysplasia (FD) is a rare, disabling disease with no established treatments. Growing evidence supports inhibiting the pro-osteoclastic factor receptor activator of nuclear Kappa-B ligand (RANKL) as a potential treatment strategy. We conducted a phase 2 trial evaluating the anti-RANKL drug denosumab in adults with FD, with an emphasis on investigating post-discontinuation bone turnover rebound, and cellular mechanisms underlying anti-RANKL effects on FD osteoprogenitors. METHODS: Eight subjects received denosumab for 6-months and were observed for 8-months post-discontinuation. Efficacy and safety were evaluated using bone turnover markers, 18F-NaF PET/CT, and lesion biopsies. RANKL neutralization effects were assessed by histology, RNASeq, and an FD mouse model. Interplay between osteoclasts and FD osteoprogenitors was assessed in an ex vivo lesion model. RESULTS: Denosumab markedly reduced bone turnover and radiographic lesional activity in all subjects. Denosumab was well-tolerated during the treatment period, however post-discontinuation turnover reached or exceeded pre-treatment in six subjects, associated with severe hypercalcemia in one. Histology and whole-exome RNA sequencing showed reduced FD cell proliferation and increased osteogenic maturation, with increased lesional bone formation. The ex vivo model supported the dependence of FD cell proliferation on osteoclast activation. CONCLUSIONS: Osteoclast inhibition by anti-RANKL decreased FD cell proliferation and lesional activity, enabling osteogenic maturation and bone formation. These findings provide new understanding of FD pathogenesis as driven by crosstalk between osteoclasts and pre-osteoblast/osteoblasts, and support denosumab as a mechanistically-driven treatment strategy. Marked bone turnover rebound with post-discontinuation hypercalcemia occurs in a subset of patients, particularly younger individuals with high disease burden. TRIAL REGISTRATION: ClinicalTrials.gov NCT03571191 FUNDING: This work was supported by the Intramural Research Program of the NIDCR, NICHD, and Clinical Center, National Institutes of Health. Clinical trial NCT03571191 was conducted as an investigator-sponsored study supported by Amgen, Inc. This research was supported in part by the NIDCR Genomics and Computational Biology Core: ZIC DC000086 and Veterinary Resources Core: ZIC DE000740-05. Work in MTC lab and LVC labs were supported by the of Research on Women's Health (ORWH) through the Bench to Bedside Program award #884515.