Metabolic Bone Disorders Unit

National Institute Of Dental & Craniofacial Research

Investigators

Linked publications & trials

Abstract

Our work focuses on fibrous dysplasia/McCune-Albright syndrome (FD/MAS), a rare and debilitating disorder with no established medical treatments. Post-zygotic Gs variants lead to proliferation and abnormal differentiation of osteoprogenitor cells. Bone lesions form and expand during childhood, resulting in progressive disability that persists into adulthood. Aim 1: Characterize the natural history of FD/MAS. Through strategic retrospective studies, we filled key knowledge gaps to support the development of new clinical trials. i. Define biomarkers: We characterized FD progression rates in children, developing critical historical controls for preventative trials. We identified osteocalcin, a serum bone formation marker, as a useful prognostic biomarker. We developed disease-specific parameters for 18F-NaF PET/CT, defining its use as a novel biomarker and surrogate endpoint for FD activity. ii. Identify clinical predictors of disease severity: We determined fracture prevalence in FD, identifying age at first fracture and Skeletal Burden Score as key risk factors. We determined that FD lesional activity is highest in the craniofacial region, and that both activity and progression rates decline with age. These results establish age and FD location as key variables to identify at-risk patients, which will facilitate development of trials and treatment guidelines. Aim 2. Characterize the role of osteoclasts in the pathogenesis and treatment of FD. We hypothesized that osteoclasts may promote osteoprogenitor cell proliferation in FD via the RANKL signaling pathway, and that RANKL inhibition will serve as a novel therapeutic strategy. i. Clinical trials of RANKL inhibition with denosumab. We completed a phase 2 trial of denosumab in adults with FD. Treatment resulted in profound beneficial effects on lesional activity in all subjects. Post-discontinuation hypercalcemia was identified as an important consideration that necessitates caution. We initiated a phase 2 trial of denosumab in children, with the goal to prevent FD lesion formation and expansion. If the results of this study are supportive, it has the potential to fundamentally alter the disease course in young individuals. ii. Mechanisms of RANKL inhibition in FD pathogenesis. We demonstrated that inhibition of RANKL-mediated osteoclastogenesis promotes lesional bone formation by enabling maturation of FD osteoprogenitors. We initiated work to understand osteoclast-osteoprogenitor coupling in FD to identify additional targets for long-term treatment. Aim 3. Investigate FGF23 excess as a driver of skeletal morbidity in FD. FD osteoprogenitors produce FGF23, a phosphaturic hormone which lowers blood phosphorus levels. i. Define FGF23-mediated effects on skeletal morbidity. In a retrospective evaluation, we determined that both frank hypophosphatemia and low-normophosphatemia were associated with increased skeletal complications. These findings demonstrate that FGF23-related morbidity impacts a larger proportion of the FD/MAS population than previously recognized. ii. Investigate the utility of burosumab in patients with FD. We initiated a phase 2 trial of a monoclonal FGF23 antibody, with the goal of achieving high normophosphatemia. If findings are supportive, this study has the potential to redefine care for hypophosphatemia in FD.