Metabolic Bone Disorders Unit

National Institute Of Dental & Craniofacial Research

Investigators

Linked publications, trials & patents

Abstract

Our work focuses on craniofacial and associated skeletal disorders, which account for the leading causes of disability affecting individuals in America and worldwide. We utilize the mosaic disorder fibrous dysplasia/McCune-Albright syndrome (FD/MAS) as a model to inform understanding of the pathogenesis and treatment of these disorders. In FD/MAS, post-zygotic Gαs 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. Below include examples of how studies of FD/MAS inform understanding of common disorders: Fractures: Fractures affect nearly 50% of American children, contributing to reduced physical activity and increasing youth sports dropout. Hip fractures are a leading cause of premature death in American adults age >65 years. Delayed fracture healing (termed “non-union fractures”) occurs in up to 2% cases, leading to chronic pain and permanent disability. Investigating how alterations in Gαs impact fractures in FD/MAS has increased our understanding of fracture risk, management, and prevention in the general US population: • NIDCR investigators discovered that abnormal phosphate metabolism is a primary contributor to fractures in FD/MAS. Ongoing work developing treatments to correct phosphate metabolism will advance understanding of how to optimize nutritional calcium/phosphate balance in healthy individuals. It will also inform management for patients with chronic diseases that impair phosphate metabolism, including renal failure (affecting up to 14% of Americans), liver disease (affecting approximately 2%), and gastrointestinal malabsorption (a leading cause of phosphate and other nutritional deficiencies). • NIDCR investigators observed that while patients with FD/MAS experience high fracture rates, they are much less likely to develop non-union fractures compared to the general population. Understanding how Gαs affects bone repair in FD/MAS will inform the development of treatments to harness the power of skeletal stem cells to improve fracture healing and reduce fracture-related disability. Developmental Craniofacial Disorders: Disruptions in craniofacial skeletal development contribute to chronic disabilities such as hearing loss (affecting up to 40% of Americans), temporomandibular joint dysfunction (affecting 5-12%), and orthodontic abnormalities (affecting millions of children and adults, leading to painful and costly orthodontic interventions). Investigating how alterations in Gαs affect the structure and shape of the craniofacial skeleton has led to critical insights into common causes of craniofacial disability: • By following a large population of FD/MAS patients over time, NIDCR investigators identified precise mechanisms of both vision and hearing loss. This work has advanced our understanding of how craniofacial development affects vital structures of the skull, and will inform the development of treatments to prevent chronic craniofacial-related disability. • Work investigating hormonal effects on skeletal stem cell proliferation in FD/MAS has provided critical insights into how endocrine dysfunction impacts skeletal development. This has important implications in identifying and treating skeletal disease in children and adults exposed to endocrine disruptors and other environmental toxins. Over the FY2025 reporting period, our work has specifically focused on the following Aims: Aim 1: Characterize the natural history of FD/MAS. We have continued recruitment for a longstanding natural history study, including phenotyping studies performed at the NIH Clinical Center. Through these efforts we have established the world’s largest systematically phenotyped cohort of patients with FD/MAS, and largest biobank of clinical specimens. This dataset is a national resource used to fill key knowledge gaps in the spectrum, course, and standard of care management in FD/MAS. These findings have been used to identify therapeutic targets and surrogate endpoints to support the development of interventional trials. Aim 2. Characterize the role of osteoclasts in the pathogenesis and treatment of FD/MAS. We hypothesized that osteoclasts promote pathogenic osteoprogenitor cell proliferation and may serve as an effective treatment strategy. We have continued to develop work focusing on the role of the RANKL inhibitor denosumab, which prevents differentiation of mature osteoclasts. Our previous work demonstrated that denosumab reduces osteoprogenitor cell proliferation, increases lesional mineralization, improves radiographic lesion activity, and reduces functional disability associated with FD/MAS in adults. However, denosumab is associated with bone turnover rebound, an important limitation that can result in hypercalcemia and other morbidity. We have expanded our studies in adults to collect natural history data on longer-term denosumab use, comparing the safety and efficacy of varying treatment regimens. We completed the treatment period for a phase 2 clinical 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. Aim 3. Investigate FGF23 excess as a driver of skeletal morbidity in FD/MAS. Osteoprogenitors produce FGF23, a phosphaturic hormone which lowers blood phosphate levels. Our work has demonstrated that dysplastic bone has increased vulnerability to the effects of hypophosphatemia, and that skeletal complications correlate with blood phosphate levels. During the reporting period we completed a phase 2 trial investigating burosumab, a monoclonal FGF23 antibody, in children and adults with FD/MAS, with the goal of achieving high normophosphatemia. Results for this study are in data analysis. If the findings are supportive, this study has the potential to redefine care for hypophosphatemia in FD.