Metabolic Bone Disorders Unit

National Institute Of Dental & Craniofacial Research

Investigators

Linked publications, trials & patents

Abstract

Project Title: RANKL Signaling in the Pathogenesis and Treatment of Fibrous Dysplasia Brief background including hypothesis and significance: FD/MAS is a chronic, disabling disorder resulting in fractures, pain, and skeletal deformities. In bone, Gs mutations lead to proliferation of undifferentiated skeletal stem cells, resulting in abnormal bone matrix, marrow fibrosis, and increased formation of bone-resorbing osteoclasts. While rehabilitative and surgical interventions may improve functional outcomes, there are currently no medical therapies capable of altering the disease course. Emerging data supports that receptor activator of nuclear kappa-B ligand (RANKL), a member of the tumor necrosis superfamily, plays a pivotal role in FD pathogenesis. RANKL and its regulatory protein osteoprotegerin are produced by osteogenic cells, and act on the RANK transmembrane receptor to regulate osteoclast differentiation. High levels of RANKL expression have been observed in FD patient tissue, serum, and cell culture, and anti-RANKL treatment in an FD mouse model increases bone formation and mineral content. We hypothesize that RANKL inhibition will serve as a novel therapeutic strategy to treat patients with FD. Research advances over past year: An open-label pilot study of denosumab treatment in adults with FD has been completed and is in the data analysis phase (NCT03571191). Project Title: Natural History of Fibrous Dysplasia/McCune-Albright Syndrome Brief background including hypothesis and significance: Natural history studies are key hypothesis-generating tools in the study of human disorders, to determine pathophysiology, identify therapeutic targets, and develop surrogate outcome measures for clinical trials. NIDCR has supported a longstanding natural history study in FD/MAS (NCT00001727) which has enrolled >300 subjects with up to 25 years of longitudinal follow-up. Since its initiation in 1998, this protocol has contributed substantially to our understanding of FD/MAS pathogenesis, disease spectrum, and clinical management. Research advances over past year: - A study published in the Journal of Bone and Mineral Research investigated the natural history of FD lesion progression in children (PMID: 35695414). Skeletal Burden Scores (SBS) were used to quantify FD involvement from serial nuclear medicine scans in 31 children. Progression rates were highest before age 8 years and declined with age (p = 0.03). Baseline disease severity was associated with subsequent disease progression (p = 0.009), with the highest FD progression rates in patients with moderate disease (baseline SBS 16-30), and lowest progression rates in those with severe disease (SBS 50). Serum levels of the bone formation marker osteocalcin were positively correlated with subsequent FD progression rate (p = 0.01, R = 0.58). These findings will allow clinicians to identify children with FD who are at higher risk for disease progression in order to develop preventative trials and identify candidates for early interventions. This data will also be used as an historical control group in an upcoming pediatric denosumab clinical trial. - Fractures are a common, painful, and potentially disabling complication of FD/MAS. In a study published in the Journal of Bone and Mineral Research, fracture prevalence and risk factors were evaluated from two large cohorts (NIH and the Leiden University Medical Center)(n=419)(PMID: 34668234). Fracture rates peaked between 6 and 10 years of age and decreased thereafter. Skeletal Burden Score was positively associated with both number of lifetime fractures and age at first fracture. Threshold levels of Skeletal Burden Score (>25) and age at first fracture (7 years) were identified to correlate with a higher total number of lifetime fractures (p < 0.01). These tools will allow clinicians to identify FD/MAS patients at risk for severe disease who may be candidates for early therapeutic interventions. - Pain is a major symptom in FD/MAS, and responses to current treatments are unpredictable. A study published in the Journal of Clinical Endocrinology and Metabolism investigated pain phenotypes in 2 large cohorts from the USA and UK (total n=249)( PMID: 35262711). One third of patients experienced neuropathic-like pain, a distinct pain type that typically does not respond to standard treatments. This group had statistically significantly worse mental well-being and sleep in comparison to those with predominately nociceptive pain (p<0.001). Findings from this study demonstrate that evaluation of pain in patients with FD/MAS should include assessment of neuropathic-like pain to guide personalized approaches to treatment and inform future research.