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. In giant cell tumors, another disorder of skeletal stem cells, RANKL inhibition with the monoclonal antibody denosumab prevents tumor growth, suggesting it has inhibitory effects on skeletal stem cell proliferation. 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 is ongoing (NCT03571191). Despite substantial challenges during the pandemic, this study completed its total enrollment and data analysis is ongoing 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 250 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 Clinical Endocrinology and Metabolism (PMID: 33512531) investigated the relative pathogenicity of the 2 most common disease-causing variants in FD/MAS (R201C and R201H)1. Sixty-one individuals were genotyped using DNA extracted from tissue or circulating cell-free DNA. Twenty-two patients (36.1%) had the R201C variant, and 39 (63.9%) had the R201H variant. FD skeletal disease burden, hypophosphatemia prevalence, fracture incidence, and ambulation status were similar between the 2 groups. These findings demonstrated that there is no clear genotype-phenotype correlation in patients with the most common FD/MAS pathogenic variants. The predominance of the R201H variant was surprising and suggests that the R201H variant is likely responsible for a larger burden of disease in the overall population of patients with FD/MAS. This will have important implications for the future development of targeted therapies. - A study published in the Journal of Bone and Mineral Research (PMID: 32644197) assessed the utility of optical coherence tomography (OCT) in evaluating optic neuropathy, a highly disabling complication of craniofacial FD that frequently leads to blindness 2. OCT is an imaging modality that detects retinal nerve fiber layer (RNFL) thinning, a sign of optic nerve atrophy. In this study we 1) assessed the ability of OCT RNFL thickness measurements to identify optic neuropathy in FD; 2) compared the performance of OCT RNFL thickness to frequently used computed tomography measurements of optic canal narrowing and optic nerve stretch; and 3) examined changes in OCT RNFL thickness over time to assess disease progression. This retrospective cohort study including 70 subjects, and the diagnostic utility of OCT was determined using receiver operator characteristic (ROC) curve analysis. The relationship between RNFL thickness and age was assessed cross-sectionally, using generalized estimating equation methodology, and longitudinally, using a generalized mixed model. Using the diagnostic criterion of 71 m, eleven subjects were identified with optic neuropathy. OCT RNFL thickness identified optic neuropathy with exceptional sensitivity and specificity (100% and 95%, respectively, ROC area under curve = 0.997, p<0.0001). RNFL thickness outperformed computed tomography measurements. Subjects with optic neuropathy exhibited a greater decrease in RNFL thickness with each year of age (-0.70 m/year, p<0.001) than subjects with normal vision (-0.16 m/year, p<0.05). When assessed longitudinally, subjects with normal vision demonstrated an increase in RNFL thickness until approximately age 20 years that decreased thereafter. In contrast, subjects with optic neuropathy exhibited an earlier decrease in RNFL thickness during adolescence. This study demonstrated that RNFL thickness of 71 m accurately identified optic neuropathy in patients with FD. By establishing the difference in rate of RNFL thinning in patients with and without optic neuropathy, clinicians may distinguish between patients at risk for optic neuropathy and intervene before irreversible damage occurs. - A study published in Bone (PMID: 32979536) investigated optic disc edema, a related but distinct ophthalmologic finding which may serve as an initial indicator of optic nerve damage 3. The purpose of this study was to investigate the prevalence and potential clinical associations of optic disc edema in patients with craniofacial FD. This was a retrospective cohort study that included 187 subjects. Computed tomography scans were evaluated for the presence of structural craniofacial abnormalities associated with optic disc edema, and craniomorphometric analyses were performed to determine optic canal diameter and intracranial volume. Statistical analyses were performed to compare clinical and radiographic features between subjects with and without optic disc edema. Optic disc edema was diagnosed in 7/187 subjects, for a prevalence of 3.7%. All subjects with optic disc edema were diagnosed before age 18 years and had mild, non-progressive disease. Radiographic structural abnormalities, including Chiari I malformation, aneurysmal bone cysts, and arachnoid cysts, were associated with higher odds of optic disc edema (odds ratio OR 24.3; 95% confidence interval CI, 4.2 to 121.4; p < 0.01) (OR 18.0; 95% CI, 3.4 to 108.2; p < 0.01). Treatment with leuprolide, a gonadotropin releasing hormone analog used for management of MAS precocious puberty, was also associated with optic disc edema (OR 26.0; 95% CI 3.3 to 177.5; p < 0.05). There was no significant association of optic disc edema with other MAS endocrinopathies, medications, optic canal diameter, or intracranial volume. These findings demonstrate that optic disc edema is an uncommon but potentially serious complication of craniofacial FD, which occurs more frequently in pediatric patients with structural craniofacial abnormalities. While optic disc edema may lead to disabling complications including vision loss, findings from this study suggest that optic disc edema in patients with FD/MAS is frequently mild and non-progressive. All patients with craniofacial FD should have routine optic disc evaluation as part of a comprehensive neuro-ophthalmologic exam. The potential association of leuprolide therapy with optic disc edema warrants further study.