Skeletal Disorders and Mineral Homeostasis Section

National Institute Of Dental & Craniofacial Research

Investigators

Linked publications & trials

Abstract

Summary: The Skeletal Disorders and Mineral Homeostasis Section (SDMHS) focuses on clinical and translational studies of mineral metabolism; centering around bone, parathyroid hormone (PTH), and FGF23. Central to this work are studies in hypoparathyroidism, tumor-induced osteomalacia, and hyperphosphatemic familial tumoral calcinosis. Hypoparathyroidism is a disorder of deficient PTH, which leads to hypocalcemia and hyperphosphatemia. Conventional treatment with calcium and calcitriol (activated vitamin D) can increase the urinary excretion of calcium and lead to nephrocalcinosis. This is especially true in the genetic disorder, autosomal dominant hypocalcemia type 1, in which gain-of-function variants of the calcium sensing receptor cause altered calcium sensing in the parathyroid glands and in the kidneys, leading to low blood calcium levels but high urinary excretion of calcium that is often complicated by nephrocalcinosis and can progress to renal failure. Altering the function of the CASR by small molecule allosteric modulators of the CASR has represented a major breakthrough in the field of mineral homeostasis. Based on our earlier successful proof of principle study (PMID: 31063613), we partnered with BridgeBio Pharma/Calcilytix as part of a public-private partnership to develop the calcilytic encaleret to treat ADH1. The phase 2 study of encaleret in ADH1 was conducted by the Principal Investigator, Dr. Rachel Gafni. This work demonstrated the ability of encaleret to restore mineral homeostasis in patients with ADH1, won Best Clinical Abstract at the annual meeting of the American Society of Bone and Mineral Research and was published in the New England Journal of Medicine (PMID: 37754292). This year, we have continued the work and have a leading role in the international multicenter phase 3 study of encaleret in ADH1. We anticipate that this drug will be a life-altering therapy for patients and families with this debilitating autosomal dominant disorder. The NIDCR has played a central role in identifying this class of drugs as a treatment for ADH1, fulfilling the mission of the NIH to relieve suffering in the patients. In addition to our work with encaleret in ADH1, this past year we initiated a study of encaleret in post-surgical hypoparathyroidism. This study was led by Principal Investigator Dr. Iris Hartley. We have presented abstracts demonstrating the ability of encaleret to restore mineral homeostasis in a PTH-independent manner. This represents the first clinical study to directly examine the effect of CaSR on mineral homeostasis independent of PTH. Tumor-induced Osteomalacia (TIO): Following on our work on the use of the pan-FGFR tyrosine kinase inhibitor, infigratinib in TIO (PMID: 32905668), we investigated the effects of this drug in dentoalveolar development, finding that there was an effect of inhibiting development, but only at very high doses and that the effect was not pronounced (PMID: 37435833). This past year, we have continued to care for and study our population of patients with TIO. We have gained much experience with the use of burosumab, a monoclonal antibody to FGF23, and treatment of high FGF23 levels. Through following our cohort, we continue to gain prospective of treatment best practices and outcomes (PMID: 37955803). Hyperphosphatemic familial tumoral calcinosis (HFTC): We continued work this year in the disorder of mineralization, HFTC. We developed the imaging modality of 18F-NaF PET/CT as a biomarker for HFTC and showed the ability to identify and quantify vascular microcalcification (PMID: 38660800). We also applied the technique more broadly and characterized soft tissue calcification and their locations in our cohort of patients (PMID: 39046425). This year, we have expanded our cohort of patients with HFTC and presented abstracts at several conferences on our collaborative work to use artificial intelligence and machine learning to develop a method to identify and quantify vascular microcalcification. We are excited to apply this technique to several disorders of vascular calcification and hope to identify vascular calcification at an earlier time point to enable early intervention. Informative preclinical translational studies in a mouse model of HFTC, led by Dr. Kelly Roszko, are ongoing. Collaborations: The SDMHS aims to support research across the NIH and throughout the world. Several key collaborations produced important work during this period. The most productive was in the area of FD/MAS. We collaborated on studying pain in a preclinical model of fibrous dysplasia, finding that nociceptive mechanisms may contribute to pain in fibrous dysplasia (40367355). We also contributed to a phase 2 clinical trial showing the safety and efficacy of moderate-dose denosumab in fibrous dysplasia (39673171).