FD/MAS: Two papers this year address the pathophysiology of FD. De Castro et al demonstrated that the RANK/RANKL/OPG pathway is activated and contributes to the pathogenesis of FD (PMID: 30496606). This pathway regulates the generation of multinucleated giant cells and bone-resorbing osteoclasts, both of which may be involved in FD lesion expansion. Evidence for this included a 16-fold increase in serum RANKL, a 24% increase OPG, and a 12-fold increase in RANKL/OPG compared to controls, all of which were significantly correlated with skeletal burden score, a validated marker of FD burden. In FD tissue, RANKL- and Ki67-expressing fibroblastic cells were observed interacting with RANK-expressing osteoclasts. High levels of RANKL were released by FD BMSCs cultures, but not control BMSCs, and induced osteoclastogenesis in monocyte co-cultures, which was prevented by denosumab, a RANKL antagonist. These data are consistent with the role of Gs-dependent RANKL as a driver in FD-induced osteoclastogenesis and support the clinical study of denosumab that we are conducting in patients with FD/MAS (ClinicalTrials.gov Identifier: NCT03571191). An important study by Florenzano et al (PMID:30645769) that addressed the underlying pathophysiology of the natural history of FD. An examination of age-related changes and effects of bisphosphonates on bone turnover and disease progression in FD found that there is an age-dependent decrease in bone turnover markers, independent of treatment with bisphosphonates, which are drugs that inhibit bone turnover and are frequently used to treat FD. Bisphosphonate treatment had little effect on the naturally occurring, age-dependent decrease in bone turnover, and had no effect on lesion progression. This study informs the natural history of FD and will serve as the backdrop for all drugs considered in the treatment of FD in the future. Three clinical studies were published this year that characterized features of FD/MAS and made important contributions to better defining the spectrum and natural history of the disease. The first by Robinson et al (PMID: 30124968) addressed the heretofore understudied topic of intraductal papillary mucinous neoplasms (IPMNs) in FD/MAS. Sporadic IPMNs are precancerous lesions, the formation of which is driven by the same GNAS mutations that cause FD/MAS. We found that 46% of 54 consecutive patients studied had IPMNs alone or in combination with other GNAS-mediated gastrointestinal pathology. Affected patients also had higher rates of pancreatitis, diabetes mellitus, and higer skeletal disease burden of FD than patients without GI disease. These data have important implications for both the care of patients with FD/MAS and implications for understanding the pathophysiology of FD/MAS- associated and sporadic IPMNs. Pan et al reported an increased prevalence of a previously understudied craniofacial feature of FD/MAS, Chiari I malformation and basilar invagination (PMID: 29924878). These are extremely important findings in which normal skull base anatomy is disrupted by FD and the brain or spinal cord displacement, constricted, and compromised. Importantly, we also identified contributing, modifiable features associated with the presence and severity of disease, including hyperthyroidism, precocious puberty, hypophosphatemia, and scoliosis. Related to the above, Berglund et al reported on the prevalence, severity, associated contributing factors, progression, and treatment of scoliosis in FD/MAS (PMID: 29669167). We found that modifiable features associated with scoliosis prevalence and severity included, leg length discrepancy, FGF23-mediated hypophosphatemia, hyperthyroidism, and bone turnover were associated; a non-modifiable but predictive feature was skeletal disease burden. Spinal fusion appeared to have lasting benefit, but bisphosphonate treatment had none. Boyce et al (PMID: 25719192) published an important review of FD/MAS this year in the highly respected, NCBI-supported GeneReviews series. This paper is the compilation of > 20 years of research in FD/MAS at the NIH and is widely accepted as the de facto definitive paper on the diagnosis and management of patients with FD/MAS. In fact, this manuscript is largely the basis for another important paper published this year, the consensus statement from the FD/MAS international consortium on the guidelines for the best practice management of FD/MAS (PMID: 31196103), a consortium in which NIDCR investigators play an important leadership role. Mineral Homeostasis: An unanswered question is what is the direct the role of the calcium-sensing receptor in bone biology. Ovejero et al addressed this by examining differences in bone biopsies from patients with autosomal dominant hypocalcemia type 1 (ADH1), a type of hypoparathyroidism due to gain-of-function mutations in the CASR, in comparison to patients with post-surgical hypoparathyroidism. (PMID: 30496603). We found that while there were no essential differences in measures of bone formation or resorption, as measured by histomorphometry, there were distinct differences in bone mineral distribution density, a measure of the degree of tissue mineralization, as assessed by back-scatter electron microscopy. Overall, bone from patients with ADH1 showed lower and more heterogenous mineralization, pointing to a direct, PTH-independent role of the CASR in bone mineralization regulation. Hypoparathyroidism treatment with replacement PTH has been investigated as a treatment option by our group for many years. While it is clear PTH can maintain blood calcium, effects on urine calcium and renal morbidity are not clear. Gafni et al examined the effect of PTH replacement on renal morbidity and found that PTH treatment, which normalized blood calcium, induced a transient renal tubular acidosis that caused hypocitraturia and resulted in increased renal calcification (nephrocalcinosis) (PMID: 29878514). This finding raises significant concerns about the safety of PTH replacement for the long-term treatment of hypoparathyroidism and emphasize the need for treatments that specifically address hypercalciuria and renal morbidity that is associated with hypoparathyroidism and its treatment. Calcilytics, antagonists of the CASR, raise blood calcium by increasing PTH secretion and renal calcium retention. Therefore, they represent a potential treatment for hypoparathyroid ADH1 patients. To test this, Roberts et al conducted a proof-of-principle, study with the repurposed calcilytic, NPSP795, in patients with ADH1 (PMID: 31063613). We found that NPSP795 significantly increased PTH in a drug concentration-dependent manner, with a similar trend on urine calcium. This study confirmed calcilytics may be a viable option for the treatment of ADH1 with implications for other disorders associated with hypercalciuria. Gafni and Collins published a review article on hypoparathyroidism this year in the New England Journal of Medicine, the preeminent journal in the field (PMID: 31063613). This invitation reflects the authors prominence in mineral homeostasis, and signals that our work is having an impact in the field. Our studies of FGF23 biology and physiology have been informed by the study of FTC, a disease caused by FGF23 deficiency. Study of a child with typical clinical findings of FTC, but with markedly atypical FGF23 levels by Roberts et al extended the spectrum of tumoral calcinosis disorders. Instead of low/undetectable levels of intact FGF23, this child had markedly elevated levels, suggesting FGF23 resistance. Further investigation revealed that this child had anti-FGF23 antibodies that bound FGF23 and blocked FGF23 downstream signaling, thus identifying the first case of autoimmune tumoral calcinosis (PMID: 31063613).
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