The Skeletal Clinical Studies Program studies human diseases as model systems through which physiologic mechanisms of skeletal and mineral metabolism can be elucidated. This is done through meticulous clinical studies wherein observations will lead to testable clinical and translational hypotheses, and evidenced-based treatments for the diseases studied. Specifically, these studies were accomplished in the ongoing studies in fibrous dysplasia (FD)/McCune-Albright syndrome (MAS), and expansion of recently initiated studies to study hormonal control of mineral metabolism by the phosphatonin, FGF-23. FD/MAS (50% Effort) Studies in FD/MAS were carried out through several study and treatment protocols (98-D-0145, 98-D-0146, 00-D-0183). FD is an uncommon skeletal disease, caused by somatic activating mutations in the G-protein, Gs-alpha, which is encoded by GNAS. These mutations result in ligand-independent cAMP signaling in affected tissues. In the skeleton, this leads to abnormal differentiation of skeletal stem cells/bone marrow stromal cells to mature osteogenic cells, resulting in replacement of normal bone by mechanically unsound fibroosseous tissue. FD can occur in isolation or as part of the MAS, which is defined clinically by some combination of FD, cafe-au-lait skin spots, and hyperfunctioning endocrinopathies. The skin and endocrine lesions are the tissue-specific manifestations of the GNAS mutations. Due to the somatic/mosaic nature of FD, there is wide variability in the extent of skeletal involvement, ranging from a single focus in a single bone to virtually every bone in the skeleton. The study and understanding of FD have been vexed by the fact that there was no objective way to quantify the ?amount? of FD. To correct this deficiency, we developed an instrument to measure the ?amount? of involved skeletal (the disease burden). The skeletal disease burden score was derived from a weighted score based on regional measurement using bone scintigraphy to estimate the amount of FD in anatomical segments. To assess biological significance, scores were correlated with markers of bone metabolism. In a group of patients who had bone scans as children and adults, the ability to predict ambulatory status was tested. We found that the scores were highly correlated with markers of bone metabolism. Demonstrating that the instrument was effective in predicting functional outcome, the mean score of patients who ambulated unassisted was significantly lower than those requiring assistance (crutch and/or wheelchair). In patients with childhood and adulthood scans, childhood scores of high disease burden (score >30) predicted assisted ambulation in adulthood, suggesting that a childhood score of >30 may be the threshold score to use to predict adult disability. Taken together, these data demonstrate that this is a validated and reliable instrument for the measurement of skeletal burden of FD and is able to predict functional outcome. To further contribute to evidence-based management of FD/MAS, we examined the impact of the scope and extent of the skeletal disease on the important parameter of health-related quality of life (HRQL) in adults and children with FD/MAS by using the standardized, validated measures of HRQL, the SF36 (adults) and the CHQ-PF50 (children). Clinical demographic data and skeletal disease burden scores were measured, and correlated with HRQL. The SF36 and CHQ-PF50 revealed lower Physical Function Summary scores in FD patients compared to the U.S. population norms. However, the SF36 and CHQ-PF50 Mental/Psychological summary scores were not different from those of U.S. population norms. The groups of adult and pediatric patients with high burden (scores >30) had decreased Physical Function Domain scores when compared to those with scores <30. One of the largest effects was seen in the parents of children with FD/MAS, who had significantly lower Parental Emotional scores than those of the parents of healthy norms, suggesting a high degree of emotional morbidity in the parents of children with FD/MAS. Again, as shown in the previous study, high disease burden in childhood portends diminished adult physical function. However, despite measurable functional limitations in adults and children, and significant parental emotional impairment, patients with FD/MAS achieve a high level of social and emotional function. These data are important for prognosis and parental reassurance. FIBROBLAST GROWTH FACTOR-23 (50%) Studies to characterize the role of FGF-23 in control of mineral metabolism were carried out through several clinical protocols (01-D-0184, 03-D-0254, 05-D-0050). Our earlier studies, which were directed at understanding the abnormalities in phosphorus metabolism in FD, revealed that the renal phosphate wasting and low serum phosphorus that occurs in FD are the result of high levels of FGF-23, reflecting the highly activated state of osteoblastic cells in FD lesions. We and others have also shown that relatively high levels of FGF-23 are measurable in the serum of normal individuals. These findings beg the question of how are serum levels of FGF-23 regulated, and what is the physiologic role(s) of FGF-23? To answer the former question, we performed a set of studies in patients with hypoparathyroidism (various forms of acquired PTH absence). This model was chosen to allow for the study of FGF-23 regulation in the absence of PTH, since PTH and FGF-23 have overlapping (and potentially counter-regulatory) actions on phosphorus and 1,25-(OH)2 vitamin D3 (1,25-D) metabolism. Our previous study looked at the effect of elevated levels of serum phosphorus in patients with hypoparathyroidism who had elevated serum phosphorus and were on stable medical treatment. The results suggested the presence of a feedback system in which serum FGF-23 responds to and regulates serum phosphorus, and that the phosphaturic effect of FGF-23 is PTH-dependent. However, we noted that one of the findings in pathological states of FGF-23 excess is suppression of renal production of the potent calcium-regulating hormone, 1,25-D. To test the hypothesis that FGF-23 may be regulated by 1,25-D in an endocrine feedback manner, we administered 1,25-D to 3 patients with various forms of hypoparathyroidism. Patient 1 had post surgical hypoparathyroidism and Munchausen?s syndrome and consumed a pharmacologic dose of calcitriol, patient 2 had post surgical hypoparathyroidism and fibrous dysplasia of bone ? a state of FGF-23 overproduction ? and was treated with increasing doses of calcitriol followed by synthetic PTH 1-34, and patient 3 had pseudohypoparathyroidism type 1B (PTH resistance at the kidney, but not the bone ? the source of FGF-23), and was treated with calcitriol. Again, we used the model of hypoparathyroidism to avoid the confounding effects of PTH on phosphorus and 1,25-D metabolism. Patient 1 had an acute and marked increase in serum FGF-23 within 24 hours in response to high-dose calcitriol administration. Patient 2 demonstrated stepwise increases in serum FGF-23 in response to increasing serum levels of 1,25-D. Patient 3 also showed a robust response in serum FGF-23 in response to treatment with 1,25-D. As in the previous study, the phosphaturic effect of FGF-23 was diminished in the absence of PTH or a PTH effect. This study showed that serum FGF-23 may be regulated by serum 1,25-D and that the phosphaturic effect of FGF-23 may be diminished in the absence of PTH. Further studies are underway to develop effective treatments and better define the clinical management for patients with FD/MAS. In addition, studies are underway to define the mechanism of FGF-23 regulation, its physiologic role, as well as effective treatments for patients with states of FGF-23 excess or deficiency.
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