P1: The role of parathyroid hormone in the pathogenesis of skeletal disease in X-

P1：甲状旁腺激素在X-骨骼疾病发病机制中的作用

• 批准号: 7910628
• 负责人: THOMAS O CARPENTER
• 金额: $ 43.15万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-01 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7910628
• 关键词: Aftercare; Age; Area Under Curve; Arthritis; Biochemical Markers; Biological Markers; Calcified; Clinical; Cross-Sectional Studies; Disease; Dose; Exostoses; Explosion; Foundations; Fracture; Height; Hyperparathyroidism; Hypophosphatemia; Incidence; Individual; Intervention Trial; Knowledge; Link; Longitudinal Studies; Measures; Mediator of activation protein; Metabolism; Modeling; National Institute of Arthritis and Musculoskeletal and Skin Diseases; Osteomalacia; Osteotomy; Outcome Measure; Parathyroid Hormones; Pathogenesis; Patients; Pharmaceutical Preparations; Phase; Phase I Clinical Trials; Phosphorus; Placebos; Questionnaires; Radionuclide Imaging; Randomized; Regression Analysis; Relative (related person); Rickets; Role; SF-36; Sampling; Secondary Hyperparathyroidism; Serum; Severity of illness; Study Subject; Symptoms; Taste Perception; Testing; Time; Vitamin D Analog; base; bone; bone turnover; capsule; clinically relevant; dental abscess; double-blind placebo controlled trial; efficacy testing; human PTH protein; inorganic phosphate; paricalcitol; primary outcome; secondary outcome; skeletal; skeletal disorder; symptomatic improvement

X-linked hypophosphatemia (XLH) is the most common heritable form of rickets/osteomalacia in the US. At all ages and irrespective of treatment there is a high incidence of hyperparathyroidism in XLH. Other manifestations include calcified entheses and arthritis. The explosion of new knowledge about phosphate metabolism makes this the right time for revisiting XLH both in terms of its pathogenesis and treatment. We hypothesize that elevated parathyroid hormone (PTH) levels make a signficiant contribution to the skeletal disease in XLH and propose to use paricalcitol, a non-hypercalcemic vitamin D analog, to suppress elevated PTH levels in this disease. In the first aim, we will perform a cross-sectional study to identify biomarkers of disease severity. We will develop a composite disease score in 70 patients with XLH using clinical parameters, radiographs, bone scintigraphy, and validated symptom questionnaires (WOMAC and SF-36). We will then assess the relationship of this composite score to the area under the curve (AUC) for circulating PTH, phosphate (P), and FGF23 levels, measured over a 24-hrs. In the second aim, we will conduct a 12-month randomized, double blind, placebo-controlled trial of paricalcitol in subjects with XLH and hyperparathyroidism. The dose will be titrated to achieve at least a 50% reduction in PTH levels. AUC for PTH during diurnal sampling performed at baseline and after 12 months of therapy will be the primary outcome measure with the dependent variables being the WOMAC/SF-36 scores, and skeletal scintigrams at performed at baseline and post-treatment. We expect correction of hyperparathyroidism to be accompanied by symptomatic improvement and scintigraphic evidence for amelioration in skeletal disease . If successful, this trial will provide proof of concept for the use of paricalcitol in the treatment of XLH. This project will establish the clinical relevance of circulating PTH, FGF23 and phosphate as markers/mediators of disease in XLH and test the efficacy of non-hypercalcemic vitamin D analog therapy in XLH-associated hyperparathyroidism. The project will also serve as a basis for comparison with later (Phase 1) studies potentially directed at suppression of FGF23 action.

X连锁低磷血症是美国最常见的可遗传形式的软骨病/软骨病。 在所有年龄段，无论接受何种治疗，XLH型甲状旁腺机能亢进症的发生率都很高。其他 表现包括钙化的凹陷和关节炎。关于磷酸盐的新知识的爆炸性增长 就其发病机制和治疗而言，新陈代谢使得现在是重温XLH的合适时机。我们 假设甲状旁腺激素(PTH)水平升高对骨骼有显著贡献 的疾病，并建议使用骨钙醇，一种非高钙维生素D类似物，以抑制 甲状旁腺素水平在本病中升高。 在第一个目标中，我们将进行一项横断面研究，以确定疾病严重程度的生物标志物。我们会 利用临床参数、X线片、骨骼等建立70例XLH患者的综合疾病评分 核素扫描和有效症状问卷(WOMAC和SF-36)。然后，我们将评估 这一综合评分与循环甲状旁腺激素、磷酸盐(P)、 和FGF23水平，在24小时内测量。 在第二个目标中，我们将进行为期12个月的随机、双盲、安慰剂对照试验。 黄体生成素和甲状旁腺功能亢进症患者的甲状旁腺激素。剂量将被滴定，以达到至少50% 甲状旁腺素水平降低。甲状旁腺激素在基线和12个月后每日采样时的AUC 将以WOMAC/SF-36为因变量的主要结果指标 在基线和治疗后进行评分和骨显像检查。我们预计会出现修正 甲状旁腺功能亢进伴症状改善和核素扫描证据 骨骼疾病的改善。如果成功，这项试验将为使用 新骨化醇治疗黄体生成性黄体生成素 该项目将建立循环甲状旁腺素、纤维生长因子23和磷酸盐的临床相关性。 XLH型疾病标志物/中介物及检测非高钙维生素D类似物治疗的疗效 在XLH型甲状旁腺机能亢进症中。该项目也将作为与后来的比较的基础 (阶段1)可能针对抑制FGF23作用的研究。