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: 7485014
• 负责人: THOMAS O CARPENTER
• 金额: $ 39.83万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-01 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7485014
• 关键词: Age; Area Under Curve; Arthritis; Biochemical Markers; Biological Markers; Calcified; Clinical; Cross-Sectional Studies; Disease; Disease Marker; Dose; Elevation; Exostoses; Explosion; Foundations; Fracture; Height; Hyperparathyroidism; Hypophosphatemia; Incidence; Individual; Intervention Trial; Knowledge; Link; Longitudinal Studies; Measures; Mediator of activation protein; Metabolism; Modeling; Numbers; Osteomalacia; Osteotomy; Outcome; 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; Score; Secondary Hyperparathyroidism; Serum; Severity of illness; Skeletal system; Study Subject; Symptoms; Taste Perception; Testing; Time; Vitamin D Analog; base; bone; bone turnover; burden of illness; capsule; clinically relevant; concept; dental abscess; double-blind placebo controlled trial; human PTH protein; inorganic phosphate; paricalcitol

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连锁低磷酸盐血症（XLH）是美国最常见的遗传性rick骨/骨乳核形式。 在所有年龄段和治疗方面，XLH中都有高甲状旁腺功能亢进症的发生率很高。其他 表现包括钙化的肠和关节炎。关于磷酸盐的新知识的爆炸 代谢使这是在其发病机理和治疗方面重新审视XLH的合适时机。我们 假设甲状旁腺激素升高（PTH）水平对骨骼做出了明显的贡献 XLH中的疾病，并建议使用二核酸醇（一种非高钙质维生素D类似物）抑制 该疾病的PTH水平升高。 在第一个目标中，我们将进行横断面研究，以鉴定疾病严重程度的生物标志物。我们将 使用临床参数，X光片，骨骼，在70例XLH患者中发展复合疾病评分 闪烁图和验证症状问卷（WOMAC和SF-36）。然后，我们将评估 对于循环PTH，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12个月的随机，双盲，安慰剂对照试验 XLH和甲状旁腺功能亢进的受试者中的二核。剂量将滴定至少达到50％ 降低PTH水平。在基线和12个月后进行的昼夜采样中的PTH AUC 治疗的主要结果指标将是因子变量是WOMAC/SF-36 在基线和治疗后进行的分数和骨骼闪烁。我们希望对 甲状旁腺功能亢进症伴随着症状改善和闪烁图证据 改善骨骼疾病。如果成功，该试验将为使用的概念证明 XLH治疗中的二醇。 该项目将建立循环PTH，FGF23和磷酸盐的临床相关性 XLH中疾病的标志物/介质，并测试非高血症性维生素D模拟疗法的功效 在XLH相关的甲状旁腺功能亢进症中。该项目还将作为以后比较的基础 （第1阶段）可能针对FGF23作用的研究。