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

基本信息

批准号：
7684863
负责人：
THOMAS O CARPENTER
金额：
$ 43.25万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-09-01 至 2011-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7684863
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

项目摘要

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（XLH）是美国最常见的佝偻病/骨软化症的遗传形式。在所有年龄段，无论是否接受治疗，XLH 患者甲状旁腺功能亢进症的发病率都很高。其他表现包括钙化附着点和关节炎。关于磷酸盐的新知识的爆炸式增长新陈代谢使得现在是重新审视 XLH 发病机制和治疗的最佳时机。我们假设甲状旁腺激素 (PTH) 水平升高对骨骼健康有重大贡献 XLH 疾病，并建议使用帕立骨化醇（一种非高钙血症维生素 D 类似物）来抑制这种疾病中 PTH 水平升高。第一个目标是，我们将进行横断面研究，以确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、骨骼对 70 名 XLH 患者制定综合疾病评分闪烁扫描和经过验证的症状问卷（WOMAC 和 SF-36）。然后我们将评估该综合评分与循环 PTH、磷酸盐 (P)、 24 小时内测量的 FGF23 水平。在第二个目标中，我们将进行一项为期 12 个月的随机、双盲、安慰剂对照试验帕立骨化醇用于 XLH 和甲状旁腺功能亢进症患者。剂量将逐步调整以达到至少 50% PTH 水平降低。基线和 12 个月后每日采样期间 PTH 的 AUC 治疗的效果将是主要结果指标，因变量为 WOMAC/SF-36 基线和治疗后进行的评分和骨骼闪烁图。我们预计修正甲状旁腺功能亢进症伴有症状改善和闪烁扫描证据改善骨骼疾病。如果成功，该试验将为使用提供概念证明帕立骨化醇治疗XLH。该项目将建立循环 PTH、FGF23 和磷酸盐的临床相关性 XLH 疾病的标志物/介质并测试非高钙血症维生素 D 类似物治疗的功效 XLH 相关的甲状旁腺功能亢进症。该项目也将作为与后续项目进行比较的基础（第一阶段）研究可能针对抑制 FGF23 的作用。