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: 7175916
• 负责人: THOMAS O CARPENTER
• 金额: $ 36.97万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-01 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7175916
• 关键词: analog; parathyroid hormones; phosphates; role; vitamin D

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）是美国最常见的佝偻病/骨软化症的遗传形式。 在所有年龄段，无论治疗，有一个高甲状旁腺功能亢进的发生率在XLH。其他 临床表现包括附着点钙化和关节炎。关于磷酸盐的新知识的爆发 代谢使这是正确的时间重新审视XLH无论是在其发病机制和治疗。我们 假设甲状旁腺激素（PTH）水平升高对骨骼肌的 并建议使用帕立骨化醇（一种非高钙维生素D类似物）来抑制 甲状旁腺激素水平升高 在第一个目标中，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线片、骨密度 脑电图和经验证的症状问卷（WOMAC和SF-36）。然后我们将评估 该综合评分与循环PTH、磷酸盐（P） 和FGF 23水平，在24小时内测量。 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， 帕立骨化醇治疗XLH和甲状旁腺功能亢进受试者。将滴定剂量，以达到至少50% 降低PTH水平。基线和12个月后进行的日间采样期间PTH的AUC 治疗的时间将是主要结局指标，因变量为WOMAC/SF-36 在基线和治疗后进行的评分和骨骼肌造影。我们预计， 甲状旁腺功能亢进伴随症状改善， 改善骨骼疾病。如果成功，该试验将为使用 帕立骨化醇治疗XLH。 该项目将确定循环PTH、FGF 23和磷酸盐的临床相关性， XLH疾病的标志物/介质，并测试非高钙维生素D类似物治疗的疗效 与XLH相关的甲状旁腺功能亢进该项目还将作为与后来的项目进行比较的基础。 （1期）研究可能针对FGF 23作用的抑制。