Treatment of Hypoparathyroidism with Parathyroid Hormone

描述(由申请人提供)： 甲状旁腺功能减退症是一种罕见的疾病，甲状旁腺激素(PTH)明显减少或消失在循环中。这是为数不多的残留的激素缺乏状态之一，到目前为止还无法用缺失的激素来替代。如果没有甲状旁腺激素，患者会出现钙稳态异常，表现为低钙血症和高尿钙排泄。目前的主要治疗方法是钙和维生素D，然而，这种方法在临床上有重要的局限性。所需的大剂量钙和维生素D与高钙血症、高钙尿症和维生素D中毒的风险有关。这种方法也不能纠正由于缺乏甲状旁腺素而导致的骨骼缺陷。由于甲状旁腺功能减退症是一种孤儿疾病，研究人员和资助机构都不愿支持甲状旁腺激素作为一种治疗方法的开发。在人们可能考虑的甲状旁腺激素分子中，最近开发的重组人甲状旁腺激素(1-84)是最有吸引力的，因为它是天然激素，正是这些人所缺少的分子。Teriparatide[重组hPTH(1-34)]是另一种潜在的治疗方法，但它的吸引力较小，因为它是PTH的氨基末端截短型，不会为甲状旁腺功能低下的患者提供天然激素。尽管特派拉定被批准用于治疗骨质疏松症，但它还没有被开发出来，也没有被批准用于治疗甲状旁腺功能减退症。甲状旁腺素(1-84)对这一人群钙稳态的治疗作用知之甚少。甲状旁腺功能减退症患者骨骼的一般质量以及甲状旁腺激素(1-84)治疗如何改善骨骼的情况更是知之甚少。这是一个重要的问题，因为在甲状旁腺功能减退症中，甲状旁腺激素缺乏与骨转换显著降低有关，这种情况会损害骨强度。这个项目的主要目标是一个治疗目标，即确定甲状旁腺激素是否是治疗甲状旁腺功能减退的有效方法。它建立在从一项较小的研究中获得的数据，该研究部分由FDA资助。通过进行一项现在是双盲和安慰剂对照的研究，研究者希望清楚地证明PTH(1-84)治疗是一种安全有效的方法，可以克服仅用钙和维生素D治疗的障碍，并改善骨骼质量。随着甲状旁腺素(1-84)试验的积极结果，研究人员希望能够让FDA审查数据，最终目标是批准甲状旁腺素(1-84)作为甲状旁腺功能减退症的治疗方法。这位赞助者兼研究人员希望甲状旁腺素(1-84)成为治疗这种孤儿疾病的首选药物。

DESCRIPTION (provided by applicant): Hypoparathyroidism is a rare disorder in which parathyroid hormone (PTH) is markedly decreased or absent from the circulation. It is one of the few remaining hormone deficiency states for which replacement with the missing hormone has been heretofore unavailable. Without PTH, patients have abnormal calcium homeostasis characterized by hypocalcemia and high urinary calcium excretion. The current mainstay of therapy is calcium and vitamin D. This approach, however, has important clinical limitations. The large doses of calcium and vitamin D required are associated with risks of hypercalcemia, hypercalciuria and vitamin D toxicity. This approach also does not correct skeletal deficiencies due to lack of PTH. Because hypoparathyroidism is an orphan disease, investigators and funding agencies have all been reluctant to support the development of PTH as a therapy. Of the parathyroid hormone molecules that one might consider, the recent development of recombinant human PTH (1-84) is the most attractive because it is the native hormone, the very molecule that is missing in these individuals. Teriparatide [recombinant hPTH(1-34)] is another potential therapy but it is less attractive since it is an amino-terminal truncated form of PTH and would not provide the hypoparathyroid patient with native hormone. Although approved for osteoporosis, teriparatide has not been developed and is not approved for the treatment of hypoparathyroidism. Very little is known about the therapeutic effects of PTH (1-84) on calcium homeostasis in this population. Even less is known about the general quality of the skeleton in hypoparathyroidism and how it could be improved with PTH (1-84) therapy. This is an important concern, since in hypoparathyroidism, PTH deficiency is associated with markedly reduced bone turnover, a situation that can compromise bone strength. The major objective of this project is a therapeutic one, namely to determine whether PTH is an effective therapy for hypoparathyroidism. It builds upon data obtained from a smaller study funded, in part, by the FDA. By conducting a study that is now double-blinded and placebo controlled, the investigator expects to demonstrate clearly that PTH (1-84) treatment is a safe and effective way to overcome obstacles of management with calcium and vitamin D alone and to improve bone quality as well. With positive results from this trial with PTH (1-84), the investigator expects to be able to have the data reviewed by the FDA with the ultimate goal being approval of PTH (1-84) as a therapy for hypoparathyroidism. This sponsor-investigator expects PTH (1-84) to become the treatment of choice for this orphan disease.