Optimizing Calcitriol Monotherapy for X-Linked Hypophosphatemia: Effects on Mineral Ions, Growth and Skeletal Parameters

X-连锁低磷血症的特征是FGF23升高，这会损害维生素的活性 并促进肾脏磷酸盐的消耗，导致骨软化和软骨病。目前的治疗方法是1，25- 二羟基维生素D(骨化三醇)和磷酸盐经常合并高钙血症和肾钙沉着症，以及 并不总是能预防甲状旁腺功能亢进症。此外，它不会使增长正常化。因此，我们承诺 骨化三醇单用与单用骨化三醇治疗HYP小鼠模型的临床前研究 FGF23阻断抗体对生长，血清和尿液矿物质离子以及组织学，组织形态计量学， 骨骼的微结构和生物力学特性。这些研究表明，骨化三醇单一疗法 促进生长，预防软骨病，改善骨骼的微结构和生物力学性能 不需要补充磷酸盐。骨化三醇的有益效果优于FGF23 使用封闭抗体，可能是因为，像在人类中一样，FGF23封闭抗体不能 维持1，25-二羟基维生素D水平的升高。值得注意的是，骨化三醇的有益效果发生在 尽管循环FGF23和骨FGF23的mRNA表达显著增加。尽管增加了 骨化三醇治疗可降低Hyp小鼠的尿磷排泄率。因此，骨化三醇有好处 在FGF23进一步增加的情况下，XLH对骨骼和肾脏磷酸盐处理的影响。 基于这些临床前数据，目前的建议旨在解决这样的假设，即优化 在没有补充磷酸盐的情况下，使用XLH进行骨化三醇治疗将会有有益的效果。我们 假设优化骨化三醇将消除对磷酸盐补充的需要，从而增加 目前治疗的依从性和减少并发症，包括肾钙质沉着症和 甲状旁腺机能亢进。优化降钙素治疗也有望从整体上改善骨骼微结构 XLH受试者，并改善儿童受试者的生长和防止脊椎病的变化。XLH型受试者 将从成人和儿科内分泌和肾脏病诊所招募。治疗将停止2次 几周后，将获得基线实验室，并开始骨化三醇治疗。骨化三醇的剂量 将在三个月内增加，以确定不会导致 高钙血症或高钙尿。主要终点将是血清磷水平，肾小管吸收 儿童的磷酸盐(TMP/GFR)、肾钙素沉着评分和软骨病评分。次要端点将是 儿童的生长发育。数据将与之前24个月获得的受试者特定值进行比较 骨化三醇的工艺优化。骨骼微结构将通过高分辨率外周QCT进行评估。这个 这些调查的结果预计将为大型多中心提供关键的初步数据 “优化骨化三醇”与骨化三醇加骨化三醇的疗效比较 磷酸盐，以及FGF23阻断抗体，如果它们是FDA批准的。

X-linked hypophosphatemia (XLH) is characterized by increased FGF23, which impairs activation of vitamin D and promotes renal phosphate wasting leading to osteomalacia and rickets. Current treatment using 1,25- dihydroxyvitamin D(calcitriol) and phosphate is often complicated by hypercalcemia and nephrocalcinosis, and does not always prevent hyperparathyroidism. Furthermore, it does not normalize growth. Thus, we undertook a pre-clinical study in the Hyp mouse model of XLH, to compare the effects of calcitriol alone vs treatment with FGF23 blocking antibodies on growth, serum and urine mineral ions as well as histological, histomorphometric, microarchitectural and biomechanical properties of bones. These studies revealed that calcitriol monotherapy improves growth, prevents rickets and improves the microarchitectural and biomechanical properties of bone without phosphate supplementation. The beneficial effects of calcitriol were superior to those of the FGF23 blocking antibody employed, perhaps because, as in humans, FGF23 blocking antibodies were not able to sustain increased levels of 1,25-dihydroxyvitamin D. It is notable that the beneficial effects of calcitriol occur in spite of a significant increase in circulating FGF23 and bone FGF23 mRNA expression. Despite increased FGF23, calcitriol treatment decreases urinary phosphate clearance in Hyp mice. Thus, calcitriol has beneficial effects on bone and renal phosphate handling in XLH, in the setting of a further increase in FGF23. Based on these pre-clinical data, the current proposal aims to address the hypothesis that optimizing calcitriol therapy in humans with XLH, without phosphate supplementation, will have beneficial effects. We hypothesize that optimizing calcitriol will obviate the need for phosphate supplementation, thus increasing compliance and decreasing complications of current therapy which include nephrocalcinosis and hyperparathyroidism. Optimizing calcitrol therapy is also expected to improve skeletal microarchitecture in all subjects with XLH, and improve growth and prevent rachitic changes in pediatric subjects. Subjects with XLH will be recruited from adult and pediatric Endocrine and Nephrology clinics. Therapy will be stopped for 2 weeks, following which baseline labs will be obtained and calcitriol therapy will be initiated. The dose of calcitriol will be increased over a three-month period to identify the highest subject-specific dose that does not lead to hypercalcemia or hypercalciuria. Primary endpoints will be levels of serum phosphate, tubular resorption of phosphate (TmP/GFR), nephrocalcinosis score, and rickets score in children. The secondary endpoint will be growth in children. Data will be compared to subject-specific values obtained in the 24 months prior to optimization of calcitriol. Skeletal microarchitecture will be evaluated by high resolution peripheral qCT. The results of these investigations are expected to provide critical preliminary data for a large multicenter randomized clinical trial examining the comparative effectiveness of “optimized calcitriol” to that of calcitriol plus phosphate, and to FGF23 blocking antibodies if they are FDA approved.