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

X连锁低磷酸盐血症（XLH）的特征是FGF 23增加，这损害了维生素C的活化。 并促进肾磷酸盐消耗，导致骨软化和佝偻病。目前的治疗使用1，25- 二羟维生素D（骨化三醇）和磷酸盐通常并发高钙血症和肾钙质沉着症， 并不总是能预防甲状旁腺功能亢进。此外，它没有使增长正常化。因此，我们承诺 在XLH的Hyp小鼠模型中进行的临床前研究，以比较单独的骨化三醇与 FGF 23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，骨化三醇单药治疗 促进生长，预防佝偻病，改善骨骼的微结构和生物力学特性 不补充磷酸盐。骨化三醇的有益效果上级于FGF 23 使用阻断抗体，可能是因为，如在人类中，FGF23阻断抗体不能 维持增加的1，25-二羟维生素D水平。值得注意的是，骨化三醇的有益效果发生在 尽管循环FGF 23和骨FGF 23 mRNA表达显著增加。尽管增加了 FGF 23、骨化三醇治疗降低Hyp小鼠中的尿磷酸盐清除率。因此，骨化三醇具有有益的 在FGF 23进一步增加的情况下，XLH对骨和肾磷酸盐处理的影响。 基于这些临床前数据，目前的建议旨在解决优化 在没有磷酸盐补充的情况下，对患有XLH的人进行骨化三醇治疗将具有有益的效果。我们 假设优化骨化三醇将减少磷酸盐补充的需要，从而增加 顺应性和减少目前治疗的并发症，包括肾钙质沉着症， 甲状旁腺机能亢进优化骨化醇治疗也有望改善所有患者的骨骼微结构。 XLH受试者，并改善儿童受试者的生长和预防佝偻病变化。XLH受试者 将从成人和儿童内分泌和肾脏科诊所招募。治疗将停止2 周，之后将获得基线实验室检查结果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 高钙血症或高钙尿症。主要终点将是血清磷酸盐水平、肾小管吸收、 磷酸盐（TmP/GFR）、肾钙质沉着症评分和儿童佝偻病评分。次要终点为 儿童的成长。将数据与24个月前获得的受试者特定值进行比较， 骨化三醇的优化。将通过高分辨率外周qCT评价骨骼微结构。的 这些研究的结果有望为大型多中心研究提供关键的初步数据。 一项随机临床试验，检查"优化骨化三醇"与骨化三醇+的比较有效性 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.