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

优化骨化三醇单一疗法治疗 X 连锁低磷血症：对矿物质离子、生长和骨骼参数的影响

• 批准号: 9761458
• 负责人: Marie Demay
• 金额: $ 22.24万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-10 至 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9761458
• 关键词: Address; Adjuvant; Adult; Affect; Alkaline Phosphatase; Animal Model; Attenuated; Biochemistry; Biomechanics; Blocking Antibodies; Bone Growth; Calcitriol; Calcium; Child; Childhood; Clinic; Clinical Data; Data; Defect; Deposition; Dihydroxycholecalciferols; Disease; Dose; Endocrine; Endopeptidases; Enrollment; Exhibits; FDA approved; Familial hypophosphatemic bone disease; General Population; Goals; Growth; Height; Histologic; Homeostasis; Hormones; Human; Hypercalcemia; Hyperparathyroidism; Hypophosphatemia; Impairment; In Vitro; Incidence; Inherited; Intestines; Investigation; Ions; Kidney; Knee; Lead; Metabolism; Minerals; Monitor; Multi-Institutional Clinical Trial; Mus; Mutation; Nephrocalcinosis; Nephrology; Osteoblasts; Osteomalacia; Peripheral; Phenotype; Pilot Projects; Property; Randomized Clinical Trials; Recommendation; Renal function; Resolution; Retrospective Studies; Rickets; Roentgen Rays; Safety; Secondary Hyperparathyroidism; Serum; Supplementation; Tubular formation; Ultrasonography; Urine; Vitamin D; Wrist; absorption; base; bone; bone strength; calcium excretion; calcium phosphate; comparative effectiveness; gastrointestinal; healing; human model; hypercalciuria; improved; inorganic phosphate; long bone; mRNA Expression; mouse model; pre-clinical; preclinical study; prevent; primary endpoint; receptor; recruit; secondary endpoint; side effect; skeletal; standard of care; trial comparing; urinary; wasting

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.

X 连锁低磷血症 (XLH) 的特点是 FGF23 增加，这会损害维生素的激活 D 并促进肾脏磷酸盐消耗，导致骨软化症和佝偻病。目前的治疗方法是使用 1,25-。 二羟基维生素 D（骨化三醇）和磷酸盐常并发高钙血症和肾钙质沉着症，并且 并不总能预防甲状旁腺功能亢进此外，它也不能使生长正常化，因此我们进行了研究。 XLH Hyp 小鼠模型的一项临床前研究，比较单独使用骨化三醇与联合使用骨化三醇治疗的效果 FGF23 阻断抗体对生长、血清和尿液矿物质离子以及组织学、组织形态学、 这些研究表明骨化三醇单一疗法。 促进生长、预防佝偻病并改善骨骼的微结构和生物力学特性 没有补充磷酸盐的情况下，骨化三醇的有益效果优于 FGF23。 使用阻断抗体，也许是因为，就像在人类中一样，FGF23 阻断抗体无法 维持 1,25-二羟基维生素 D 水平的增加。值得注意的是，骨化三醇的有益作用发生在 尽管增加 FGF23、骨化三醇治疗可降低 Hyp 小鼠的尿磷酸盐清除率，因此，骨化三醇具有有益作用。 在 FGF23 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，当前的提案旨在解决以下假设：优化 在不补充磷酸盐的情况下，骨化三醇治疗 XLH 患者将会产生有益的效果。 认为优化骨化三醇将消除补充磷酸盐的需要，从而增加 当前治疗的依从性和减少并发症，包括肾钙质沉着症和 优化甲状旁腺功能亢进症也有望改善所有骨骼微结构。 患有 XLH 的受试者，可以改善儿科受试者的生长并预防佝偻病的变化。 将从成人和儿科内分泌和肾脏病诊所招募 治疗将停止 2 年。 几周后，将获得基线实验室数据并开始骨化三醇治疗。 将在三个月内增加，以确定不会导致受试者特定的最高剂量 高钙血症或高钙尿症的主要终点是血清磷酸盐水平、肾小管吸收。 次要终点是儿童磷酸盐 (TmP/GFR)、肾钙质沉着症评分和佝偻病评分。 数据将与之前 24 个月获得的特定主题值进行比较。 骨化三醇的优化将通过高分辨率外周 qCT 进行评估。 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 随机临床试验检查“优化骨化三醇”与骨化三醇加的效果比较 磷酸盐，以及 FGF23 阻断抗体（如果它们获得 FDA 批准）。