Vitamin D and fibroblast growth factor 23 physiology in adolescent girls

描述（由申请人提供）：成纤维细胞生长因子23 （FGF23）是一种激素，在调节循环磷酸盐（Pi）水平和维生素D代谢中起核心作用。一些人类疾病以FGF23过量为特征，包括x连锁低磷血症、常染色体显性低磷佝偻病和肿瘤诱导的骨软化症。这些疾病的特点是生长衰竭、严重的骨病和肌病。FGF23缺乏导致高磷血症家族性肿瘤钙质沉着症，其特征是软组织钙沉积和骨生长异常。虽然人们对FGF23在疾病中的作用的了解越来越多，但其在维持健康状态下Pi和维生素D稳态中的作用却知之甚少。特别是，FGF23在儿童生长过程中调节骨矿化的作用尚未得到很好的探索。知识上的其他空白包括循环FGF23水平在年龄和青春期的变化，以及在健康状态下FGF23分泌的主要刺激因素的确定。本提案旨在解决这些空白，以便进一步了解这一关键激素的功能和调控。我们将招募100名9-18岁的健康女孩，进行循环FGF23水平和骨矿化的横断面研究。我们将通过双发射x射线吸收仪（DXA）和高分辨率外围定量计算机断层扫描获得骨成像。我们将研究FGF23与骨矿物质密度、骨微结构和骨强度的关系。我们将获得骨骼年龄x光片，并通过体格检查评估青春期阶段，并使用回归分析，确定FGF23水平在实际年龄和/或青春期阶段是否存在变化。我们还将测量骨矿物质代谢中的其他关键因素的循环水平，包括钙、Pi、25-羟基维生素D （25OHD）、1,25-二羟基维生素D、甲状旁腺激素和骨转换标志物。30名患有维生素D缺乏症（25OHD水平为20 ng/mL）的青春期前和青春期早期女孩将被纳入一项前瞻性、随机、安慰剂对照试验，并接受每周50,000国际单位麦角钙化醇或安慰剂治疗，为期16周。我们将通过曲线下面积分析来研究循环FGF23的变化。这些研究将提供关于儿科人群FGF23生理学的关键数据，这将有助于指导矿物离子疾病的识别，并可能提出新的治疗方式。此外，对骨矿化调节的更好理解可能会转化为优化骨矿物质密度的新疗法，从而在整个生命周期中预防骨折。

DESCRIPTION (provided by applicant): Fibroblast growth factor 23 (FGF23) is a hormone with a central role in regulating circulating phosphate (Pi) levels and vitamin D metabolism. Several human diseases are characterized by FGF23 excess, including X-linked hypophosphatemia, autosomal dominant hypophosphatemic rickets, and tumor-induced osteomalacia. These diseases are characterized by growth failure, severe bone disease, and myopathy. FGF23 deficiency causes hyperphosphatemic familial tumoral calcinosis, characterized by calcium deposition in soft tissues and aberrant bone growth. While there is growing understanding of the role of FGF23 in disease, its role in maintaining Pi and vitamin D homeostasis in the healthy state is less well-understood. In particular, the role of FGF23 in regulating bone mineralization during childhood growth has not been well-explored. Additional gaps in knowledge include the age- and pubertal-stage variation in circulating FGF23 levels and the identification of the primary stimulus for FGF23 secretion in the healthy state. This proposal aims to address these gaps in order to further understand the function and regulation of this critical hormone. We will recruit 100 healthy girls, aged 9-18 years, for a cross-sectional study of circulating FGF23 levels and bone mineralization. We will obtain bone imaging by both dual-emission X-ray absorptiometry (DXA) and high-resolution peripheral quantitative computed tomography. We will examine the association of FGF23 with measures of bone mineral density, bone microarchitecture, and bone strength. We will obtain bone age x- rays and assess pubertal stage on physical exam and, using regression analyses, determine what, if any, variation in FGF23 levels exists by chronological age and/or pubertal stage. We will also measure circulating levels of other key factors in bone mineral metabolism including calcium, Pi, 25-hydroxyvitamin D (25OHD), 1,25-dihydroxyvitamin D, parathyroid hormone, and bone turnover markers. 30 pre-pubertal and early-pubertal girls with vitamin D deficiency (25OHD level 20 ng/mL) will be co-enrolled in a prospective, randomized, placebo-controlled trial and treated with ergocalciferol 50,000 international units weekly or placebo for 16 weeks. We will examine the change in circulating FGF23 with area-under-the-curve analyses. These studies will provide key data regarding FGF23 physiology in pediatric populations which will help guide identification of mineral ion disorders and may suggest new treatment modalities. In addition, an improved understanding of the regulation of bone mineralization may translate into novel therapies for optimizing bone mineral density and thus fracture prevention throughout the lifespan. PUBLIC HEALTH RELEVANCE: Fibroblast growth factor 23 (FGF23) is a hormone which regulates phosphate and vitamin D metabolism; FGF23 may also be critical for normal bone development independent of its phosphate and vitamin D effects. While its role in several rare diseases is increasingly well-described, less is known about its function and regulation in healthy people, particularly in children. The research described in this proposal will help better define the function of FGF23 in healthy children to enhance our understanding of bone and mineral metabolism and bone mass accrual during childhood.