Acid-Base Status as a Novel Risk Factor for Fractures

项目总结/摘要 骨折是一个主要的公共卫生负担，其相关的残疾，成本，发病率和死亡率。在 近年来，髋部骨折的发病率高于预期，脊椎骨折的发病率似乎 特别是在75岁以后。越来越多的研究表明，即使是酸中毒， 亚临床时，直接影响骨骼，并可能对骨骼代谢和健康产生有害影响。 酸中毒可抑制成骨细胞功能和骨形成，同时促进骨吸收和分解， 从而削弱了骨骼修复日常磨损和累积的微损伤的能力 随着年龄的增长，并可能导致更高的骨折风险。护士健康研究（NHS）I和II 卫生专业人员随访研究（HPFS）是正在进行的大规模队列研究， 随访和丰富的饮食和生活方式数据，以及存档的生物样本。整合代谢组学技术 以人口为基础的研究正在成为一个有价值的研究工具，可以提供新的见解， 影响骨折风险的细胞过程。因此，本提案的目标是前瞻性地研究 通过膳食酸负荷评估的酸碱状态、血浆碳酸氢盐水平和 血浆代谢物和意外骨折的风险。我们假设酸碱平衡紊乱 通过饮食依赖性和非依赖性机制导致酸中毒增加， 骨折风险更高。我们将前瞻性地研究饮食酸负荷与髋关节意外风险之间的关系。 NHS I和II以及HPFS中的椎体骨折（目标1）。我们将采用巢式病例对照研究， 骨折病例（n=650）和匹配的对照组（n=650），以研究 血浆碳酸氢盐水平（Aim 2）、血浆代谢物（Aim 3）和髋部骨折风险之间的关系， 女人和男人将测量髋部骨折诊断前采集的存档血浆样本， 代谢物，使用最先进的高通量液相或气相色谱法，然后进行质谱分析 质谱分析（LC/MS/MS和GC/MS）平台。使用先进的计算和生物统计方法， 代谢组学和高维数据分析，我们将使用有针对性的代谢组学方法，以及 使用所有可用的血浆代谢物数据建立不同代谢物特征的不可知方法， 区分髋部骨折病例和对照组。最终，我们希望这些研究能够产生新的见解， 骨折的发展，可能导致新的方法来预防和治疗。

Project Summary/Abstract Fractures are a major public health burden with its associated disability, cost, morbidity and mortality. In recent years, hip fracture rates are higher than expected and the incidence of vertebral fracture appears to be rising dramatically, especially after age 75 years. A growing body of research suggests that acidosis, even when subclinical, directly affects bone and can have detrimental effects on bone metabolism and health. Acidosis can inhibit osteoblast function and bone formation while promoting bone resorption and breakdown, thus impairing the bone’s ability to repair microdamage that occurs with daily wear and tear and accumulates with aging, and potentially contributing to higher fracture risk. The Nurses’ Health Studies (NHS) I and II and the Health Professionals Follow-up Study (HPFS) are ongoing large-scale cohort studies with decades of follow-up and rich dietary and lifestyle data, and archived biosamples. Integrating metabolomics technology into population-based studies is emerging as a valuable research tool which could provide novel insights into cellular processes that affect fracture risk. Therefore, this proposal’s goal is to prospectively study the association between acid-base status, assessed through dietary acid load, plasma bicarbonate level and plasma metabolites, and risk of incident fracture. We hypothesize that perturbations in acid-base status through diet-dependent and independent mechanisms resulting in increased acidosis will be associated with higher fracture risk. We will prospectively examine the association of dietary acid load with risk of incident hip and vertebral fracture in NHS I and II and HPFS (Aim 1). We will use a nested case-control study of hip fracture cases (n=650) and matched controls (n=650) within these three cohorts to study the association between plasma bicarbonate level (Aim 2), plasma metabolites (Aim 3) and risk of incident hip fracture in women and men. Archived plasma samples collected pre-hip fracture diagnosis will be measured for metabolites using state-of-the art, high-throughput liquid or gas chromatography followed by mass spectrometry (LC/MS/MS and GC/MS) platforms. Using advanced computational and biostatistical methods in metabolomics and high-dimensional data analyses, we will use a targeted metabolomics approach as well as an agnostic approach to build distinct metabolite signatures using all of the available plasma metabolite data to distinguish hip fracture cases from controls. Ultimately, we expect these studies to produce new insights into the development of fractures that may lead to new approaches to their prevention and treatment.