Urine cadmium and risk of fracture and bone loss

尿镉与骨折和骨丢失风险 摘要 骨质疏松症和相关骨折是美国和全球发病率和死亡率的主要原因。 从骨器官和细胞培养系统的机制研究表明，镉（Cd）动员骨矿物质 从骨骼组织中提取镉是一种重金属，存在于土壤中的自然元素，随着浓度的增加， 农田里的磷肥和污水污泥因此，人类的饮食暴露 从1990年到2003年增加了26%。此外，镉在人体骨骼中的含量增加了10- 自工业时代以来，摄入后，镉被储存在肾脏中，在那里停留数十年（半个月）。 寿命：10-30年）。一小部分的镉在尿液中缓慢排出，使尿镉（U-Cd）成为一种良好的- 长期暴露的生物标志物。横断面研究将镉与低骨矿物质联系起来 密度，骨质疏松症和骨折，表明潜在的人口归因分数为30%，假设有 是一种因果关系然而，目前缺乏大型前瞻性研究。 我们建议利用美国两个最大的前瞻性骨质疏松队列的现有样本和数据 研究对U-Cd、骨丢失和骨折进行深入研究，包括长期随访 长达20年使用：1）男性骨质疏松性骨折（MrOS）研究和2）骨质疏松性骨折研究 骨折（SOF）。目的1：使用有效的病例队列研究设计，我们将调查前瞻性 在1,321名MrOS男性和1,578名SOF女性中， 从每个队列中随机选择1500人进行匹配。镉、肌酐、渗透压摩尔浓度和 将在尿液中分析可替宁。目的2：评估U-Cd与丢失率之间的前瞻性关联 亚组人群中男性和女性的总髋部骨矿物质密度（BMD），以及发生骨折的病例。 目的3：利用骨代谢和结构的标志物，为细胞和结构提供新的见解。 镉可能对骨骼产生不利影响的机制。评估U-Cd与以下指标之间的相关性： 骨形成（PINP）和骨吸收（CTX）在男性和女性。在使用现有数据的子研究中 在男性中，评估U-Cd与骨结构之间的关联（HR-pQCT）。此外，在一个探索性的子目标中， 运用基于反事实框架的方法进行调解分析，以估计Cd的 对骨丢失的影响可能通过骨代谢的生物标志物（血清PINP、CTX）介导。 大部分美国老年男性和女性都记录了镉暴露。高精度测量Cd 与强大的流行病学队列相关的暴露提供了一种独特的、具有成本效益的方法， 公共卫生问题。这些研究将改变镉骨研究领域，并具有很高的影响潜力。 美国和全球的政策决定。

Urine cadmium and risk of fracture and bone loss Abstract Osteoporosis and related fractures are a major cause of morbidity and mortality in the United States and globally. Mechanistic studies from bone organ and cell culture systems suggest cadmium (Cd) mobilizes bone minerals from skeletal tissue. Cd is a heavy metal and natural element found in soil, with increasing concentrations linked to phosphate fertilizers and sewage sludge found in croplands. As a result, human dietary exposures have increased over time by 26% dating from 1990 through 2003. In addition, Cd has increased in human bones ten- fold since pre-industrial times. Following intake, Cd is stored in the kidney, where it remains for decades (half- life: 10-30 years). A small portion of Cd is slowly excreted in the urine, making urinary Cd (U-Cd) a well- established biomarker of long-term exposure. Cross-sectional studies have linked Cd to low bone mineral density, osteoporosis, and fracture, suggesting a potential population attributable fraction of 30% assuming there is a causal relationship. However, currently lacking are large prospective studies. We propose to leverage existing samples and data from the two largest prospective US osteoporosis cohort studies to perform an in depth study of U-Cd, bone loss, and fractures that will include long-term follow-up of up to 20 years using: 1) The Osteoporotic Fractures in Men (MrOS) Study and 2) the Study of Osteoporotic Fractures (SOF). Aim 1: Using efficient case-cohort study designs we will investigate the prospective association between U-Cd and incident fractures in 1,321 MrOS men and 1,578 SOF women who will be sex matched with 1500 randomly selected persons from each respective cohort. Cd, creatinine, osmolality, and cotinine will be analyzed in urine. Aim 2: Evaluate the prospective association between U-Cd and rate of loss of total hip bone mineral density (BMD) in men and women from the subcohorts, and in incident fracture cases. Aim 3: Utilize markers of bone metabolism and structure to provide novel insights into the cellular and structural mechanisms by which Cd may adversely affect bone. Evaluate the association between U-Cd and markers of bone formation (PINP) and bone resorption (CTX) in men and women. In a substudy using data already available in men, evaluate the association between U-Cd and bone structure (HR-pQCT). Also, in an exploratory subAim, apply mediation analyses using a counterfactual framework based approach to estimate the extent to which Cd’s influence on bone loss might be mediated via biomarkers of bone metabolism (serum PINP, CTX). A large fraction of older US men and women have documented Cd exposure. Highly accurate measures of Cd exposure linked to powerful epidemiological cohorts provide a unique, cost effective approach to this important public health issue. These studies will transform the field of Cd-bone research and have high potential to impact policy decisions in the US and globally.