Urine cadmium and risk of fracture and bone loss

尿镉与骨折和骨丢失的风险 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。 来自骨器官和细胞培养系统的机制研究表明，镉(Cd)可以动员骨矿物质 从骨骼组织中提取。Cd是一种重金属和天然元素，存在于土壤中，随着浓度的增加而增加 到农田中发现的磷肥和污水污泥。因此，人类饮食暴露有 从1990年到2003年，随着时间的推移，增长了26%。此外，人体骨骼中的镉含量增加了10- 从前工业时代起就倒闭了。摄入后，Cd被储存在肾脏中，在那里保留数十年(一半- 寿命：10-30岁)。一小部分镉在尿液中缓慢排泄，使尿镉(U-Cd)成为一种 建立了长期接触的生物标记物。横断面研究已将镉与低骨矿物质联系起来 密度、骨质疏松症和骨折，表明假设有30%的潜在人口归因率 是一种因果关系。然而，目前缺乏大型前瞻性研究。 我们建议利用来自美国两个最大的潜在骨质疏松症队列的现有样本和数据 对U-CD、骨丢失和骨折进行深入研究的研究将包括对 长达20年的应用：1)男性骨质疏松性骨折(MROS)研究和2)骨质疏松研究 骨折(SOF)。目的1：使用有效的病例队列研究设计，我们将调查 1321名MRO男性和1578名SOF女性性行为中U-CD与意外骨折的关系 与从每个队列中随机选择的1500人进行匹配。Cd、肌酐、渗透压和 可替宁将在尿液中进行分析。目标2：评估U-CD和损失率之间的前瞻性关联 亚队列中的男性和女性的总髋部骨密度(BMD)，以及发生骨折的病例。 目的3：利用骨代谢和结构的标记物，提供对细胞和结构的新见解 镉可能对骨骼产生不利影响的机制。评价U-CD与尿毒症标志物的相关性 男女的骨形成(PINP)和骨吸收(CTX)。在一项使用已有数据的子研究中 在男性中，评估U-CD与骨结构(HR-pQCT)的相关性。另外，在一个探索性的子目标中， 使用基于反事实框架的方法应用调解分析，以估计CD的 对骨丢失的影响可能是通过骨代谢的生物标志物(血清PINP、CTX)介导的。 很大一部分美国老年男性和女性都有接触过CD的记录。高精度的镉测量 与强大的流行病学队列有关的暴露提供了一种独特的、具有成本效益的方法来应对这一重要的 公共卫生问题。这些研究将改变CD-bone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.