Urine cadmium and risk of fracture and bone loss

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.