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      Low‐Level Cadmium Exposure Is Associated With Decreased Bone Mineral Density and Increased Risk of Incident Fractures in Elderly Men: The MrOS Sweden Study

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          ABSTRACT

          One risk factor for osteoporosis that has attracted increasing attention in recent years is exposure to cadmium. The aim of this study was to examine the associations between low‐level cadmium exposure, from diet and smoking, and bone mineral density (BMD) and incident fractures in elderly men. The study population consisted of 936 men from the Swedish cohort of the Osteoporotic Fractures in Men (MrOS) study, aged 70 to 81 years at inclusion (years 2002 to 2004), with reliable data on cadmium in urine (U‐Cd) analyzed using inductively coupled plasma mass spectrometry in baseline samples. The participants also answered a questionnaire on lifestyle factors and medical history. BMD was measured at baseline using dual‐energy X‐ray absorptiometry (DXA) in the total body, hip, and lumbar spine. During the follow‐up period (until 2013), all new fractures were registered by date and type. Associations between BMD and U‐Cd were assessed using multiple linear regression, and associations between incident fractures and baseline U‐Cd were analyzed using Cox regression. In both cases, a number of potential confounders and other risk factors (eg, age, smoking, body mass index [BMI], and physical activity) were included in the models. We found significant negative associations between U‐Cd and BMD, with lower BMD (4% to 8%) for all sites in the fourth quartile of U‐Cd, using the first quartile as the reference. In addition, we found positive associations between U‐Cd and incident fractures, especially nonvertebral osteoporosis fractures in the fourth quartile of U‐Cd, with hazard ratios of 1.8 to 3.3 in the various models. U‐Cd as a continuous variable was significantly associated with nonvertebral osteoporosis fractures (adjusted hazard ratio 1.3 to 1.4 per μg Cd/g creatinine), also in never‐smokers, but not with the other fracture groups (all fractures, hip fractures, vertebral fractures, and other fractures). Our results indicate that even relatively low cadmium exposure through diet and smoking increases the risk of low BMD and osteoporosis‐related fractures in elderly men. © 2015 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research (ASBMR).

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          Bone quality: the determinants of bone strength and fragility.

          Bone fragility is a major health concern, as the increased risk of bone fractures has devastating outcomes in terms of mortality, decreased autonomy, and healthcare costs. Efforts made to address this problem have considerably increased our knowledge about the mechanisms that regulate bone formation and resorption. In particular, we now have a much better understanding of the cellular events that are triggered when bones are mechanically stimulated and how these events can lead to improvements in bone mass. Despite these findings at the molecular level, most exercise intervention studies reveal either no effects or only minor benefits of exercise programs in improving bone mineral density (BMD) in osteoporotic patients. Nevertheless, and despite that BMD is the gold standard for diagnosing osteoporosis, this measure is only able to provide insights regarding the quantity of bone tissue. In this article, we review the complex structure of bone tissue and highlight the concept that its mechanical strength stems from the interaction of several different features. We revisited the available data showing that bone mineralization degree, hydroxyapatite crystal size and heterogeneity, collagen properties, osteocyte density, trabecular and cortical microarchitecture, as well as whole bone geometry, are determinants of bone strength and that each one of these properties may independently contribute to the increased or decreased risk of fracture, even without meaningful changes in aBMD. Based on these findings, we emphasize that while osteoporosis (almost) always causes bone fragility, bone fragility is not always caused just by osteoporosis, as other important variables also play a major role in this etiology. Furthermore, the results of several studies showing compelling data that physical exercise has the potential to improve bone quality and to decrease fracture risk by influencing each one of these determinants are also reviewed. These findings have meaningful clinical repercussions as they emphasize the fact that, even without leading to improvements in BMD, exercise interventions in patients with osteoporosis may be beneficial by improving other determinants of bone strength.
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            Historical perspectives on cadmium toxicology.

            The first health effects of cadmium (Cd) were reported already in 1858. Respiratory and gastrointestinal symptoms occurred among persons using Cd-containing polishing agent. The first experimental toxicological studies are from 1919. Bone effects and proteinuria in humans were reported in the 1940's. After World War II, a bone disease with fractures and severe pain, the itai-itai disease, a form of Cd-induced renal osteomalacia, was identified in Japan. Subsequently, the toxicokinetics and toxicodynamics of Cd were described including its binding to the protein metallothionein. International warnings of health risks from Cd-pollution were issued in the 1970's. Reproductive and carcinogenic effects were studied at an early stage, but a quantitative assessment of these effects in humans is still subject to considerable uncertainty. The World Health Organization in its International Program on Chemical Safety, WHO/IPCS (1992) (Cadmium. Environmental Health Criteria Document 134, IPCS. WHO, Geneva, 1-280.) identified renal dysfunction as the critical effect and a crude quantitative evaluation was presented. In the 1990's and 2000 several epidemiological studies have reported adverse health effects, sometimes at low environmental exposures to Cd, in population groups in Japan, China, Europe and USA (reviewed in other contributions to the present volume). The early identification of an important role of metallothionein in cadmium toxicology formed the basis for recent studies using biomarkers of susceptibility to development of Cd-related renal dysfunction such as gene expression of metallothionein in peripheral lymphocytes and autoantibodies against metallothionein in blood plasma. Findings in these studies indicate that very low exposure levels to cadmium may give rise to renal dysfunction among sensitive subgroups of human populations such as persons with diabetes.
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              Plasma osteocalcin is inversely related to fat mass and plasma glucose in elderly Swedish men.

              The osteoblast-derived protein osteocalcin has recently been shown to affect adiposity and glucose homeostasis in mice, suggesting that the skeleton influences energy metabolism through an endocrine mechanism. The aim of this study was to investigate the relationship between plasma osteocalcin and parameters reflecting fat mass and glucose homeostasis in humans. Fasting levels of plasma osteocalcin, plasma glucose, serum insulin, and lipids were analyzed in elderly men (75.3 +/- 3.2 yr of age) in the Gothenburg part (all subjects, n = 1010; nondiabetic, n = 857; diabetic, n = 153) of the MrOS Sweden study. Fat mass and lean mass were analyzed using DXA. Diabetic subjects had lower plasma osteocalcin (-21.7%, p < 0.001) than nondiabetic subjects. For both all subjects and nondiabetic subjects, plasma osteocalcin was clearly inversely related to body mass index (BMI), fat mass, and plasma glucose (p < 0.001), whereas it was not associated with height or lean mass. Plasma osteocalcin explained a substantial part (6.3%) of the variance in plasma glucose, whereas it associated moderately with serum insulin. Multiple linear regression models adjusting for serum insulin and fat mass showed that plasma osteocalcin was an independent negative predictor of plasma glucose (p < 0.001). We herein, for the first time in humans, show that plasma osteocalcin is inversely related to fat mass and plasma glucose. Although one should be cautious with mechanistic interpretations of cross-sectional association studies, our human data support recently published experimental studies, showing endocrine functions of osteoblast-derived osteocalcin on glucose and fat homeostasis.
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                Author and article information

                Journal
                J Bone Miner Res
                J. Bone Miner. Res
                10.1002/(ISSN)1523-4681
                JBMR
                Journal of Bone and Mineral Research
                John Wiley and Sons Inc. (Hoboken )
                0884-0431
                1523-4681
                06 December 2015
                April 2016
                : 31
                : 4 ( doiID: 10.1002/jbmr.v31.4 )
                : 732-741
                Affiliations
                [ 1 ] Department of Occupational and Environmental Medicine, Institute of Medicine, Sahlgrenska Academy University of Gothenburg, and Sahlgrenska University Hospital GothenburgSweden
                [ 2 ] Department of Occupational and Environmental MedicineSkåne University Hospital LundSweden
                [ 3 ] Departments of Orthopedics and Clinical SciencesLund University, Skåne University Hospital MalmöSweden
                [ 4 ] Centre for Bone and Arthritis Research (CBAR), Department of Internal Medicine, Institute of Medicine Sahlgrenska Academy, University of Gothenburg GothenburgSweden
                [ 5 ] Department of Geriatric Medicine, Internal Medicine, Institute of Medicine, Sahlgrenska Academy University of Gothenburg GothenburgSweden
                Author notes
                [*] [* ] Address correspondence to: Maria Wallin, MD, Department of Occupational and Environmental Medicine, Sahlgrenska Academy, University of Gothenburg, PO Box 414, SE‐405 30 Gothenburg, Sweden. E‐mail: maria.wallin@ 123456amm.gu.se

                Article
                JBMR2743
                10.1002/jbmr.2743
                4832374
                26572678
                65a9907d-031b-4f58-bf04-e8721b79ad48
                © 2015 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research (ASBMR)

                This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

                History
                : 03 July 2015
                : 11 November 2015
                : 11 November 2015
                Page count
                Pages: 10
                Funding
                Funded by: Swedish Research Council
                Categories
                Original Article
                Original Articles
                Custom metadata
                2.0
                jbmr2743
                April 2016
                Converter:WILEY_ML3GV2_TO_NLMPMC version:4.8.6 mode:remove_FC converted:15.04.2016

                Human biology
                osteoporosis,dxa,fracture risk assessment,epidemiology,diseases and disorders of/related to bone

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