Urinary Cadmium and Osteoporosis in U.S. Women >/= 50 Years of Age: NHANES
Urinary Cadmium and Osteoporosis in U.S. Women >/= 50 Years of Age: NHANES
Background: Urinary cadmium (U-Cd) has been associated with decreased peripheral bone mineral density (BMD) and osteoporosis. This association, however, has not been confirmed using femoral BMD, the international standard for diagnosing osteoporosis, at levels < 1.0 µg Cd/g creatinine.
Objectives: Our goal was to investigate the statistical association between U-Cd, at levels ≤ 1 µg/g creatinine, and osteoporosis, as indicated by hip BMD and self-report in a population-based sample of U.S. women ≥ 50 years of age.
Methods: We drew data from the National Health and Nutrition Examination Surveys for 1988-1994 (n = 3,207) and 1999-2004 (n = 1,051) . Osteoporosis was indicated by hip BMD cutoffs based on the international standard and self-report of physician diagnosis. We analyzed U-Cd levels for association with osteoporosis using multiple logistic regression.
Results: Women ≥ 50 years of age with U-Cd levels between 0.50 and 1.00 µg/g creatinine were at 43% greater risk for hip-BMD-defined osteoporosis, relative to those with levels ≤ 0.50 µg/g (odds ratio = 1.43 ; 95% confidence interval, 1.02-2.00 ; p = 0.04) . We observed similar effect estimates using self-report of physician-diagnosed osteoporosis. Smokers did not show a statistically increased risk.
Conclusions: Results suggest that U.S. women are at risk for osteoporosis at U-Cd levels below the U.S. Occupational Safety and Health Administration's 3-µg/g safety standard. Given null findings among smokers, dietary Cd, rather than tobacco, is the likely source of Cd-related osteoporosis risk for the U.S. female population ≥ 50 years of age.
Osteoporosis, a deterioration of bone tissue that results in low bone mineral density (BMD) and risk of fracture [World Health Organization (WHO) 2003], poses a disease burden that exceeds that of hypertension and breast cancer (WHO 2004). The Joint Food and Agricultural Organization of the United Nations/WHO Expert Committee on Food Additives (JECFA) recently concluded that substantial uncertainty remains regarding the long-term significance of the effects of cadmium on bone (JECFA 2005), citing mixed results from epidemiologic studies that investigated the association between low-level environmental exposure to Cd and its direct effects on bone.
Cadmium is a toxic metal that is released into the environment from industrial activity, including mining and smelting, fuel combustion (e.g., coal-fired power plants), disposal of metal-containing products, and application of municipal sludge or phosphate fertilizer [Agency for Toxic Substances and Disease Registry (ATSDR) 1999]. Human exposure to Cd is primarily through food [International Programme on Chemical Safety (IPCS) 1992], with low levels of Cd found in all foods (ATSDR 1999). Smokers may have up to twice the Cd intake compared with nonsmokers because cigarette smoke contains Cd taken up by the tobacco plant (ATSDR 1999). The U.S. Food and Drug Administration's Total Diet Study update reported a 26% increase in dietary Cd exposure from 1990 through 2003, from 8.81 to 11.06 µg/person/day; the latter exposure constitutes 21% of the provisional tolerable weekly intake (PTWI) (Egan et al. 2007).
Cadmium accumulates in the human body, particularly the kidney, where it can remain for many years. A small portion of Cd is slowly excreted in urine (ATSDR 1999). Urinary Cd (U-Cd) is a biomarker for lifetime Cd body burden in people with lower exposures because, in the absence of episodes of high-level exposure, Cd-binding sites are not saturated, and the urine Cd level increases in proportion to the amount of Cd stored in the body [Centers for Disease Control and Prevention (CDC) 2005; IPCS 1992].
U-Cd has been inversely associated with forearm BMD in studies from Sweden and Belgium (Akesson et al. 2006; Alfven et al. 2000; Staessen et al. 1999); however, mixed results were reported in Japan. Honda et al. (2003) found that ultrasound-measured stiffness index, an index of calcaneal bone mass, was significantly inversely correlated with U-Cd, in the absence of kidney damage, whereas Horiguchi et al. (2005) reported no association between Cd and bone effects after adjustment for renal effects. Tubular renal dysfunction has been found at U-Cd levels as low as 1 µg/g creatinine (Jarup et al. 2000). Chen et al. (2006) investigated the relationship between U-Cd and ß2-microglobulinuria, a biomarker of Cd-induced renal tubular damage, in a type 2 diabetic population and showed statistically significant increased odds of tubular renal dysfunction at U-Cd levels ≥1 µg/g creatinine relative to U-Cd levels <1.0 µg/g creatinine. Akesson et al. (2006) reported associations between increasing overall Cd levels and decreasing forearm BMD and a direct effect on bone, that is, increasing bone resorption. They did not, however, compare risks for osteoporosis associated with specific Cd levels. The Osteoporosis-Cadmium as a Risk Factor (OSCAR) study (Jarup and Alfven 2004) identified a dose-response relationship between U-Cd 3 µg/g creatinine and higher and low BMD, but additional studies are needed to clarify the risk of osteoporosis associated with widespread exposure and U-Cd at levels < 1.0 g/g creatinine associated with renal tubular dysfunction. Additionally, these studies used peripheral bone density measures, whereas the international reference standard is based on a femoral neck BMD measure (WHO 2004). Moreover, fracture rates vary substantially worldwide (WHO 2004), and there is a dearth of evidence concerning the association between Cd and osteoporosis in North American populations.
Our primary objective was to investigate the association between U-Cd, particularly at levels ≤ 1.0 µg/g creatinine, and hip BMD at levels indicative of osteoporosis according to WHO criterion in a population-based sample of U.S. women ≥ 50 years of age. Our secondary objective was to investigate the associations between U-Cd and survey-respondent-reported physician diagnosis of osteoporosis, and to compare the results of the two outcome measures. We hypothesized that higher levels of U-Cd might be associated with greater odds for osteoporosis, and that Cd levels between 0.50 and 1.0 µg/g creatinine might suggest a significant exposure-effect relationship relative to the reference group with the lowest Cd levels.
Abstract and Introduction
Abstract
Background: Urinary cadmium (U-Cd) has been associated with decreased peripheral bone mineral density (BMD) and osteoporosis. This association, however, has not been confirmed using femoral BMD, the international standard for diagnosing osteoporosis, at levels < 1.0 µg Cd/g creatinine.
Objectives: Our goal was to investigate the statistical association between U-Cd, at levels ≤ 1 µg/g creatinine, and osteoporosis, as indicated by hip BMD and self-report in a population-based sample of U.S. women ≥ 50 years of age.
Methods: We drew data from the National Health and Nutrition Examination Surveys for 1988-1994 (n = 3,207) and 1999-2004 (n = 1,051) . Osteoporosis was indicated by hip BMD cutoffs based on the international standard and self-report of physician diagnosis. We analyzed U-Cd levels for association with osteoporosis using multiple logistic regression.
Results: Women ≥ 50 years of age with U-Cd levels between 0.50 and 1.00 µg/g creatinine were at 43% greater risk for hip-BMD-defined osteoporosis, relative to those with levels ≤ 0.50 µg/g (odds ratio = 1.43 ; 95% confidence interval, 1.02-2.00 ; p = 0.04) . We observed similar effect estimates using self-report of physician-diagnosed osteoporosis. Smokers did not show a statistically increased risk.
Conclusions: Results suggest that U.S. women are at risk for osteoporosis at U-Cd levels below the U.S. Occupational Safety and Health Administration's 3-µg/g safety standard. Given null findings among smokers, dietary Cd, rather than tobacco, is the likely source of Cd-related osteoporosis risk for the U.S. female population ≥ 50 years of age.
Introduction
Osteoporosis, a deterioration of bone tissue that results in low bone mineral density (BMD) and risk of fracture [World Health Organization (WHO) 2003], poses a disease burden that exceeds that of hypertension and breast cancer (WHO 2004). The Joint Food and Agricultural Organization of the United Nations/WHO Expert Committee on Food Additives (JECFA) recently concluded that substantial uncertainty remains regarding the long-term significance of the effects of cadmium on bone (JECFA 2005), citing mixed results from epidemiologic studies that investigated the association between low-level environmental exposure to Cd and its direct effects on bone.
Cadmium is a toxic metal that is released into the environment from industrial activity, including mining and smelting, fuel combustion (e.g., coal-fired power plants), disposal of metal-containing products, and application of municipal sludge or phosphate fertilizer [Agency for Toxic Substances and Disease Registry (ATSDR) 1999]. Human exposure to Cd is primarily through food [International Programme on Chemical Safety (IPCS) 1992], with low levels of Cd found in all foods (ATSDR 1999). Smokers may have up to twice the Cd intake compared with nonsmokers because cigarette smoke contains Cd taken up by the tobacco plant (ATSDR 1999). The U.S. Food and Drug Administration's Total Diet Study update reported a 26% increase in dietary Cd exposure from 1990 through 2003, from 8.81 to 11.06 µg/person/day; the latter exposure constitutes 21% of the provisional tolerable weekly intake (PTWI) (Egan et al. 2007).
Cadmium accumulates in the human body, particularly the kidney, where it can remain for many years. A small portion of Cd is slowly excreted in urine (ATSDR 1999). Urinary Cd (U-Cd) is a biomarker for lifetime Cd body burden in people with lower exposures because, in the absence of episodes of high-level exposure, Cd-binding sites are not saturated, and the urine Cd level increases in proportion to the amount of Cd stored in the body [Centers for Disease Control and Prevention (CDC) 2005; IPCS 1992].
U-Cd has been inversely associated with forearm BMD in studies from Sweden and Belgium (Akesson et al. 2006; Alfven et al. 2000; Staessen et al. 1999); however, mixed results were reported in Japan. Honda et al. (2003) found that ultrasound-measured stiffness index, an index of calcaneal bone mass, was significantly inversely correlated with U-Cd, in the absence of kidney damage, whereas Horiguchi et al. (2005) reported no association between Cd and bone effects after adjustment for renal effects. Tubular renal dysfunction has been found at U-Cd levels as low as 1 µg/g creatinine (Jarup et al. 2000). Chen et al. (2006) investigated the relationship between U-Cd and ß2-microglobulinuria, a biomarker of Cd-induced renal tubular damage, in a type 2 diabetic population and showed statistically significant increased odds of tubular renal dysfunction at U-Cd levels ≥1 µg/g creatinine relative to U-Cd levels <1.0 µg/g creatinine. Akesson et al. (2006) reported associations between increasing overall Cd levels and decreasing forearm BMD and a direct effect on bone, that is, increasing bone resorption. They did not, however, compare risks for osteoporosis associated with specific Cd levels. The Osteoporosis-Cadmium as a Risk Factor (OSCAR) study (Jarup and Alfven 2004) identified a dose-response relationship between U-Cd 3 µg/g creatinine and higher and low BMD, but additional studies are needed to clarify the risk of osteoporosis associated with widespread exposure and U-Cd at levels < 1.0 g/g creatinine associated with renal tubular dysfunction. Additionally, these studies used peripheral bone density measures, whereas the international reference standard is based on a femoral neck BMD measure (WHO 2004). Moreover, fracture rates vary substantially worldwide (WHO 2004), and there is a dearth of evidence concerning the association between Cd and osteoporosis in North American populations.
Our primary objective was to investigate the association between U-Cd, particularly at levels ≤ 1.0 µg/g creatinine, and hip BMD at levels indicative of osteoporosis according to WHO criterion in a population-based sample of U.S. women ≥ 50 years of age. Our secondary objective was to investigate the associations between U-Cd and survey-respondent-reported physician diagnosis of osteoporosis, and to compare the results of the two outcome measures. We hypothesized that higher levels of U-Cd might be associated with greater odds for osteoporosis, and that Cd levels between 0.50 and 1.0 µg/g creatinine might suggest a significant exposure-effect relationship relative to the reference group with the lowest Cd levels.
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