Arsenic, cadmium, and selenium exposures and bone mineral density-related endpoints: The HORTEGA study

Abstract

Background and objectives: Experimental data suggest that trace elements, such as arsenic (As), cadmium (Cd), and selenium (Se) can influence the bone remodeling process. We evaluated the cross-sectional association between As, Cd, and Se biomarkers with bone mineral density (BMD) measured at the calcaneus, in a representative sample of a general population from Spain. As secondary analyses we evaluated the associations of interest in subgroups defined by well-established BMD determinants, and also conducted prospective analysis of osteoporosis-related incident bone fractures restricted to participants older than 50 years-old.

Methods: In N = 1365 Hortega Study participants >20 years-old, urine As and Cd were measured by inductively coupled-plasma mass spectrometry (ICPMS); plasma Se was measured by atomic absorption spectrometry (AAS) with graphite furnace; and BMD at the calcaneus was measured using the Peripheral Instaneuous X-ray Imaging system (PIXI). As levels were corrected for arsenobetaine (Asb) to account for inorganic As exposure.

Results: The median of total urine As, Asb-corrected urine As, urine Cd, and plasma Se was 61.3, 6.53 and 0.39 μg/g creatinine, and 84.9 μg/L, respectively. In cross-sectional analysis, urine As and Cd were not associated with reduced BMD (T-score < -1 SD). We observed a non-linear dose-response of Se and reduced BMD, showing an inverse association below ~105 μg/L, which became increasingly positive above ~105 μg/L. The evaluated subgroups did not show differential associations. In prospective analysis, while we also observed a U-shape dose-response of Se with the incidence of osteoporosis-related bone fractures, the positive association above ~105 μg/L was markedly stronger, compared to the cross-sectional analysis.

Conclusions: Our results support that Se, but not As and Cd, was associated to BMD-related disease. The association of Se and BMD-related disease was non-linear, including a strong positive association with osteoporosis-related bone fractures risk at the higher Se exposure range. Considering the substantial burden of bone loss in elderly populations, additional large prospective studies are needed to confirm the relevance of our findings to bone loss prevention in the population depending on Se exposure levels.

Keywords: Arsenic; Bone mineral density; Cadmium; Osteoporosis; Selenium.

Figure 1.. Odds ratio (95% CI) of reduced Bone Mineral Density and Hazard Ratio (95% CI) of Osteoporosis-Related Bone Fractures by plasma Se concentrations (μg/L) in the subsample of individuals older than 50 years (n= 702 and 638, for the cross-sectional and prospective analysis, respectively).

The curve (gray shades) represent the odds ratio (95% confidence interval) of reduced BMD levels (BMD below −1.0 SD) and hazard ratio (95% confidence interval) of osteoporosis-related fractures based on restricted quadratics splines with knots at the 10^th, 50^th and 90^th percentiles of plasma Se distribution (29.92, 84.46 and 115 μg/L, respectively). The reference value was set at the 10^th of plasma Se distribution (29.9 μg/L). Odds ratio and Hazard ratio were estimated with logistic and cox proportional hazards models, for the cross-sectional and prospective analysis, respectively. Models were adjusted for age, sex, education, body mass index, smoking status (never, former and current), cumultavie smoking (pack-years), urine cotinine levels (34, 34–500 y >500 ng/ml), alcohol intake (never, former and curent), glomerular filtration rate (ml/min/1.73m²) and physical activity (METs min/week). The histogram represents the frequency distribution of plasma Se in the study sample.