Bone Resorption and Environmental Exposure to Cadmium in Women
Background: Environmental exposure to cadmium decreases bone density indirectly through hypercalciuria resulting from renal tubular dysfunction.
Objective: We sought evidence for a direct osteotoxic effect of cadmium in women.
Methods: We randomly recruited 294 women (mean age, 49.2 years) from a Flemish population with environmental cadmium exposure. We measured 24-hr urinary cadmium and blood cadmium as indexes of lifetime and recent exposure, respectively. We assessed the multivariate-adjusted association of exposure with specific markers of bone resorption, urinary hydroxylysylpyridinoline (HP) and lysylpyridinoline (LP) , as well as with calcium excretion, various calciotropic hormones, and forearm bone density.
Results: In all women, the effect sizes associated with a doubling of lifetime exposure were 8.4% (p = 0.009) for HP, 6.9% (p = 0.10) for LP, 0.77 mmol/day (p = 0.003) for urinary calcium, -0.009 g/cm (p = 0.055) for proximal forearm bone density, and -16.8% (p = 0.065) for serum parathyroid hormone. In 144 postmenopausal women, the corresponding effect sizes were -0.01223 g/cm (p = 0.008) for distal forearm bone density, 4.7% (p = 0.064) for serum calcitonin, and 10.2% for bone-specific alkaline phosphatase. In all women, the effect sizes associated with a doubling of recent exposure were 7.2% (p = 0.001) for urinary HP, 7.2% (p = 0.021) for urinary LP, -9.0% (p = 0.097) for serum parathyroid hormone, and 5.5% (p = 0.008) for serum calcitonin. Only one woman had renal tubular dysfunction (urinary retinol-binding protein > 338 µg/day).
Conclusions: In the absence of renal tubular dysfunction, environmental exposure to cadmium increases bone resorption in women, suggesting a direct osteotoxic effect with increased calciuria and reactive changes in calciotropic hormones.

Cadmium is a persistent environmental toxicant (Hogervorst et al. 2007; Lauwerys and Hoet 2001). Sources of cadmium pollution are past and present emissions from nonferrous industries, waste incineration, use of cadmium-containing phosphate fertilizers and sewage sludge, and the burning of fossil fuels (Lauwerys and Hoet 2001). Human exposure to cadmium occurs through consumption of contaminated food or water (Hogervorst et al. 2007; Watanabe et al. 2004) or by inhalation of tobacco smoke or polluted air (Hogervorst et al. 2007). Cadmium accumulates in the human body, in particular in the liver and kidneys, and has an elimination half-life of 10-30 years (Järup et al. 1998). The urinary excretion of cadmium over 24 hr is a biomarker of lifetime exposure (Järup et al. 1998). Cadmium causes glomerular and tubular renal dysfunction (Staessen et al. 1994) and increases calciuria (Staessen et al. 1991).

200 million people worldwide have osteoporosis and that the prevalence of this disease is escalating (Reginster and Burlet 2006). Staessen et al. (1999) showed that low-level environmental cadmium exposure promotes osteoporosis and leads to a higher risk of fractures, especially in postmenopausal women. Women are at greater risk of developing cadmium toxicity than are men (Choudhury et al. 2001). Animal (Wang et al. 1994) and in vitro (Regunathan et al. 2003) studies suggest that cadmium might have direct toxic effects on bone, but convincing evidence for such an effect in humans does not exist. The development of biochemical assays that measure pyridinium crosslinks of collagen, which are specific markers of bone resorption (McLaren et al. 1992), greatly facilitates the exploration of cadmium's osteotoxicity. In view of the epidemic of osteoporosis (Reginster and Burlet 2006) and the ubiquitous distribution of cadmium pollution (Lauwerys and Hoet 2001), we used urinary crosslinks as a marker to investigate the possible direct osteotoxicity of cadmium (over and beyond its indirect effects on bone via increased calciuria) (Staessen et al. 1991) in Flemish women living in districts with low to moderate environmental cadmium pollution.