Guoying Zhu

Influence of Environmental Cadmium Exposure on Forearm Bone Density

Cadmium may have both direct and indirect effects on bone turnover. It is nephrotoxic and can interfere with vitamin D metabolism. Such perturbation may result in osteoporosis and osteomalacia. In this study, a total of 790 persons (302 males and 488 females) participated; they were all over 35 years old and resided in an area near a cadmium smelter in southeast China. All participants completed a questionnaire, and bone mineral density was measured by SPA‐4 single‐photon absorptiometry at the radius and ulna. Cadmium content of urine was determined by graphite‐furnace atomic absorption spectrophotometry as a measure of dose. The decline in bone mineral density with age in a heavily polluted area was greater than that in a control area for subjects over 60 years of age of both sexes (p < 0.05). In single regression, forearm bone densities were negatively correlated with urinary cadmium excretion in both males and females (p < 0.001), whereas stepwise regression showed that forearm bone density decreased linearly with age (p < 0.001) and urinary cadmium (p < 0.01) in both sexes, suggesting a dose‐effect relationship between cadmium dose and bone mineral density. Based on the World Health Organization criteria, (bone mineral density < −2.5 SDs below the normal young adult), the prevalence of osteoporosis in women increased from 34.0% in the control area to 51.9% in the heavily polluted area (p < 0.01) among subjects over 50 years old, and the odds ratio value was 2.09 (95% CI: 1.08–4.03) for the highly polluted area compared with the control area. A striking observation in the study was the marked increase of the prevalence of fracture in the cadmium‐polluted area in both sexes. It was concluded that environmental exposure to cadmium is associated with an increased loss of bone mineral density in both males and females, leading to osteoporosis and increased risk of fractures, especially in the elderly and in females.

Effects of cadmium on osteoblasts and osteoclasts in vitro

Cadmium (Cd) may have direct effects on bone metabolism and the mechanism is not fully understood. To investigate the effects of Cd on bone metabolism, effects of Cd on osteoblasts and osteoclasts in vitro were observed at cellular and molecular levels. Osteoblasts were cultured by sequential enzyme digestion from Sprague-Dawley rats calvarial bone and osteoclasts were isolated from long bones of new-born male and female Sprague-Dawley rats, and then cells were exposed to different concentrations of Cd (0-2.0 μ mol/L for osteoblasts; 0.03 μmol/L for osteoclasts). As for osteoblasts, cell viability, alkaline phosphatase (ALP) activity, and mineralization were determined. Osteoprotegerin (OPG) and receptor activator of NF-kB ligand (RANKL) were studied via reverse transcription-polymerase chain reaction (RT-PCR). For osteoclasts, after exposure to Cd (0.03 μmol/L) for 72 h and 120 h, number of osteoclasts and pits formation was observed. Cd inhibited the viability, ALP activity, mineralization and up-regulated RANKL mRNA expression in osteoblasts. But Cd had no obvious effect on OPG mRNA expression. For osteoclasts, cadmium (0.03 μmol/L) could increase the numbers of osteoclasts (p<0.05) and enhance pits formation (p<0.05). These results suggested that Cd could inhibit bone formation at high concentrations and enhance bone resorption at low level. OPG/RANKL may constitute an important pathway of Cd effects on bone.

Effects of cadmium on forearm bone density after reduction of exposure for 10 years in a Chinese population.

The main focus of this study was to evaluate long term effects of cadmium on forearm bone mineral density after stopping ingestion of cadmium-polluted rice for 10 years in a Chinese population. A total of 532 persons (338 women and 194 men), living in control, moderately and heavily polluted areas, were included in this study. The residents living in the polluted area ceased ingesting cadmium-polluted rice in 1996. All participants were require to answer a questionnaire and the bone mineral density (BMD) was measured by dual energy X-ray absorptiometry (DXA) at the proximal radius and ulna. Samples of urine and blood were collected for determination of cadmium in urine (UCd) and blood (BCd).The BMD of subjects living in the heavily polluted area was significantly lower than that of those living in control area in both men and women (p<0.01). For the people living in the moderately polluted area, only the womens BMD was greatly lower compared to that in the control area (p<0.05). The BMD declined with the increasing BCd and UCd in both sexes, especially in the highest level (BCd >5 microg/L, UCd >10 microg/g crea) groups (p<0.01). It was found that there were significant differences in the prevalence of osteoporosis among the different areas (chi(2)=13.046, p=0.0003) and different UCd groups (chi(2)=4.511, p=0.0337) in women, but not in men (chi(2)=0.962, p=0.3268; chi(2)=1.906, p=0.1675). But a significant difference exists in the prevalence of osteoporosis among different BCd groups in both genders (chi(2)=9.304, p=0.00229, in women; chi(2)=4603, p=0.0319, in men). This study suggested that cadmium could play a long-term role on bone and more attention should be paid to cadmium effects on bone metabolism after reduction of exposure.

Effects of lead and cadmium co-exposure on bone mineral density in a Chinese population.

It has been indicated that both cadmium (Cd) and lead (Pb) may have adverse effects on the bone. However, most studies have only focused on a single factor. The primary and main and interactive effects of Cd and Pb on bone mineral density (BMD) in a Chinese population were observed in this study. A total of 321 individuals (202 women and 119 men), aged 27 years and older, living in control and polluted areas, were recruited to participate in this study. The BMD was measured through dual energy X-ray absorptiometry (DXA) at the proximal radius and ulna. The samples of urine and blood were collected to determine the levels of Cd and Pb in the urine (UCd and UPb) and blood (BCd and BPb). The Cd and Pb levels of people living in the polluted area were significantly higher than those living in the control area (p<0.05). The BMD of women living in polluted area was significantly lower than that of women living in the control area (p<0.05). Furthermore, the BMD decreased with increasing of BCd (p<0.05), BPb and UPb in women. The likelihood of low BMD was associated with higher BCd in women (OR=2.5, 95% CI: 1.11-5.43) and BPb in men (OR=4.49, 95% CI: 1.37-14.6). The relative extra risk index of low BMD for female and male subjects with both high levels of BCd and BPb was 0.45 and 1.16, respectively. This study strengthens previous evidence that cadmium and lead may influence the bone and also demonstrates that cadmium and lead may have interactive effects on BMD.

Bone mineral density is related with previous renal dysfunction caused by cadmium exposure

Relationship between bone mineral density (BMD) and previous renal dysfunction caused by cadmium exposure was investigated. A total of 457 persons, living in polluted and control areas, were followed up in this study. The inhabitants living in exposure areas ceased ingesting cadmium-contaminated rice in 1996. Blood and urinary cadmium levels and BMD in 1998 and 2006 were measured. Urinary N-acetyl-β-d-glucosaminidase and albumin determined in 1998 and 2006 were used to evaluate kidney status. BMD of subjects with tubular damage was significant lower than those without damage in female (p < 0.05). The prevalence of osteoporosis was significantly different between those with and without kidney damage (p = 0.003, in total population; p = 0.039, in female) and those with and without tubular damage (p = 0.0005, in total population; p = 0.007, in female). The results suggested that BMD was correlated with previous kidney impairment caused by cadmium exposure, especially to tubular damage and especially for female.

Osteoporosis in a Chinese Population Due to Occupational Exposure to Lead

BACKGROUND Recent studies indicate that lead may exert actions both directly on osteoblast and osteoclast function, and indirectly via kidney dysfunction on bone turnover. The main focus of this study was to investigate whether occupational lead exposure is associated with low bone mass in a population working in a storage battery plant. METHODS Monophoton absorptiometry was used to measure bone mineral density (BMD) in the population and the Z score was introduced to define osteoporosis (Z score <-2). Lead concentration of urine and blood was determined by graphite-furnace atomic absorption spectrophotometry as an exposure biomarker. A total of 249 persons (191 males and 58 females) participated and completed a questionnaire in order to obtain information on height, weight, age, medical and drug history, cigarette smoking, alcohol consumption, job position, work year, physical exercise, etc. RESULTS The BMD was significantly decreased in the groups of the high urinary lead (UPb) level compared with the low UPb level with a significant difference (P < 0.05) in both genders, but no such significant difference was observed in the relationship between blood lead (BPb) and BMD. The prevalence of osteoporosis would increase significantly with the increase of the UPb (P < 0.01) in the linear correlation manner (P < 0.01). There was also such a significant relationship between BPb and osteoporosis (P < 0.01). There was a dose-response relationship between lead exposure and prevalence of osteoporosis. CONCLUSIONS In contrast to BPb, UPb had a more close relationship with osteoporosis caused by lead. It was concluded that occupational exposure to lead is associated with osteoporosis.

Benchmark dose for estimation of cadmium reference level for osteoporosis in a Chinese female population

In this study, the reference level of cadmium in urine and blood related with bone damage was assessed using benchmark dose in a Chinese female population. Total of 338 women was recruited, and urine and blood samples were collected from each individual for determination of cadmium in urine (UCd) and blood (BCd). Bone mineral density was measured by dual energy X-ray absorptiometry. BMD and BMDL were calculated corresponding to additional risk of 5% and 10%. With benchmark response (BMR) of 5%/10%, the BMD of BCd, UCd related with osteoporosis was 1.88μg/L/3.23μg/L and 5.30μg/g crea/9.06μg/g crea, and the BMDL-05 was 1.39μg/L/2.38μg/L and 3.78μg/g crea/6.36μg/g crea; the BMD of BCd, UCd related with low bone mass was 0.95μg/L/3.12μg/L and 3.12μg/g crea/5.87μg/g crea, and the BMDL-05 was 0.72μg/L/1.35μg/L and 2.14μg/g crea/3.99μg/g crea. The BMD of UCd in people over 60years old was much lower than that of people less than 60years old. BMD value was related with ages and effects biomarkers. Our data showed that BMD of UCd associated with osteoporosis was lower than that previously estimated.

A polymorphism in metallothionein 1A (MT1A) is associated with cadmium-related excretion of urinary beta 2-microglobulin

OBJECTIVES Cadmium (Cd) toxicity of the kidney varies between individuals despite similar exposure levels. In humans Cd is mainly bound to metallothioneins (MT), which scavenge its toxic effects. Here we analyzed whether polymorphisms in MT genes MT1A and MT2A influence Cd-related kidney damage. METHODS In a cross-sectional study N=512 volunteers were selected from three areas in South-Eastern China, which to varying degree were Cd-polluted from a smelter (control area [median Cd in urine U-Cd=2.67 μg/L], moderately [U-Cd=4.23 μg/L] and highly [U-Cd=9.13 μg/L] polluted areas). U-Cd and blood Cd (B-Cd) concentrations were measured by graphite-furnace atomic absorption spectrometry. MT1A rs11076161 (G/A), MT2A rs10636 (G/C) and MT2A rs28366003 (A/G) were determined by Taqman assays; urinary N-Acetyl-beta-(D)-Glucosaminidase (UNAG) by spectrometry, and urinary β2-microglobulin (UB2M) by ELISA. RESULTS Higher B-Cd (natural log-transformed) with increasing number of MT1A rs11076161 A-alleles was found in the highly polluted group (p-value trend=0.033; all p-values adjusted for age, sex, and smoking). In a linear model a significant interaction between rs11076161 genotype and B-Cd was found for UNAG (p=0.001) and UB2M concentrations (p=0.001). Carriers of the rs11076161 AA genotype showed steeper slopes for the associations between Cd in blood and natural log-transformed UB2M (β=1.2, 95% CI 0.72-1.6) compared to GG carriers (β=0.30, 95% CI 0.15-0.45). Also for UNAG (natural log-transformed) carriers of the AA genotype had steeper slopes (β=0.55, 95% CI 0.27-0.84) compared to GG carriers (β=0.018, 95% CI -0.79-0.11). CONCLUSIONS MT1A rs11076161 was associated with B-Cd concentrations and Cd-induced kidney toxicity at high exposure levels.

Changes in bone mineral density 10 years after marked reduction of cadmium exposure in a Chinese population

The main focus of this study was to evaluate the long-term effects of Cd on forearm bone mineral density after the cessation of the ingestion of Cd-polluted rice. A total of 458 persons (294 women, 164 men) from three Cd exposure areas (low, moderately, and heavy) participated in this study. Those living in the moderate and heavy exposure areas ceased ingesting Cd-polluted rice (0.51 and 3.7mg/kg, respectively) in 1996 (10 years prior to present analysis). The participants completed a questionnaire and bone mineral density (BMD) was measured by dual energy X-ray absorptiometry (DXA) at the proximal radius and ulna. The changes and change percentage in forearm bone density and the prevalence of osteoporosis between 1998 and 2006 were used as markers of bone recovery. The Cd concentrations in urine (UCd) and blood (BCd) in 1998 were used as Cd exposure markers. The values of the BMD change and change percentage of groups in which UCd was above 5microg/g creatinine (microg/g crea) and BCd was above 10microg/L were significantly higher than those of the low-exposure groups (in women, p<0.001; in men, p>0.05). The BMD change and change percentage correlated positively with the UCd and BCd (in women, p<0.01; in men, p>0.05). Analysis of the Z-score revealed that the prevalence of osteoporosis in 2006 was higher than that in 1998 and increased along with the level of UCd and BCd in both women and men, especially for those subjects with the higher BCd [BCd>5microg/L, OR=3.45 (0.95-13.6); BCd>10microg/L, OR=4.51(1.57-13.54)] and UCd [UCd>10microg/g crea, OR=4.74 (1.82-12.81)] in women. It is concluded that decreasing dietary cadmium exposure at the population level is not associated with bone recovery at the individual level, and the adverse bone effects of Cd exposure persisted after the main source of Cd exposure had been blocked, especially in women.

The efficacy and safety of calcitriol and/or Caltrate D in elderly Chinese women with low bone mass.

AbstractAim:To observe the efficacy and safety of Rocaltrol (calcitriol) and/or Caltrate D (calicum carbonate plus vitamin D) in elderly Chinese women with osteopenia or osteoporosis.Methods:One hundred fifty Chinese women aged over 65 years with osteopenia or osteoporosis from three centers were randomly divided into two groups. Seventy-six participants received Caltrate D as one pill daily; the other 74 participants received 0.25 μg Caltrate D plus Rocaltrol daily. The changes in bone mineral density (BMD) served as primary end-points. Height changes, the presence of new vertebral fractures, muscle strength and balance were evaluated.Results:The following are the mean percentage changes (and SD) in BMD over 12 months: at L2-L4, 0.83±3.88 in the Caltrate D group and 2.84±4.04 in the Rocaltrol+Caltrate D group (P=0.003, by ANCOVA); at the femoral neck, 0.04±3.94 in the Caltrate D group and 2.01±5.45 in the Rocaltrol+Caltrate D group (P=0.085, by ANCOVA); and in the trochanter, 1.59±4.57 in the Caltrate D group and 3.76±6.25 in the Rocaltrol+Caltrate D group (P=0.053, by ANCOVA). The stand and maximal forward reach test (SMFRT) was significantly enhanced in both groups during the 12 months of treatment, but no significant differences were found between these two groups. No severe adverse event related to these medications occurred throughout the study.Conclusion:Treatment with Rocaltrol plus Caltrate D or Caltrate D for 12 months in elderly Chinese postmenopausal women effectively increased BMD at the lumbar spine. Rocaltrol plus Caltrate D was more effective at the lumbar spine than Caltrate D alone.