In summary, in unadjusted analyses, significant correlations were seen between Pb level and levels of uNTX-I, uCTX-II, and COMP among women and levels of uCTX-II, COMP, CPII, and [C2C:CPII] among men. After adjustment, among women, we identified statistically significant positive associations between whole blood Pb level and urine NTX-I and CTX-II, markers of bone and calcified cartilage turnover, respectively. Among men, there was a statistically significant positive association between blood Pb and COMP after adjustment. Blood Pb was not significantly associated with serum C2C, CPII, the ratio [C2C:CPII], or HA, in adjusted analyses in men or women.
The positive association among women between blood Pb and uCTX-II level in this analysis signifies a potential association between Pb exposure and joint tissue metabolism, although we cannot determine the direction of this effect from the present cross-sectional study. It is unclear whether this finding reflects a direct effect of Pb on cartilage, or an indirect effect mediated by adverse effects of Pb on bone. Urine CTX-II is a quantitative marker of radiographic osteoarthritis (Meulenbelt et al. 2006
;Reijman et al. 2004
), and may be a relatively specific biomarker of calcified cartilage turnover at the junction of cartilage and subchondral bone (Tomiya et al. 2008
;Bay-Jensen et al. 2008
). Given the reported propensity for accumulation of Pb at the tidemark, the area of transition between calcified and more metabolically active non-calcified cartilage (Zoeger et al. 2006
), and the report that CTX-II is primarily derived from sites at or near the junction of cartilage and subchondral bone (Bay-Jensen et al. 2008
), uCTX-II may be a specific biomarker for the joint tissue most affected by Pb toxicity. We have identified significant associations between blood Pb and uCTX-II among women in our cohort; confirmation of this finding in other populations will provide a better understanding of its potential implications.
The strongest association between Pb and a biomarker among women was for uNTX-I, a marker of bone turnover in osteoporosis (Scariano et al. 1998
) and in osteoarthritis (Bettica et al. 2002
). Consistent with prior studies of markers of bone turnover and blood Pb levels (Potula et al. 2005
;Machida et al. 2009
), uNTX-I was highly associated with blood Pb level in the current analysis. Despite known variations in uNTX-I by menopausal and hormone replacement status, there was no difference after adjustment for these factors in the current analysis, potentially due to small numbers of premenopausal women and of women on hormone replacement therapy. The observed association i n the current analysis between elevated levels of uNTX-I and higher levels of blood Pb is likely related to increased release of Pb into blood from bone in this population of primarily post-menopausal women in a high bone turnover state, consistent with prior reports (Machida et al. 2009
). Although we did not identify an association between uNTX-I and blood Pb in men, in a study of elderly men participating in the VA Normative aging study, there was evidence of increased blood Pb with increasing uNTX-I levels, although this was not the focus of the study (Nie et al. 2009
). The men in that study were older (mean age 69 years) with a higher median blood Pb level (5µg/dL) compared to the current analysis, which may at least partly explain this difference.
No significant associations were identified between Pb and serum CPII (marker of collagen synthesis), serum C2C (marker of cartilage degradation), or their ratio [C2C:CPII] in adjusted analyses, despite significant correlations between Pb level and CPII and [C2C:CPII] among men. There was a significant interaction between age and C2C among women, but the association between Pb and serum C2C was not significant in either age group. A lack of association between radiographic osteoarthritis and serum C2C has been reported (Mazzuca et al. 2006
;Cahue et al. 2007
;Cibere et al. 2009
), and may represent a lack of a detectable relationship between the effects of Pb on uncalcified cartilage degradation, as reflected by serum C2C. Therefore, urine C2C is recommended for future studies, as unlike serum C2C this biomarker has revealed alterations in cartilage collagen degradation with the onset of knee osteoarthritis (Cibere et al. 2009
). The lack of association between Pb and the ratio [C2C:CPII], despite evidence in the literature that such marker ratios may provide additional information beyond that from individual markers in isolation (Cahue et al. 2007
;Cibere et al. 2009
), may be in part due to adjustment of the models for race (associated with C2C) and smoking (associated with CPII).
The lack of association between blood Pb and serum HA, often considered a marker of synovial inflammation (Wells et al. 1992
;Sharif et al. 1995a
), among men or women, is not supportive of a Pb effect on synovium. Studies have shown an effect of Pb on cultured synovial cells, including decreased proliferation and protein synthesis, but only in an in vitro experiment using 10-fold higher concentrations of Pb, so it is unclear how those findings relate to Pb level and serum HA as analyzed in the current study (Goldberg et al. 1983
There are some limitations to the current study. Whole blood Pb measurements were used as a biomarker for Pb exposure. Specialized x-ray fluorescence techniques to assess bone Pb are considered the “gold standard” for measurement of Pb storage in bone, but this procedure is expensive and not widely available (Barbosa et al. 2005
). Since blood Pb levels reflect recent exposure as well as mobilization of Pb from bone (Barbosa et al. 2005
;Nie et al. 2009
), and blood Pb has been associated with all-cause mortality, cardiovascular disease, and renal disease (Staessen et al. 1992
;Jain et al. 2007
;Martin et al. 2006
;Schober et al. 2006
;Weisskopf et al. 2009
;Khalil et al. 2009
), this measure of Pb was used as a readily available and economical alternative biomarker for Pb exposure (Barbosa et al. 2005
). The current study is also limited due to its cross-sectional design, although the potential for future longitudinal studies of Pb in this population exist. Bone density measurements have been collected as part of the parent study but were not interpreted or analyzed at the time of this analysis. The strengths of this study include a population-based, biracial sample and the inclusion of multiple biomarkers representing turnover of different joint tissues.