Bone Density-related Predictors of Blood Lead Level among Peri- and Postmenopausal Women in the United States

The Third National Health and Nutrition Examination Survey, 1988–1994

Denis Nash1,2 , Laurence S. Magder2, Roger Sherwin3, Robert J. Rubin4 and Ellen K. Silbergeld2,4

1 Center for Urban Epidemiologic Studies, New York Academy of Medicine, New York, NY.
2 Department of Epidemiology and Preventive Medicine, School of Medicine, University of Maryland, Baltimore, MD.
3 Department of Epidemiology, School of Public Health, Tulane University, New Orleans, LA.
4 Department of Environmental Health Sciences, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD.

Received for publication February 10, 2003; accepted for publication June 1, 2004.


    ABSTRACT
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Because of the long half-life of lead stored in bone (years), skeletal lead stores may be a source of endogenous lead exposure during periods of increased bone demineralization, such as menopause. To test the hypothesis that postmenopausal bone resorption increases blood lead levels, the authors examined cross-sectional associations of bone density-related factors with blood lead levels among women aged 40–59 years from the Third National Health and Nutrition Examination Survey (1988–1994). Factors related to bone turnover were significant predictors of blood lead level. Bone mineral density was significantly inversely related to blood lead levels in log-linear multivariate models that adjusted for age, race/ethnicity, smoking, education, household income, alcohol use, and residence (urban/rural). With menopausal status added to the model, naturally and surgically menopausal women had adjusted median blood lead levels that were 25% and 30% higher, respectively, than those of premenopausal women (2.0 µg/dl). Current use of hormone replacement therapy was associated with significantly lower adjusted median blood lead levels (1.8 µg/dl) than past use (2.6 µg/dl) and never use (2.2 µg/dl). Lead stored in bone may significantly increase blood lead levels in perimenopausal women because of postmenopausal bone mineral resorption. Attention to factors that prevent bone loss may lessen or prevent this endogenous lead exposure.

bone density; bone resorption; hormone replacement therapy; lead; menopause; women

Abbreviations: Abbreviations: BMD, bone mineral density; HRT, hormone replacement therapy; NHANES, National Health and Nutrition Examination Survey.


    INTRODUCTION
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Despite major reductions in environmental lead exposure for much of the US population (1), lead poisoning remains a significant public health problem (2). While young children and some adults continue to be at risk from exogenous sources of lead exposure, new evidence suggests that some persons may be at risk for recurring endogenous exposure to lead previously accumulated over time in the skeleton (36). Like calcium, lead is a bone-seeking element. Over 90 percent of the total burden of lead in the body resides in the skeleton, where it has a half-life on the order of years to decades (710). Thus, exposure to lead over the course of a lifetime results in accumulation of lead in the skeletal compartment (1113) such that bone lead levels are generally higher among older persons (14). Of particular concern is the potential for renewed exposure to lead released from bone in older persons who were excessively exposed to environmental lead, by current standards, prior to its removal from gasoline (1978–1990) and paint (1977) (15).

The human skeleton is a dynamic physiologic compartment of mineral metabolism. Mineral absorption and resorption are affected by many factors, including age, diet, weight-bearing activity, trauma, metabolic disorders, hormonal status, pregnancy, lactation, and menopause (1620). In response to these factors, both lead and calcium are deposited in the skeleton and may act similarly (4, 21, 22). Lead competes with calcium for transport and binding sites, and when calcium is released from bone, lead is also liberated (2330). Additionally, lead does not accumulate uniformly throughout the skeleton but is selectively taken up at different sites and in different types of bone (e.g., trabecular bone more than cortical bone) (8, 26, 31, 32). These events may be of particular importance to women because of the changing dynamics of bone mineral metabolism related to events such as pregnancy, lactation, and menopause (33, 34). Over her lifetime, a woman loses up to 50 percent of trabecular bone and 30 percent of cortical bone, and 30–50 percent of this bone loss occurs in the early postmenopausal years (3539). Estrogen deficiency appears to play a significant role in bone loss (37, 40), and hormone replacement therapy (HRT) after menopause has been shown to prevent bone loss (38, 4146) or even increase bone density (47).

There is mounting observational evidence that lead may be mobilized from the skeleton during periods of increased bone demineralization, such as pregnancy and lactation (4851), very old age (52), and menopause (3, 6, 53, 54). Increases in blood lead associated with menopause are of concern because recent research has linked lead in the blood, at levels previously thought to be safe, to a number of adverse health outcomes in adults, including increased blood pressure (5558), reduced kidney function (59), decrements in neurocognitive function (60, 61), and increased risks of atherosclerosis and cardiovascular disease mortality (62). Two cross-sectional studies of US women that used data from the Second National Health and Nutrition Examination Survey (NHANES II; 1976–1980) and the Hispanic Health and Nutrition Examination Survey (1982–1984) documented that postmenopausal women have significantly higher blood lead levels than premenopausal women, after results are controlled for age and other factors related to exogenous lead exposure (3, 6). A cross-sectional study conducted in the early 1990s found an inverse relation between blood lead levels and bone-related factors, including menopause (63). Another study also identified menopausal status as an independent predictor of blood lead levels in a random sample of Scandinavian women (53). However, these studies were carried out at a time when environmental exposures and population blood lead levels were much higher than they are at present. More recently, among perimenopausal women from the Nurses’ Health Study who were not using HRT, investigators found higher blood lead levels and observed that bone lead was more strongly associated with blood lead in comparison with current HRT users (64). In a study of women from the Third National Health and Nutrition Examination Survey (NHANES III), Nash et al. (58) reported the association between blood lead and diastolic hypertension to be most pronounced in postmenopausal women. A recent study of women in Mexico City, Mexico, where environmental exposure to lead is high, found no association between blood lead and bone mineral density (BMD) (65). However, to our knowledge, the association has never been examined in the context of lower environmental lead exposures, where the contribution of endogenous lead to blood lead may be more relevant.

The goal of this investigation was to test whether BMD and other factors related to bone status (menopausal status, time since menopause, and use of HRT) are associated with blood lead levels in ways consistent with the hypothesis that postmenopausal bone density loss results in increased endogenous lead exposure in the context of low exogenous exposure to lead.


    MATERIALS AND METHODS
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Study population
The study population included adult females from NHANES III. NHANES III comprised a cross-sectional population sample that was obtained through a complex survey design and was intended to be representative of the US civilian, noninstitutionalized population. Over a 6-year period (1988–1994), participants took part in a household survey interview and an in-depth physical examination with laboratory tests. Other details on the survey design have been published by the National Center for Health Statistics (66).

The present investigation focused on the 2,575 women aged 40–59 years who took part in the NHANES III survey interview. From this group, women were excluded for the following reasons: 212 did not undergo physical examination or blood testing; 77 did not have information on blood lead levels; 181 had bone density measurements that were considered unreliable by the technicians performing the dual-energy x-ray absorptiometry; and 70 had an indeterminate menopausal status because of missing information. A further 121 women of ethnicities other than non-Hispanic Black, non-Hispanic White, and Mexican-American were excluded because of low numbers in any single category of self-reported ethnicity. The remaining 1,914 women constituted the sample used in the present analyses.

Definitions
Blood lead
Blood samples were obtained by venipuncture from all adult participants during the physical examination. Blood lead was measured by graphite furnace atomic absorption spectrophotometry at the laboratories of the Center for Environmental Health, Centers for Disease Control and Prevention (Atlanta, Georgia). The assay detection limit was 1.0 µg/dl. Each sample analysis was performed in duplicate, and the average of both measurements was used in these analyses. Persons with blood lead levels less than 1.0 µg/dl (n = 201) were assigned a value of 0.5 µg/dl for consistency with previous analyses of NHANES III data by other investigators (2).

Covariates
Information on race/ethnicity (non-Hispanic Black, non-Hispanic White, or Mexican-American), age (years), smoking (current, former, or never), household income, and education was obtained from the household interview. The poverty income ratio, a ratio of household income to the federal poverty-level income (for a given family size, adjusted to the poverty threshold for the year of the interview), was used to create a three-level household income variable. A participant was assigned a household income level above the poverty line if the poverty income ratio was greater than 1 and a household income level at or below the poverty line if the poverty income ratio was less than or equal to 1; data were considered missing if the survey participant did not report household income. A four-level education variable was created on the basis of the number of years of education reported by the survey participant: less than high school (<12 years), completion of high school (12 years), some college (>12–<16 years), and completion of college or more (≥16 years). A dichotomous variable based on area of residence (urban/rural) was also included.

Information on participants’ alcohol use (frequency and amount consumed per week) was obtained using the examination-associated interview questionnaire. A four-level categorical variable for weekly alcohol intake was created, with the following levels: none; <1 drink per week; 1–<3 drinks per week; and ≥3 drinks per week.

Menopausal status
A variable was created to categorize women as premenopausal (ovarian function intact), surgically menopausal (both ovaries removed surgically before cessation of menses), or naturally menopausal (nonsurgical loss of ovarian function). Participants without a history of reproductive surgery were classified as premenopausal if they reported having had a menstrual period during the previous 12 months and postmenopausal if they did not, consistent with World Health Organization criteria. Women who had undergone a hysterectomy (without ovariectomy) that coincided with the date of the last menstrual period were assigned a menopausal classification on the basis of age (<51 years, premenopausal; ≥51 years, naturally menopausal). Women without a history of hysterectomy or ovariectomy who were current users of HRT were classified in the same way. Women who had undergone bilateral ovariectomy that coincided with the date of the last menstrual period were classified as surgically menopausal. Women who had undergone hysterectomy or ovariectomy after the date of the last menstrual period were classified as naturally menopausal.

HRT status
Women were classified as current users, past users, or never users of HRT on the basis of self-reported data from the examination questionnaire. Duration of HRT use in years was also ascertained by self-report at the time of the examination.

Time since menopause
Information on time since menopause was estimated as the difference in years between age at the time of the NHANES interview and self-reported age at the time of the last menstrual period or ovariectomy, whichever came first. Women aged 51 years or more whose last menstrual period coincided with hysterectomy were assumed to be postmenopausal.

Bone mineral density
BMD was measured in five regions of the femur by dual-energy x-ray absorptiometry in the NHANES III medical examination: femoral neck, intertrochanter, trochanter, Ward’s triangle, and total. All five measurements were examined in bivariate analyses of BMD and blood lead level. For multivariate analyses, the BMD value from the trochanter region was used.

Statistical methods
The associations of blood lead level with trochanter BMD, menopause, time since menopause, and HRT were modeled using multiple linear regression, controlling for other factors related to blood lead level. Because the distribution of blood lead values was nonnormal, as has been found by other investigators using NHANES data and other data sets (2), we used natural logarithmic transformation of the blood lead variable in multiple linear regression analyses. Covariates included age, race/ethnicity, smoking, education, household income, alcohol use, and residence.

The statistical analyses were conducted using SAS (67), incorporating the examination sampling weights and survey design of NHANES III (66). Tests for trend for categorical variables were carried out in regression models by coding levels as integers (scores) and evaluating tests for the probability that the slope of the regression line was nonzero. SUDAAN statistical software (68) was used to calculate standard errors for the estimates, accounting for both the weights and the complex survey design. All estimates presented here were calculated incorporating the sampling weights. Adjusted geometric mean blood lead levels were obtained using the LSMEANS statement in SUDAAN.


    RESULTS
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Sample characteristics
A demographic description of the sample is provided in table 1. The distribution of menopausal status among women aged 40–59 years varied significantly by race/ethnicity (p = 0.0136). As compared with White women, non-Hispanic Blacks appeared to be overrepresented among surgically menopausal women, whereas non-Hispanic Whites and Mexican Americans were slightly underrepresented. The mean age of the sample was 48.1 years, and, as expected, menopausal status was strongly correlated with age. Postmenopausal women were more likely to abstain from weekly alcohol use (by self-report) and less likely to have a college education than premenopausal women.


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TABLE 1. Characteristics of women aged 40–59 years participating in the Third National Health and Nutrition Examination Survey, 1988–1994
 
Distributions of data on BMD and other bone density-related factors
Menopausal status was significantly associated with BMD measurements from all five regions of the femur (p < 0.0001), with premenopausal women having a higher BMD than surgically and naturally menopausal women (table 2). Postmenopausal women were more likely than premenopausal women to be either current or past users of HRT (p < 0.0001). Current users of HRT had been undergoing HRT for a longer amount of time than past users (a mean of 6 years vs. 2.9 years). Current users of HRT who were menopausal had the longest duration of HRT use (6.9 years). Surgically menopausal women were, on average, further away in time from menopause than naturally menopausal women (12.7 years vs. 9.5 years; p < 0.0001).


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TABLE 2. Distributions of values for bone density-related variables among women aged 40–59 years, Third National Health and Nutrition Examination Survey, 1988–1994
 
Blood lead levels for bone density-related predictor variables
Premenopausal women had a geometric mean blood lead level of 1.9 µg/dl, as compared with 2.7 µg/dl and 2.9 µg/dl for surgically menopausal women and naturally menopausal women, respectively (table 3). Current users of HRT had a lower geometric mean blood lead level than women who reported never having used HRT (1.9 µg/dl vs. 2.2 µg/dl). Past users of HRT had a geometric mean blood lead level of 3.0 µg/dl. Women who had never used HRT and women who had used HRT for at least 1 year had lower mean blood lead levels than women who had been using HRT for less than 1 year. Relative to premenopausal women, geometric mean blood lead levels peaked among women who were 0–2 years past menopause and were lowest among postmenopausal women who were 9 or more years beyond menopause. Blood lead levels were significantly related to menopausal status and BMD. In bivariate analyses, BMD measured in all five regions of the femur was significantly inversely associated with blood lead level (table 4).


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TABLE 3. Geometric mean blood lead levels according to bone density-related predictor variables among women aged 40–59 years, Third National Health and Nutrition Examination Survey, 1988–1994
 

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TABLE 4. Geometric mean blood lead levels (µg/dl) according to quartile of bone mineral density among 1,914 women aged 40–59 years, Third National Health and Nutrition Examination Survey, 1988–1994
 
Age-stratified analyses
Compared with premenopausal women of the same age, postmenopausal women had significantly higher geometric mean blood lead levels in every age group (figure 1), with the greatest differences being observed in the group aged 45–49 years. In addition, for every age category, current users of HRT had lower geometric mean blood lead levels than past or never users (figure 2).



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FIGURE 1. Adjusted geometric mean blood lead levels by age and menopausal status, Third National Health and Nutrition Examination Survey, 1988–1994. (*Statistically significant difference in blood lead levels relative to premenopausal women.)

 


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FIGURE 2. Adjusted geometric mean blood lead levels by age and use of hormone replacement therapy, Third National Health and Nutrition Examination Survey, 1988–1994. (*Statistically significant difference in blood lead levels relative to premenopausal women.)

 
Multivariable analyses
BMD in the trochanter region was significantly inversely associated with blood lead level (natural log), even after adjustment for age, ethnicity, residence, household income, smoking, and alcohol use (table 5, model with BMD only). A one-unit change in BMD was associated with a 0.6-µg/dl lower geometric mean blood lead level. Age was positively associated with blood lead. Non-Hispanic Blacks had significantly higher blood lead levels than non-Hispanic Whites. Persons living in urban or suburban areas had higher blood lead levels than those living in more rural areas. Having a household income at or below the poverty line was associated with a significantly higher blood lead level than having an income above the poverty line. Education was not significantly associated with blood lead. Nonusers of alcohol had significantly lower blood lead levels than frequent users. Current and former smokers had significantly higher blood lead levels than persons who had never smoked.


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TABLE 5. Regression coefficients from multiple linear regression analysis of log blood lead levels (µg/dl) on established predictors of blood lead and menopausal status among 1,905 pre- and postmenopausal women, Third National Health and Nutrition Examination Survey, 1988–1994
 
Menopausal status
When menopausal status was added to the model, the association of BMD with blood lead (log-transformed) remained significant. Differences in blood lead level between pre- and postmenopausal women also withstood multivariable adjustment for the established predictors of blood lead level (table 5, model with BMD and menopausal status). Naturally menopausal women had a significantly higher geometric mean blood lead level than premenopausal women (2.5 µg/dl vs. 2.0 µg/dl; p = 0.0126) after adjustment for age, race/ethnicity, urban/rural residence, household income, educational level, alcohol use, and smoking status. Surgically menopausal women also had a significantly higher adjusted blood lead level than premenopausal women (2.6 µg/dl vs. 2.0 µg/dl; p = 0.0009).

HRT use
HRT use was significantly associated with log blood lead level in a model that adjusted for BMD, menopausal status, and other covariates (table 5, model with BMD, menopausal status, and HRT). The addition of HRT to the model did not materially alter the association of BMD or menopausal status with blood lead level. Among postmenopausal women, never users of HRT had a significantly higher adjusted geometric mean blood lead level than women who were currently using HRT (2.2 µg/dl vs. 1.8 µg/dl; p = 0.0006). Former users of HRT also had a significantly higher adjusted blood lead level than current users (2.6 µg/dl vs. 1.8 µg/dl; p = 0.0004).

Time since menopause
Time (years) since menopause was a significant predictor of blood lead level among women who were not current users of HRT (table 5, model with time since menopause). Postmenopausal women who were closer in time to the last menstrual period tended to have significantly higher blood lead levels than both premenopausal women and postmenopausal women who were further away in time (≥9 years) from the menopausal transition.


    DISCUSSION
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
These analyses suggest that menopause and bone status are predictors of blood lead level among women aged 40–59 years in the US population. BMD was significantly inversely associated with blood lead level after adjustment for other factors traditionally associated with blood lead. Menopausal status and HRT use, both of which are associated with BMD, were important predictors of blood lead level independently of age and other factors. Despite recent declines in environmental lead exposure, the estimated effects of menopause observed in this study are similar to those reported for NHANES II (1976–1980) by Silbergeld et al. (3) and later by other investigators (6, 63, 65). Among women not currently on HRT, time since menopause, a potential marker of bone density loss, was significantly associated with blood lead, with postmenopausal women closer in time to the menopausal transition tending to have higher blood lead levels than those further away from menopause. These associations withstood multivariate adjustment for current BMD, race/ethnicity, age, smoking, alcohol use, education, household income, and urbanicity. In the absence of HRT, time since the menopausal transition was associated with bone demineralization; these observations are consistent with the hypothesis that bone demineralization increases the blood lead levels of menopausal women.

To our knowledge, this study is the first to have examined the relation between BMD measured by dual-energy x-ray absorptiometry and blood lead level. A statistically significant association between concurrent measurements of BMD and blood lead level was observed after multivariate adjustment for menopausal status. A low BMD measurement may reflect either recent decline in BMD or longstanding bone mineral status. It is possible that lead may affect BMD, rather than BMD’s affecting lead. Experimental studies in rats demonstrate that the effects of lead in decreasing bone growth and density are associated with perinatal exposures (69, 70). Because of the cross-sectional design of NHANES III, inferences about the temporal nature of any of the associations reported here cannot be made on the basis of these data alone.

Women who were current users of HRT had adjusted blood lead levels lower than those of past or never users, independently of age. This observation is consistent with the findings of other investigators (64) and supports the hypothesis that blood lead levels among postmenopausal women are partly driven by factors that affect bone loss. However, the possibility cannot be ruled out that differing lead exposure profiles between these groups of women were responsible for the observed effect, despite our attempt to control for this through multivariate adjustment for factors known to be associated with lead exposure. Women who choose to use HRT may be different from women who do not with regard to many health behaviors and exposures, both known and unknown (71). However, it is unlikely that this is the only explanation, since no differences between former users and never users of HRT were observed after multivariate adjustment.

Our results reinforce the possibility that blood lead stores may represent an endogenous source of lead exposure. Although the differences in average blood lead levels reported here are relatively small, increases in blood lead by these amounts may still pose a risk to women who experience significant bone loss or have higher bone lead levels at the start of menopause. Moreover, small increases in blood lead level are associated with decrements in neurocognitive performance (72) and increased risks of atherosclerosis and hypertension (57, 58, 73). Significant increases in risk of peripheral arterial disease were reported in adults with increases in blood lead within the range found in this study (74).

The magnitude of postmenopausal changes in blood lead level may depend on a number of factors, including the amount and bioavailability of lead stored in bone prior to menopause and the rate and magnitude of bone mineral loss. Initial bone lead stores at menopause may differ among different ethnic groups on the basis of prior exposures (2). Moreover, there is evidence that BMD and rates of loss after menopause may differ by ethnicity (7577). Bone lead measurements taken over time may provide additional insights into these issues.

There is some evidence that lead mobilized from bone stores may be preferentially partitioned into plasma as compared with erythrocytes; this suggests that lead released from bone may be more toxicologically relevant than lead entering the bloodstream from environmental sources (78), though there is also evidence to suggest that this is not the case (79). If this is the case, increases in the release of endogenous lead may result in transfers of more lead to critical compartments in soft tissue (10, 78). Although this theory has not been proven directly, this observation may explain recent findings that bone lead is more predictive of outcomes such as hypertension in older persons than is blood lead (57, 80), as well as observations that the relation between blood lead and diastolic hypertension appears to be stronger among postmenopausal women (58). We recommend that investigators studying health outcomes associated with lead exposure in women during the menopausal transition measure bone lead levels in addition to blood lead levels.


    ACKNOWLEDGMENTS
 
This research was supported by the Centers for Disease Control and Prevention through a cooperative agreement (no. TS 288-14/14) with the Association of Teachers of Preventive Medicine.

The authors acknowledge the important contributions of Dr. Paul Stolley (University of Maryland School of Medicine) and Debra Brody (National Center for Health Statistics), both of whom provided guidance and invaluable comments on this project and this paper.


    NOTES
 
Correspondence to Dr. Denis Nash, Center for Urban Epidemiologic Studies, New York Academy of Medicine, 1216 Fifth Avenue, New York, NY 10029 (e-mail: dnash{at}nyam.org). Back


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 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
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