Bone Mass and the Risk of Colon Cancer among Postmenopausal Women

The Framingham Study

Yuqing Zhang1,2, David T. Felson1, R. Curtis Ellison2, Bernard E. Kreger2,3,4,5, Arthur Schatzkin6, Joanne F. Dorgan7, L. Adrienne Cupples8, Daniel Levy3,4 and Douglas P. Kiel9,10

1 Boston University Arthritis Center, Boston University School of Medicine, Boston, MA.
2 Section of Preventive Medicine and Epidemiology, Boston University School of Medicine, Boston, MA.
3 Section of General Internal Medicine, Evans Department of Medicine, Boston University School of Medicine, Boston, MA.
4 Framingham Heart Study, Framingham, MA.
5 National Heart, Lung, and Blood Institute, Bethesda, MD.
6 Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD.
7 Division of Population Science, Fox Chase Cancer Center, Philadelphia, PA.
8 Department of Epidemiology and Biostatistics, Boston University School of Public Health, Boston, MA.
9 Hebrew Rehabilitation Center for Aged, Boston, MA.
10 Harvard Medical School Division on Aging, Boston, MA.


    ABSTRACT
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Although postmenopausal estrogen use has been associated with a lower risk of colon cancer in women, some studies do not confirm such findings. No known study has examined the effect of cumulative estrogen exposure on colon cancer risk. Bone mass has been proposed as a marker of cumulative exposure to endogenous and exogenous estrogens. By using data on 1,394 Massachusetts women in the Framingham Study who underwent hand radiography in 1967–1970, the authors examined the association between bone mass (from relative areas of the second metacarpal) and colon cancer incidence. Over 27 years of follow-up, 44 incident colon cancer cases occurred. Colon cancer incidence decreased from 2.19 per 1,000 person-years among the women in the lowest age-specific tertile of bone mass to 1.59 and 1.08 among women in the middle and the highest tertiles, respectively. After adjustment for age and other potential confounding factors, the rate ratios of colon cancer were 1.0, 0.7 (95% confidence interval: 0.3, 1.3), and 0.4 (95% confidence interval: 0.2, 0.9) from the lowest to the highest tertile (p for trend = 0.033). No association was found between bone mass and rectal cancer. The findings suggest that women with higher bone mass, perhaps reflecting greater cumulative estrogen exposure, have a decreased risk of colon cancer.

bone density; cohort studies; colorectal neoplasms; estrogens

Abbreviations: CI, confidence interval


    INTRODUCTION
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
In the early 1980s, on the basis of gender difference and secular trends in the age-specific incidence and mortality of colon cancer in western countries, McMichael and Potter hypothesized that exposure to exogenous estrogen may protect women against colon cancer (1Go). Since then, numerous epidemiologic studies have examined estrogen exposure in relation to the risk of colorectal cancer (2GoGoGoGoGoGoGoGoGoGoGoGoGoGoGoGoGoGo–20Go. While a majority of epidemiologic studies conducted to date have suggested an inverse association between postmenopausal estrogen use and colon cancer risk (5GoGoGoGoGoGoGo–12Go, 16Go, 18GoGo–20Go), several have failed to confirm such a finding (2GoGo–4Go, 13GoGo–15Go, 17Go). Of the studies that found a protective effect of postmenopausal estrogen use, some showed that a significantly reduced risk was limited to current users (5Go, 18Go, 19Go), and others suggested that the effect was stronger among long-term users (6Go, 9Go, 20Go).

Several investigators have explored some reproductive factors that may reflect endogenous estrogen exposure, such as age at menarche, age at menopause, and parity, in relation to colon cancer (3Go, 4Go, 6GoGo–8Go, 10Go, 12Go, 13Go, 19GoGo–21Go). Results from these studies, however, have been inconsistent. In general, none of these factors was found to be associated with the risk of colon cancer.

A few studies also examined the association between postmenopausal estrogen use and the risk of adenomatous polyps, a precursor of colorectal cancer (18Go, 22GoGo–24Go). Two studies reported that hormone users experienced a significantly decreased risk of colorectal adenoma (23Go, 24Go), and one study found that current hormone users had an approximately 25 percent reduced risk for large adenomas (18Go).

If postmenopausal estrogen use does reduce the risk of colon cancer, women with higher cumulative endogenous and exogenous estrogen exposure should have a lower risk of colon cancer. However, assessment of cumulative estrogen exposure using repeatedly collected blood and urine samples poses methodological and logistic difficulties. It has long been recognized that estrogens play an important role in maintenance of bone health and that insufficient levels of estrogen predispose a woman's skeleton to bone loss and osteoporotic fracture (25Go). Several investigators have proposed that skeletal status may serve as a marker of a woman's lifetime exposure to endogenous and exogenous estrogens (26GoGoGo–29Go). To date, at least three studies (26Go, 30Go, 31Go) have reported that women with greater bone mass or bone mineral density had a much higher risk of breast cancer than those with lower bone mass or bone mineral density, suggesting that skeletal status may serve as a predictor for the risk of estrogen-related cancers in women.

We used data from the Framingham Study to examine the relation of bone mass to the subsequent risk of colon cancer. Bone mass was estimated from assessment of the metacarpal cortical area in middle-aged and elderly women.


    MATERIALS AND METHODS
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Study population
The Framingham Study began in 1948 in Framingham, Massachusetts. The original cohort included 2,873 women aged 28–62 years at the first examination. Subjects have been examined biennially since then. At each examination, participants receive a medical history interview, a physical examination, and a series of laboratory tests.

Bone mass assessment
Between 1967 and 1970, during biennial examinations 10 and 11 of the Framingham Study, a postero-anterior radiograph of the right hand was taken as part of an osteoporosis study. Of the 1,760 women seen at those visits, 1,394 underwent postero-anterior hand radiography. Two readers, who were blinded to the cancer status of study participants, assessed the relative cortical area of the second metacarpal. Hand radiographs were placed flat on a lighted view box, and cortical external width (R) and medullary width (r) were measured with a digital caliper halfway up the second metacarpal. Calipers were calibrated to the nearest 0.01 mm, and measurements were recorded to the nearest 0.1 mm. To assess the intraobserver and interobserver reliability of the measurement of cortical width, we selected 25 hand radiographs and provided them to each of two readers twice for blinded readings. The intraobserver correlation coefficients for external and medullary width were, respectively, 0.99 and 0.94; the corresponding interobserver correlation coefficients were also 0.99 and 0.94. In this study, we used the relative metacarpal cortical area, calculated as 100 x (R2r2)/R2, as an indicator of bone mass.

Identification of colon and rectal cancer cases
Methods to identify cancer cases in the Framingham Study have been described in detail by Kreger et al. (32Go). Briefly, cases were initially identified by self-report at each examination, surveillance of admissions to the only local hospital, and review of all death records. Subjects who missed a regularly scheduled examination were contacted by telephone or mail to solicit information regarding medical events during the time interval since their last examination. For nonrespondents or subjects whose vital status was unknown, we searched the National Death Index to obtain vital status and cause of death. Pertinent medical records (pathology reports, operation notes, and autopsies) were obtained from hospitals and physicians. For each suspected cancer case, we reviewed the Framingham records to confirm the diagnosis and to determine the date of earliest diagnosis and the location of the cancer in the colon. Pathology reports were available for all cases in this analysis. All cases were coded by using International Classification of Diseases for Oncology code 153 for colon cancer and code 154 for rectal cancer (33Go).

Other variables
Information on potential colon cancer risk factors, including age, height, weight, number of years of education, and age at menopause, was obtained from each subject. For 112 women who underwent hysterectomy without bilateral oophorectomy, we used the median age at menopause for the entire cohort (age 50 years) as their age at menopause. At examinations 2 (1951–1954) and 7 (1960–1964), women were asked to quantify their monthly consumption of beer, wine, and mixed drinks of hard liquor. Total alcohol consumption was computed by multiplying the average quantities of alcohol in beer, wine, and mixed drinks by the quantity consumed. Alcohol consumption was estimated by averaging alcohol consumption reported at examinations 2 and 7. Cigarette smoking has been asked about repeatedly. As a baseline variable for smoking, we used the mean number of cigarettes smoked per day from the time of entry into the Framingham Study (1948–1952) to the date prior to hand radiography.

Habitual physical activity was assessed at the fourth examination (1954–1958) by using the Framingham Physical Activity Index (34Go). Subjects were asked how many hours a day they usually spent sleeping and resting and, during work and leisure time, engaging in sedentary (e.g., standing), slight (e.g., walking), moderate (e.g., greater than walking but less than running), and heavy (e.g., running) activities. Aspirin use was assessed at examination 12 around the time of radiography (1971–1972). If this information was not available at examination 12, we substituted data collected at examination 13 (1973–1974). Postmenopausal estrogen use was assessed at each biennial examination after 1960. The total number of years of postmenopausal estrogen use for each woman was summed from the time of hand radiography to the time of colon cancer diagnosis or the time of censoring (the date of the last contact for women lost to follow-up or December 31, 1995, when the study was closed).

Statistical analysis
Since age is an important determinant of colon cancer, and women with lower bone mass, on average, are older than those with higher bone mass, we adjusted for age by using the age-specific relative metacarpal cortical area. Specifically, we stratified all women into 2-year age groups and assigned each woman to one of three tertiles of bone mass according to the distribution of the relative metacarpal cortical area for her age group.

We compared the characteristics of the women according to the age-specific tertiles of bone mass and the presence or absence of colon cancer by using analysis of variance for continuous variables and a chi-square test for categorical variables. Person-years of follow-up for each woman were computed as the amount of time from the date of hand radiography to the date of the first of the following events: colon cancer diagnosis; last contact date for those lost to follow-up; death; or December 31, 1995, when the study was closed. Incidence rates of colon cancer for each age-specific tertile of bone mass were calculated by dividing the number of events by the person-years of follow-up. We plotted Kaplan-Meier survival curves to examine cumulative incidence for each age-adjusted tertile of bone mass (35Go).

We assessed the relation of age-specific tertile of metacarpal bone mass to the risk of colon cancer by using a Cox proportional hazards model. In this multivariate model, we adjusted for education, height, body mass index, average number of cigarettes smoked, average alcohol consumption, level of physical activity, aspirin use, and number of years of estrogen use over the follow-up period. We tested the significance of the trend in the risk of colon cancer by including a single variable for the age-specific tertile of metacarpal bone mass in the multivariate model.

To determine whether the association between bone mass and colon cancer was modified by other risk factors, we examined the association between bone mass tertiles and risk of colon cancer within strata of other risk factors. We tested for modification of the effect by including an interaction term (between tertile of bone mass and a particular risk factor) in the regression model.


    RESULTS
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Of the 1,394 women who underwent hand radiography between 1967 and 1970, excluded from the analysis were 9 women with a history of colon cancer prior to hand radiography and 1 lost to follow-up just after the hand radiographs were taken. During the follow-up period, 44 women developed colon cancer. The median age at the time of diagnosis was 74.2 years (range, age 57.4–89.2 years), and the median follow-up after hand radiography was 23.0 years (range, 0.1–27.5 years).

Table 1 shows the characteristics of the women with colon cancer and those without colon cancer. Although cases were slightly older than noncases at the time of hand radiography, the distribution of other potential confounding factors between the two groups was quite similar.


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TABLE 1. Characteristics of 1,384 women in the Framingham Study according to the presence or absence of colon cancer diagnosed in 1969–1995, Framingham, Massachusetts

 
The characteristics of women in relation to age-specific bone mass tertiles are presented in table 2. Compared with women in the lowest tertile of bone mass, those in the middle and highest tertiles were heavier (p < 0.001), had a later age at menopause (p < 0.001), and received more education (p < 0.001). While women in the highest tertile of bone mass tended to smoke fewer cigarettes and to be more likely long-term (6 years or more) postmenopausal estrogen users, these associations were not statistically significant.


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TABLE 2. Characteristics of women participants in the Framingham Study, according to age-specific relative metacarpal cortical areas, Framingham, Massachusetts, 1967–1995

 
The cumulative incidence of colon cancer was highest among women in the lowest age-adjusted tertile of metacarpal bone mass over the entire follow-up period (figure 1). As shown in table 3, the incidence rates were 2.19 per 1,000 person-years among women in the lowest tertile of bone mass and 1.59 and 1.08 per 1,000 person-years in the middle and highest tertiles of bone mass, respectively. Compared with women in the lowest tertile, the colon cancer rate ratios for women in the middle and highest tertiles of metacarpal bone mass were 0.7 (95 percent confidence interval (CI): 0.3, 1.4) and 0.4 (95 percent CI: 0.2, 0.9), respectively. A test for trend was statistically significant (p = 0.033).



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FIGURE 1. Cumulative incidence of colon cancer among 1,384 Massachusetts women in the Framingham Study, according to age-specific tertile of metacarpal bone mass, 1967–1995

 

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TABLE 3. Relation of age-specific tertile of relative metacarpal cortical area to the risk of colon cancer, Framingham Study, Framingham, Massachusetts,1967–1995

 
Women in the highest age-specific tertile of bone mass had a decreased risk of colon cancer across almost all strata of other risk factors (table 4), except women whose physical activity levels were equal to or above the median of the Framingham Physical Activity Index. None of the interaction terms was statistically significant.


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TABLE 4. Rate ratios for the risk of colon cancer, according to the age-specific tertile of relative metacarpal cortical areas and other risk factors, Framingham Study, Framingham, Massachusetts, 1967–1995

 
Only 14 women developed rectal cancer during the follow-up period. The incidence rates were 0.5, 0.2, and 0.9 per 1,000 person-years for each increased bone mass category, respectively. Compared with women in the lowest tertile of bone mass, the rate ratios for those in the middle and highest tertiles were 0.5 (95 percent CI: 0.1, 2.5) and 1.8 (95 percent CI: 0.6, 6.1), respectively.


    DISCUSSION
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
The results from this population-based cohort study suggest that metacarpal bone mass in middle-aged and elderly women is associated with a reduced risk of colon cancer. Women in the highest tertile of bone mass were half as likely to develop colon cancer compared with those in the lowest tertile.

The relation of estrogen level to bone mass has been recognized for decades (36Go). Estrogen plays an important role in maintaining bone mass in women by suppressing cancellous bone remodeling and balancing osteoblast and osteoclast activity (37Go). Premenopausal women who become hypoestrogenic, either because of anorexia nervosa or secondary to treatment with gonadotropin-releasing hormone agonists, suffer significant bone loss (38Go, 39Go). Low serum or urine estrogen levels are also strongly associated with low bone mineral density in both peri- and postmenopausal women and with fracture in postmenopausal women (40GoGoGoGoGo–45Go). Furthermore, women receiving estrogen replacement therapy, especially long-term users, have significantly higher bone mineral density (46GoGo–48Go). These findings, in conjunction with our own and with other investigators' reports on the association between bone mass or bone mineral density and breast cancer risk (26Go, 30Go, 31Go), suggest that skeletal status may serve as a proxy for cumulative estrogen exposure and that high levels of such exposure protect against the development of colon cancer.

While many studies have reported the beneficial effects of postmenopausal estrogen use on colon cancer and colorectal adenomas, findings on the duration of hormone use in relation to the risk of colon cancer have been less consistent (5Go, 6Go, 9Go, 17GoGoGo–20Go). In our study, compared with nonusers, women who used estrogen 6 years or more after hand radiography may have had a decreased risk of colon cancer as well (rate ratio = 0.6, 95 percent CI: 0.1, 4.2). Fewer studies have examined the relation between postmenopausal estrogen use and the risk of rectal cancer (49Go). In general, the studies of rectal cancer, including ours, were smaller than those of colon cancer, and results were less consistent mainly because of limited study power. To our knowledge, no study has examined the effect of cumulative endogenous as well as exogenous estrogen exposures on the risk of colon cancer.

The biologic mechanisms linking estrogen exposure to the risk of colon cancer are not fully understood; several hypotheses have been proposed to explain such an inverse association. Exogenous estrogens have been shown to decrease concentrations of secondary bile acids (50Go), thus potentially reducing the ability of these bile acids to promote tumors in the colon (1Go). A low concentration of bile acids may also reduce the ability of intestinal microflora to produce diacylglycerol, an activator for a key enzyme in growth stimulation and tumor production (51Go). More recently, several investigators have suggested that exogenous estrogens may protect colonic mucosa from neoplastic transformation by suppressing methylation of the promoter region of the estrogen receptor gene (52Go). This methylation-associated loss of estrogen receptor gene expression is thought to result in deregulated growth of colonic mucosa.

Several characteristics of this study are noteworthy. The data are from a population-based cohort of women followed over a long period of time; all cases of colon cancer were confirmed by pathology reports; and the rate of colon cancer occurrence in the Framingham Study is similar to that in the Surveillance, Epidemiology, and End Results Program (32Go). Thus, we believe that all clinically detected incident cases of colon cancer were ascertained. Information on several potential confounding factors, including physical activity level and aspirin use, was collected, and these factors were adjusted for in the analysis. Both age- and multivariate-adjusted rate ratios were essentially the same, suggesting that except for age, other potential confounding factors did not materially change the relation of bone mass to colon cancer. Nevertheless, information on several risk factors for colon cancer, such as family history of colon cancer, polyps of the colon, inflammatory bowel disease, and dietary factors, was not collected in our study. Thus, the potential residual confounding effects due to these factors should be considered when the current findings are interpreted. While the number of incident colon cancer cases was small, apparent differences in colon cancer risk by tertiles of bone mass were evident throughout the follow-up period.

In our study, women who were in the middle and highest bone mass categories also tended to have more years of education than those in the lowest category. It is quite possible that women who were more highly educated were more likely to seek health care, including flexible sigmoidoscopy or colonoscopy, which resulted in detection and removal of adenomatous polyps early and, consequently, in lowering of their risk of colon cancer. On the other hand, this potential bias, if present, may also increase the possibility of detecting colon cancer among women with more education. Nevertheless, Newcomb and Storer (5Go) demonstrated that an inverse association between hormone use and colon cancer risk still existed after adjusting for sigmoidoscopy use, suggesting that the protective effect of hormone use was not due to increased surveillance. Furthermore, adjustment for education level in our study did not change the magnitude of the observed association between bone mass and colon cancer.

In conclusion, the results of this population-based prospective cohort study suggest that bone mass in middle-aged and elderly women is a predictor for colon cancer risk. The biologic mechanisms linking bone mass to the risk of colon cancer are not fully understood; however, cumulative exposure to estrogen may play a role.


    ACKNOWLEDGMENTS
 
Supported by grants from the National Institutes of Health (N01-HC-38-38, AR 20613, and AR41398) and the Institute on Lifestyle and Health, Boston University School of Medicine.


    NOTES
 
Reprint requests to Dr. Yuqing Zhang, Room A-203, Boston University Medical Center, 80 East Concord Street, Boston, MA 02115 (e-mail: yuqing{at}bu.edu).


    REFERENCES
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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Received for publication December 2, 1999. Accepted for publication April 10, 2000.