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.
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ABSTRACT |
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bone density; cohort studies; colorectal neoplasms; estrogens
Abbreviations: CI, confidence interval
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INTRODUCTION |
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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 (3, 4
, 6
8
, 10
, 12
, 13
, 19
21
). 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 (18, 22
24
). Two studies reported that hormone users experienced a significantly decreased risk of colorectal adenoma (23
, 24
), and one study found that current hormone users had an approximately 25 percent reduced risk for large adenomas (18
).
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 (25). Several investigators have proposed that skeletal status may serve as a marker of a woman's lifetime exposure to endogenous and exogenous estrogens (26
29
). To date, at least three studies (26
, 30
, 31
) 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.
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MATERIALS AND METHODS |
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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 (R2 r2)/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. (32). 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 (33
).
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 (19511954) and 7 (19601964), 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 (19481952) to the date prior to hand radiography.
Habitual physical activity was assessed at the fourth examination (19541958) by using the Framingham Physical Activity Index (34). 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 (19711972). If this information was not available at examination 12, we substituted data collected at examination 13 (19731974). 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 (35).
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.
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RESULTS |
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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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DISCUSSION |
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The relation of estrogen level to bone mass has been recognized for decades (36). Estrogen plays an important role in maintaining bone mass in women by suppressing cancellous bone remodeling and balancing osteoblast and osteoclast activity (37
). Premenopausal women who become hypoestrogenic, either because of anorexia nervosa or secondary to treatment with gonadotropin-releasing hormone agonists, suffer significant bone loss (38
, 39
). 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 (40
45
). Furthermore, women receiving estrogen replacement therapy, especially long-term users, have significantly higher bone mineral density (46
48
). 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 (26
, 30
, 31
), 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 (5, 6
, 9
, 17
20
). 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 (49
). 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 (50), thus potentially reducing the ability of these bile acids to promote tumors in the colon (1
). 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 (51
). 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 (52
). 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 (32). 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 (5) 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.
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ACKNOWLEDGMENTS |
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NOTES |
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REFERENCES |
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