Affiliations of authors: J. M. Zmuda, J. A. Cauley, L. H. Kuller, Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, PA; D. C. Bauer, S. R. Cummings (Department of Epidemiology and Biostatistics), B.-M. Ljung (Department of Pathology), University of California, San Francisco.
Correspondence to: Joseph M. Zmuda, Ph.D., Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, 130 DeSoto St., Pittsburgh, PA 15261 (e-mail: epidjmz{at}pitt.edu).
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ABSTRACT |
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INTRODUCTION |
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To further evaluate the relationship between bone mass and breast cancer risk, we expanded our initial analysis of the SOF cohort to include additional women affected with breast cancer during a 6.5-year follow-up period. In addition, we collected information on the stage of breast cancer at the time of diagnosis for all of the women to analyze the association between BMD and the risk of early- and advanced-stage breast cancers.
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SUBJECTS AND METHODS |
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All of the women in our study were participants in the SOF, a prospective study of 9704 white women at least 65 years of age. Women were recruited for the SOF during the period from 1986 through 1988 from population-based lists (e.g., voter registration, health maintenance organizations, and motor vehicle tapes) at clinical centers located at the University of Maryland (Baltimore), the University of Minnesota (Minneapolis), the University of Pittsburgh (PA), and The Kaiser Permanente Center for Health Research (Portland, OR) (17). Women were excluded from the SOF if they reported a bilateral hip replacement or were unable to walk without assistance. African-American women were also excluded from the SOF because of their low inherent risk of hip fracture. The institutional review boards at each institution approved the study. All women provided written informed consent at study entry and at each clinical examination.
Breast Cancer Ascertainment
One year after completing the baseline examination required for entry into the SOF, each woman was asked to complete a follow-up questionnaire that included information about her personal and family history of breast cancer. Incident cases of breast cancer were identified by self-report on follow-up questionnaires that were completed by each woman every 2 years during subsequent clinic examinations and by a review of death records obtained from state health departments. On each questionnaire, we asked if breast cancer had been diagnosed and, if so, the date of diagnosis. Women who missed an examination or who moved out of state were contacted by mail or telephone to obtain information about medical events, including a diagnosis of breast cancer, since their last examination or contact date. All women who reported that they had been diagnosed with breast cancer (or the next-of-kin, as listed on the study questionnaires, for decedents) were asked to provide permission for us to obtain and review relevant hospital records and histopathology reports to confirm their self-reported diagnoses. Histopathology reports were available for all women with breast cancer who were identified in this analysis. Breast cancers were staged according to the American Joint Committee on Cancer methodology by use of the standard tumorlymph nodemetastasis (TNM) staging criteria (18).
Women who reported a history of breast cancer before the first annual questionnaire (defined as year 1) (n = 513) were considered to be prevalent case subjects and were excluded from further analysis. We also excluded 101 women who died before year 1, 13 women who provided no breast cancer information at year 1, 28 women who had no medical records for breast cancer at the time of this analysis, and 144 women whose BMD measurements were missing. Thus, information on breast cancer was collected on 8905 women for this analysis.
Measurement of BMD
At study entry, BMD was measured at the proximal radius (forearm), distal radius (wrist), and calcaneus (heel) of each participant by single-photon absorptiometry with the use of OsteoAnalyzers (Siemens-Osteon, Wahiawa, HI). Measurements of BMD were made at more than one skeletal site because the composition and metabolism of bone are not uniform throughout the skeleton. The measurement methods and densitometry quality-control procedures have been described in detail previously (19). The mean coefficients of variation for the forearm, wrist, and heel BMD measurements were 1.3%, 1.5%, and 2.0%, respectively (17).
Covariate Information
Each woman was weighed at study entry. A modified body mass index (BMI), i.e., weight in kilograms divided by height in meters squared, was calculated with the use of each woman's self-reported height at age 25 years. This value for height was used because it was thought to be a more accurate reflection of each woman's adult height than her current height, since women with low bone mass often experience a reduction in height because of vertebral fractures. Reproductive history was obtained by questionnaire and personal interview and included information on ages at menarche and menopause, parity, type of menopause, history of benign breast disease, and family history (maternal or sister) of breast cancer. Participants were asked about current and past estrogen use (by pill, patch, or injection) since age 40 years. We confirmed self-reported use of estrogen by asking participants to bring their current medications to clinic visits. We also collected information on current cigarette and alcohol use. Alcohol consumption was measured in drinks per week and was adjusted for atypical, especially heavy, drinking in the 30 days before the clinic visit. Women were asked whether they walked for exercise. At year 3, participants were asked whether they had received a mammogram since entry in the study.
Statistical Analysis
Descriptive characteristics of women with and without breast cancer were compared by Student's t tests for continuous variables or chi-squared tests for categorical variables. We calculated the incidence rates for each exposure category by dividing the number of new cases of breast cancer by the number of person-years of follow-up and then multiplying by 1000. The duration of follow-up for each participant was defined as the time from completion of the first annual questionnaire during the period from 1987 through 1990 to the date of breast cancer diagnosis, the date of death, the date of the last follow-up contact, or September 28, 1998, the prespecified end of the study period for the present analysis, whichever occurred first. We used Cox proportional hazards models to assess the relationship between BMD and breast cancer risk, adjusting for age, modified BMI, and other potential confounding factors. We also adjusted for educational level, walking for exercise, alcohol consumption, smoking, parity, ages at menarche and menopause, use of estrogen replacement therapy, family history of breast cancer, and history of benign breast disease. BMD was modeled as a continuous variable to estimate the relative risk (RR) of breast cancer per 1 standard deviation (SD) increase in BMD. The values for BMD measured at each skeletal site were also divided into quartiles based on the distribution of those values in the entire cohort, and the RR of breast cancer was estimated for each quartile of BMD with the use of the lowest BMD quartile as the referent group. Separate models were constructed for BMD measurements obtained at each of the three skeletal sites (distal radius, proximal radius, and calcaneus). All statistical tests were two-sided.
Because BMD measurements at the three skeletal sites were correlated only modestly with each other (range, r = .64 to r = .76), we also determined the risk of breast cancer among women with BMD in the highest quartile at one, two, or three skeletal sites as compared with that among women with BMD in the lowest quartile at all three sites. To determine if risks differed by the stage of breast cancer at the time of diagnosis, we assigned each woman with breast cancer to one of two categories: 1) those with early-stage disease, representing in situ or TNM stage I tumors, and 2) those with advanced-stage disease, representing TNM stage II, III, or IV tumors. Two women with missing information on axillary lymph node status were included in the advanced-stage category based on the size of their tumors (T2).
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RESULTS |
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Traditional risk factors for breast cancer, including ages at menarche and menopause as well as nulliparity, were similar for women who did and did not develop breast cancer (Table 1). Walking habits, use of alcohol and tobacco, and current and past use of estrogen replacement therapy also did not differ between women with and without breast cancer. Women diagnosed with breast cancer were slightly younger, weighed more, and were taller at age 25 years than women without breast cancer. A history of breast cancer in first-degree relatives was more common among women diagnosed with breast cancer, but this association was statistically significant only for women who had earlier stage cancers at diagnosis. A history of benign breast disease was also reported more frequently by women with breast cancer than by women without breast cancer.
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DISCUSSION |
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A gradation in risk associated with high BMD by stage of breast cancer at diagnosis suggests that biologic factors associated with high BMD may affect the growth rate of tumors and their progression to clinically advanced disease. However, we could not perform a more detailed examination of BMD and the aggressiveness of breast cancer because additional information on the biologic characteristics of tumors, such as histologic grading, was not available and too few women had distant metastases or fatal breast cancer. Nevertheless, it will be important in future studies to determine if women with high BMD are likely to develop a more aggressive form of breast cancer, as defined by high histologic grading, presence of distant metastases at diagnosis, and mortality.
Our results are consistent with the those of the Framingham Study (16), which found that, among 1373 middle-aged and elderly women, those with the highest metacarpal bone mass had a 3.5-fold (95% CI = 1.8 to 6.8) greater risk of breast cancer than those with the lowest metacarpal bone mass. Our results are also consistent with reports that link fractures with the risk of breast cancer (21,22). For example, the incidence of breast cancer was 46% lower (95% CI = 3% to 73%) than expected among women who had a distal forearm fracture (22) and 16% lower (95% CI = 5% to 26%) among women who experienced a hip fracture (21). These observations suggest a link between osteoporosis and breast cancer, two of the most common conditions affecting an older woman's health.
Our findings suggest that BMD is one of the most powerful predictors of breast cancer, especially advanced breast cancer, among elderly women (23). The gradient of increased breast cancer risk associated with BMD is similar to the gradient of fracture risk associated with BMD (24). Many women routinely undergo clinical assessments of BMD to determine their risk of fracture. This raises the possibility that BMD measurements taken at one or more skeletal sites could be used, perhaps in combination with other risk factors, to identify women at high risk for breast cancer who might benefit from preventive therapies, such as treatment with selective estrogen receptor modulators (25,26). Moreover, recent decision and cost-effectiveness analyses (27) suggest that continuing screening mammography in women older than 69 years results in relatively small gains in life expectancy, is moderately cost-effective in women with high BMD, and is less cost-effective for women with low BMD. Thus, BMD measurements might also assist with decision-making about continuing screening mammography in elderly women (27).
It is unlikely that estrogen use has confounded the association between BMD and breast cancer risk. We found similar frequencies of current and past estrogen use among women who did and did not develop breast cancer, and adjusting for estrogen use had little effect on the association between BMD and breast cancer risk. In addition, we found a similar association between BMD and breast cancer risk after excluding current estrogen users (data not shown). Likewise, the magnitude of the association between metacarpal bone mass and breast cancer risk in the Framingham study (16) was similar among women who did and did not use estrogen.
An association between BMD and breast cancer risk is also unlikely to be confounded by body size. Obesity, weight gain, and fat distribution are major determinants of bone mass (28,29) and potential risk factors for breast cancer among postmenopausal women (30). In our study, women who developed breast cancer weighed more and had higher BMIs than did women who did not develop breast cancer. However, adjusting for BMI had no appreciable effect on the association between BMD and breast cancer risk. Height is also strongly and positively related to bone mass (31) and, in several cohort studies (30,3239), it is associated with breast cancer risk. In our study, although women who developed breast cancer were statistically significantly taller than women without breast cancer, the absolute difference in height between these groups was small and unlikely to explain the strong association between BMD and breast cancer risk.
Another possible confounder is differential use of mammography according to BMD. Women with low BMD were less likely to have had a mammogram during the first 3 years of our study. For instance, 74% of the women in the lowest quartile of proximal radius BMD had had a mammogram, compared with 82% of the women in the highest quartile. However, we found a similar association between BMD and breast cancer risk after excluding women who did not have a mammogram during the first 3 years of the study (data not shown). Moreover, increased use of screening mammography among women with high BMD would be expected to increase the detection rate of otherwise undetectable in situ tumors, and we found a stronger association between BMD and the risk of later stage disease. Thus, detection bias is an unlikely explanation for the association between BMD and breast cancer risk.
Endogenous levels of hormones, growth factors, or cytokines may provide a link between BMD and breast cancer risk. Prospective studies (310) have demonstrated that higher levels of serum estrogen and testosterone are associated with an increased risk of breast cancer among older women. We (40) have shown previously, however, that the association between BMD and breast cancer risk is not dependent on levels of bioavailable estrogen or free testosterone. Serum levels of insulin are positively associated with bone mass (41), and exogenous insulin stimulates mammary cell proliferation in vitro (42). Insulin-like growth factors are also important determinants of bone mass (43), and their levels have been associated with increased breast cancer risk in premenopausal women (44). Increased levels of transforming growth factor- (TGF-
) have been reported among osteoporotic women (45), and TGF-
may suppress the growth of normal mammary epithelial and breast carcinoma cells in vitro (46). Finally, increased production of proinflammatory cytokines has been noted among osteoporotic women (47,48). In vitro data suggest that proinflammatory cytokines may have growth-inhibitory effects on breast cancer cells (49,50). The relationship between bone mass and breast cancer risk, therefore, may involve a complex interplay of hormones, growth factors, and cytokines.
This study has several potential limitations. First, because women enrolled in the SOF were white volunteers who resided in one of four specific communities and were in generally good health, our cohort may not be representative of older women in the United States. However, the incidence rate of breast cancer in the SOF cohort was similar to that reported in the Surveillance, Epidemiology, and End Results (SEER) Program1 for white women aged 65 years and older (15). Nevertheless, the observation that BMD is a strong predictor of breast cancer in older white women should be confirmed among younger women and women of other ethnicities. Second, some established risk factors for breast cancer, such as age at menarche, were not associated with breast cancer risk in our study participants. Recall of such characteristics might be more difficult for older women, thus diluting the strength of their association with breast cancer in the elderly women in our study. Third, relatively few women in our study had advanced breast cancer at the time of diagnosis, which resulted in wide CIs in analyses stratified by stage of disease. Thus, our finding that women with low BMD have a very low risk of more advanced breast cancer requires further study and validation in a larger sample.
In summary, these results suggest that bone mass is a powerful predictor of breast cancer, especially more advanced cancer, among older women. Identifying the factors linking osteoporosis and breast cancer could have important implications by suggesting new directions for studying the etiology, prevention, and treatment of both conditions.
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APPENDIX |
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University of California, San Francisco (Coordinating Center): S. R. Cummings (principal investigator), M. C. Nevitt (co-investigator), D. C. Bauer (co-investigator), K. Stone (project director), D. M. Black (study statistician), H. K. Genant (director, central radiology laboratory), P. Mannen (research associate), T. Blackwell, W. S. Browner, M. Dockrell, T. Duong, C. Fox, S. Harvey, M. Jaime-Chavez, L. Y. Lui, G. Milani, L. Nusgarten, L. Palermo, E. Williams, D. Tanaka, and C. Yeung.
University of Maryland, Baltimore: M. Hochberg (principal investigator), J. C. Lewis (project director), D. Wright (clinic coordinator), R. Nichols, C. Boehm, L. Finazzo, B. Hohman, T. Page, S. Trusty, and C. Williams.
University of Minnesota, Minneapolis: K. Ensrud (principal investigator), K. Margolis (co-investigator), P. Schreiner (co-investigator), K. Worzala (co-investigator), M. Oberdorfer (project director), E. Mitson (clinic coordinator), C. Bird, D. Blanks, F. Imker-Witte, K. Jacobson, K. Knauth, N. Nelson, E. Penland-Miller, and G. Saecker.
University of Pittsburgh, PA: J. A. Cauley (principal investigator), L. H. Kuller (co-principal investigator), M. Vogt (co-investigator), L. Harper (project director), L. Buck (clinic coordinator), C. Bashada, D. Cusick, G. Engleka, A. Flaugh, A. Githens, M. Gorecki, K. McCune, D. Medve, M. Nasim, C. Newman, S. Rudovsky, and N. Watson.
The Kaiser Permanente Center for Health Research, Portland, OR: T. Hillier (principal investigator), E. Harris (co-principal investigator), E. Orwoll (co-investigator), H. Nelson (co-investigator), M. Aiken (biostatistician), M. Erwin (project administrator), M. Rix (clinic coordinator), J. Wallace, K. Snider, K. Canova, K. Pedula, and J. Rizzo.
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NOTES |
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See "Appendix" section for the names and affiliations of the investigators in the Study of Osteoporotic Fractures Research Group.
Supported in part by Public Health Service research grants AR35582, AR35583, AR35584, and 1P60AR44811 (National Institute of Arthritis and Musculoskeletal and Skin Diseases) and AG05407 and AG05394 (National Institute on Aging), National Institutes of Health, Department of Health and Human Services; and by grant DAMD17-96-6114 from the U.S. Army Medical Research and Material Command.
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Manuscript received September 7, 2000; revised March 20, 2001; accepted April 10, 2001.
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