1 University of Wisconsin Comprehensive Cancer Center, Madison, WI.
2 Fred Hutchinson Cancer Research Center, Seattle, WA.
3 Department of Epidemiology, Harvard School of Public Health, Boston, MA.
4 Department of Community Medicine, Norris Cotton Cancer Center, Dartmouth-Hitchcock Medical Center, Lebanon, NH.
5 Department of Nutrition, Harvard School of Public Health, Boston, MA.
6 Channing Laboratory, Department of Medicine, Harvard Medical School, and Brigham and Women's Hospital, Boston, MA.
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ABSTRACT |
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breast neoplasms; case-control studies; endometrial neoplasms; fractures; hormones; postmenopause
Abbreviations: BMI, body mass index; CI, confidence interval; LCL, lower confidence limit; OR, odds ratio
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INTRODUCTION |
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The possibility of common etiologic factors for these conditions has been evaluated in follow-up studies of fractures, focusing on breast cancer (1215
) and endometrial cancer (12
, 13
, 16
). Inverse associations between fracture and cancer were observed in two (12
, 13
) of four breast cancer studies, and a similar pattern was suggested in two (12
, 16
) endometrial cancer studies. Most convincingly, two recent prospective studies reported that higher bone density was associated with two- to threefold increases in postmenopausal breast cancer risk (17
, 18
). In one of these studies, the association between bone mineral density and breast cancer was significantly stronger in women with a family history of breast cancer (19
). In all previous studies of fracture, the small number of cancer cases has limited interpretation of the results. We had the opportunity to evaluate fracture history as a marker of underlying estrogen levels in our concurrent population-based case-control studies of breast and endometrial cancer.
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MATERIALS AND METHODS |
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Of the 6,839 eligible breast cancer cases, physicians refused contact for 158 (2.3 percent), 293 (4.3 percent) were deceased, 83 (1.2 percent) could not be located, and 620 (9.1 percent) refused to participate. Thus, data on 5,685 women with breast cancer were available for general analysis, for an overall response rate of 83.1 percent. Of the 856 eligible endometrial cancer cases, physicians denied contact for 6 (0.7 percent), 53 (6.2 percent) were deceased, 50 (5.8 percent) could not be located, and 2 (0.2 percent) refused to participate. Therefore, data on 745 women with endometrial cancer were available, for an overall response rate of 87.0 percent. Ninety-eight percent of the breast and endometrial cancer cases had histologically confirmed invasive carcinoma. Interviewers of 26 of the breast cancer cases and none of the endometrial cancer cases noted that the data were inconsistent or were unreliable according to standard protocol; fracture information was missing for 100 breast cancer cases and 6 endometrial cancer cases. These women were excluded; thus, information on 5,559 breast cancer cases and 739 endometrial cancer cases was retained for analysis.
Identification of controls
In each state, community controls were randomly selected by using two sampling frames: controls less than age 65 years were chosen from a list of licensed drivers; controls for subjects aged 6579 years were selected from a roster of Medicare beneficiaries compiled by the Health Care Financing Administration. Computer files for potential controls were obtained annually. Controls were selected randomly to yield an age distribution similar to that of the cases, and they met the eligibility criteria of having a listed telephone number and a driver's license (if they were aged <65 years) or a Medicare card (if aged 65 years). Controls were eligible for the breast cancer study if they reported no previous diagnosis of breast cancer and, similarly, for the endometrial cancer study if they reported no previous diagnosis of uterine cancer.
Of the 7,655 potential controls for the breast cancer analysis, 183 (2.4 percent) had died, 124 (1.6 percent) could not be located, and 1,397 (18.2 percent) refused to participate; 5,951 (77.7 percent) completed the study interview. For the endometrial cancer analysis, 88 women (2 percent) had died, 35 (0.8 percent) could not be located, and 521 (11.8 percent) refused to participate, for a response rate of 85.2 percent. After the interview, controls for the endometrial cancer analysis were excluded if they reported a history of hysterectomy (n = 1,304). The interviewers noted that, for 23 controls for the breast cancer analysis and 6 controls for the endometrial cancer analysis, the data were inconsistent or were unreliable; fracture information on 99 controls for the breast cancer analysis and 74 controls for the endometrial cancer analysis was missing. These women were also excluded, leaving 5,829 controls for the breast cancer analysis and 2,334 controls for the endometrial cancer analysis.
Data collection
A letter briefly introducing the study was mailed to cases and controls before they were contacted by telephone. To improve recall of postmenopausal hormone use, a pictorial display of commonly used preparations (20) was included with the letter. The 45-minute telephone interview elicited information on known or suspected risk factors for breast and endometrial cancer, including fracture history (as a surrogate for bone density). Information was collected on exposures occurring only prior to diagnosis for cases; for controls, a reference date was assigned based on the frequency of the dates of diagnosis of the cases (on average, this date was 1 year prior to interview and varied slightly between study sites). Women were asked whether they had a history of any broken bones ("Did a doctor ever tell you that you had a fracture?" If yes, "What was your age at the most recent fracture?"). The type of fracture was not assessed. The interview also covered reproductive experiences, complete history of exogenous hormone use, physical activity, selected dietary elements, height at age 20 years and height at the reference date, weight at the reference date, medical history, and demographic factors. Calcium intake from milk and selected diet items; alcohol intake from beer, wine, and liquor; and recent recreational, vigorous physical activity, such as basketball and lap swimming, were ascertained. Information about a woman's personal and family history of breast cancer was obtained at the end of the interview to maintain blinding. For 87 percent of the breast cancer cases and 82 percent of the endometrial cancer cases, and for 96 percent of the controls, the interviewers remained unaware of the case-control status of the subjects until the end of the interview.
Reliability substudy
After an average of 3.5 months (range, 26 months), we reinterviewed a sequential sample of 186 cases (response rate, 71 percent) and 190 controls (response rate, 71 percent) from Massachusetts and Wisconsin to assess reliability of the questionnaire. Cohen's kappa (and the 95 percent lower confidence limit (LCL)) (21) for reporting a recent history (within 5 years) of bone fracture was 0.63 (LCL: 0.44) for cases and 0.84 (LCL: 0.73) for controls. The intraclass correlation coefficient for age at most recent bone fracture was 0.98 (LCL: 0.96) for cases and 0.93 (LCL: 0.89) for controls.
Analyses
Age was defined as the age at diagnosis or at the reference date. Menopausal status was defined as "postmenopausal" if the subject reported a natural menopause or a bilateral oophorectomy prior to the diagnosis or to the reference date. An intact uterus as of the reference date was a requirement for all controls in the endometrial cancer analysis. Controls in the breast cancer analysis who reported hysterectomy alone were classified as postmenopausal if their age at surgery was more than or equal to the 90th percentile of age at natural menopause for the control group (age 55 years for both smokers and nonsmokers). Menopausal status was considered unknown for breast cancer controls who had had a hysterectomy without bilateral oophorectomy if they were younger than age 55 years.
Postmenopausal hormone therapy was defined as use of oral, injectable, or transdermal noncontraceptive hormones, including estrogens and/or progestins, for 6 cumulative months or more. Body mass index (BMI) was defined as weight (in kilograms) divided by height (in meters) squared at age 20 years. Quartiles of BMI were based on the distri-bution of values in the cancer-specific control series. Women were defined as having a positive history of breast or endometrial cancer if they reported a diagnosis for their mother, sister(s), or daughter(s).
Odds ratios and 95 percent confidence intervals obtained from logistic regression models were used to evaluate relative risks. Conditional models stratified by age and US state (age only for the endometrial cancer analysis) were used to accommodate the slightly different age distributions of the cases and controls in each state studied. Age at first full-term pregnancy (nulliparous; aged <20 years, 2024 years, 2529 years, 30 years), age (<45, 4549, 5054,
55 years) at and type (natural or surgical) of menopause, family history of breast cancer (present, absent), BMI (quartiles), and education (less than high school, high school graduate, some college, college graduate or higher) were included in all models as potential confounders for the breast cancer analysis. The endometrial cancer analyses included parity (continuous), smoking status (never, former, current), BMI (quartiles), and education in all models. In the breast and endometrial cancer analyses that included all women, odds ratios were also adjusted for use of postmenopausal hormone therapy (never, ever). Subjects with unknown values for any variables were incorporated as a separate category (as was true for family history of breast cancer, BMI, age at menopause, and hormone use). Effect modification was evaluated by including interaction terms in the model and computing likelihood ratio tests (22
); continuous variables were used in the interaction tests when appropriate.
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RESULTS |
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The age-adjusted prevalence of a history of fracture within the past 5 years was 6.3 percent for breast cancer cases and 8.3 percent for controls. Compared with women without a fracture, women reporting a fracture in the past 5 years had an adjusted odds ratio of breast cancer of 0.80 (95 percent confidence interval (CI): 0.68, 0.94). Fractures that occurred more than 5 years previously were not associated with risk. The odds ratio for breast cancer in women who reported a history of any fracture was 0.96 (95 percent CI: 0.88, 1.05) compared with women who reported no fractures (table 1). Limiting the analysis to women who reported never using postmenopausal hormone therapy did not substantially affect the risk estimates; among these women, recent fracture (within the past 5 years) was associated with an odds ratio of 0.79 (95 percent CI: 0.65, 0.95) compared with women without a fracture history. The association was slightly attenuated for women who had ever used postmenopausal hormone therapy (odds ratio (OR) = 0.82, 95 percent CI: 0.59, 1.13).
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Endometrial cancer
Compared with controls, women who had endometrial cancer were more likely to be nulliparous, to have a high BMI, and to be nonsmokers (24). The mean age of cases and controls was 63 years.
The age-adjusted frequency of a recent fracture was 4.7 percent for endometrial cancer cases and 7.4 percent for controls. For women who had had a fracture within the 5-year period before the reference date, the odds ratio was 0.59 (95 percent CI: 0.40, 0.89) compared with women without a fracture history (table 1). Compared with women who never reported a fracture, a positive history of any bone fracture was not associated with risk of endometrial cancer (OR = 0.95, 95 percent CI: 0.77, 1.16). The association was similar for women who never used postmenopausal hormones (OR = 0.55, 95 percent CI: 0.33, 0.92 for a recent fracture). The association was attenuated for women who had ever used postmenopausal hormones (OR = 0.70, 95 percent CI: 0.32, 1.52).
The relation between endometrial cancer and recent bone fracture was not significantly modified by age at diagnosis, smoking status, recent vigorous physical activity, or BMI (table 3). However, there was a suggestion that, for women who consumed relatively large quantities of calcium-rich foods, fractures were associated with slightly lower risks of endometrial cancer than for women who consumed less calcium.
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DISCUSSION |
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To our knowledge, this study is the largest to date to report an inverse association between recent fracture and breast and endometrial cancer risk. In previous studies, all prospective in design, the risk reduction ranged from 15 percent to 45 percent for breast cancer (12, 13
) and from 13 percent to 40 percent for endometrial cancer (12
, 16
). Two other studies based on cohorts of cancer patients failed to find any association (14
, 15
). However, since these studies ascertained fractures subsequent to breast cancer diagnosis, the relevant hormonal milieu may have been perturbed by breast cancer and its treatments. Consistent with our results, recent cohort studies have shown that women with low bone density have a substantially decreased risk of breast cancer compared with women with high bone density (17
, 18
). In these studies, the magnitude of the association between bone density and breast cancer risk was considerably greater than in our evaluation. In our study, many of the women with low bone density may not have experienced fractures. This difference likely reflects some misclassification of our marker of bone density and a more precise measure of bone mass. However, dissimilarity in the study populations may also account for differences in effect, since the Study of Osteoporotic Fractures was limited to older women at high risk of fracture (17
), while our population-based sample had no such constraints. Activity reduces the incidence of osteoporosis (25
), so that a high-risk sedentary group represents those women for whom the estrogen effect is most likely to be manifest. In our study, there was no association between fracture and breast cancer risk for the more physically active women.
This study was not specifically designed to evaluate the relation between osteoporotic fracture history and cancer risk; therefore, our data are somewhat limited. First, all reported fractures, including both traumatic and osteoporotic, were necessarily considered in our evaluation. We reduced misclassification by focusing on recent fractures in this postmenopausal population. In older adults, the great majority of fractures are osteoporotic (26). However, many factors other than bone density can influence fractures, and fractures in certain sites, for example, the ankle, elbow, fingers, and face, tend not to be associated with bone mass (25
29
). Inclusion of fractures unlikely to be osteoporotic (e.g., due to trauma) would lead to an underestimate of the true association. Similarly, we cannot rule out the possibility that some reported fractures in cancer cases were a result of metastatic disease, although the proportion of women initially diagnosed with advanced-stage cancer was low: 2.3 percent of breast cancer cases and 2.3 percent of endometrial cancer cases. Such misclassification, if any, might also lead to an underestimate of the true risk. Finally, women in our study were required to have a telephone number available from a publicly available source. Women with a history of disabling fractures may have been institutionalized (30
) and therefore not included in our study. If loss of these women was more common among controls, it may have resulted in an underestimation of the true relative risk. Thus, these limitations all may have attenuated the relation between fracture and cancer risk.
It is possible that the observed association reflects other characteristics, including other hormonal factors, that also may increase the risk of breast cancer, endometrial cancer, or both. We found that the age- and multivariable-adjusted risk estimates were similar, suggesting that confounding was unlikely. Adjustment for other factors associated with fracture risk, including recent physical activity and calcium intake, also did not materially change the risk estimates for either breast or endometrial cancer. Osteoporosis is an indication for postmenopausal hormone use, and failure to adjust for such treatment might be expected to introduce bias (31). After adjustment, we observed only modest attenuation of the increase associated with recent fractures and an inverse relation in hormone users as well as never users. However, the possibility remains that factors other than estrogen could explain this association, such as insulin-like growth factors that stimulate cell division in the bone (32
, 33
) and are potent mitogens in breast tissue culture (34
). Higher blood levels of insulin-like growth factor have been associated with breast cancer risk (35
).
Additional evidence from several sources supports our assertion that fractures reflect estrogen status in women. Estrogen reduction at menopause is the major cause of age-related bone loss (25, 36
, 37
). Bone loss that occurs before menopause also appears related to low estrogen levels (38
), such as those found in women who are amenorrheic (39
). Among postmenopausal women, the prevalence of low bone mineral density is higher for those with oophorectomy or early menopause (40
, 41
) and with low body mass (25
, 42
, 43
) as well as for smokers (42
)all conditions associated with low endogenous estrogens. Most definitively, there is a strong, positive correlation between serum or urinary estrogen levels and bone mineral density in pre- and postmenopausal women (44
46
).
Lower estrogen levels are also associated with lower breast and endometrial cancer risk. Breast cancer incidence continues to increase with age, but at menopause there is a distinct slowing of the rate of increase (47). A similar change in endometrial cancer rates occurs at menopause (48
). Characteristics that reduce endogenous estrogen levels, such as low body mass (45
, 49
, 50
), are associated with a decreased risk of postmenopausal breast (51
, 52
) and endometrial (9
) cancer. Most directly, women with low estradiol (or estrone) levels tend to have a lower risk for breast cancer than women with higher levels (50
). Prospective data are lacking on the relation between circulating estrogens and endometrial cancer, but, in postmenopausal women, low estrogen levels also appear to be associated with a reduced incidence of endometrial cancer (53
, 54
).
Exogenous estrogen reduces bone mineral loss and lowers the risk of vertebral and extremity fractures (4, 6
, 7
, 55
). However, it also increases both breast (8
) and endometrial (9
) cancer risk through the direct stimulation of these tissues. The effect of recent unopposed estrogen use on cancer risk is considerably less strong in the breast (relative risk
1.3) than in the endometrium (relative risk
6.0), supporting the view that endometrial cancer is more estrogen dependent (although other hormones or aspects of susceptibility are also likely important). This view is consistent with our finding that fractures are associated with a greater reduction in the risk of endometrial cancer than in breast cancer.
This study supports an association between fracture and both breast and endometrial cancer. The etiologies of these two tumors share many similarities; however, the relative differences in the magnitude of their association with bone fracture and potential modification by other factors suggest that the relevant characteristics of estrogen exposure may differ in the breast and endometrium.
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ACKNOWLEDGMENTS |
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The authors are indebted to the tumor registrars, study managers, interviewers, and programmers who worked on this study. They are also grateful to Drs. Barry E. Storer, Patrick L. Remington, and E. Robert Greenberg for their advice and consultation at various stages of this project and to Mary Pankratz for technical support.
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NOTES |
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Reprint requests to Dr. Polly A. Newcomb, University of Wisconsin Comprehensive Cancer Center, Room 4760 Medical Science Center, 1300 University Avenue, Madison, WI 53706 (e-mail: pnewcomb{at}fhcrc.org).
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REFERENCES |
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