Bone Mass and the Risk of Breast Cancer among Postmenopausal Women
Yuqing Zhang, D.Sc., M.B., Douglas P. Kiel, M.D., M.P.H., Bernard E. Kreger, M.D., M.P.H., L. Adrienne Cupples, Ph.D., R. Curtis Ellison, M.D., Joanne F. Dorgan, Ph.D., M.P.H., Arthur Schatzkin, M.D., Dr.Ph., Daniel Levy, M.D., and David T. Felson, M.D., M.P.H.
Background Recent studies have shown a direct relation betweenserum estrogen levels assessed at a single point in time andthe risk of breast cancer, but no evidence links estrogen levelsassessed repeatedly over an extended interval to the risk ofbreast cancer. Bone mass has been proposed as a marker of cumulativeexposure to estrogen in women. We therefore studied the associationbetween bone mass and the incidence of breast cancer.
Methods Between 1967 and 1970, 1373 women who were 47 to 80years old and had no history of breast cancer underwent posteroanteriorhand radiography in the Framingham Study. We used radiogrametryto measure the cortical width of each woman's second metacarpal.Participants were followed until the end of 1993. All incidentcases of breast cancer were confirmed by pathological reports.We used a Cox proportional-hazards model to examine the relationof metacarpal bone mass to the risk of postmenopausal breastcancer.
Results Postmenopausal breast cancer developed in 91 subjects.Incidence rates per 1000 person-years increased from 2.0 amongthe women in the lowest age-specific quartile of metacarpalbone mass to 2.6, 2.7, and 7.0 among the women in the second,third, and highest quartiles, respectively. After adjustmentsfor age and other potential confounding factors, the rate ratiosfor the risk of breast cancer were 1.0, 1.3, 1.3, and 3.5 fromthe lowest quartile to the highest (P for trend, <0.001).
Conclusions Women in the highest quartile of bone mass are athigher risk for postmenopausal breast cancer than those in thelowest quartile. The mechanisms underlying this relation arenot understood, but cumulative exposure to estrogen may playa part.
High levels of estrogen are considered to be a risk factor forbreast cancer,1,2,3 but it has been difficult to assess thisassociation. Measurement of estrogen levels in blood or urineposes many methodologic and logistic problems, including fluctuationsin estrogen levels during the menstrual cycle,4,5,6 the highcosts of storing specimens for long periods, and variationsin assay methods over time and among studies.7 In addition,it is unclear whether a single measurement of serum or urinaryestrogen indicates a woman's cumulative exposure to estrogen.
Assessment of the effects of exogenous estrogens, such as postmenopausalestrogen replacement, is also complex.3 Many women take replacementestrogens for only a few years, making it difficult to studylong-term exposure to estrogen. Furthermore, many factors associatedwith estrogen therapy are also related to breast cancer,8,9thus requiring careful adjustment for potential confoundingeffects.
Since estrogens are important determinants of bone mineral density,several investigators have proposed that bone mineral densitymay serve as a marker of cumulative estrogen exposure in women.10,11,12,13,14Two studies12,13 have reported that women with fractures hada low risk of breast cancer. However, many factors other thanbone density can influence the risk of fracture, and not allthe women with fractures necessarily had low estrogen levels.Cauley et al. recently reported that during four years of follow-up,the risk of breast cancer was two to two and a half times higheramong women with bone mineral density above the lowest quartilethan among women with bone mineral density in the lowest quartile.14
We used data from the Framingham Study to examine the relationof metacarpal bone mass to the subsequent risk of postmenopausalbreast cancer.
Methods
The Framingham Study began in 1948 in Framingham, Massachusetts.The original cohort included 2873 women who were 28 to 62 yearsold at the first examination. The subjects have been examinedapproximately biennially since then. At each examination, amedical history is taken, and a physical examination and a seriesof laboratory tests are performed.
Assessment of Bone Mass
Between 1967 and 1970, at the time of biennial examination 10or 11, a posteroanterior radiograph of the right hand was takenas part of a study of osteoporosis. Of the 1760 women seen atthose visits, 1394 underwent posteroanterior hand radiography.We used radiogrametry to measure the bone mass of the secondmetacarpal.15 We chose the second metacarpal because it is oneof the largest bones of the hand, has a more constant shapethan the other metacarpals,16 and is approximately circularat the midshaft, with the medullary cavity nearly centered inthe tubular bone cylinder.16,17
Two readers, who were unaware of the status of the study participantswith respect to breast cancer, assessed bone mass accordingto a standard protocol. Hand radiographs were placed flat ona lighted viewing box, and measurements of cortical externalwidth (R) and medullary width (r) were made halfway up the secondmetacarpal with a digital caliper. Calipers were calibratedto the nearest 0.01 mm, and measurements were recorded to thenearest 0.1 mm. To assess intraobserver and interobserver reliabilityin the measurement of cortical width, we gave 25 hand radiographsto each of the two readers twice for blinded readings. The intraobservercorrelation coefficients for external and medullary width were0.99 and 0.94, respectively; the corresponding interobservercorrelation coefficients were identical. We used the relativemetacarpal cortical area, calculated as 100 x (R2 - r2) ÷R2, as an indicator of bone mass.
Identification of Breast-Cancer Cases
Methods used to identify cases of breast cancer in the FraminghamStudy cohort have been described in detail by Kreger et al.18Briefly, cases were identified by self-report at each biennialexamination, by surveillance of admissions to the only localhospital, and by a review of all death records obtained fromstate health departments. Cohort members who missed a biennialexamination were contacted by telephone or mail to obtain informationabout medical events during the two years since their last examination.In addition, for the nonrespondents and the subjects whose vitalstatus was unknown, we searched the National Death Index toidentify those who had died and to determine the cause of death.The entire Framingham Study file for each suspected case ofcancer was then reviewed to determine the date of the diagnosis,the location of the tumor in the breast, and the histopathologicaldetails. Pathology reports were available for all cases identifiedin this analysis. All cases of breast cancer were coded accordingto the International Classification of Diseases for Oncology19 (topography code 174).
Other Variables
Information on other risk factors for breast cancer, includingage, number of years of education, height, weight, age at firstpregnancy, parity, and age at menopause, was obtained. For the115 women whose menstrual periods had stopped because they hadundergone hysterectomy without bilateral oophorectomy, we usedthe median age at menopause for the entire cohort (50 years)as their age at menopause. At examinations 2 (1951 to 1954)and 7 (1960 to 1964), the women were asked to estimate the numberof drinks of beer, wine, or spirits consumed each month. Totalalcohol consumption was computed by multiplying the averageamount of alcohol in a single drink of beer, wine, or spiritsby the average of the numbers of drinks reported at examinations2 and 7. Cigarette smoking has been recorded at each examinationfor the past 45 years. We used the mean number of cigarettessmoked per day before the date of hand radiography as the base-linevariable for smoking. Habitual physical activity was assessedat the fourth examination (between 1954 and 1958) with use ofthe Framingham Physical Activity Index.20 Postmenopausal estrogenuse has been assessed at each biennial examination since 1960.For each woman, the total number of years of postmenopausalestrogen use was summed from the time of hand radiography toeither the date of a diagnosis of breast cancer or the dateon which the data were censored (the date of the last contact,for women lost to follow-up, or December 31, 1993, when thestudy was closed).
Statistical Analysis
Since age is an important determinant of breast cancer and thewomen with lower bone mass were older on average than thosewith higher bone mass, we adjusted for age by using the age-specificrelative metacarpal cortical area. Specifically, we stratifiedall women into two-year age groups and then assigned each womanto one of four quartiles of bone mass according to the distributionof the relative metacarpal cortical area for her age group.
Using an analysis of variance for continuous variables and achi-square test for categorical variables, we compared the characteristicsof the participants according to the presence or absence ofbreast cancer and the quartile of bone mass. Person-years offollow-up for each woman were computed as the amount of timefrom the date the radiograph was obtained to the date of thefirst of the following events: a diagnosis of breast cancer;the last date of contact, for those lost to follow-up; death;or December 31, 1993, when the study was closed. Incidence ratesof breast cancer for each age-specific quartile of bone masswere calculated by dividing the number of cases of cancer bythe number of person-years of follow-up. We plotted Kaplan–Meiersurvival curves to determine the cumulative incidence rate foreach quartile of bone mass.21
We fitted a Cox proportional-hazards model to determine therelation of the age-specific quartile of metacarpal bone massto the risk of breast cancer.21 In the multivariate Cox proportional-hazardsmodel, we adjusted for education, height, body-mass index, ageat first pregnancy, parity, age at menopause, average alcoholconsumption, average number of cigarettes smoked, level of physicalactivity, and use or nonuse of postmenopausal estrogen. Thesignificance of the trend in the risk of breast cancer was determinedby including a single variable for the age-specific quartileof metacarpal bone mass in the multivariate model.
To determine whether the association between bone mass and breastcancer was modified by other risk factors, we examined the effectof the quartile of metacarpal bone mass within strata of otherrisk factors. We tested for a modification of the effect byincluding an interaction term (between the quartile of metacarpalbone mass and a particular risk factor) in the multivariateregression model.
Results
Of the 1394 women who underwent hand radiography between 1967and 1970, 21 had a history of breast cancer and were excludedfrom the analysis. During the follow-up period, postmenopausalbreast cancer developed in 91 women. The median age at the timeof the diagnosis was 74 years (range, 54 to 92), and the medianfollow-up after hand radiography was 22.1 years (range, 0.1to 25.9).
Table 1 shows the characteristics of the women with breast cancerand those without breast cancer. The women with breast cancerwere significantly older at the time of their first pregnancy(P = 0.02). However, there were no statistically significantdifferences between the two groups of women in terms of ageat the time of radiography, height, body-mass index, age atmenopause, education, parity, years of postmenopausal estrogenuse, alcohol consumption, cigarette smoking, or level of physicalactivity.
Table 1. Characteristics of 1373 Women in the Framingham Study, According to the Presence or Absence of Breast Cancer Diagnosed between 1969 and 1993.
Table 2 shows the distribution of potential risk factors forbreast cancer according to the age-specific quartile of bonemass. As compared with the women in the lower quartiles of bonemass, those in the higher quartiles had a higher body-mass index(P<0.001), were older at menopause (P<0.001), had moreyears of education (P = 0.018), and had used postmenopausalestrogen-replacement therapy for a longer period (P = 0.036).Bone mass also varied according to parity (P = 0.037).
Table 2. Characteristics of Study Participants According to the Age-Specific Quartile of Relative Metacarpal Cortical Area.
The cumulative incidence of breast cancer increased most rapidlyamong the women in the highest age-specific quartile of metacarpalbone mass (Figure 1). As compared with the risk of breast canceramong the women in the lowest quartile, the rate ratios forthe women in the second, third, and highest quartiles were 1.3(95 percent confidence interval, 0.6 to 2.8), 1.3 (95 percentconfidence interval, 0.6 to 2.7), and 3.5 (95 percent confidenceinterval, 1.8 to 6.8), respectively (P for trend, <0.001)(Table 3). Adjusting for additional potential confounding variablesdid not affect the association.
Figure 1. Cumulative Incidence of Breast Cancer among 1373 Postmenopausal Women in the Framingham Study, According to the Age-Specific Quartile of Metacarpal Bone Mass.
Table 3. Relation of Age-Specific Quartile of Relative Metacarpal Cortical Area to the Risk of Breast Cancer.
Women in the highest age-specific quartile of bone mass hadan increased risk of breast cancer across almost all strataof other factors (Table 4). The relative effects of greaterbone mass on the risk of breast cancer were stronger among tallerwomen (P = 0.01 for the interaction term). None of the otherinteraction terms were statistically significant.
Table 4. Rate Ratios for the Risk of Breast Cancer According to the Age-Specific Quartile of Relative Metacarpal Cortical Area and Other Risk Factors.
Discussion
With the exception of age, race or ethnic group, and familyhistory of breast cancer, most of the known risk factors forbreast cancer carry a relative risk of 2.0 or less.22 The effectsof some of these risk factors, such as age at menarche, ageat birth of first child, and age at menopause, may be limitedbecause of relatively small variations in their distributionin the United States and most other industrialized countries.The results of our study indicate that metacarpal bone massin middle-aged and elderly women is a strong predictor of postmenopausalbreast cancer.
Estrogen may be the link between bone mass and the risk of breastcancer. Because of its influence on the mitotic activity ofbreast cells, estrogen may play a critical part in the developmentof breast cancer. Seven cohort studies have assessed the relationof a woman's serum estrogen level at a single point in timeto her risk of breast cancer.23,24,25,26,27,28,29 Three of thesestudies reported an increased risk among women with higher levelsof serum estradiol27,28,29 and higher percentages of estradiolin the bioavailable fractions.27 In four of six meta-analysesof estrogen-replacement therapy and the risk of breast cancer,30,31,32,33,34,35long-term estrogen users had an increased risk of breast cancer.32,33,34,35Colditz et al. recently reported that women in the Nurses' HealthStudy who were currently using estrogen and had done so forfive or more years had a 46 percent increase in the risk ofbreast cancer, and the effect was greater among older women.36The most convincing epidemiologic evidence of an associationbetween estrogen and breast cancer would require studies inwhich estrogen levels in each woman were assessed repeatedlyover a long period of time. Because of methodologic and logisticaldifficulties, such studies have not been performed.
Several investigators have hypothesized that bone mass or bonemineral density may indicate the effect of cumulative exposureto estrogen.10,11,12,13,14 There is a strong positive associationbetween serum or urinary estrogen levels and bone mineral densityin premenopausal and postmenopausal women, and the skeletaleffects of low levels of estrogens are clearly seen after menopauseor removal of the ovaries.37,38,39,40,41,42,43,44,45,46 In addition,women who have been receiving estrogen-replacement therapy,especially long-term estrogen users, have significantly higherbone mineral density and a lower risk of osteoporotic fracturesthan women who have never used estrogens.47,48,49,50,51
The relation between bone mass and breast cancer may also involveendogenous androgens, which are determinants of bone mass52,53and are also associated with a risk of breast cancer.2
Two studies have examined the association between fracturesand the risk of breast cancer or death from breast cancer.12,13The risk was 16 percent lower in women with hip fractures (standardizedincidence ratio, 0.84; 95 percent confidence interval, 0.74to 0.95)13 and 58 percent lower in women with forearm fractures(standardized mortality ratio, 0.42)12 than in those withoutfractures. However, factors other than bone density contributeto the risk of fractures. Cauley et al.14 recently reportedthat, over four years of follow-up, women with bone mineraldensity above the lowest quartile had a risk of breast cancerthat was two to two and a half times higher than the risk inthose with bone mineral density in the lowest quartile. Withmore than 20 years of follow-up, we were able to examine thelong-term relation of bone mass to the risk of breast cancer.
Measurements of relative metacarpal cortical area can be usedto draw inferences about the relation of bone mass to the riskof breast cancer. Dual-energy x-ray absorptiometry is the standardmethod for measuring bone mass, but radiogrametry of the secondmetacarpal cortical area is precise54,55 and accurate.56,57Relative metacarpal cortical area is highly correlated withthe metacarpal-ash mineral content (r = 0.85),56 and the mineralcontent of the meta-carpals correlates well with that at otherbone sites (r ranges from 0.75 to 0.95).57 In the present study,both interobserver and intraobserver correlations of radiographicreadings were above 0.9.
All cases of breast cancer in this study were confirmed by histologicreports. We believe that virtually all clinically detected incidentcases of breast cancer were ascertained, since the incidenceof cancer in the Framingham Study is similar to that in theSurveillance, Epidemiology, and End Results Program.18
Adjustment for risk factors other than age had little, if any,effect on the relation of bone mass to the risk of breast cancer.Information on a family history of breast cancer and age atmenarche was not collected in the Framingham Study. Althoughthe risk of breast cancer is two to three times higher for womenwith a family history of breast cancer than for those withoutsuch a history,22 less than 10 percent of women in the generalpopulation have a family history of breast cancer.58 Age atmenarche is a significant predictor of breast cancer, but themagnitude of its association with the risk of breast canceris unlikely to account for the present findings.
In conclusion, the results of our study suggest that bone massin middle-aged and elderly women is a strong predictor of therisk of postmenopausal breast cancer. Although the biologicmechanisms linking bone mass to the risk of breast cancer arenot fully understood, cumulative exposure to estrogen may havea role.
Supported by grants from the National Institutes of Health (N01-HC-38038,AR20613, and AR41398) and the Institute on Lifestyle and Health,Boston University School of Medicine.
We are indebted to Lisa McAllister and Harry K. Genant, M.D.,who performed all the cortical-width measurements.
Source Information
From the Boston University Arthritis Center (Y.Z., D.T.F.), the Section of Preventive Medicine and Epidemiology (Y.Z., B.E.K., R.C.E., D.L.), and the Section of General Internal Medicine (B.E.K.), Evans Department of Medicine, Boston University School of Medicine; the Hebrew Rehabilitation Center for Aged and the Division on Aging, Harvard Medical School (D.P.K.); and the Department of Epidemiology and Biostatistics, Boston University School of Public Health (L.A.C.) — all in Boston; the Division of Cancer Prevention and Control, National Cancer Institute, Bethesda, Md. (J.F.D., A.S.); and the Framingham Study, Framingham, Mass., and the National Heart, Lung, and Blood Institute, Bethesda, Md. (D.L.).
Address reprint requests to Dr. Zhang at Rm. B-612, Boston University Medical Center, 88 E. Newton St., Boston, MA 02118.
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Extract |
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N Engl J Med 1997;
337:199-200, Jul 17, 1997.
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