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American Journal of Clinical Nutrition, Vol. 87, No. 5, 1400-1404, May 2008
© 2008 American Society for Nutrition

ORIGINAL RESEARCH COMMUNICATION

Multivitamin-multimineral supplement use and mammographic breast density1,2,3

Sylvie Bérubé, Caroline Diorio and Jacques Brisson

1 From Unité de Recherche en Santé des Populations, Centre Hospitalier Affilié Universitaire de Québec, Québec, Canada (SB, CD, and JB); Centre des Maladies du sein Deschênes-Fabia, Centre Hospitalier Affilié Universitaire de Québec, Québec, Canada (SB and JB); Département de Médecine Sociale et Préventive, Université Laval, Québec, Canada (CD and JB); and Breast Cancer Functional Genomics Group and McGill Centre for Bioinformatics, McGill University, Montréal, Canada (CD)

2 Supported by a grant from the Canadian Breast Cancer Research Alliance and the Canadian Institutes of Health Research. CD was supported by post-doctoral fellowships from The Cancer Research Society Inc and Canadian Institutes of Health Research.

3 Reprints not available. Address correspondence to J Brisson, Unité de Recherche en Santé des Populations, Hôpital St-Sacrement du Centre Hospitalier Affilié Universitaire de Québec, 1050 Chemin Sainte-Foy, Québec, Canada G1S 4L8. E-mail: jacques.brisson{at}uresp.ulaval.ca.


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Background: The effect of multivitamin-multimineral supplements on the occurrence of chronic diseases, such as breast cancer, is unclear. Breast density is increasingly used as a biomarker of breast cancer risk.

Objective: The present study evaluated the association of multivitamin-multimineral supplement use with breast density.

Design: Premenopausal (n = 777) and postmenopausal (n = 783) women were recruited at the time of screening mammography. Anthropometric measurements were taken at recruitment. Demographic characteristics, behavioral factors, and health conditions were documented by telephone interview. Diet and multivitamin-multimineral and individual vitamin and mineral supplement use were assessed with a self-administered food-frequency questionnaire. Breast density from screening mammograms was measured using a computer-assisted method. Crude and adjusted means in breast density were evaluated according to multivitamin-multimineral supplement use using generalized linear models.

Results: Current multivitamin-multimineral supplement use was reported by 21.7% of women (20.7% and 22.6% of premenopausal and postmenopausal women, respectively). Premenopausal women who were currently using multivitamin-multimineral supplements had higher adjusted mean breast density (45.5%) than past (42.9%) or never (40.2%) users (P for heterogeneity = 0.03, P for trend = 0.009). Of the current users, breast density was not related to duration of multivitamin-multimineral supplement use. In postmenopausal women, multivitamin-multimineral supplement use was not associated with breast density (P for heterogeneity = 0.53, P for trend = 0.40).

Conclusion: Regular use of multivitamin-multimineral supplements may be associated with higher mean breast density among premenopausal women. The relations of multivitamin-multimineral supplement use to breast density and breast cancer risk need to be clarified.


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
In 1999–2000, 57% of US women reported taking dietary supplements; 38% reported taking multivitamin-multimineral supplements (1). In 2001–2002, these percentages were 55.8% and 21.7%, respectively, among women recruited at the time of screening mammography in Quebec City (2, 3). The majority of dietary supplement users believe that the use of such supplements improves their health and contributes to prevent chronic diseases, such as cancer (4, 5). However, the influence that some dietary supplements, especially multivitamin-multimineral supplements, may have on the occurrence of chronic diseases is largely unknown, and there is a potential for adverse effects associated with their use (6).

Two case-control and one cohort studies assessed the influence of multivitamins, with or without minerals, on breast cancer risk (reviewed in references 5, 7) with mixed results. Contrary to expectations, findings from a case-control study in Denmark suggested an increased risk of breast cancer associated with the use of several multivitamin types; statistical significance was reached for the more common combination (vitamins A, B, C, D, and E and minerals) (8). In another case-control study, multivitamin use was not associated with breast cancer risk in North Carolinian women (9). The Nurses’ Health Study (10) is the only known cohort study that looked at the association of commonly used multivitamins with breast cancer risk; null results were found among premenopausal and postmenopausal women.

We know of no randomized placebo-controlled trial of the effect of commonly used multivitamin-multimineral supplements on cancer risk in general or on breast cancer risk specifically. Two large randomized trials have been conducted of specific combinations of vitamins and minerals (mainly antioxidants) with cancer occurrence as the primary endpoint (reviewed in reference 11). In the first trial, a combination of vitamin E, β-carotene, and selenium was found to reduce cancer mortality in a poorly nourished Chinese population (12). In the second trial, a combination of vitamin E, β-carotene, selenium, vitamin C, and zinc reduced cancer incidence in French men but not in French women (13). Only the second trial reported on breast cancer incidence and, in this trial, the incidence of breast cancer in the intervention group was similar to that in the control group.

Mammographic breast density is increasingly used as a biomarker of breast cancer risk (14) because of its strong positive relation to the risk of the disease. Breast density has been hypothesized to reflect the quantity of breast tissue (15) and the population of breast cells at risk of carcinogenic transformation (16). The extent of breast density has been repeatedly associated with breast epithelial atypia and carcinoma in situ (17-23)—histologic changes known to be related with invasive breast cancer risk (24). A number of factors that affect the growth (proliferation and apoptosis) and/or differentiation of breast tissue, such as pregnancy, menopause, hormone replacement therapy, insulin-like growth factor I, and insulin-like growth factor binding protein 3, are associated with breast density (15). We know of no study of the relation of commonly used multivitamin-multimineral supplements to breast density. Thus, the present study was carried out to assess this relation.


   SUBJECTS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 SUBJECTS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Study population
The study design and methods were published previously (2, 3). Briefly, study participants (777 premenopausal and 783 postmenopausal women) were recruited at a screening mammography in Quebec City, Canada. Eligible women had to be classified as premenopausal or postmenopausal, have no personal history of cancer or breast surgery, have no endocrine diseases, have never taken selective estrogen-receptor modulators, not be pregnant, and have not used exogenous sex hormones in 3 mo before mammography. The study was approved by the Research Ethics Committee at our center.

Data collection
Anthropometric measurements and blood samples were taken at recruitment. Personal characteristics, behavioral factors, and health conditions were documented by telephone interview. Diet was assessed with a self-administered food-frequency questionnaire (97GP copyrighted at Harvard University, Boston, MA). In this questionnaire, women reported their intake of 161 specific food items in the past year. They indicated whether they had ever used multivitamin-multimineral supplements on a regular basis, and current regular users provided the brand and type used as well as the frequency and duration of use. Women also reported their use of specific individual vitamin and mineral supplements (vitamin A, β-carotene, niacin, vitamin B-6, folic acid, vitamin C, vitamin D, vitamin E, calcium, iron, magnesium, potassium, selenium, and zinc). To calculate the nutrient content of the diet (including total energy intake), the Harvard laboratory used food-composition data based primarily on US Department of Agriculture publications but also on a comprehensive database on multivitamin-multimineral preparations available in the United States. Finally, women reported whether they were currently following a special diet.

Assessment of mammographic breast density
Breast density was assessed by one reviewer (CD) using a computer-assisted method without information on women (2). Breast density is the proportion of the breast projection showing tissue density on one randomly selected cranio-caudal view for each woman. The within-batch intraclass correlation coefficient was 0.98, and the between-batch CV was 4%.

Statistical analysis
Crude and multivariate-adjusted means in mammographic breast density were compared between never, past, and current users of multivitamin-multimineral supplements using analysis of variance (generalized linear models) in premenopausal and postmenopausal women separately. Adjustments were made for a large set of potential confounders. P values for heterogeneity are based on an F test that evaluated the differences between means. P values for trend are based on the F test of the linear contrast in mean breast density between never, past, and current users of multivitamin-multimineral supplements. Finally, current multivitamin-multimineral supplement users were further classified according to duration of use (<5 or ≥5 y). Statistical significance was based on 2-sided P values. All statistical analyses were carried out by using the SAS version 9.1 software system (SAS Institute Inc, Cary, NC).


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 SUBJECTS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Current multivitamin-multimineral supplement use was reported by 21.7% of women (20.7% and 22.6% of premenopausal and postmenopausal women, respectively). Most women's characteristics varied little according to multivitamin-multimineral supplement use, including age, body mass index, and parity (Table 1Go). However, individual vitamin-mineral supplement use was more likely to be reported by current multivitamin-multimineral supplement users than by past or never users among premenopausal women (60.2%, 42.1%, and 24.9%, respectively; P < 0.001) and postmenopausal women (75.7%, 57.6%, and 47.1%, respectively; P < 0.001). Among postmenopausal women, smoking was less frequent in current users (6.8%) than in past (17.2%) or never (14.2%) users (P = 0.009).


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  		TABLE 1 Characteristics of premenopausal and postmenopausal women according to multivitamin-multimineral supplement use1

 
Multivitamin-multimineral supplement use was related to higher mean breast density in premenopausal women (crude and adjusted P for heterogeneity = 0.04 and 0.03, respectively) (Table 2Go). Crude mean mammographic breast density was 5.0% higher among current users of multivitamin-multimineral supplements compared with those who had never used such supplements, and the trend in higher mean mammographic breast density with recency of multivitamin-multimineral supplement use (classified as never, past, or current use) was statistically significant (P for trend = 0.03). The discrepancy in mean breast density between current and never users was of 5.3% when means were adjusted for a large set of factors identified as a priori potential confounders, and the trend in higher mean mammographic breast density with recency of use was slightly strengthened (P for trend = 0.009). Among current users, 62% reported using multivitamin-multimineral supplements for <5 y, and 38% reported using these for ≥5 y. Adjusted means in breast density (adjusting for the same covariates as in Table 2Go) were similar among current users of multivitamin-multimineral supplements for ≥5 y (45.7%) and those with shorter duration of use (45.4%).


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  		TABLE 2 Relation of multivitamin-multimineral supplement use to mammographic breast density in premenopausal and postmenopausal women

 
Among postmenopausal women, multivitamin-multimineral supplement use was not associated with breast density (P for heterogeneity = 0.53; P for trend = 0.40). A priori, we planned to analyze pre- and postmenopausal women separately. Nevertheless, the P for interaction between supplement use and menopausal status reached 0.06. Finally, among postmenopausal women, effect modification by current use of hormone replacement therapy could not be assessed because women currently using exogenous sex hormones were not eligible for the present study. However, multivitamin-multimineral supplements was not associated with breast density among postmenopausal women who reported having previously used hormone replacement therapy (P for heterogeneity = 0.39).


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Regular multivitamin-multimineral supplement use was found to be associated with higher mean breast density among premenopausal women. To our knowledge, this is the first report concerning multivitamin-multimineral supplement use and breast density. Because breast density is strongly and positively related to breast cancer risk, these findings do not support any benefit from multivitamin-multimineral supplement use on breast cancer risk. Instead, they suggest that such multivitamin-multimineral supplement use should be studied for its possible association with an increased risk of breast cancer.

An absolute difference of about 5% in breast density is relevant in terms of public health. For instance, in our data, the difference in breast density between women who had a child before age 20 y compared and nulliparous women reached 5.3% (3), and nulliparous women are known to have a substantially greater breast cancer risk than women who had at least one child before age 20 y (25). In another area, 40–54 mo of tamoxifen use resulted in an absolute reduction of 5.8–6.4% in breast density compared with placebo (26, 27). Administration of tamoxifen was associated with a reduction in breast cancer risk of 30–50% (28, 29).

Multivitamin-multimineral supplements have no standard definition and can refer to products with widely varying compositions (30, 31). A definition recently proposed (4, 11) refers to any supplement containing ≥3 vitamins and minerals but no herbs, hormones, or drugs, with each component at a dose less than the tolerable upper level determined by the US Food and Nutrition Board. However, difficulties related to assessment and classification of use of multivitamin-multimineral supplements are similar irrespective of breast density and, thus, are unlikely to explain observed associations among premenopausal women.

The association of multivitamin-multimineral supplement use with breast density remained even after adjustment for covariates known or suspected to be related to breast density [age; menstrual, reproductive, and anthropometric variables; menopause; hormonal interventions; personal history of breast biopsy; family history of breast cancer; and nutritional factors such as fat, alcohol, vitamin D, and calcium intakes (3, 15, 32)] or dietary supplement use (age, education, body mass index, physical activity, alcohol, smoking, healthy diet, medical conditions, and use of single vitamin and mineral supplements; 33, 34). Nevertheless, residual confounding is still possible. For instance, multivitamin-multimineral supplement users may be more likely to use dietary supplements other than vitamins and minerals with possible unsuspected adverse effects on breast density.

Among current users, breast density was not related to duration of multivitamin-multimineral supplement use. However, in our data, information was obtained only for broad categories of duration of use. Thus, our data did not allow detailed examination of changes in breast density in the initial months of use, a period when changes in breast density associated with changes in exposures may be more evident (32).

The possibility that multivitamin-multimineral supplements may have detrimental effects on breast density and/or breast cancer risk is biologically plausible (reviewed in reference 6, 11). First, several nutrients included in multivitamin-multimineral preparations are known to have biologic effects. Most of these anticipated effects are expected to be beneficial, but some may be detrimental. For instance, vitamin C intake may be related to increases in insulin-like growth factor I concentrations (35), which itself has been associated with increases in breast density (2) and breast cancer risk in premenopausal women. In addition, β-carotene has been associated with an increased lung cancer risk among smokers or asbestos-exposed persons (36, 37). Folate supplementation has been associated with an increase rather than a decrease in colorectal adenoma incidence (38). Second, the biological effects of a nutrient are heavily dependent on its absorption, transport, tissue uptake, function, and metabolism, which in turn could be affected by the presence of other nutrients. Hence, concurrent ingestion of several nutrients, such as multivitamin-multimineral supplements that can include 30 active ingredients, may conceivably modify each other's effects. Finally, for women with a low baseline nutrient intake, an increase in exposure to some nutrients included in such supplements may be beneficial but, at higher baseline intakes, additional increases may be detrimental.

To further investigate the effect of multivitamin-multimineral supplements, accurate information on the nutrient composition of the great diversity of dietary supplements will be essential, and premenopausal and postmenopausal women will need to be studied separately. There is a large variability in the composition of multivitamin-multimineral supplements (39), and the range of available products can differ substantially from one region to the other. For instance, the composition of most brands of multivitamin-multimineral supplements used by our participants was not documented in the Harvard dietary database from which our nutrient intakes were estimated. Thus, packages used to assess dietary intake from food-frequency questionnaires will need to take into account detailed data on the exact composition of all multivitamin-multiminerals as well as other dietary supplements used by the study population. Furthermore, the apparent association of current use of multivitamin-multimineral supplements with higher breast density seems to be stronger in premenopausal women. Our previous findings of a potential role for vitamin D or calcium in decreasing breast density was also restricted to premenopausal women (3), which emphasizes the need to study premenopausal and postmenopausal women separately.

These findings suggest that multivitamin-multimineral supplement use is associated with higher breast density among premenopausal women. Given the increasingly common use of multivitamin-multimineral supplements and the strong relation of breast density to breast cancer risk, the effect of such supplements on these outcomes needs to be clarified.


   ACKNOWLEDGMENTS
 
We are grateful to the Clinique Radiologique Audet and the Clinique de Radiologie Saint-Pascal for their excellent collaboration. We thank Caty Blanchette and Myrto Mondor (Unité de Recherche en Santé des Populations) for their help with the data analysis.

The authors’ responsibilities were as follows—JB and SB: involved in the study design; and SB, CD, and JB: involved in the data collection, statistical analyses, and writing of the manuscript. None of the authors had a personal or financial conflict of interest.


   REFERENCES
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 ABSTRACT
 INTRODUCTION
 SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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Received for publication August 24, 2007. Accepted for publication November 28, 2007.





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