Bone Mass and the Risk of Breast Cancer among Postmenopausal Women

Zhang, Yuqing; Kiel, Douglas P.; Be, Kreger; Cupples, L. Adrienne; Ellison, R. Curtis; Dorgan, JF; Schatzkin, Arthur; Levy, Daniel; Felson, David T.

doi:10.1056/nejm199702273360903

Cited by 279 publications

(125 citation statements)

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“…In the majority of older adults, bone mineral density (BMD) predictably decreases with age, with osteoporotic fractures as an end product (Cauley et al 2009). Osteoporosis traits have been associated with risk for multiple diseases, including coronary disease in women (Samelson et al 2004), and with risk for breast, colon and prostate cancer (Zhang et al 1997(Zhang et al , 2002, memory impairment (Zhang et al 2001) and dementia in women (Tan et al 2005) and a higher risk of mortality independent of age and comorbidities (Van Der Klift et al 2002;Bauer et al 2002). Most recently, Cauley et al (2009) suggested that maintenance of BMD may represent a clinical phenotype of successful aging.…”

Section: Biomarkers Of Agingmentioning

confidence: 99%

“…The process of bone and muscle involution is a general phenomenon and a typical manifestation of tissue atrophy with age (Plato et al 1994). Studying the musculoskeletal aging provides a "local" model from which "global" inference for aging can be driven since the musculoskeletal biomarkers are linked to the state of many vital functions, age-related conditions of different bodily systems (Zhang et al 1997;Samelson et al 2004;Browner et al 1993), cardiovascular disease (Hak et al 2000;Kiel et al 2001), cancer, mortality, disability, and ultimately survival rates (Kiel et al 2001;Johansson et al 1998). We therefore postulate that by studying musculoskeletal aging-as a proof of principle-we can come closer to the understanding of an organism's aging.…”

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confidence: 99%

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How pleiotropic genetics of the musculoskeletal system can inform genomics and phenomics of aging

Karasik

2010

AGE

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Genetic study can provide insight into the biologic mechanisms underlying inter-individual differences in susceptibility to (or resistance to) organisms' aging. Recent advances in molecular genetics and genetic epidemiology provide the necessary tools to perform a study of the genetic sources of biological aging. However, to be successful, the genetic study of a complex condition requires a heritable phenotype to be developed and validated. Genome-wide association studies offer an unbiased approach to identify new candidate genes for human diseases. It is hypothesized that convergent results from multiple aging-related traits will point out the genes responsible for the general aging of the organism. This perspective focuses on the musculoskeletal aging as an example of an approach to identify a downstream common pathway that summarizes aging processes. Since the musculoskeletal traits are linked to the state of many vital functions, disability, and ultimately survival rates, we postulate that there is significance in studying musculoskeletal aging. Construction of an integrated phenotype of aging can be achieved based on shared genetics among multiple musculoskeletal biomarkers. Valid biomarkers from other systems of the organism should be similarly explored. The new composite aging score needs to be validated by determining whether it predicts all-cause mortality, incidences of major chronic diseases, and disability late in life. Comprehensive databases on biomarkers of musculoskeletal aging in multiple large cohort studies, along with information on various health outcomes, are needed to validate the proposed measure of biological aging.

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Section: Biomarkers Of Agingmentioning

confidence: 99%

mentioning

confidence: 99%

How pleiotropic genetics of the musculoskeletal system can inform genomics and phenomics of aging

Karasik

2010

AGE

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“…High serum oestrogen levels (Toniolo et al, 1995;Thomas et al, 1997;Hankinson et al, 1998;Cauley et al, 1999;Key et al, 2002;Missmer et al, 2004) and surrogates for long-term high oestrogen exposure, such as bone (Zhang et al, 1997) density, are known to be associated with an increased risk for breast cancer. However, exposure to anti-oestrogens has been shown to decrease the risk for breast cancer and recurrent disease (Baum et al, 2002;Cuzick et al, 2003).…”

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Serum oestrogen receptor α and β bioactivity are independently associated with breast cancer: a proof of principle study

et al. 2009

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BACKGROUND: Oestrogens play a crucial role in breast carcinogenesis. Earlier studies have analysed the serum levels of endogenous hormones measured by conventional assays. In this study, we analysed the capacity of serum from breast cancer cases and controls to transactivate the oestrogen receptor a (ER-a) and b (ER-b). METHODS: We used a receptor oestrogen-responsive element (ERE) -the green fluorescent protein (GFP)-reporter test system in Saccharomyces cerevisiae. Oestrogen receptor-a or ER-b bioactivity was determined in serum from 182 randomly chosen postmenopausal women with breast cancer and from 188 age-matched controls. RESULTS: High serum ER-a and ER-b bioactivity were independently associated with the presence of breast cancer. Women whose levels of serum ER-a and ER-b bioactivity were in the highest quintile among controls had a 7.57-(95% confidence interval (CI): 2.46 -23.32; P ¼ 0.0004) and a 10.14 (95% CI: 3.19 -32.23; Po0.0001)-fold risk for general and oestrogen receptor-positive breast cancer, respectively. CONCLUSION: The use of serum ER-a and ER-b bioactivity assays as clinical tools in the management of breast cancer warrants further research. Future studies will dictate whether surrogate markers of ER-a and ER-b bioactivity will provide a means to monitor the efficacy of anti-endocrine, adjuvant and chemopreventive strategies.

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“…Regression analyses of these log-transformed values therefore were used to evaluate their relationship with age and menopausal status and showed that these variables needed to be accounted for when comparing androgen levels with respect to breast cancer risks. To achieve this we classified women according to strata defined by age and menopause categories and, within each stratum, assigned women into A and E tertiles, adapting the method described by Zhang et al (1997) (see Appendix). Stratum-specific rates for breast cancer incidence were then estimated for these age-and menopause-adjusted tertiles of androgen levels and for categories of the potential confounders for which information had been collected: age at menarche (≤ 12, 13, >13), parity (0, 1+), age at first birth (≤ 20, 21-25, > 25, nulliparous), self-reported height and weight (both in tertiles) and body mass index (BMI = (wt (kg))/(ht(m)) 2 ; also in tertiles).…”

Section: Methodsmentioning

confidence: 99%

Urinary androgens and breast cancer risk: results from a long-term prospective study based in Guernsey

2000

Climacteric

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It would be very useful if it were possible to identify, within an apparently normal population, those who will develop breast cancer. Although this can be achieved by genetic testing for mutations of BRCA1 and BRCA2, such susceptibility genes are involved in the aetiology of only about 5% of breast cancer cases (Lynch and Lynch, 1986). By contrast, events related to a woman's menstrual and reproductive history, which have been widely recognized as determinants of breast cancer incidence, are not impressive predictors of individual risks. Such poor predictive performance could result from these epidemiological variables being only manifestations of other underlying factors. Indeed the size of the effects of the menstrual and reproductive variables and the observation that breast cancer rates change over a woman's life have stimulated investigation of endogenous sex hormones as potential causes underlying these observed effects (Key and Pike, 1988;Toniolo et al, 1995;Key et al, 1996). Methodological issues related to hormone measurements, however, complicate the study of their relationship with breast cancer. Furthermore, there is no general consensus regarding which biological forms of these hormones are actually associated with the observed changes in incidence rates.The role of steroids in the aetiology of breast cancer is uncertain. Extensive analysis of the scientific literature shows a highly significant increase in blood oestradiol levels in post-menopausal women with breast cancer (Thomas et al, 1997). The position of oestrogens and premenopausal women is uncertain (Key and Pike, 1988; Thomas et al, 1997). Androgens have been studied less extensively than oestrogens and no meta-analysis has yet been undertaken.The first prospective study in this field was performed by Bulbrook and Hayward who showed that levels of androsterone (A) and aetiocholanolone (E) were abnormally low in women who subsequently developed breast cancer (Bulbrook and Hayward, 1967;Bulbrook et al, 1971). Most of the cases were premenopausal and the abnormality was present up to 11 years before the clinical diagnosis of the disease, suggesting that high levels of androgen metabolites might have a protective effect, at least in younger women. However, other mainly retrospective casecontrol studies have claimed that high androgen excretion is positively associated with breast cancer risk (e.g. Secreto and Zumoff, 1994). Such contrasting results could be reconciled if the effects of androgens depended on menopausal status. This would occur if the androgens acted as oestrogen inhibitors in premenopausal women and as oestrogen enhancers (or even oestrogens) in the postmenopausal (Secreto and Zumoff, 1994;Adams, 1998 Summary Between 1961 and 1967 a cohort of over 5000 women volunteered for a prospective study to determine the relationship between the urinary androgen metabolites, androsterone (A) and aetiocholanolone (E), and risk of breast cancer. During the first 10 years of the study the concentration of urinary A and E was determined in 1...

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Bone Mass and the Risk of Breast Cancer among Postmenopausal Women

Abstract: Women in the highest quartile of bone mass are at higher risk for postmenopausal breast cancer than those in the lowest quartile. The mechanisms underlying this relation are not understood, but cumulative exposure to estrogen may play a part.

Cited by 279 publications

References 58 publications

How pleiotropic genetics of the musculoskeletal system can inform genomics and phenomics of aging

How pleiotropic genetics of the musculoskeletal system can inform genomics and phenomics of aging

Serum oestrogen receptor α and β bioactivity are independently associated with breast cancer: a proof of principle study

Urinary androgens and breast cancer risk: results from a long-term prospective study based in Guernsey

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