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Bone Density and Cancer Risk: A Follow-Up Study of Women in the Fracture Intervention Trial (BFIT)

Bone density has emerged as a potentially important predictor of risk for certain cancers that are influenced by hormones, such as breast and endometrial cancers. In 1992, over 25,000 postmenopausal women volunteered for FIT, a clinical trial to determine whether the drug alendronate could reduce the incidence of osteoporosis fractures. The BFIT study is a retrospective cohort study that uses data from the FIT clinical trial to evaluate how bone mineral density of the hip is related to subsequent cancer risk; including a nested case-cohort study of circulating sex steroid hormones in relation to breast, endometrial, ovarian, and colorectal cancer risk.

NCI and FIT investigators contacted FIT volunteers to identify incident cancers, and to evaluate whether risk factor information collected in 1992, such as measured bone mineral density, lifestyle factors, and certain growth factors, predicts subsequent cancer risk. Collection of additional risk factor information during this follow-up, including updated lifestyle factors and a buccal cell sample for genetic analyses, is allowing investigators to further explore the complex relationships between bone mass and other risk factors for breast, endometrial, and other cancers. Currently underway are efforts to understand associations between androgens and androgen metabolites as well as progesterone-related metabolites and breast cancer risk and the interrelationships between bone mass and endogenous hormones and risk of breast, endometrial, and other cancers.

Serum Estrogen Metabolites and Cancer Risk in the BFIT Study

Although circulating estrogens have been evaluated in prior epidemiological studies of cancer, numerous questions remain with regard to the role of estrogen metabolites in the development of hormone-related cancers. Investigators conducted a case-cohort study within BFIT to examine circulating estrogens and estrogen metabolites in relation to four specific cancer endpoints. Women who were screened for participation in the trial completed a risk factor questionnaire, provided a baseline blood sample and underwent a bone mineral density scan. As part of the BFIT study, these women were followed (median 10.3 years) to ascertain incident cancer outcomes and incident fractures through the period of 2001-2004.

A comprehensive profile of endogenous estrogens, including 15 estrogens and estrogen metabolites, were measured in pre-diagnostic serum using the LC-MS/MS assay developed at the Protein Characterization Laboratory at the Frederick National Cancer Center. These measures were examined in relation to breast (n~420), endometrial (n~62), ovarian (n~65), and colorectal (n~178) cancers. Elevated circulating estradiol levels were found associated with increased breast cancer risk.  Further, elevated levels of metabolites in the 2- and 4-hydroxylation pathways to parent estrogens were inversely related to risk. A higher ratio of the 2/16-hydroxylation pathway was also associated with reduced risk. Elevated estradiol levels were also related to increases in endometrial cancer risk, without meaningful associations with individual metabolites. In contrast, neither parent estrogens nor metabolites were found to be related to either ovarian or colorectal cancer risks.

Adipocytokines and Endometrial Cancer Risk in the BFIT Study

Obesity is a well-established risk factor for endometrial cancer and may independently affect endometrial cancer risk, even after adjustment for sex steroids. Adipose tissue produces several adipocytokines, including leptin and adiponectin, and although few studies have assessed these markers in relation to endometrial cancer risk, the majority of studies have utilized post-diagnostic blood samples. Investigators are currently conducting a nested case-control study to examine circulating pre-diagnostic levels of adiponectin, high molecular weight adiponectin, leptin, and C-peptide in relation to endometrial cancer risk among a subset of postmenopausal women (~60 cases/120 controls) in the BFIT follow-up study. Within this study, investigators will also be able to evaluate a full panel of circulating estrogens and estrogen metabolites as well as investigate relationships with obesity metrics such as body mass index and waist-to-hip ratio. 

View publications from the BFIT Study.

For more information, contact Britton Trabert.

Metabolic Epidemiology Branch - Research Areas