Bone Mineral Density and Subsequent Cancer Risk
Condition: Endometrial Cancer; Breast Cancer
MeSH terms: Endometrial Neoplasms
Study type: Observational

Summary: 
      Recent cohort studies demonstrated reduced breast cancer risks among women with a history of
      fractures or low bone mineral density (BMD). In the Study of Osteoporotic Fractures, each
      standard deviation increase in distal radius BMD was associated with a 50% increased risk
      over three years of follow-up, while in the Framingham study, women in the highest quartile
      of metacarpal bone mass had a 3.5-fold higher risk than women in the lowest quartile. The
      impact of the severity and timing of bone loss on risk has not yet been investigated, and the
      extent to which other risk factors (family history, anthropometric factors, physical
      activity, and exogenous hormones) modify the relationship with BMD is unknown.

      To elaborate on these research questions, we are conducting a follow-up study of 22,695
      postmenopausal women who volunteered for the Fracture Intervention Trial (FIT), a trial of
      the bone-enhancing drug alendronate. This large cohort includes extensive baseline
      information on major breast cancer risk factors, and thus is ideal for evaluating potential
      interactions with BMD and the effects of BMD on other cancer sites. Endometrial cancer has
      been reported to occur more frequently among women with a history of fracture, but no
      previous studies have specifically investigated its relationship to BMD.

      We are investigating whether BMD of the proximal femur predicts breast cancer risk; whether
      breast cancer risk factors among postmenopausal women modify the relationship with BMD;
      whether BMD predicts endometrial or other cancers; and whether measurable biomarkers offer
      further etiologic clues about BMD and cancer risk.

      We have contacted the surviving members of FIT to ascertain incident cancers. Risk factors
      and fracture history are being updated through a self-administered questionnaire. To
      supplement the serum samples collected at baseline, we are using a nested case-control study
      approach to collect buccal cell specimens, which may be useful for measuring a variety of
      biomarkers, including endogenous hormones and genetic polymorphisms involved in either bone
      growth (e.g., vitamin D receptor) or hormone metabolism (e.g., CYP17, COMT). Retrieval of
      operative and pathology reports is being used to validate self-reported cancers. The social
      security numbers and contacts names provided by FIT participants when they completed the
      baseline questionnaire are facilitating comprehensive follow-up and a National Death Index
      search for those who cannot be located. The baseline data, the established cooperation of
      this study population, and the collection of additional biospecimens should enable this study
      to answer important questions about BMD in breast and endometrial cancers.
    

Detailed description: 
      Recent cohort studies demonstrated reduced breast cancer risks among women with a history of
      fractures or low bone mineral density (BMD). In the Study of Osteoporotic Fractures, each
      standard deviation increase in distal radius BMD was associated with a 50% increased risk
      over three years of follow-up, while in the Framingham study, women in the highest quartile
      of metacarpal bone mass had a 3.5-fold higher risk than women in the lowest quartile. The
      impact of the severity and timing of bone loss on risk has not been investigated, and the
      extent to which other risk factors (family history, lifestyle, and exogenous hormones) modify
      the relationship with BMD is unknown.

      To elaborate on these research questions, we conducted a follow-up study of postmenopausal
      women who volunteered for the Fracture Intervention Trial (FIT), a trial of the
      bone-enhancing drug alendronate. The BFIT follow-up study includes 15,595 of the 22,695 FIT
      volunteers. Surviving members of FIT were contacted to ascertain incident cancers and to
      provide updated risk factor and fracture history through a self-administered questionnaire.
      To supplement baseline serum samples, we used a nested case-control approach to collect
      buccal cell specimens for biomarker measurement, including endogenous hormones and genetic
      polymorphisms involved in either bone growth (e.g., vitamin D receptor) or hormone metabolism
      (e.g., CYPI7, COMT). Operative and pathology reports were used to validate self-reported
      cancers. The social security numbers and contact names provided by FIT participants at
      baseline facilitated comprehensive follow-up and a National Death Index search for those who
      could not be located.

      This large cohort includes extensive baseline information on major breast cancer risk
      factors, and thus is ideal for evaluating potential interactions with BMD and the effects of
      BMD on other cancer sites. Endometrial cancer has been reported to occur more frequently
      among women with a history of fracture, but no previous studies have investigated its
      relationship to BMD. We are investigating whether proximal femur BMD predicts breast cancer
      risk; whether breast cancer risk factors among postmenopausal women modify the relationship
      with BMD; whether BMD predicts cancer risk; and whether biomarkers offer etiologic clues
      about BMD and cancer risk. Currently, we are examining: 1) the relationship of serum
      adipocytokines to endometrial cancer risk, and 2) the relationships of serum estrogens and
      metabolites to postmenopausal breast cancer risk. The baseline and follow-up data and the
      collection of additional biospecimens should enable us to answer important questions about
      BMD and other cancers.
    

Observational model: Cohort
Time perspective: Prospective
Sampling method: Non-Probability Sample
Study population: 
        The B FIT study included 15,595 of the 22,695 who were screened for participation in the
        Fracture Intervention Trial (FIT), a randomized clinical trial originally designed to test
        whether alendronate, a bispohosphonate, would reduce the rate of fractures in women with
        low bone mineral density (Black et al. 1993). The FIT clinical trial (1992-1998) enrolled
        approximately 6000 volunteers who had low BMD. The B FIT follow-up study includes all women
        (regardless of baseline BMD) who volunteered for FIT. In 1992-1993, postmenopausal women
        (ages 55-80) completed an extensive questionnaire, donated a baseline blood sample,
        underwent a bone mineral density scan, and provided clinical examination data. As part of
        the B FIT study, these women were followed (median 10.3 years) to ascertain incident cancer
        outcomes and incident fractures through the period of 2001-2004.
      
Keywords: Supplemental Hormone Use; Osteoporosis; Endogenous Sex Hormones