Bone Mineral Density and Subsequent Cancer Risk

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.