Aromatase inhibitors (AIs) substantially decrease estrogen levels in postmenopausal women; thus, they have the potential to prevent breast cancer, but they also have the potential to adversely affect bone. Previous animal data from our group suggests that exemestane, a steroid AI, may have a more favourable effect on bone metabolism than the non-steroidal AIs. Over the past few years, we have been conducting a 2-year companion study in a subset of women participating in the 5-year MAP.3 trial-- a primary breast cancer prevention trial conducted by the NCIC Clinical Trials Group (NCIC CTG) to examine the effects of exemestane on the prevention of breast cancer. This companion study is conducted at 3 geographic locations (Toronto, Canada; Mayo Clinic in Rochester (US) and at the University of California Davis in California (US)) in postmenopausal women who do not have osteoporosis at baseline, to investigate the effects of exemestane on bone structure and density in the first 2 years of taking exemestane.

On November 5 2010, the MAP.3 study reached an early primary breast cancer event-driven endpoint. Data analysis conducted March 2011 showed that after a median follow up of 35 months, exemestane was superior to placebo in breast cancer prevention. Based upon the positive results of the MAP.3 trial, and the relatively low incidence of adverse events seen in women receiving exemestane as compared to those receiving placebo, the trial committee and NCIC CTG have agreed not to close the study. Instead, a modified observational study will continue. We have also extended this 2-year study for another 3 years. Recent data suggests that there is a difference in changes in BMD (and perhaps fractures) in women with breast cancer, with the earlier effects (\< 2 years) being worse than the late effects. As exemestane was found to be effective in the prevention of breast cancer, it is likely going to be used for 5 years. By extending this companion study for another 3 years, we will be able to determine the long term (up to 5 years) effects of exemestane on bone structure and density, and to compare the effects observed from 2 to 5 years of follow-up to those observed from baseline to 2 years.

The primary objectives of our original 2-year study and this extension study are to determine whether exemestane will cause a clinically and statistically significant difference in percent change in total volumetric bone mineral density (BMD) at the distal radius as measured by high-resolution peripheral quantitative computed tomography (HRpQCT) from baseline to 2 years and from 2 to 5 years, and 2 years post therapy,as compared to placebo. Our secondary objectives are: 1) to determine the effects of exemestane on cortical and trabecular volumetric BMD as measured by pQCT scans at 1, 2, 3 and 5 years; 2) to examine the effects of exemestane on other bone geometric parameters such as cortical thickness, trabecular thickness, trabecular separation and trabecular number at 1, 2, 3 and 5 years; 3) to investigate the effect of exemestane on the percent change in BMD at the lumbar spine (L1-L4) and the total hip as measured by dual energy X-ray absorptiometry (DXA) from baseline to 1, 2, 3 and 5 years as compared to placebo; and 4) to determine the effect of 2 years of exemestane on bone strength index as compared to placebo. We will also compare the early (baseline to 2 years) and late (2 to 5 years) effects of exemestane on bone. All participants in this companion study are provided with calcium and vitamin D supplementation. Measurements of volumetric BMDs and bone geometric parameters are obtained by HRpQCT using Xtreme CT, and measurements of areal BMDs are obtained by DXA using Hologic or Lunar densitometers at baseline, 1, 2, 3 and 5 years, according to standard protocols.

The results of the proposed extension to the companion study will help us understand the long term effects and long term safety of exemestane on bone health in postmenopausal women at risk of developing breast cancer. Data on healthy postmenopausal women taking long term (2-5 years) exemestane does not exist at this time. Information from this study will help clinicians and women weigh the risks and benefits of using exemestane and make informed decisions regarding breast cancer prevention.