Trial Information

Effects of Exemestane on Bone Strength in Postmenopausal Women at Increased Risk of Developing Breast Cancer

Aromatase inhibitors (AIs) are a new class of endocrine therapy for the treatment and
prevention of breast cancer in postmenopausal women. They are more efficacious than
tamoxifen in treating advanced breast cancer. Because of their ability to almost completely
deplete estrogen levels in the circulation, they have the potential to adversely affect bone
metabolism in postmenopausal women. Previous animal data from our group suggests that
exemestane, a steroidal AI, may have a more favourable effect on bone metabolism than the
non-steroidal AIs. As osteoporosis poses a significant health risk in postmenopausal women,
determining the long-term effects of exemestane on bone is crucial for women considering
long-term use of this type of therapy for breast cancer prevention. Currently, the National
Cancer Institute of Canada Clinical Trials Group (NCIC CTG) is conducting a primary breast
cancer prevention trial, MAP.3, examining the effects of exemestane for the prevention of
breast cancer. This is a multicentre double-blind placebo-controlled randomized trial
involving 4560 postmenopausal women at increased risk of developing breast cancer. This is
being conducted at approximately 60 sites across Canada, the United States and Spain.
Postmenopausal women at risk of developing breast cancer are randomized to receive either
exemestane or placebo for five years. We propose to conduct a 2-year companion study in a
subset of 300 women participating in 3 geographic locations (Toronto, Canada; Mayo Clinic in
Rochester (US)and UC Davis in California (US)) who do not have osteoporosis at baseline, to
investigate the effects of exemestane on bone structure and density. Our primary objective
is 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 (pQCT)
from baseline to 2 years 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 and 2 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 and 2 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 and 2 years as compared to placebo; and
4) to determine the effect of 2 years of exemestane on bone strength index as compared to
placebo. All participants in this companion study will be provided with calcium and vitamin
D supplementation. Measurements of volumetric BMDs and bone geometric parameters will be
obtained by pQCT using Xtreme CT, and measurements of areal BMDs will be obtained by DXA
using Hologic or Lunar densitometers at baseline, 1 year and 2 years, according to standard
protocols. The three participating centres will undergo pQCT and DXA quality control
procedures standard in multicentre protocols. All pQCT and DXA scans will be centrally
analyzed at University Health Network Bone Density Laboratory by an International Society of
Clinical Densitometry (ISCD) certified technologist.

The results of this companion study will help us understand the long-term effects of
exemestane on bone health in postmenopausal women at risk of developing breast cancer. This
information will help clinicians establish practice guidelines on BMD screening and
osteoporosis prevention in postmenopausal women on long-term exemestane therapy for the
prevention of breast cancer.