Effects of Exemestane on Bone Strength

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.

Inclusion Criteria:

Women participating in the MAP.3 clinical trial at centres with access to HR-pQCT

Exclusion Criteria:

1. Women with osteoporosis;

2. Women with T-score of -2.0 or below at the lumbar spine (L1-L4), total hip or femoral
neck;

3. Women with a fragility fracture after age 40;

4. Women who have been on any bone drug, such as hormone replacement therapy, selective
estrogen receptor modulators, bisphosphonates, teriparatide, parathyroid hormone,
sodium fluoride, strontium, calcitonin and high dose vitamin D (more than 2000iu of
vitamin D3 daily),in the past 3 months;

5. Women who have ever been on a bisphosphonate for more than 6 months;

6. Women who have ever been on strontium for more than 1 month;

7. Women who are on chronic oral steroids (the equivalent of 5mg of prednisone a day or
higher for more than 2 weeks within the past 6 months and will likely require ongoing
therapy);

8. Women with Paget's disease, Cushing's disease, hyperparathyroidism, uncontrolled
hyperthyroidism or other metabolic bone diseases;

9. Women with decompensated diseases of the liver, bowel, kidney, pancreas, lung, or
heart.