Effects of Exemestane on Bone Strength (MAP3BSS)

Currently, NCIC CTG is conducting an international breast cancer prevention trial (MAP.3) examining the effects of a new therapy (exemestane) for breast cancer prevention in postmenopausal women at increased risk of developing this disease. Exemestane blocks estrogen production, which may be beneficial for preventing breast cancer, but may have negative effects on bone. Studies in rats showed that exemestane might have a more favourable bone profile than others in its class, but data is lacking in women. As postmenopausal women are at risk for developing osteoporosis, determining whether exemestane causes bones to weaken is crucial for women considering it for long-term use. Dr. Cheung's team will follow the bone health of 354 women in MAP.3 in detail over 2-5 years to delineate the effects of exemestane on bone strength. This research will inform us on the safety of exemestane for breast cancer prevention.

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.

Women randomized to the MAP.3 study from 5 participating locations were consecutively approached for participation in this companion study.

• Osteoporosis
• Breast Cancer

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.