www.thelancet.com/oncology Vol 13 March 2012 275 Articles Lancet Oncol 2012; 13: 275–84 Published Online February 7, 2012 DOI:10.1016/S1470- 2045(11)70389-8 See Comment page 221 University Health Network (A M Cheung MD, L Tile MD, S Cardew MD, G Tomlinson PhD, M K Kapral MD, M Erlandson PhD, J Scher MSc, H Hu MSc, A Demaras MSc), the Marvelle Koffler Breast Centre, Mount Sinai Hospital (C Elser MD), Women’s College Hospital (Prof L Lickley MD), University of Toronto, Toronto, ON, Canada; Endocrine Research Unit (Prof S Khosla MD), Mayo Clinic Rochester, Rochester, MN, USA (S Pruthi MD, Prof J Ingle MD); Department of Radiology, University of California, San Francisco, San Francisco, USA (Prof S Majumdar PhD); University of California Davis Medical Center, Sacramento, CA, USA (Prof J Robbins MD); Juravinski Cancer Centre, McMaster University, Hamilton, ON, Canada (L Bordeleau MD); Queens University, Cancer Research Institute, Kingston, ON, Canada (H Richardson PhD); and Massachusetts General Hospital, Boston, MA, USA (Prof P E Goss MD) Correspondence to: Dr Angela M Cheung, University Health Network, 200 Elizabeth Street, 7 Eaton North—Room 221, Toronto, ON M5G 2C4, Canada angela.cheung@uhn.ca Bone density and structure in healthy postmenopausal women treated with exemestane for the primary prevention of breast cancer: a nested substudy of the MAP.3 randomised controlled trial Angela M Cheung, Lianne Tile, Savannah Cardew, Sandhya Pruthi, John Robbins, George Tomlinson, Moira K Kapral, Sundeep Khosla, Sharmila Majumdar, Marta Erlandson, Judy Scher, Hanxian Hu, Alice Demaras, Lavina Lickley, Louise Bordeleau, Christine Elser, James Ingle, Harriet Richardson, Paul E Goss Summary Background Exemestane can prevent breast cancer in postmenopausal women. Because of potential widespread use, we examined the safety of exemestane on bone health. Methods In this nested safety substudy of the MAP.3 trial (a randomised, placebo-controlled, double-blind trial of exemestane 25 mg a day for the primary prevention of breast cancer), we included postmenopausal women from five centres who were eligible to participate in MAP.3, not osteoporotic, not receiving drugs for bone-related disorders, with baseline lumbar spine, total hip, and femoral neck T-scores above –2·0. The primary endpoint was percent change from baseline to 2 years in total volumetric bone mineral density (BMD) at the distal radius by high-resolution peripheral quantitative CT. The primary analysis was per protocol using a non-inferiority margin. This analysis was done earlier than originally planned because of the impending announcement of MAP.3 results and subsequent unmasking of patients to treatment assignment. This study is registered with ClinicalTrials.gov, number NCT01144468, and has been extended to 5 years of unmasked follow-up. Findings 351 women (176 given exemestane, 175 given placebo; median age 61·3 years [IQR 59·2–64·9]) met our inclusion criteria and completed baseline assessment. At the time of clinical cutoff, 242 women had completed 2-year follow-up (124 given exemestane, 118 given placebo). From baseline to 2 years, the mean percent change in total volumetric BMD at the distal radius was –6·1% (95% CI –7·0 to –5·2) in the exemestane group and –1·8% (–2·4 to –1·2) in the placebo group (difference –4·3%, 95% CI –5·3 to –3·2; p<0·0001). The lower limit of the 95% CI was lower than our non-inferiority margin of negative 4% (one-sided test for non-inferiority p=0·70), meaning the hypothesis that exemestane was inferior could not be rejected. At the distal tibia, the mean percent change in total volumetric BMD from baseline to 2 years was –5·0% (95% CI –5·5 to –4·4) in the exemestane group and –1·3% (–1·7 to –1·0) in the placebo group (difference –3·7%, 95% CI –4·3 to –3·0; p<0·0001). The mean percent change in cortical thickness was –7·9% (SD 7·3) in the exemestane group and –1·1% (5·7) in the placebo group at the distal radius (difference –6·8%, 95% CI –8·5 to –5·0; p<0·0001) and –7·6% (SD 5·9) in the exemestane group and –0·7% (4·9) in the placebo group at the distal tibia (difference –6·9%, –8·4 to –5·5; p<0·0001). Decline in areal BMD, as measured by dual-energy x-ray absorptiometry, in the exemestane group compared with the placebo group occurred at the lumbar spine (–2·4% [95% CI –3·1 to –1·7] exemestane vs –0·5% [–1·1 to 0·2] placebo; difference –1·9%, 95% CI –2·9 to –1·0; p<0·0001), total hip (–1·8% [–2·3 to –1·2] exemestane vs –0·6% [–1·1 to –0·1] placebo; difference –1·2%, –1·9 to –0·4; p=0·004), and femoral neck (–2·4% [–3·2 to –1·7] exemestane vs –0·8% [–1·5 to 0·1] placebo; difference –1·6%, –2·7 to –0·6; p=0·002). Interpretation 2 years of treatment with exemestane worsens age-related bone loss in postmenopausal women despite calcium and vitamin D supplementation. Women considering exemestane for the primary prevention of breast cancer should weigh their individual risks and benefits. For women taking exemestane, regular bone monitoring plus adequate calcium and vitamin D supplementation are important. To assess the effect of our findings on fracture risk, long-term follow-up is needed. Funding Canadian Breast Cancer Research Alliance (Canadian Institutes of Health Research/Canadian Cancer Society). Introduction Breast cancer is the most commonly diagnosed cancer and the leading cause of cancer-related death among women worldwide. 1 In the adjuvant setting, aromatase inhibitors are superior to the selective oestrogen- receptor modulator tamoxifen for preventing breast cancer recurrence, with 16% to 32% reduction in risk compared with tamoxifen. 2–4 Recently, the NCIC clinical trials group Mammary Prevention 3 [MAP.3] trial showed that exemestane (a steroidal aromatase inhibitor) 25 mg per day reduced the risk of invasive breast cancer (annual incidence 0·19% for women given exemestane