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

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• 作者：Dr Angela M Cheung ; MD^a ; ^{angela.cheung@uhn.ca} ; Lianne Tile ; MD^a ; Savannah Cardew ; MD^a ; Sandhya Pruthi ; MD^e ; Prof John Robbins ; MD^g ; George Tomlinson ; PhD^a ; Moira K Kapral ; MD^a ; Prof Sundeep Khosla ; MD^d ; Prof Sharmila Majumdar ; PhD^f ; Marta Erlandson ; PhD^a ; Judy Scher ; MSc^a ; Hanxian Hu ; MSc^a ; Alice Demaras ; MSc^a ; Prof Lavina Lickley ; MD^c ; Louise Bordeleau ; MD^h ; Christine Elser ; MD^b ; Prof James Ingle ; MD^e ; Harriet Richardson ; PhDⁱ ; Prof Paul E Goss ; MD^j
• 刊名：Lancet Oncology
• 出版年：2012
• 期刊代码：184_14702045
• 类别：med
• 出版时间：March, 2012
• 卷：13
• 期：3
• 页码：275-284
• 文件大小：220 K

摘要

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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 鈭?路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 , number , and has been extended to 5 years of unmasked follow-up.

Findings

351 women (176 given exemestane, 175 given placebo; median age 61路3 years [IQR 59路2-64路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 鈭?路1%(95%CI 鈭?路0 to 鈭?路2) in the exemestane group and 鈭?路8%(鈭?路4 to 鈭?路2) in the placebo group (difference 鈭?路3%, 95%CI 鈭?路3 to 鈭?路2; p<0路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路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 鈭?路0%(95%CI 鈭?路5 to 鈭?路4) in the exemestane group and 鈭?路3%(鈭?路7 to 鈭?路0) in the placebo group (difference 鈭?路7%, 95%CI 鈭?路3 to 鈭?路0; p<0路0001). The mean percent change in cortical thickness was 鈭?路9%(SD 7路3) in the exemestane group and 鈭?路1%(5路7) in the placebo group at the distal radius (difference 鈭?路8%, 95%CI 鈭?路5 to 鈭?路0; p<0路0001) and 鈭?路6%(SD 5路9) in the exemestane group and 鈭?路7%(4路9) in the placebo group at the distal tibia (difference 鈭?路9%, 鈭?路4 to 鈭?路5; p<0路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 (鈭?路4%[95%CI 鈭?路1 to 鈭?路7] exemestane vs 鈭?路5%[鈭?路1 to 0路2] placebo; difference 鈭?路9%, 95%CI 鈭?路9 to 鈭?路0; p<0路0001), total hip (鈭?路8%[鈭?路3 to 鈭?路2] exemestane vs 鈭?路6%[鈭?路1 to 鈭?路1] placebo; difference 鈭?路2%, 鈭?路9 to 鈭?路4; p=0路004), and femoral neck (鈭?路4%[鈭?路2 to 鈭?路7] exemestane vs 鈭?路8%[鈭?路5 to 0路1] placebo; difference 鈭?路6%, 鈭?路7 to 鈭?路6; p=0路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).