P2-19-01: Impact of Zoledronic Acid on Fractures, Bone Mineral Density and Bone Remodeling in the AZURE Trial (BIG 01–04).

Abstract

Abstract Background: The AZURE trial was designed to determine whether the addition of zoledronic acid (ZOL) to standard adjuvant therapy improves disease free survival (DFS) in patients (pts) with stage II/III breast cancer. Although in a recent analysis after 752 events and a median follow-up of 59 months no difference in overall DFS was seen between ZOL and control pts, significant benefits were seen in women >5years post menopause. Here, we report the impact of ZOL on fractures in the main study, and on bone mineral density (BMD) and bone remodeling evaluated within a sub-study. Materials and methods: 3360 pts were randomized to receive (neo) adjuvant chemotherapy (CT) and/or endocrine therapy with (n=1681) or without (n=1678) up to 19 doses of ZOL 4mg over 5 years. Pts with osteoporosis and those using bisphosphonates, either at baseline or in the previous year, were excluded from study entry. BMD was assessed in 228 patients within a sub-study; 40 of these also underwent quantitative bone scanning (QBS), a novel imaging technique that yields values for 99mTc-MDP/HMDP whole skeleton plasma clearance (Kbone) as a surrogate for the rate of bone remodeling and enables assessment of specific regions of interest within the skeleton. Results: Fractures occurred in 152 (4.5%) pts; 60 (3.6%) ZOL pts compared with 92 (5.5%) control (CTRL) pts (difference −1.9%; 95%CI −3.3%, −0.5%). The difference in fracture incidence appeared early and persisted throughout the follow-up period. Fifty-six (86.2%) of the fractures in the ZOL group and 68 (61.8%) in the CTRL group occurred in the absence of, or prior to a DFS event. The fracture rates before disease recurrence were similar at 3.0% (51 pts) in the ZOL group and 3.4% (57 pts) in the CTRL group (difference −0.4%; 95%CI −1.6%, 0.8%). In contrast, 2.1% (8 ZOL pts) and 9.1% (34 CTRL pts) experienced a fracture after a DFS event (difference −6.9%; 95% CI −10.2%, −3.7%). For pts with a DFS event, the majority of fractures occurred after a skeletal recurrence; 87.5% (7 of 8) ZOL and 88.2% (30 of 34) CTRL pts. BMD Z-scores at completion of protocol treatment were higher in patients treated with ZOL. Kbone was lower in ZOL patients (26.5 vs 29.8 ml min−1 using 99mTc-MDP and 34.3 vs 39.3 ml min−1 with 99mTc-HMDP). Expressed as a percentage of whole skeleton clearance, regional values in the mandible were similar 1.15% (ZOL) vs. 1.22% (CTRL). Conclusions: Adjuvant ZOL given in the schedule studied in AZURE reduced the fracture rate in patients who developed recurrence of breast cancer. BMD was higher and the rate of bone remodeling less in patients treated with ZOL. Further follow-up will determine the duration and clinical relevance of these effects on bone health. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P2-19-01.