Effect of zoledronic acid (ZA) on bone mineral density (BMD) in premenopausal women who develop ovarian failure (OF) due to adjuvant chemotherapy (AdC): First results from CALGB trial 7980

Abstract

512 Background: OF causes accelerated bone loss in premenopausal women receiving AdC of greater magnitude than natural menopause or aromatase inhibitor therapy in postmenopausal women. CALGB 79809 compared the effect of early ZA (with AdC) or late (one year after AdC) on change in BMD in the lumbar spine (LS). We report the effect of early ZA versus no ZA (Control) at 12 months after randomization. Methods: Eligible women (≥ 40 years; stages I-III breast cancer; and last menstrual period ≤ 6 months prior to entry) were randomized to either ZA 4 mg IV every 3 months beginning 1–3 months (Arm A) after the start of AdC or no ZA. BMD of LS, serum FSH, estradiol, and β-HCG were performed at baseline (≤ 28 days prior to randomization) and repeated at 12 months. OF was prospectively defined at the 12 month study visit as ≥ 3 months of amenorrhea with an FSH ≥ 30. All women were told to take 1,000 mg of calcium and 400 IU of vitamin D and compliance (by self-report) and toxicity were assessed every 3 months. Assuming an attrition rate of 20% and that only 50% of women would develop OF, a sample size of 200 per arm was required to have 80% power to detect a mean difference of 0.09 g/cm2 in LS BMD at 12 months with at a two-sided significance level of 0.05. A prespecified boundary for early stopping for superiority was crossed at the first interim analysis. Results: From 12/01 to 12/06, 439 women enrolled and 166 (38%) met the criteria for OF at 12 months. Median age was 47 years (range 40–58); white-92%; performance status 0–91%; stage I-25%; and stage II- 56%. Compliance with calcium and vitamin D was nearly 100%. The majority of ZA-related toxicities were grades 1 or 2; grade 3 included fever- 3%, fatigue-2%, and pain-3%. There was 1(0.5%) woman with possible jaw osteonecrosis after trauma to the jaw and 2 doses of ZA. The results are described in the Table. Conclusions: ZA adds minimal toxicity and prevents the accelerated bone loss that occurs in women who develop OF receiving AdC. Arm A (n=81) Control (n=85) p Mean Percent Change in LS BMD (SD) +2.6 (6.4) −6.4 (6.7) <0.0001 Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Novartis