Single-Dose Zoledronate Provides Comparable 5-Year Outcomes in Early Breast Cancer: NEJM
Breast Cancer
In this randomized trial of postmenopausal patients with early breast cancer, a single 4 mg infusion of Zoledronate was compared with 6-monthly dosing over 3 years. Earlier analyses showed that single-dose therapy offered greater convenience, lower toxicity, and fewer treatment discontinuations. At final 5-year follow-up, recurrence-free survival, bone metastasis–free survival, and overall survival appeared similar between the two treatment strategies, with no clear survival advantage for more frequent dosing. The study was published in The New England Journal of Medicine by Mark C. and colleagues.
The study population involved early-stage breast cancer patients in a post-menopausal state that either occurred naturally because of age or had been achieved by medical means through chemotherapy and endocrine suppressor treatments. Patients were randomly allocated into one of two groups on a precise 1:1 ratio basis where the de-escalated group was administered 4 mg zoledronate through intravenous therapy only once as a single dose while the control group was administered 4 mg zoledronate through intravenous route on a six-month cycle for three years.
Following three years of follow-up period, the study team proceeded with their investigation through five year planned analysis period. The secondary endpoints observed over five years involved overall survival rate, recurrence free survival time, bone metastasis free survival and specific skeletal toxicities like jaw osteonecrosis and unforeseen fragility fractures.
Key findings:
- A successful randomization of a total of 211 postmenopausal women diagnosed with early-stage breast cancer to either the experimental single-infusion arm (n=107) or the control semi-annual infusion arm (n=104) was carried out.
- At the five-year follow-up period, the recurrence-free survival rates were found to be equally high in both the arms, that is, 88.7% in the single-infusion arm and 84.1% in the every-six-months infusion group, resulting in a hazard ratio of 0.71 (95% CI: 0.34–1.51).
- The rates of bone metastasis-free survival were equally consistent, with 90.6% recorded among patients who received the single zoledronic acid dose and 86.0% among those in the multi-infusion group (HR=0.68, 95% CI: 0.30–1.52).
- The rate of overall survival five years after a single dose of zoledronate was found to be 91.6%, whereas, the survival rate in the semi-annual infusion arm was observed to be 88.0%.
- No significant differences between the two groups could be found, with HR = 0.79 (95% CI: 0.34–1.82).
- The overall incidence of osteonecrosis of the jaw, which constitutes a rare but life-threatening adverse outcome associated with bisphosphonates, occurred equally in 0% patients in each of the two arms.
Overall, a single dose of zoledronate has already been shown to have benefits in terms of being more convenient for patients, having less toxicity, and reduced likelihood of treatment discontinuation, compared to treatment every six months. As for the current study, where five years of follow-up were assessed, there is no indication that there would be any difference in outcomes as far as patient survival rate goes. Given the results obtained from this long-term study, there is plenty of reason to change guidelines for breast cancer treatment around the world.
Reference:
Clemons, M., Stober, C., Pond, G. R., Conter, H., Simos, D., Dhesy-Thind, S., Mates, M., Trinkaus, M., Hilton, J., Savard, M.-F., Fergusson, D., Vandermeer, L., & Awan, A. A. (2026). Every six-month versus single-dose adjuvant zoledronate in early breast cancer. NEJM Evidence, 5(6), EVIDoa2500202. https://doi.org/10.1056/EVIDoa2500202
