Comparing a Single-Dose vs. Twice Yearly Zoledronate in Patients With Early Stage Breast Cancer (REaCT-ZOL)

Breast cancer patients are at an increased risk of recurrence in bone and bone density loss (osteopenia/osteoporosis) and consequently fragility fractures due to: age, systemic therapy with aromatase inhibitors, and premature induction of menopause by chemotherapy or ovarian ablation. Bone is the most common site of breast cancer recurrence. The use of bone modifying agents, such as Zoledronate may reduce the risk of bone metastases and fragility fractures. Despite the widespread use of adjuvant Zoledronate, it is not known what the optimal number of infusions is to reduce the risk of bone metastases and the risk of fragility fractures. Indeed, the recent CCO and ASCO Practice Guideline, 'Bottom line recommendations' specifically states, "More research is recommended comparing different bone-modifying agents, doses, dosing intervals, and durations." In the metastatic setting, for nearly 2 decades biphosphonates (i.e. Zoledronate) have been given to patients every 3-4 weeks. This dosing interval was selected based on convenience of co-administration with standard anti-cancer agents and not on the long biological effect of these agents on osteoclasts, the cells responsible for excess bone breakdown. Furthermore, in the bone density preservation setting, despite the usual administration of Zoledronate once a year a single dose of Zoledronate was associated with a sustained increase in bone mineral density 5 years later. A recent systematic review in the adjuvant setting, showed that BTA at any particular dose or route of administration showed superiority over the other. In other words, the lowest dose appears to be just as good as the highest dose. This study will compare the single dose of Zoledronate to Zoledronate given every 6 months for 3 years. The primary outcome for this study will be feasibility of conducting this trial. The secondary outcome will assess bone-metastasis risk, fragility rates, quality of life, and cost-effectiveness. In this study it is hypothesized that a single dose of Zoledronate will be non-inferior to every 6 months in terms of bone-metastasis free survival, time to first bone metastasis and fragility fractures. It is also hypothesized that a single dose of Zoledronate will have less toxicities associated with Zoledronate compared to every 6 months.