Bisphosphonates and breast cancer survival: a meta-analysis and trial sequential analysis of 81508 participants from 23 prospective epidemiological studies

Background: We assessed the effect of bisphosphonates (BPs) on breast cancer (BCa) patient survival and explored how long the effect can persist after treatment. Methods: We performed a meta-analysis and trial sequential analysis (TSA) of prospective studies including randomized controlled trials (RCTs) and cohort studies. We performed extensive sensitivity analyses to assess the robustness of the findings. Results: Seventeen RCTs and eight cohorts with 81508 BCa patients were identified. A significant beneficial effect of BPs on BCa survival was found (RR, 0.725; 95% CI, 0.627-0.839), and the TSA results also suggested firm evidence for this beneficial effect. Both summarized results from RCTs and cohorts provided firm evidence for this effect, although the effect estimates were stronger from cohorts than RCTs (RR, 0.892; 95% CI, 0.829-0.961; 0.570; 95% CI, 0.436-0.745; respectively). This beneficial effect was confirmed for bone-metastases (RR, 0.713; 95% CI, 0.602-0.843) and postmenopausal women (RR, 0.737; 95% CI, 0.640-0.850). Importantly, our results demonstrated that this beneficial effect was retained at least 1-2 years after treatment completion (RR, 0.780; 95% CI, 0.638-0.954) and could persist for up to more than 4 years after treatment completion (RR, 0.906; 95% CI, 0.832-0.987). Extensive sensitivity analyses showed the robustness of our results. The GRADE quality of evidence was generally judged to be moderate to high. Conclusions: The present study provides firm evidence for a significant beneficial effect of BPs on BCa survival in patients with early-stage BCa, and this effect was retained at least 1-2 years after BP treatment completion.