Bisphosphonates and primary breast cancer risk: an updated systematic review and meta-analysis involving 963,995 women

IMPORTANCE: Prevention of primary breast cancer (BCa) in women is of great public health importance. The existing results from observational epidemiologic studies focused on the association between bisphosphonates and primary BCa risk have been inconsistent. OBJECTIVE: To update this systematic review and meta-analysis to assess the effect of bisphosphonates on primary BCa risk. DATA SOURCES: We comprehensively searched MEDLINE, EMBASE, Cochrane libraries, ProQuest, and Web of Science through June 25, 2018 for relevant studies. STUDY SELECTION: Epidemiological studies that assessed the effect of bisphosphonates on the risk of primary BCa in women. DATA EXTRACTION AND SYNTHESIS: We reported this meta-analysis according to the PRISMA guidelines. Available multivariable-adjusted effect estimates and corresponding 95% CIs were pooled with a random-effects model. MAIN OUTCOMES AND MEASURES: The prespecified main outcome was the risk of primary BCa. RESULTS: In total, five cohort studies involving 657,558 women and 12,991 primary BCa patients, three population-based case-control studies involving 54,701 primary BCa cases and 237,962 healthy controls and two randomized controlled trials (RCTs) involving 13,774 women and 165 primary BCa patients were included in this meta-analysis. Bisphosphonates were associated with a 12% decreased risk of primary BCa (RR, 0.88; 95% CI, 0.83–0.94). However, when we analyzed study designs separately, the pooled results from observational studies were inconsistent with that from RCTs. The observed association of primary BCa risk with long-term use (≥1 year) of bisphosphonates seemed to be more robust and stronger than that of short-term use (<1 year) (RR, 0.75; 95% CI, 0.66–0.84; and 0.90; 95% CI, 0.84–0.97; respectively). CONCLUSION: This meta-analysis adds to the body of evidence for an association between bisphosphonates and a significantly decreased risk of primary BCa. However, future large-scale RCTs are required to validate this concern.