Aim: To perform a meta-analysis of observational studies to further elucidate the relationship between oral bisphosphonate use and gastrointestinal cancer risk.

Methods: Systematic literature search was conducted in MEDLINE, EMBASE, and the Cochrane Library to identify studies through January 2011. Search terms were "bisphosphonates" or trade names of the drugs, and "observational studies" or "cohort studies" or "case-control studies". Two evaluators reviewed and selected articles on the basis of predetermined selection criteria as followed: (1) observational studies (case-control or cohort studies) on bisphosphonate use; (2) with at least 2 years of follow-up; and (3) reported data on the incidence of cancer diagnosis. The DerSimonian and Laird random effects model were used to calculate the pooled relative risk (RR) with 95% confidence interval (CI). Two-by-two contingency table was used to calculate the outcomes not suitable for meta-analysis. Subgroup meta-analyses were conducted for the type of cancer (esophageal, gastric and colorectal cancers). Sensitivity analyses were performed to examine the effect sizes when only studies with long-term follow-up (mean 5 years; subgroup 3 years) were included.

Results: Of 740 screened articles, 3 cohort studies and 3 case-control studies were included in the analyses. At first, 4 cohort studies and 3 case-control studies were selected for the analyses but one cohort study was excluded because the cancer outcomes were not categorized by type of gastrointestinal cancer. More than 124,686 subjects participated in the 3 cohort studies. The mean follow-up time in all of the cohort studies combined was approximately 3.88 years. The 3 case-control studies reported 3070 esophageal cancer cases and 15,417 controls, 2018 gastric cancer cases and 10,007 controls, and 11,574 colorectal cancer cases and 53,955 controls. The percentage of study participants who used bisphosphonate was 2.8% among the cases and 2.9% among the controls. The meta-analysis of all the studies found no significant association between bisphosphonate use and gastrointestinal cancer. Also no statistically significant association was found in a meta-analysis of long-term follow-up studies. There was no negative association between bisphosphonate use and the incidence of esophageal cancer in the overall analysis (RR 0.96, 95% CI: 0.65-1.42, I(2) = 52.8%, P = 0.076) and no statistically significant association with long-term follow-up (RR 1.74, 95% CI: 0.97-3.10, I(2) = 58.8%, P = 0.119). No negative association was found in the studies reporting the risk of gastric cancer (RR 0.89, 95% CI: 0.71-1.13, I(2) = 0.0%, P = 0.472). In case of colorectal cancer, there was no association between colorectal cancer and bisphosphonate use (RR 0.62, 95% CI: 0.30-1.29, I(2) = 88.0%, P = 0.004) and also in the analysis with long-term follow-up (RR 0.61, 95% CI: 0.28-1.35, I(2) = 84.6%, P = 0.011).

Conclusion: Oral bisphosphonate use had no significant effect on gastrointestinal cancer risk. However, this finding should be validated in randomized controlled trials with long-term follow-up.