The most common adverse effects of bisphosphonates are gastrointestinal. Trials reported esophageal ulcerations from all bisphosphonates except zoledronic acid. One trial of etidronate versus placebo showed a statistically significant increase in esophageal ulceration (OR, 1.33 [CI, 1.05 to 1.68]) (118). Mild upper gastrointestinal events (acid reflux, esophageal irritation, nausea, vomiting, and heartburn) were more common with etidronate in a pooled analysis (OR, 1.33 [CI, 1.21 to 1.46]) (32,42,53 - 54,64,112,118 - 128) and with pamidronate (OR, 3.14 [CI, 1.93 to 5.21]) (75,79,129 - 133). Pooled analysis showed no difference in occurrence of mild upper gastrointestinal events between alendronate, ibandronate, risedronate, or zoledronic acid and placebo. However, pooled analysis of head-to-head trials showed a higher risk for mild upper gastrointestinal events with alendronate than with etidronate (OR, 5.89 [CI, 1.61 to 32.7]), calcitonin (OR, 3.42 [CI, 1.79 to 7.00]), or estrogen (OR, 1.57 [CI, 1.00 to 2.46]). The pooled estimate from 3 studies showed that etidronate users were at increased risk for perforations, ulcerations, and gastrointestinal bleeding events (OR, 1.32 [CI, 1.04 to 1.67]) (59,118,134), whereas the pooled estimate from 2 studies showed that ibandronate had a lower risk for serious gastrointestinal adverse events (OR, 0.33 [CI, 0.14 to 0.74]) (68,135). Case reports and case series have documented increased osteonecrosis of the jaw in patients receiving bisphosphonates, but the most cases of osteonecrosis have occurred in patients with cancer who received high doses of intravenous bisphosphonates (136). However, we could not calculate the risk for this event from the available studies. Some studies showed a link between atrial fibrillation and either zoledronic acid or alendronate (5,137).