Comparative gastrointestinal safety of bisphosphonates in primary osteoporosis: a network meta-analysis

Osteoporos Int. 2014 Apr;25(4):1225-35. doi: 10.1007/s00198-013-2576-2. Epub 2013 Nov 28.


We completed a network meta-analysis of published papers to compare bisphosphonate gastrointestinal safety. We found that zoledronic acid had the highest chance of causing gastrointestinal adverse events. Etidronate had the highest chance of discontinuation due to an adverse event. No difference was found for serious adverse events.

Introduction: Bisphosphonates are first-line treatment for osteoporosis. Gastrointestinal (GI) adverse events (AE) are the primary reason for non-adherence. Little is known about the comparative GI safety of bisphosphonates.

Purpose: Leverage published clinical trial data to examine the comparative GI safety of bisphosphonates.

Methods: We completed a systematic review of all English-language clinical trials that assessed bisphosphonate safety and/or efficacy in primary osteoporosis through to 2012. Randomized, blinded, and controlled studies were eligible. The primary outcome was any GI-related AE. Subanalyses were completed for upper GI symptoms, serious GI, nausea, esophageal-related events, and discontinuation due to AE. A Bayesian-based network meta-analysis was completed to allow for indirect comparisons. Results were reported as the probability that a specific drug had the highest number of events.

Results: We identified 50 studies: 32 alendronate, 12 risedronate, 5 etidronate, and 7 zoledronic acid. Zoledronic acid had the highest probability of having the highest number of any GI AE (91%) and nausea (70%). Etidronate (70%) and zoledronic acid (28%) had the highest probability of having the greatest attrition due to AE. Etidronate had the highest probability (56%) of having the greatest number of upper GI symptoms among oral bisphosphonates.

Conclusion: Zoledronic acid had the highest probability of causing the greatest number of GI AE, possibly related to nausea. These results question the assumption that annual zoledronic acid will translate into better adherence. Little difference was found between alendronate and risedronate for serious AE. More research into real-world implications of the comparative safety of bisphosphonates is needed.

Publication types

  • Comparative Study
  • Meta-Analysis
  • Research Support, Non-U.S. Gov't
  • Systematic Review

MeSH terms

  • Bone Density Conservation Agents / adverse effects*
  • Bone Density Conservation Agents / therapeutic use
  • Diphosphonates / adverse effects*
  • Diphosphonates / therapeutic use
  • Gastrointestinal Diseases / chemically induced*
  • Humans
  • Imidazoles / adverse effects
  • Nausea / chemically induced
  • Osteoporosis / drug therapy*
  • Randomized Controlled Trials as Topic
  • Zoledronic Acid


  • Bone Density Conservation Agents
  • Diphosphonates
  • Imidazoles
  • Zoledronic Acid