Use of acid-suppressive drugs and risk of fracture: a meta-analysis of observational studies

Ann Fam Med. May-Jun 2011;9(3):257-67. doi: 10.1370/afm.1243.


Purpose: Previous studies have reported inconsistent findings regarding the association between the use of acid-suppressive drugs such as proton pump inhibitors (PPIs) and histamine 2 receptor antagonists (H(2)RAs) and fracture risk. We investigated this association using meta-analysis.

Methods: We searched MEDLINE (PubMed), EMBASE, and the Cochrane Library from inception through December 2010 using common key words. We included case-control, nested case-control, and cohort studies. Two evaluators independently reviewed and selected articles. We determined pooled effect estimates by using random-effects meta-analysis, because of heterogeneity.

Results: Of 1,809 articles meeting our initial inclusion criteria, 5 case-control studies, 3 nested case-control studies, and 3 cohort studies were included in the final analyses. The pooled odds ratio (OR) for fracture was 1.29 (95% confidence interval [CI], 1.18-1.41) with use of PPIs and 1.10 (95% CI, 0.99-1.23) with use of H(2)RAs when compared with nonuse of the respective medications. Long-term use of PPIs increased the risk of any fracture (adjusted OR = 1.30; 95% CI, 1.15-1.48) and hip fracture risk (adjusted OR = 1.34; 95% CI, 1.09-1.66), whereas long-term H(2)RA use was not significantly associated with fracture risk.

Conclusions: We found possible evidence linking PPI use to an increased risk of fracture, but no association between H(2)RA use and fracture risk. Widespread use of PPIs with the potential risk of fracture is of great importance to public health. Clinicians should carefully consider their decision to prescribe PPIs for patients already having an elevated risk of fracture because of age or other factors.

Publication types

  • Meta-Analysis
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anti-Ulcer Agents / adverse effects
  • Cimetidine / adverse effects
  • Confidence Intervals
  • Fractures, Bone / chemically induced*
  • Fractures, Bone / epidemiology
  • Fractures, Bone / etiology
  • Gastric Acid / metabolism
  • Gastroesophageal Reflux / drug therapy
  • Histamine H2 Antagonists / adverse effects*
  • Histamine H2 Antagonists / therapeutic use
  • Humans
  • Odds Ratio
  • Proton Pump Inhibitors / adverse effects*
  • Proton Pump Inhibitors / therapeutic use
  • Risk Assessment / methods
  • Risk Factors


  • Anti-Ulcer Agents
  • Histamine H2 Antagonists
  • Proton Pump Inhibitors
  • Cimetidine