Clinical research study
Proton Pump Inhibitors and Risk of Fractures: A Meta-Analysis of 11 International Studies

https://doi.org/10.1016/j.amjmed.2011.01.007Get rights and content

Abstract

Background

Concerns have been raised about the risk of fractures with acid-suppressive medications, such as proton pump inhibitors and histamine2-receptor antagonists.

Methods

This meta-analysis evaluated the association between proton pump inhibitor or histamine2-receptor antagonist use and fractures. We performed a systematic search of published literature (1970 to October 10, 2010) in MEDLINE, EMBASE, and other sources. Ten publications reporting 11 studies were considered eligible for analysis.

Results

All studies were observational case-control or cohort studies and primarily evaluated older adults. The summary effect estimate for risk of hip fracture increased modestly among individuals taking proton pump inhibitors (relative risk [RR] 1.30, 95% confidence interval [CI], 1.19-1.43). There also was an increase in spine (RR 1.56, 95% CI, 1.31-1.85) and any-site fractures (RR 1.16, 95% CI, 1.04-1.30) among proton pump inhibitor users. These findings were similar in both men and women and after stratification by duration of use. In contrast, histamine2-receptor antagonist use was not significantly associated with increased risk of hip fracture (RR 1.12, 95% CI, 0.97-1.30).

Conclusion

In this meta-analysis of observational studies, proton pump inhibitors modestly increased the risk of hip, spine, and any-site fractures, whereas histamine2-receptor antagonists were not associated with fracture risk. The possibility of residual confounding cannot be excluded. Further skeletal evaluation should be considered for patients who are taking proton pump inhibitors and also at risk for osteoporotic fracture.

Section snippets

Eligibility Criteria

Methods of the analysis were prespecified in a protocol. To be eligible, studies had to examine the risk of bone fracture attributable to the use of proton pump inhibitors or histamine2-receptor antagonists, and include a comparator control group. Medication use had to be documented before occurrence of fracture. Analyses had to be adjusted at minimum for age and gender.

Search Strategy

PubMed/MEDLINE (National Center for Biotechnology Information), EMBASE (Elsevier), Web of Science (ISI Web of Knowledge), and

Study Selection

The systematic search of MEDLINE, EMBASE, and other sources provided a total of 642 citations, after adjusting for duplicates. Of these, 573 were excluded after initial abstract screening. The full texts of the remaining 69 articles were examined in more detail. Twelve publications met inclusion criteria;8, 9, 10, 11, 12, 14, 15, 16, 17, 18, 20, 21 however, 3 of these analyzed the same database (General Practice Research Database [GPRD]);8, 15, 17 only 1 was included in the meta-analysis to

Discussion

In this study level meta-analysis, proton pump inhibitor use was associated with a modestly increased risk of hip fractures. Spine fractures were more frequent among individuals taking proton pump inhibitors, and there also was a slight increase in risk of any-site fractures. These findings were similar in both men and women. Although the FDA advisory based on non-quantitative review of the data states that “patients at highest risk for fractures … used a PPI for one year or more,”13 our

Conclusions

This meta-analysis of observational studies found that proton pump inhibitor use modestly increased the risk of hip, spine, and any-site fractures, whereas histamine2-receptor antagonist use was not associated with increased fracture risk. The biologic mechanism is not yet clear, and we cannot rule out the possibility of residual confounding. But even a slight increase in fracture risk due to proton pump inhibitors may lead to a large number of additional fractures on a public health scale. The

Acknowledgments

The authors thank Dr Yu-Xiao Yang, Dr Douglas Corley, Dr Shelley Gray, Dr Laure Gossec, Dr Frank de Vries, Dr Peter Vestergaard, and Terri Blackwell for providing additional data for this meta-analysis.

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    Funding: Dr Bauer is supported by National Institutes of Health Grant K24 ARO51895.

    Conflict of Interest: None.

    Authorship: All authors had access to the data and played a role in writing this manuscript.

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