Elsevier

Bone

Volume 48, Issue 4, 1 April 2011, Pages 768-776
Bone

Meta-analysis: Risk of fractures with acid-suppressing medication,☆☆,

https://doi.org/10.1016/j.bone.2010.12.015Get rights and content

Abstract

Aims

Recent studies have suggested an increased risk of fractures with proton pump inhibitors (PPIs) and histamine-2 receptor antagonists (H2RAs). We planned to perform a meta-analysis of fractures in patients taking PPIs and H2RAs.

Methods

We searched MEDLINE and EMBASE in September 2010 for observational studies reporting on the risk of fractures with acid-suppressing medication (PPIs and H2RA). We also checked the references lists of included studies and regulatory authority websites for additional data. We performed random effects meta-analysis of odds ratios (OR) according to fracture type and conducted subgroup analyses by duration of exposure. Heterogeneity was assessed using the I2 statistic.

Results

Our review included 12 studies covering 1,521,062 patients. Pooled analysis of PPI use showed significant risk for spine fractures (4 studies, OR 1.50, 95% CI 1.32–1.72, p < 0.001, I2 = 0%) but this was not significant for H2RA (3 studies, OR 1.05, 95% CI 0.92–1.19, p = 0.50, I2 = 0%). Similarly for hip fractures, there was a significant risk of fractures with PPIs (10 studies, OR 1.23, 95% CI 1.11–1.36, p < 0.001, I2 = 72%), but not for H2RAs (9 studies, OR 1.12, 95% CI 0.99–1.27, p = 0.06, I2 = 75%), respectively). Analysis of fractures overall (based on all 12 studies covering a mixture of fracture types) yielded an OR of 1.20 (95% CI 1.11–1.30, p < 0.001, I2 = 78%) for PPIs, and OR of 1.08 (95% CI 1.00–1.18, p = 0.06, I2 = 82%) for H2RA. However, aside from the risk of spine fractures, all the other analyses were limited by substantial heterogeneity. One study that reported on a direct comparison between acid-suppressing medications found an increased risk with PPIs vs. H2RA for hip fractures, OR 1.34 (95% CI 1.14–1.38).

Conclusion

There is some evidence for a modest association between PPI use and risk of fractures, which was not seen with H2RA exposure. The association is most consistent for spine fractures, while there is substantial heterogeneity in the magnitude of risk for other fractures. Clinicians who are concerned about patients with high fracture risk may wish to consider the option of H2RAs instead of PPIs.

Research Highlights

► Studies have suggested a link between acid-suppressing medication and fractures. ► We performed a meta-analysis of fracture with acid-suppressing medications. ► We found a modest link between PPIs and fractures, particularly spine fractures. ► No consistent evidence supports the association between H2RAs and fractures. ► Direct and indirect evidence suggests that H2RAs have less fracture risk than PPIs.

Introduction

Proton pump inhibitors (PPIs) and histamine-2 receptor antagonists (H2RAs) are widely used, but there is growing concern that these agents may increase the risk of fractures. One of the first studies to demonstrate an increased hip fracture risk with PPIs was a nested case control conducted by Yang et al. [1]. Since then, there have been more reports of fracture risk with PPI therapy [1], [2], [3], [4], [5] and with H2RAs [2], [4]. However, other studies have failed to confirm fracture risk of with PPIs [6], [7] or H2RA therapy [3], [5], [8], [9]. More recently, the US Food and Drug Administration issued a safety alert regarding the possible risk of PPI and fractures, with proposed labelling changes to the safety information [10]. In their safety review, the FDA commented that randomized controlled trials had not identified an increased risk of fractures, but also noted that the trials did not cover long durations of treatment or higher doses. Both the FDA review and a recent publication by Heidelbaugh [11] have narratively summarized the evidence without pooling in a meta-analysis. At present, the exact magnitude of harm (if any) is unclear and we do not have robust quantitative estimates on the differences between PPIs and H2RAs. As such, we aimed to systematically evaluate the risk of fractures with acid suppressive medication and compare the relative effects between PPIs and H2RAs.

Section snippets

Eligibility criteria

We selected observational studies that reported on fractures associated with PPI or H2RA exposure. For the observational studies, we selected case-control or controlled cohort (prospective or retrospective) studies that evaluated the association of fracture risk with concomitant PPI or H2RA exposure. The specific inclusion criteria were that the studies had to report odds ratios /risk ratios for fractures with acid suppressing drugs, or to report sufficient raw data to allow for calculation of

Results

The search results yielded 12 observational studies from 11 articles reporting on fractures with acid-suppression medication covering 1,521,062 patients [1], [2], [3], [4], [5], [6], [8], [9], [17], [18]. We found 4 prospective cohort studies, and 8 retrospective studies (of which 6 were case-control in design). Where duration of follow up was reported, this ranged from a median of 6.5 weeks to a mean of 7.8 years. Of the studies that were included in the analysis of PPIs, 4 studies reported on

Discussion

The overall pooled estimates suggest that there is an increased risk of fractures with PPI use but not with H2RA use. This increased risk with PPIs is present for fracture subtypes covering the hip and spine, notably with no heterogeneity in the meta-analysis of spine fractures. Although there is substantial heterogeneity surrounding the pooled estimate of overall fracture risk, the direction of effect shows a consistently elevated risk in eight of the ten PPI datasets, thus suggesting that the

Conclusions

In conclusion, the findings of this meta-analysis suggest that there is a modest link between PPI use and fractures (particularly spine), which was not found for H2RA. Clinicians should carefully evaluate the risk factors for osteoporosis in a patient before routinely prescribing PPIs, and make a careful judgement as to whether H2RA may be safer alternatives for patients at high risk of fractures.

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    Contributors: YKL and CSK conceptualised the review, developed the protocol and analysed data. YKL, CSK and JKY abstracted data and wrote the manuscript. YKL will act as the guarantor for the paper.

    ☆☆

    Funding: None.

    Competing interests: YK Loke, JK Yeong and CS Kwok have no competing interests to declare. No funding was received.

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