Meta-analysis: Risk of fractures with acid-suppressing medication☆,☆☆,★
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.
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Funding: None.
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Competing interests: YK Loke, JK Yeong and CS Kwok have no competing interests to declare. No funding was received.