Elsevier

Life Sciences

Volume 218, 1 February 2019, Pages 213-223
Life Sciences

Proton pump inhibitors therapy and risk of bone diseases: An update meta-analysis

https://doi.org/10.1016/j.lfs.2018.12.058Get rights and content

Abstract

Aims

Large observational studies have yielded conflicting results regarding whether the use of proton pump inhibitors (PPI) increases the risk of bone diseases. Here, we performed a meta-analysis to examine the link between PPI and risk of bone fractures, osteoporosis and bone mineral density (BMD) loss.

Materials and methods

We systematically performed a search for published reports on PubMed, EMBASE and the Cochrane Library. We considered articles published in English, and restricted the search to studies on human participants. Studies that reported adjusted Hazard ratio (HR) estimates with 95% confidence intervals (CI) for the associations of interest were included. Data from the articles which can be used to estimate standardized mean difference (SMD) were also obtained and utilized to assess the risk of BMD loss.

Key findings

Compared with patients not taking PPI, those taking PPI, had the increased risk of developing any-site fractures (HR: 1.30; 95%CI: 1.16 to 1.45), hip fracture (HR:1.22; 95%CI:1.15 to 1.31), spine fracture (HR:1.49; 95%CI:1.31 to 1.68), and osteoporosis (HR:1.23; 95%CI:1.06 to 1.42) based on a random model, but there was no correlation with developing BMD loss in the femoral (SMD: −0.27; 95%CI: −0.62 to 0.09), or in the spine (SMD: −0.06; 95%CI: −0.54 to 0.41).

Significance

Results of this meta-analysis suggest that PPI may moderately increase the risk of any-site, hip, spine fracture. Due to the widespread use of PPI and the impact of fractures on human health, clinicians should carefully evaluate the patient condition before prescribing PPI therapy.

Introduction

Proton pump inhibitors are among the most widely used acid-suppressive medicines with the capacity to treat a broad range of acid-related diseases, including heart-burn symptoms, dyspepsia, chronic cough, gastroesophageal reflux disease and peptic ulcers, or for the prevention of the gastric injuries induced by non-steroidal anti-inflammatory drugs (NSAIDs) and surgery, through a mechanism involving the inhibition of gastric acid secretion [1,2]. PPIs are generally well tolerated by the majority of patients and have traditionally been considered to be relatively safe. However, there have been reports linking PPI use to incidence of hypomagnesemia, pneumonia, Clostridium difficile-associated diarrhea, pancreatic cancer and dementia [[3], [4], [5], [6], [7]]. Particularly, there have been concerns related to the potential association between the use of PPI and the risk of bone events, such as bone fractures, osteoporosis, and BMD loss. This association was first reported by Yang et al. [8], where persons taking PPI suffered were 1.44 times more likely to develop hip fracture compared to controls. In 2011, the Food and Drug Administration (FDA) published a cautionary note on the increased risk of fractures with the use of high dose and/or long-term PPI [9]. Subsequently, several observational studies having been performed to determine the association of PPI use with osteoporosis or BMD loss. Although numerous observational studies supported this notion, some studies have reported conflicting results. These inconsistencies could be partly explained by different types of study designs, population characteristics, and different baseline levels. Furthermore, the association between bone diseases and PPI use may be over-estimated due to the existence of other confounders. Actually, the mechanism by which PPI increases the risk of fracture, osteoporosis, and BMD loss has yet to be elucidated.

Given this background, the use of PPI needs to be re-evaluated to guide clinical treatment decisions. Analysis of large numbers of cases may enhance the statistical power of meta-analysis to assess the relationship between exposure and outcome. To close this gap, we conducted an update meta-analysis to determine the link between PPI use and fractures, osteoporosis, and BMD loss.

Section snippets

Search strategy

We searched for articles published on PubMed, EMBASE and the Cochrane Library from inception up to May 2018, using the following key words and text in combination, both as Mesh terms and text words: (“bone mineral density” OR “bone density” OR “osteoporosis” OR “osteoporoses” OR bone Loss” OR “fractures, Bone” OR “broken bones” OR “bone, broken” OR “bones, broken” OR “broken bone” OR “bone fractures” OR “bone fracture” OR “fracture, bone” OR “fractures” OR “fracture”) and (“proton pump

Literature search

We initially retrieved 1313 articles, of which 147 articles were excluded after adjusting for duplicates. Of the remaining 1166 articles, 1112 were excluded after the initial title and abstract screening, because they were review articles, laboratory studies, or irrelevant to our study purpose. The full texts of the remaining 54 articles were examined in detail, of which 23 articles were excluded according to the eligibility criteria (Fig. 1). Among the included studies, one of them reported

Discussion

This is an update meta-analysis of 32 observational studies involving 2-181-546 individuals which evaluated the effect of PPI use on the risk of bone diseases, such as bone fractures, osteoporosis and BMD loss. Our meta-analysis found that there was a moderate increased risk of any-site fractures, hip fracture, spine fracture and osteoporosis in people using PPI, but found no correlation between PPI use and BMD loss. In stratified analysis, the association of PPI use with any-site fractures or

Conclusion

Results of this meta-analysis suggest that PPI may moderately increase the risk of any-site, hip, spine fracture. However, the relationship between PPI and BMD remains uncertain. Due to the widespread use of PPI and the impact of fractures on human health, clinicians should carefully evaluate the patient condition before prescribing PPI therapy.

The following is the supplementary data related to this article.

. The Pooled HR of several categories among seven studies separately.

Conflict of interest

The authors declare that there are no conflicts of interest.

Acknowledgments

We thank Prof. Jiaming Sun for his assistance in structuring the search strings and linguistic advice. This work was supported by the National Natural Science Foundation of China (No. 81701922 to Zhenxing Wang, No. 81601701 to Jiecong Wang).

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