Elsevier

Bone

Volume 81, December 2015, Pages 675-682
Bone

Original Full Length Article
The effect of dose and type of proton pump inhibitor use on risk of fractures and osteoporosis treatment in older Australian women: A prospective cohort study

https://doi.org/10.1016/j.bone.2015.08.024Get rights and content

Highlights

  • Proton pump inhibitor (PPI) use in elderly (> 77 years) women was associated with increased risk of decreased bone health.

  • Increased risk of subsequent osteoporosis medication was associated with the most commonly prescribed PPI, esomeprazole.

  • Rabeprazole, and use of multiple different PPIs, were associated with subsequent osteoporosis medication and fractures.

  • There may be a dose–response relationship between PPI use and osteoporosis medication or fractures.

  • Risks of harms need careful assessment before prescribing PPIs to ensure benefits outweigh potential adverse effects on bone.

Abstract

Objectives

Proton pump inhibitors (PPIs) are among the most prescribed medications worldwide, however, there is growing concern regarding potential negative effects on bone health. The aim was to examine the effect of dose and type of PPI use on subsequent use of osteoporosis medication and fractures in older Australian women.

Methods

Data were included from 4432 participants (born 1921–26) in the 2002 survey of the Australian Longitudinal Study on Women's Health. Medication data were from the national pharmaceutical administrative database (2003–2012, inclusive). Fractures were sourced from linked hospital datasets available for four major States of Australia. Competing risk regression models used PPI exposure as a time-dependent covariate and either time to first osteoporosis medication prescription or fracture as the outcome, with death as a competing risk.

Results

Of the 2328 PPI users and 2104 PPI non-users, 827 (36%) and 550 (26%) became users of osteoporosis medication, respectively. PPI use was associated with an increased risk of subsequent use of osteoporosis medication (adjusted sub-hazard ratio [SHR] = 1.28; 95% confidence interval [CI] = 1.13–1.44) and subsequent fracture (SHR = 1.29, CI = 1.08–1.55). Analysis with PPI categorized according to defined daily dose (DDD), showed some evidence for a dose–response effect (osteoporosis medication: <400 DDD: SHR = 1.23, CI = 1.06–1.42 and ≥400 DDD: SHR = 1.39, CI = 1.17–1.65, compared with non-users; SHRs were in the same range for fractures). Esomeprazole was the most common PPI prescribed (22.9%). Analysis by type of PPI use showed an increased subsequent risk for: (1) use of osteoporosis medication for rabeprazole (SHR = 1.51, CI = 1.08–2.10) and esomeprazole (SHR = 1.48, CI = 1.17–1.88); and (2) fractures for rabeprazole (SHR = 2.06, CI = 1.37–3.10). Users of multiple types of PPI also had increased risks for use of osteoporosis medication and fractures.

Conclusion

An appropriate benefit/risk assessment should be made when prescribing PPIs, especially for esomeprazole and rabeprazole, as osteoporosis and fracture risks were increased in this cohort of elderly females subsequent to PPI prescription.

Introduction

Acid-related upper gastrointestinal disorders are common in the developed world [1]. Consequently, proton pump inhibitors (PPIs) to treat these disorders are among the most widely prescribed medications worldwide [1], [2]. PPIs are indicated for several acid-related upper gastrointestinal disorders, including gastro-oesophageal disease (GERD), dyspepsia, peptic ulcer disease and as prophylaxis for non-steroidal anti-inflammatory drugs-associated upper gastrointestinal complications [3]. Due to their effectiveness and perceived short-and long-term safety, PPIs account for 95% of acid suppressing medication prescriptions [1]. In Australia, PPI prescribing tripled from 45 in 2001 to 130 defined daily dose (DDD)/1000 concession beneficiaries/day in 2005 [4]. With 6.9 million prescriptions in 2014, PPIs are the third most prescribed drug group by volume and the fourth highest cost prescribed drug group in Australia [5]. The total number of dispensed prescriptions for PPIs increased by 28% from approximately 74 million prescriptions in 2002 to 95 million prescriptions in 2009 [6].

More recently, a growing concern is the safety of PPIs; several adverse effects of long term PPI use have been reported, including decreased bone quality [3], [7]. Warnings about PPIs and potentially increased fracture risk have been issued in Australia and in the US [8], [9]. In 2011, a meta-analysis by Kwok et al. [7] (observing 4 prospective cohort studies and 8 retrospective studies, of which 6 case–control studies) confirmed an increased risk of fracture following PPI use, presumably due to the development of osteoporosis. In 2014, a prospective cohort study by Moberg et al. [10] found that postmenopausal women using PPI's were having a more than double increased fracture risk (odds ratio = 2.53, confidence intervals (CI) = 1.28–4.99). If a causal relationship exists between PPIs and fractures, the predisposing factors for fractures are expected to be affected. However, studies examining associations between PPI use and bone mineral density (BMD) found none or little evidence for an association between PPI use and the development of osteoporosis [11], [12], [13], [14], [15]. In contrast, a study by Maggio et al. [16] found that PPI use was significantly associated with decreased trabecular BMD, possibly an early marker of osteoporosis. One study found that PPI-users were more likely to subsequently be prescribed osteoporosis medication than non-users and that increased duration of therapy was associated with higher risks of osteoporosis medication prescription [1]. Three studies examining the effect of PPI use on calcium uptake used the dual isotope test (golden standard for intestinal calcium absorption) and these showed no evidence for decreased calcium absorption among PPI users [17], [18], [19]. Overall, it remains unclear whether PPIs indeed have a significant effect on bone metabolism [7].

Previous studies typically compared all PPI users with non-users, while the effect may depend on dose or type of PPI. Investigation of dose and type of PPI use not only gives more insight into the reported adverse effects on bone health, but also may have important implications for prescribing. The study objective was to examine the effect of dose and type of PPI use on subsequent use of osteoporosis medication and fractures in older Australian women from 2003 to 2011. It was hypothesized that PPI use negatively influences bone health resulting in both increased osteoporosis medication prescription and fracture incidence.

Section snippets

Study sample

Data were from the Australian Longitudinal Study on Women's Health (ALSWH), a prospective study of demographic, social, physical, psychological, and behavioural variables and their effect on women's health, well-being and health service use [20]. In 1996, participants were selected from the database of the Health Insurance Commission that ran the national health insurance scheme (Medicare). All Australian citizens and permanent residents, regardless of age or income, were included in the

Results

During an average follow-up of 6.6 years for use of osteoporosis medication, 2328 of the 4432 participants started PPI therapy. During an average follow-up of 7.6 years for fractures, 1396 of the 2734 participants with available linked hospital data started PPI therapy (Fig. 1). PPI-users were more likely than PPI non-users to score lower on self-reported health; have a higher BMI and more chronic conditions; have lower physical functioning; and use other medications (i.e. glucocorticoids, SSRI

Discussion

The results from this prospective cohort study support the hypothesis that PPI use is associated with an increased risk of subsequent use of osteoporosis medication and fractures in older women. These associations were strongest in the users of esomeprazole and rabeprazole. There was some evidence for a dose–response association.

Osteoporosis medications are subsidized on PBS for women with a BMD T-score of <−3 or a minimal trauma fracture, which means that this outcome includes women with a low

Conclusion

PPI use was associated with significantly increased subsequent use of osteoporosis medication and fractures. These associations existed for use of rabeprazole and esomeprazole. This is important as esomeprazole was the most commonly prescribed PPI (22.9% of PPI users). The current results support the hypothesis that PPI use negatively affects bone health. These findings foreshadow the need for a more cautious approach than the current widespread prescribing of PPIs. Different PPIs may have

Conflict of interest

The authors declare that they have no conflict of interest.

Authors' contributions

GP and ST were responsible for the concept and design of the study. MH, GP and AD were responsible for the analyses. All were involved in interpretation of the results. MH was responsible for the writing of the manuscript, other authors contributed to revisions of the manuscript. All authors have approved the final version.

Acknowledgments

The research on which this paper is based was conducted as part of the Australian Longitudinal Study on Women's Health, the University of Newcastle and the University of Queensland. We are grateful to the Australian Government Department of Health for funding and to the women who provided the survey data. We acknowledge Medicare Australia for providing the PBS data; the assistance of the Data Linkage Unit at the Australian Institute of Health and Welfare (AIHW) for undertaking the data linkage

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