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Concomitant use of oral glucocorticoids and proton pump inhibitors and risk of osteoporotic fractures among patients with rheumatoid arthritis: a population-based cohort study
  1. Shahab Abtahi1,2,3,
  2. Johanna H M Driessen1,2,3,4,
  3. Andrea M Burden1,5,
  4. Patrick C Souverein2,
  5. Joop P van den Bergh6,7,8,
  6. Tjeerd P van Staa2,9,
  7. Annelies Boonen6,10,
  8. Frank de Vries1,2,3,11
  1. 1 Department of Clinical Pharmacy and Toxicology, Maastricht University Medical Centre, Maastricht, The Netherlands
  2. 2 Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands
  3. 3 Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, The Netherlands
  4. 4 NUTRIM School for Nutrition and Translational Research in Metabolism, Maastricht University Medical Centre, Maastricht, The Netherlands
  5. 5 Institute of Pharmaceutical Sciences, Department of Chemistry and Applied Biosciences, ETH-Zurich, Zurich, Switzerland
  6. 6 Department of Internal Medicine, Division of Rheumatology, Maastricht University Medical Centre, Maastricht, The Netherlands
  7. 7 Faculty of Medicine and Life Sciences, Hasselt University, Hasselt, Belgium
  8. 8 Department of Internal Medicine, VieCuri Medical Centre, Venlo, The Netherlands
  9. 9 Centre for Health Informatics, Division of Informatics, Imaging and Data Science, School of Health Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, UK
  10. 10 Care and Public Health Research Institute (CAPHRI), Maastricht University, Maastricht, The Netherlands
  11. 11 MRC Epidemiology Lifecourse Unit, Southampton General Hospital, Southampton, UK
  1. Correspondence to Professor Frank de Vries, Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, PO BOX 80082, 3508 TB, Utrecht, The Netherlands; f.devries{at}


Background Patients with rheumatoid arthritis (RA) commonly use oral glucocorticoids (GCs) and proton pump inhibitors (PPIs), both associated with osteoporotic fractures. We investigated the association between concomitant use of oral GCs and PPIs and the risk of osteoporotic fractures among patients with RA.

Methods This was a cohort study including patients with RA aged 50+ years from the Clinical Practice Research Datalink between 1997 and 2017. Exposure to oral GCs and PPIs was stratified by the most recent prescription as current use (<6 months), recent use (7–12 months) and past use (>1 year); average daily and cumulative dose; and duration of use. The risk of incident osteoporotic fractures (including hip, vertebrae, humerus, forearm, pelvis and ribs) was estimated by time-dependent Cox proportional-hazards models, statistically adjusted for lifestyle parameters, comorbidities and comedications.

Results Among 12 351 patients with RA (mean age of 68 years, 69% women), 1411 osteoporotic fractures occurred. Concomitant current use of oral GCs and PPIs was associated with a 1.6-fold increased risk of osteoporotic fractures compared with non-use (adjusted HR: 1.60, 95% CI: 1.35 to 1.89). This was statistically different from a 1.2-fold increased osteoporotic fracture risk associated with oral GC or PPI use alone. Most individual fracture sites were significantly associated with concomitant use of oral GCs and PPIs. Among concomitant users, fracture risk did not increase with higher daily dose or duration of PPI use.

Conclusions There was an interaction in the risk of osteoporotic fractures with concomitant use of oral GCs and PPIs. Fracture risk assessment could be considered when a patient with RA is co-prescribed oral GCs and PPIs.

  • osteoporosis
  • rheumatoid arthritis
  • glucocorticoids
  • epidemiology

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  • Handling editor Josef S Smolen

  • Twitter @Sh_Abtahi, @ETH_PharmEpi

  • Correction notice This article has been corrected since it published Online First. The corresponding address has been corrected.

  • Contributors SA, AMB, AB and FV contributed to intellectual concept and design of the research. JD and PS carried out the data acquisition. SA and JD conducted the data analysis. All authors contributed to data interpretation. SA wrote the manuscript. All authors were involved in editing or quality control. All authors are accountable for their own contribution, in addition to all aspects of the manuscript. All authors have approved the (re)submitted version of the manuscript.

  • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

  • Competing interests JvB reports grants from Amgen, Eli Lilly and UCB, outside the submitted work. AB received research grants to her department from Celgene and AbbVie, and speakers’ fees or honoraria from Sandoz, UCB, Lilly, Novartis and Biogen, and Gilead also to her department, not related to this study. FV supervises three PhD students who are employed with F. Hoffmann La Roche (Basel, Switzerland/Welwyn Garden City, UK). He has not received any fees or reimbursements for this, and the topics of their PhD thesis are not related to the current study proposal. SA, JD, AMB, PCS and TPvS have no competing interests.

  • Patient consent for publication Not required.

  • Ethics approval This study was reviewed and approved by the Independent Scientific Advisory Committee of the Clinical Practice Research Datalink (reference 19_018R), which is responsible for reviewing protocols for scientific quality.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data availability statement No additional data are available.

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.

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