Proton-pump inhibitors and risk of fractures: an update meta-analysis

Abstract

Summary

To identify the relationship between proton-pump inhibitors (PPIs) and the risk of fracture, we conducted an update meta-analysis of observational studies. Results showed that PPI use was associated with a modestly increased risk of hip, spine, and any-site fracture.

Introduction

Many studies have investigated the association of proton-pump inhibitors (PPIs) with fracture risk, but the results have been inconsistent. To evaluate this question, we performed a meta-analysis of relevant observational studies.

Methods

A systematic literature search up to February 2015 was performed in PubMed. We combined relative risks (RRs) for fractures using random-effects models and conducted subgroup and stratified analyses.

Results

Eighteen studies involving a total of 244,109 fracture cases were included in this meta-analysis. Pooled analysis showed that PPI use could moderately increase the risk of hip fracture [RR = 1.26, 95 % confidence intervals (CIs) 1.16–1.36]. There was statistically significant heterogeneity among studies (p < 0.001; I 2 = 71.9 %). After limiting to cohort studies, there was also a moderate increase in hip fracture risk without evidence of study heterogeneity. Pooling revealed that short-term use (<1 year) and longer use (>1 year) were similarly associated with increased risk of hip fracture. Furthermore, a moderately increased risk of spine (RR = 1.58, 95 % CI 1.38–1.82) and any-site fracture (RR = 1.33, 95 % CI 1.15–1.54) was also found among PPI users.

Conclusion

In this update meta-analysis of observational studies, PPI use modestly increased the risk of hip, spine, and any-site fracture, but no evidence of duration effect in subgroup analysis.

This is a preview of subscription content, log in to check access.

Fig. 1
Fig. 2
Fig. 3

References

  1. 1.

    Dennison E, Mohamed MA, Cooper C (2006) Epidemiology of osteoporosis. Rheum Dis Clin N Am 32:617–629

    Article  Google Scholar 

  2. 2.

    Osnes EK, Lofthus CM, Meyer HE, Falch JA, Nordsletten L, Cappelen I, Kristiansen IS (2004) Consequences of hip fracture on activities of daily life and residential needs. Osteoporos Int 15:567–574

    PubMed  Article  CAS  Google Scholar 

  3. 3.

    Kushner PR, Peura DA (2011) Review of proton pump inhibitors for the initial treatment of heartburn: is there a dose ceiling effect? Adv Ther 28:367–388

    PubMed  Article  CAS  Google Scholar 

  4. 4.

    Mönnikes H, Schwan T, van Rensburg C, Straszak A, Theek C, Lühmann R, Sander P, Tholen A (2013) Possible etiology of improvements in both quality of life and overlapping gastroesophageal reflux disease by proton pump inhibitor treatment in a prospective randomized controlled trial. BMC Gastroenterol 13:145

    PubMed  PubMed Central  Article  Google Scholar 

  5. 5.

    Tsoi KK, Hirai HW, Sung JJ (2013) Meta-analysis: comparison of oral vs. intravenous proton pump inhibitors in patients with peptic ulcer bleeding. Aliment Pharmacol Ther 38:721–728

    PubMed  Article  CAS  Google Scholar 

  6. 6.

    Ye X, Liu H, Wu C, Qin Y, Zang J, Gao Q, Zhang X, He J (2011) Proton pump inhibitors therapy and risk of hip fracture: a systematic review and meta-analysis. Eur J Gastroenterol Hepatol 23:794–800

    PubMed  Article  CAS  Google Scholar 

  7. 7.

    Yu EW, Bauer SR, Bain PA, Bauer DC (2011) Proton pump inhibitors and risk of fractures: a meta-analysis of 11 international studies. Am J Med 124:519–526

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  8. 8.

    Eom CS, Park SM, Myung SK, Yun JM, Ahn JS (2011) Use of acid-suppressive drugs and risk of fracture: a meta-analysis of observational studies. Ann Fam Med 9:257–267

    PubMed  PubMed Central  Article  Google Scholar 

  9. 9.

    Ngamruengphong S, Leontiadis GI, Radhi S, Dentino A, Nugent K (2011) Proton pump inhibitors and risk of fracture: a systematic review and meta-analysis of observational studies. Am J Gastroenterol 106:1209–1218, quiz 1219

    PubMed  Article  CAS  Google Scholar 

  10. 10.

    FDA Drug Safety Communication (2010) Possible increased risk of fractures of the hip, wrist, and spine with the use of proton pump inhibitors. U.S. Food and Drug Administration, Rockville

    Google Scholar 

  11. 11.

    Moher D, Liberati A, Tetzlaff J, Altman DG (2009) Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. Ann Intern Med 51(264–269):W264

    Article  Google Scholar 

  12. 12.

    Wells GA, Shea B, O’Connell D, Peterson J, Welch V, Losos M, et al (2012) The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses. http://www.ohri.ca/programs/clinical_epidemiology/oxford.asp

  13. 13.

    DerSimonian R, Laird N (1986) Meta-analysis in clinical trials. Control Clin Trials 7:177–188

    PubMed  Article  CAS  Google Scholar 

  14. 14.

    Higgins JPT, Thompson SG (2002) Quantifying heterogeneity in a meta-analysis. Stat Med 21:1539–1558

    PubMed  Article  Google Scholar 

  15. 15.

    Egger M, Davey Smith G, Schneider M, Minder C (1997) Bias in meta-analysis detected by a simple, graphical test. BMJ 315:629–634

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  16. 16.

    Yang YX, Lewis JD, Epstein S, Metz DC (2006) Long-term proton pump inhibitor therapy and risk of hip fracture. JAMA 296:2947–2953

    PubMed  Article  CAS  Google Scholar 

  17. 17.

    Vestergaard P, Rejnmark L, Mosekilde L (2006) Proton pump inhibitors, histamine H2 receptor antagonists, and other antacid medications and the risk of fracture. Calcif Tissue Int 79:76–83

    PubMed  Article  CAS  Google Scholar 

  18. 18.

    Targownik LE, Lix LM, Metge CJ, Prior HJ, Leung S, Leslie WD (2008) Use of proton pump inhibitors and risk of osteoporosis-related fractures. CMAJ 179:319–326

    PubMed  PubMed Central  Article  Google Scholar 

  19. 19.

    Yu EW, Blackwell T, Ensrud KE, Hillier TA, Lane NE, Orwoll E, Bauer DC (2008) Acid-suppressive medications and risk of bone loss and fracture in older adults. Calcif Tissue Int 83:251–259

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  20. 20.

    Roux C, Briot K, Gossec L, Kolta S, Blenk T, Felsenberg D, Reid DM, Eastell R, Glüer CC (2009) Increase in vertebral fracture risk in postmenopausal women using omeprazole. Calcif Tissue Int 84:13–19

    PubMed  Article  CAS  Google Scholar 

  21. 21.

    Corley DA, Kubo A, Zhao W, Quesenberry C (2010) Proton pump inhibitors and histamine-2 receptor antagonists are associated with hip fractures among at-risk patients. Gastroenterology 139:93–101

    PubMed  PubMed Central  Article  Google Scholar 

  22. 22.

    Gray SL, LaCroix AZ, Larson J, Robbins J, Cauley JA, Manson JE, Chen Z (2010) Proton pump inhibitor use, hip fracture, and change in bone mineral density in postmenopausal women: results from the Women’s Health Initiative. Arch Intern Med 170:765–771

    PubMed  PubMed Central  Article  Google Scholar 

  23. 23.

    Chiu HF, Huang YW, Chang CC, Yang CY (2010) Use of proton pump inhibitors increased the risk of hip fracture: a population-based case-control study. Pharmacoepidemiol Drug Saf 19:1131–1136

    PubMed  Article  Google Scholar 

  24. 24.

    Pouwels S, Lalmohamed A, Souverein P, Cooper C, Veldt BJ, Leufkens HG, de Boer A, van Staa T, de Vries F (2011) Use of proton pump inhibitors and risk of hip/femur fracture: a population-based case-control study. Osteoporos Int 22:903–910

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  25. 25.

    Khalili H, Huang ES, Jacobson BC, Camargo CA Jr, Feskanich D, Chan AT (2012) Use of proton pump inhibitors and risk of hip fracture in relation to dietary and lifestyle factors: a prospective cohort study. BMJ 344, e372

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  26. 26.

    Fraser LA, Leslie WD, Targownik LE, Papaioannou A, Adachi JD, CaMos Research Group (2013) The effect of proton pump inhibitors on fracture risk: report from the Canadian Multicenter Osteoporosis Study. Osteoporos Int 24:1161–1168

    PubMed  Article  CAS  Google Scholar 

  27. 27.

    Reyes C, Formiga F, Coderch M, Hoyo J, Ferriz G, Casanovas J, Monteserín R, Brotons C, Rojas M, Moral I (2013) Use of proton pump inhibitors and risk of fragility hip fracture in a Mediterranean region. Bone 52:557–561

    PubMed  Article  CAS  Google Scholar 

  28. 28.

    Moberg LM, Nilsson PM, Samsioe G, Borgfeldt C (2014) Use of proton pump inhibitors (PPI) and history of earlier fracture are independent risk factors for fracture in postmenopausal women. The WHILA study. Maturitas 78:310–315

    PubMed  Article  CAS  Google Scholar 

  29. 29.

    Cea Soriano L, Ruigómez A, Johansson S, García Rodríguez LA (2014) Study of the association between hip fracture and acid-suppressive drug use in a UK primary care setting. Pharmacotherapy 34:570–581

    PubMed  Article  CAS  Google Scholar 

  30. 30.

    Lewis JR, Barre D, Zhu K, Ivey KL, Lim EM, Hughes J, Prince RL (2014) Long-term proton pump inhibitor therapy and falls and fractures in elderly women: a prospective cohort study. J Bone Miner Res 29:2489–2497

    PubMed  Article  Google Scholar 

  31. 31.

    Ding J, Heller DA, Ahern FM, Brown TV (2014) The relationship between proton pump inhibitor adherence and fracture risk in the elderly. Calcif Tissue Int 94:597–607

    PubMed  Article  CAS  Google Scholar 

  32. 32.

    Adams AL, Black MH, Zhang JL, Shi JM, Jacobsen SJ (2014) Proton-pump inhibitor use and hip fractures in men: a population-based case-control study. Ann Epidemiol 24:286–290

    PubMed  Article  Google Scholar 

  33. 33.

    Kaye JA, Jick H (2008) Proton pump inhibitor use and risk of hip fractures in patients without major risk factors. Pharmacotherapy 28:951–959

    PubMed  Article  CAS  Google Scholar 

  34. 34.

    de Vries F, Cooper AL, Cockle SM, van Staa TP, Cooper C (2009) Fracture risk in patients receiving acid-suppressant medication alone and in combination with bisphosphonates. Osteoporos Int 20:1989–1998

    PubMed  Article  CAS  Google Scholar 

  35. 35.

    Abrahamsen B, Vestergaard P (2013) Proton pump inhibitor use and fracture risk—effect modification by histamine H1 receptor blockade. Observational case-control study using National Prescription Data. Bone 57:269–271

    PubMed  Article  CAS  Google Scholar 

  36. 36.

    Mello M, Weideman RA, Little BB, Weideman MW, Cryer B, Brown GR (2012) Proton pump inhibitors increase the incidence of bone fractures in hepatitis C patients. Dig Dis Sci 57:2416–2422

    PubMed  Article  CAS  Google Scholar 

  37. 37.

    O’Connell MB, Madden DM, Murray AM, Heaney RP, Kerzner LJ (2005) Effects of proton pump inhibitors on calcium carbonate absorption in women: a randomized crossover trial. Am J Med 118:778–781

    PubMed  Article  CAS  Google Scholar 

  38. 38.

    Wright MJ, Sullivan RR, Gaffney-Stomberg E, Caseria DM, O’Brien KO, Proctor DD, Simpson CA, Kerstetter JE, Insogna KL (2010) Inhibiting gastric acid production does not affect intestinal calcium absorption in young, healthy individuals: a randomized, crossover, controlled clinical trial. J Bone Miner Res 25:2205–2211

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  39. 39.

    Famularo G, Gasbarrone L, Minisola G (2013) Hypomagnesemia and proton-pump inhibitors. Expert Opin Drug Saf 12:709–716

    PubMed  Article  CAS  Google Scholar 

Download references

Author information

Affiliations

Authors

Corresponding author

Correspondence to J. Liu.

Ethics declarations

Conflicts of interest

None.

Additional information

B. Zhou and Y. Huang contributed equally to this work.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Zhou, B., Huang, Y., Li, H. et al. Proton-pump inhibitors and risk of fractures: an update meta-analysis. Osteoporos Int 27, 339–347 (2016). https://doi.org/10.1007/s00198-015-3365-x

Download citation

Keywords

  • Fracture
  • Meta-analysis
  • Proton-pump inhibitors
  • Risk