Proton pump inhibitors and risk of hip fracture: a meta-analysis of observational studies

Abstract

Summary

We performed a meta-analysis of relevant studies to quantify the magnitude of the association between proton pump inhibitors (PPIs) and risk of hip fracture. Patients with PPIs had a greater risk of hip fracture than those without PPI therapy (RR 1.20, 95% CI 1.14–1.28, p < 0.0001). These results could be taken into consideration with caution, and patients should also be concerned about the inappropriate use of PPIs.

Introduction

Proton pump inhibitors (PPIs) are generally considered as first-line medicine with great safety profile, commonly prescribed for gastroesophageal reflux disease (GERD) and peptic ulcer disease. However, several epidemiological studies documented that long-term use of PPIs may be associated with an increased risk of hip fracture. Although, the optimal magnitude of the hip fracture risk is still undetermined. We, therefore, performed a meta-analysis of relevant studies to quantify the magnitude of the association between PPIs and risk of hip fracture.

Methods

We collected relevant articles using MEDLINE, EMBASE, Google Scholar, and Web of Science from January 1, 1990, to March 31, 2018. We included only the large (n ≥ 500) observational studies with a follow-up duration of at least one year in which the hip fracture patients were identified by a standard procedure. Two of the authors extracted data from each included study independently according to a standardized protocol.

Results

A total of 24 observational studies with 2,103,800 participants (319,568 hip fracture patients) met all the eligibility criteria. Patients with PPIs had a greater risk of hip fracture than those without PPI therapy (RR 1.20, 95% CI 1.14–1.28, p < 0.0001). An increased association was also observed in both low and medium doses of PPI taken and hip fracture risk (RR 1.17, 95% CI 1.05–1.29, p = 0.002; RR 1.28, 95% CI 1.14–1.44, p < 0.0001), but it appeared to be even greater among the patients with higher dose (RR 1.30, 95% CI 1.20–1.40, p < 0.0001). Moreover, the overall pooled risk ratios were 1.20 (95% CI 1.15–1.25, p < 0.0001) and 1.24 (95% CI 1.10–1.40, p < 0.0001) for the patients with short- and long-term PPI therapy, respectively, compared with PPI non-users.

Conclusion

Our results suggest that PPI use is significantly associated with an increased risk of hip fracture development, which is not observed in H2RA exposure. Physicians should, therefore, exercise caution when considering a long-term PPI treatment to their patients who already have an elevated risk of hip fracture. In addition, patients should be concerned about the inappropriate use of PPIs; if necessary, then, they should continue to receive it with a clear indication.

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

Fig. 1
Fig. 2
Fig. 3
Fig. 4

References

  1. 1.

    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

    CAS  PubMed  Article  Google Scholar 

  2. 2.

    Jordan K, Cooper C (2002) Epidemiology of osteoporosis. Best Pract Res Clin Rheumatol 16:795–806

    CAS  PubMed  Article  Google Scholar 

  3. 3.

    Bass E, French DD, Bradham DD, Rubenstein LZ (2007) Risk-adjusted mortality rates of elderly veterans with hip fractures. Ann Epidemiol 17:514–519

    PubMed  Article  Google Scholar 

  4. 4.

    Bakken MS, Engeland A, Engesæter LB, Ranhoff AH, Hunskaar S, Ruths S (2014) Risk of hip fracture among older people using anxiolytic and hypnotic drugs: a nationwide prospective cohort study. Eur J Clin Pharmacol 70:873–880

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  5. 5.

    Elaine WY, 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

    Article  CAS  Google Scholar 

  6. 6.

    Islam MM, Poly TN, Walther BA, Dubey NK, Ningrum DNA, Shabbir S-A, Li Y-CJ (2018) Adverse outcomes of long-term use of proton pump inhibitors: a systematic review and meta-analysis. Eur J Gastroenterol Hepatol 30:1395–1405

    CAS  PubMed  Article  Google Scholar 

  7. 7.

    Wan QY, Wu XT, Li N, Du L, Zhou Y (2018) Long-term proton pump inhibitors use and risk of gastric cancer: a meta-analysis of 926 386 participants. Gut 2018.

  8. 8.

    Lambert AA, Lam JO, Paik JJ, Ugarte-Gil C, Drummond MB, Crowell TA (2015) Risk of community-acquired pneumonia with outpatient proton-pump inhibitor therapy: a systematic review and meta-analysis. PLoS One 10:e0128004

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  9. 9.

    Nochaiwong S, Ruengorn C, Awiphan R, Koyratkoson K, Chaisai C, Noppakun K, Chongruksut W, Thavorn K (2017) The association between proton pump inhibitor use and the risk of adverse kidney outcomes: a systematic review and meta-analysis. Nephrol Dial Transplant 33:331–342

    Article  CAS  Google Scholar 

  10. 10.

    Sun S, Cui Z, Zhou M, Li R, Li H, Zhang S, Ba Y, Cheng G (2017) Proton pump inhibitor monotherapy and the risk of cardiovascular events in patients with gastro-esophageal reflux disease: a meta-analysis. Neurogastroenterol Motil 29:e12926

    Article  CAS  Google Scholar 

  11. 11.

    Batchelor R, Gilmartin JFM, Kemp W, Hopper I, Liew D (2017) Dementia, cognitive impairment and proton pump inhibitor therapy: a systematic review. J Gastroenterol Hepatol 32:1426–1435

    CAS  PubMed  Article  Google Scholar 

  12. 12.

    Filion KB, Chateau D, Targownik LE, Gershon A, Durand M, Tamim H, Teare GF, Ravani P, Ernst P, Dormuth CR (2013) CNODES Investigators. Proton pump inhibitors and the risk of hospitalisation for community-acquired pneumonia: replicated cohort studies with meta-analysis. Gut 63(4):552–8.

  13. 13.

    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 

  14. 14.

    De Vries F, Cooper A, Cockle S, van Staa T-P, Cooper C (2009) Fracture risk in patients receiving acid-suppressant medication alone and in combination with bisphosphonates. Osteoporos Int 20:1989–1998

    CAS  PubMed  Article  Google Scholar 

  15. 15.

    Chen C-H, Lin C-L, Kao C-H (2016) Gastroesophageal reflux disease with proton pump inhibitor use is associated with an increased risk of osteoporosis: a nationwide population-based analysis. Osteoporos Int 27:2117–2126

    CAS  PubMed  Article  Google Scholar 

  16. 16.

    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 

  17. 17.

    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

    CAS  PubMed  Article  Google Scholar 

  18. 18.

    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

    CAS  PubMed  Article  Google Scholar 

  19. 19.

    Zhou B, Huang Y, Li H, Sun W, Liu J (2016) Proton-pump inhibitors and risk of fractures: an update meta-analysis. Osteoporos Int 27:339–347

    CAS  PubMed  Article  Google Scholar 

  20. 20.

    Hussain S, Siddiqui AN, Habib A, Hussain MS, Najmi AK (2018) Proton pump inhibitors’ use and risk of hip fracture: a systematic review and meta-analysis. Rheumatology international. 2018 Aug 29:1-6.24.Poly TN, Islam MM, Yang HC, Li YC. Non-steroidal anti-inflammatory drugs and risk of Parkinson’s disease in the elderly population: a meta-analysis. Eur J Clin Pharmacol 1:1–0.

  21. 21.

    Moher D, Liberati A, Tetzlaff J, Altman DG (2009) Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. Ann Intern Med 151:264–269

    PubMed  Article  Google Scholar 

  22. 22.

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

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  23. 23.

    Higgins JP, Thompson SG, Deeks JJ, Altman DG (2003) Measuring inconsistency in meta-analyses. BMJ: Br Med J 327:557–560

    Article  Google Scholar 

  24. 24.

    Poly TN, Islam MMR, Yang H-C, Li Y-CJ (2018) Non-steroidal anti-inflammatory drugs and risk of Parkinson’s disease in the elderly population: a meta-analysis. Eur J Clin Pharmacol:1–10

  25. 25.

    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

    CAS  PubMed  Article  Google Scholar 

  26. 26.

    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

    CAS  PubMed  Article  Google Scholar 

  27. 27.

    Lee J, Youn K, Choi N-K, Lee J-H, Kang D, Song H-J, Park B-J (2013) A population-based case–control study: proton pump inhibition and risk of hip fracture by use of bisphosphonate. J Gastroenterol 48:1016–1022

    CAS  PubMed  Article  Google Scholar 

  28. 28.

    Pouwels S, Lalmohamed A, Souverein P, Cooper C, Veldt B, Leufkens H, 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

    CAS  PubMed  Article  Google Scholar 

  29. 29.

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

    Article  Google Scholar 

  30. 30.

    Khalili H, Huang ES, Jacobson BC, Camargo CA, 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 

  31. 31.

    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 

  32. 32.

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

    CAS  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

    CAS  PubMed  Article  Google Scholar 

  34. 34.

    Lai S-W, Lin C-H, Lin C-L, Liao K-F (2018) Proton pump inhibitors therapy and the risk of hip fracture in older people in Taiwan. Eur Geriatr Med 9:169–174

    Article  Google Scholar 

  35. 35.

    Lenihan CR, Nair SS, Vangala C, Ramanathan V, Montez-Rath ME, Winkelmayer WC (2017) Proton pump inhibitor use and risk of hip fracture in kidney transplant recipients. Am J Kidney Dis 69:595–601

    CAS  PubMed  Article  Google Scholar 

  36. 36.

    Lin S-M, Yang S-H, Liang C-C, Huang H-K (2018) Proton pump inhibitor use and the risk of osteoporosis and fracture in stroke patients: a population-based cohort study. Osteoporos Int 29:153–162

    CAS  PubMed  Article  Google Scholar 

  37. 37.

    Fraser L, Leslie W, Targownik L, Papaioannou A, Adachi J, Group CR (2013) The effect of proton pump inhibitors on fracture risk: report from the Canadian Multicenter Osteoporosis Study. Osteoporos Int 24:1161–1168

    CAS  PubMed  Article  Google Scholar 

  38. 38.

    Elaine WY, 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

    Article  CAS  Google Scholar 

  39. 39.

    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 

  40. 40.

    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 

  41. 41.

    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

    CAS  PubMed  Article  Google Scholar 

  42. 42.

    Torvinen-Kiiskinen S, Tolppanen AM, Koponen M, Tanskanen A, Tiihonen J, Hartikainen S, Taipale H (2018) Proton pump inhibitor use and risk of hip fractures among community-dwelling persons with Alzheimer's disease—a nested case-control study. Aliment Pharmacol Ther 47:1135–1142

    CAS  PubMed  Article  Google Scholar 

  43. 43.

    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

    CAS  PubMed  Article  Google Scholar 

  44. 44.

    Wang L, Li M, Cao Y, Han Z, Wang X, Atkinson EJ, Liu H, Amin S (2017) Proton pump inhibitors and the risk for fracture at specific sites: data mining of the FDA adverse event reporting system. Sci Rep 7:5527

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  45. 45.

    Datta H, Ng W, Walker J, Tuck S, Varanasi S (2008) The cell biology of bone metabolism. J Clin Pathol 61:577–587

    CAS  PubMed  Article  Google Scholar 

  46. 46.

    Mizunashi K, Furukawa Y, Katano K, Abe K (1993) Effect of omeprazole, an inhibitor of H+, K+-ATPase, on bone resorption in humans. Calcif Tissue Int 53:21–25

    CAS  PubMed  Article  Google Scholar 

  47. 47.

    Hansen KE, Jones AN, Lindstrom MJ, Davis LA, Ziegler TE, Penniston KL, Alvig AL, Shafer MM (2010) Do proton pump inhibitors decrease calcium absorption? J Bone Miner Res 25:2786–2795

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  48. 48.

    Joo MK, Park J-J, Lee BJ, Kim JH, Yeon JE, Kim JS, Byun KS, Bak Y-T (2013) The effect of a proton pump inhibitor on bone metabolism in ovariectomized rats. Mol Med Rep 7:1267–1272

    CAS  PubMed  Article  Google Scholar 

  49. 49.

    Kocsis I, Arató A, Bodánszky H, Szönyi L, Szabó A, Tulassay T, Vásárhelyi B (2002) Short-term omeprazole treatment does not influence biochemical parameters of bone turnover in children. Calcif Tissue Int 71:129–132

    CAS  PubMed  Article  Google Scholar 

  50. 50.

    Sharara AI, El-Halabi MM, Ghaith OA, Habib RH, Mansour NM, Malli A, El Hajj-Fuleihan G (2013) Proton pump inhibitors have no measurable effect on calcium and bone metabolism in healthy young males: a prospective matched controlled study. Metabolism 62:518–526

    CAS  PubMed  Article  Google Scholar 

  51. 51.

    Agréus L, Svärdsudd K, Talley NJ, Jones MP, Tibblin G (2001) Natural history of gastroesophageal reflux disease and functional abdominal disorders: a population-based study. Am J Gastroenterol 96:2905–2914

    PubMed  Article  Google Scholar 

  52. 52.

    Scarpignato C, Gatta L, Zullo A, Blandizzi C (2016) Effective and safe proton pump inhibitor therapy in acid-related diseases—a position paper addressing benefits and potential harms of acid suppression. BMC Med 14:179

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  53. 53.

    Grimes DA, Schulz KF (2012) False alarms and pseudo-epidemics: the limitations of observational epidemiology. Obstet Gynecol 120:920–927

    PubMed  Article  Google Scholar 

  54. 54.

    Leontiadis GI, Moayyedi P (2014) Proton pump inhibitors and risk of bone fractures. Curr Treat Options Gastroenterol 12:414–423

    PubMed  Article  Google Scholar 

Download references

Acknowledgments

This work was financially supported by the “TMU Research Center of Cancer Translational Medicine” from The Featured Areas Research Center Program within the framework of the Higher Education Sprout Project by the Ministry of Education (MOE) in Taiwan and the Health and Welfare surcharge of tobacco grants MOHW-106-TDU-B-144001.

Author information

Affiliations

Authors

Corresponding author

Correspondence to Y.-C.(.J.). Li.

Ethics declarations

Conflicts of interest

All the authors (Tahmina Nasrin Poly, Md. Mohaimenul Islam, Hsuan-Chia Yang, Chieh Chen Wu, Yu-Chuan (Jack) Li) declare that they do not have any conflict of interest.

Electronic supplementary material

ESM 1

(DOCX 325 kb)

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Poly, T., Islam, M., Yang, H. et al. Proton pump inhibitors and risk of hip fracture: a meta-analysis of observational studies. Osteoporos Int 30, 103–114 (2019). https://doi.org/10.1007/s00198-018-4788-y

Download citation

Keywords

  • Bone fracture
  • Gastroesophageal reflux disease
  • Hip fracture
  • Osteoporosis
  • Proton pump inhibitors