J Bone Metab.  2018 Aug;25(3):141-151. 10.11005/jbm.2018.25.3.141.

Proton-pump Inhibitor Use and Fracture Risk: An Updated Systematic Review and Meta-analysis

• Nassar Y
• Richter S

• KMID: 2419841
• DOI: http://doi.org/10.11005/jbm.2018.25.3.141

Abstract

BACKGROUND
This study's objective was to evaluate the association between proton-pump inhibitor (PPI) use and bone fracture incidence and bone mineral density (BMD) by meta-analyzing the estimates reported by epidemiological and cohort studies.
METHODS
Data were acquired from studies identified after a literature search in electronic databases. Odds ratios (ORs), hazard ratios (HRs), and risk ratios (RRs) between PPI use and bone fracture incidence were pooled under the random effects model, and meta-analysis of standardized mean differences between PPI users and controls in cross-sectional values and BMD changes was conducted.
RESULTS
Thirty-three studies fulfilled the eligibility criteria. These studies provided data from 2,714,502 individuals with a mean age of 66.91 years (95% confidence interval [CI], 63.37-70.46); 33.21% (95% CI, 30.44-35.99) were males and 64.61% (95% CI, 60.73-68.49) were females. Overall, fracture incidence was 22.04% (95% CI, 16.10-27.97) in PPI users and 15.57% (95% CI, 12.28-18.86) in controls. The overall effect size of the point estimate was 1.28 (95% CI, 1.22-1.35) between PPI use and bone fracture incidence. There was a trend towards increased fracture incidence from short duration use: OR 1.29 (95% CI, 1.19-1.40), medium duration use: OR 1.33 (95% CI, 1.12-1.55) and long duration use: OR 1.62 (95% CI, 1.33-1.90). There was no significant difference in the standardized mean differences between PPI users and controls, either in cross-sectional BMD values or in the BMD change observed in longitudinal studies.
CONCLUSIONS
Pooling of ORs, HRs, and RRs suggested that PPI use might increase fracture risk. However, there was no effect of PPI use on BMD.

Keyword

Fracture; Meta-analysis; Proton-pump inhibitors

MeSH Terms

Bone Density
Cohort Studies
Female
Fractures, Bone
Humans
Incidence
Longitudinal Studies
Male
Odds Ratio

Figure

• 

  Fig. 1 A flowchart of study screening and selection process after the literature search.

• 

  Fig. 2 A forest graph showing the outcomes of a subgroup meta-analysis conducted to evaluate the effect of proton-pump inhibitor (PPI) use on fracture incidence with respect to the duration of PPI use. ES, effect sizes; CI, confidence interval.

• 

  Fig. 3 A forest graph showing the outcomes of a subgroup meta-analysis conducted to evaluate the effect of proton-pump inhibitor (PPI) use on fracture incidence with respect to the intensity of PPI use. ADD, average daily dose; DDD, defined daily dose; SDD, standard daily dose; PDC, proportion of days covered; ES, effect sizes; CI, confidence interval.

• 

  Fig. 4 (A) A forest graph showing the meta-analysis of standardized mean differences between proton-pump inhibitor (PPI) users and non-users in cross-sectional bone mineral density (BMD) values observed in individual studies. (B) A forest graph showing the meta-analysis of standardized mean differences between PPI users and non-users in the BMD changes observed in longitudinal studies. SD, standard deviation; CI, confidence interval; df, degrees of freedom.

Reference

1. Farrell B, Pottie K, Thompson W, et al. Deprescribing proton pump inhibitors: evidence-based clinical practice guideline. Can Fam Physician. 2017; 63:354–364.

2. Lanza FL, Chan FK, Quigley EM. Guidelines for prevention of NSAID-related ulcer complications. Am J Gastroenterol. 2009; 104:728–738.

3. Wolfe MM, Soll AH. The physiology of gastric acid secretion. N Engl J Med. 1988; 319:1707–1715.

4. Eusebi LH, Rabitti S, Artesiani ML, et al. Proton pump inhibitors: risks of long-term use. J Gastroenterol Hepatol. 2017; 32:1295–1302.

5. Richards JB, Goltzman D. Proton pump inhibitors: balancing the benefits and potential fracture risks. CMAJ. 2008; 179:306–307.

6. Laine L. Proton pump inhibitors and bone fractures? Am J Gastroenterol. 2009; 104:S21–S26.

7. Zhou B, Huang Y, Li H, et al. Proton-pump inhibitors and risk of fractures: an update meta-analysis. Osteoporos Int. 2016; 27:339–347.

8. Abrahamsen B, Eiken P, Eastell R. Proton pump inhibitor use and the antifracture efficacy of alendronate. Arch Intern Med. 2011; 171:998–1004.

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

10. Adams AL, Black MH, Zhang JL, et al. Proton-pump inhibitor use and hip fractures in men: a population-based case-control study. Ann Epidemiol. 2014; 24:286–290.

11. Arj A, Razavi Zade M, Yavari M, et al. Proton pump inhibitors use and change in bone mineral density. Int J Rheum Dis. 2016; 19:864–868.

12. Bahtiri E, Islami H, Hoxha R, et al. Esomeprazole use is independently associated with significant reduction of BMD: 1-year prospective comparative safety study of four proton pump inhibitors. J Bone Miner Metab. 2016; 34:571–579.

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

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

15. Ding J, Heller DA, Ahern FM, et al. The relationship between proton pump inhibitor adherence and fracture risk in the elderly. Calcif Tissue Int. 2014; 94:597–607.

16. Fraser LA, Leslie WD, Targownik LE, et al. The effect of proton pump inhibitors on fracture risk: report from the Canadian Multicenter Osteoporosis Study. Osteoporos Int. 2013; 24:1161–1168.

17. Freedberg DE, Haynes K, Denburg MR, et al. Use of proton pump inhibitors is associated with fractures in young adults: a population-based study. Osteoporos Int. 2015; 26:2501–2507.

18. Gray SL, LaCroix AZ, Larson J, et al. 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. 2010; 170:765–771.

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

20. Khalili H, Huang ES, Jacobson BC, et al. Use of proton pump inhibitors and risk of hip fracture in relation to dietary and lifestyle factors: a prospective cohort study. BMJ. 2012; 344:e372.

21. Kumar S, Drake MT, Schleck CD, et al. Incidence and predictors of osteoporotic fractures in patients with Barrett's oesophagus: a population-based nested case-control study. Aliment Pharmacol Ther. 2017; 46:1094–1102.

22. Lee J, Youn K, Choi NK, et al. A population-based case-control study: proton pump inhibition and risk of hip fracture by use of bisphosphonate. J Gastroenterol. 2013; 48:1016–1022.

23. Lenihan CR, Sukumaran Nair S, Vangala C, et al. Proton pump inhibitor use and risk of hip fracture in kidney transplant recipients. Am J Kidney Dis. 2017; 69:595–601.

24. Lewis JR, Barre D, Zhu K, et al. Long-term proton pump inhibitor therapy and falls and fractures in elderly women: a prospective cohort study. J Bone Miner Res. 2014; 29:2489–2497.

25. Lin SM, Yang SH, Liang CC, et al. Proton pump inhibitor use and the risk of osteoporosis and fracture in stroke patients: a population-based cohort study. Osteoporos Int. 2018; 29:153–162.

26. Maggio M, Lauretani F, Ceda GP, et al. Use of proton pump inhibitors is associated with lower trabecular bone density in older individuals. Bone. 2013; 57:437–442.

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

28. Ozdil K, Kahraman R, Sahin A, et al. Bone density in proton pump inhibitors users: a prospective study. Rheumatol Int. 2013; 33:2255–2260.

29. Pouwels S, Lalmohamed A, Souverein P, et al. Use of proton pump inhibitors and risk of hip/femur fracture: a population-based case-control study. Osteoporos Int. 2011; 22:903–910.

30. Reyes C, Formiga F, Coderch M, et al. Use of proton pump inhibitors and risk of fragility hip fracture in a Mediterranean region. Bone. 2013; 52:557–561.

31. Roux C, Goldstein JL, Zhou X, et al. Vertebral fracture efficacy during risedronate therapy in patients using proton pump inhibitors. Osteoporos Int. 2012; 23:277–284.

32. Solomon DH, Diem SJ, Ruppert K, et al. Bone mineral density changes among women initiating proton pump inhibitors or H2 receptor antagonists: a SWAN cohort study. J Bone Miner Res. 2015; 30:232–239.

33. Targownik LE, Lix LM, Metge CJ, et al. Use of proton pump inhibitors and risk of osteoporosis-related fractures. CMAJ. 2008; 179:319–326.

34. Targownik LE, Lix LM, Leung S, et al. Proton-pump inhibitor use is not associated with osteoporosis or accelerated bone mineral density loss. Gastroenterology. 2010; 138:896–904.

35. Targownik LE, Leslie WD, Davison KS, et al. The relationship between proton pump inhibitor use and longitudinal change in bone mineral density: a population-based study [corrected] from the Canadian Multicentre Osteoporosis Study (CaMos). Am J Gastroenterol. 2012; 107:1361–1369.

36. Targownik LE, Goertzen AL, Luo Y, et al. Long-term proton pump inhibitor use is not associated with changes in bone strength and structure. Am J Gastroenterol. 2017; 112:95–101.

37. van der Hoorn MMC, Tett SE, de Vries OJ, et al. 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. Bone. 2015; 81:675–682.

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

39. Yang YX, Lewis JD, Epstein S, et al. Long-term proton pump inhibitor therapy and risk of hip fracture. JAMA. 2006; 296:2947–2953.

40. Zirk-Sadowski J, Masoli JA, Strain WD, et al. Proton-pump inhibitors and fragility fractures in vulnerable older patients. Am J Gastroenterol. 2017; 112:520–523.

41. Abraham NS. Proton pump inhibitors: potential adverse effects. Curr Opin Gastroenterol. 2012; 28:615–620.

42. de la Coba Ortiz C, Argüelles Arias F, Martin de Argila de Prados C, et al. Proton-pump inhibitors adverse effects: a review of the evidence and position statement by the Sociedad Espanola de Patologia Digestiva. Rev Esp Enferm Dig. 2016; 108:207–224.

43. Heidelbaugh JJ. Proton pump inhibitors and risk of vitamin and mineral deficiency: evidence and clinical implications. Ther Adv Drug Saf. 2013; 4:125–133.

44. Li T, Xie Y, Al-Aly Z. The association of proton pump inhibitors and chronic kidney disease: cause or confounding? Curr Opin Nephrol Hypertens. 2018; 27:182–187.

45. Costa-Rodrigues J, Reis S, Teixeira S, et al. Dose-dependent inhibitory effects of proton pump inhibitors on human osteoclastic and osteoblastic cell activity. Febs j. 2013; 280:5052–5064.

46. Sheraly AR, Lickorish D, Sarraf F, et al. Use of gastrointestinal proton pump inhibitors to regulate osteoclast-mediated resorption of calcium phosphate cements in vivo. Curr Drug Deliv. 2009; 6:192–198.

47. Sugiyama T, Watarai K, Oda T, et al. Proton pump inhibitors and fracture: they impair bone quality and increase fall risk? Osteoporos Int. 2016; 27:1675–1676.

48. Gage BF, Birman-Deych E, Radford MJ, et al. Risk of osteoporotic fracture in elderly patients taking warfarin: results from the National Registry of Atrial Fibrillation 2. Arch Intern Med. 2006; 166:241–246.

49. Turner MR, Camacho X, Fischer HD, et al. Levothyroxine dose and risk of fractures in older adults: nested case-control study. BMJ. 2011; 342:d2238.

50. Marks R, Allegrante JP, Ronald MacKenzie C, et al. Hip fractures among the elderly: causes, consequences and control. Ageing Res Rev. 2003; 2:57–93.

51. Tolppanen AM, Taipale H, Tanskanen A, et al. Comparison of predictors of hip fracture and mortality after hip fracture in community-dwellers with and without Alzheimer's disease - exposure-matched cohort study. BMC Geriatr. 2016; 16:204.

52. Shiraev TP, Bullen A. Proton pump inhibitors and cardiovascular events: a systematic review. Heart Lung Circ. 2018; 27:443–450.

53. Ho PM, Maddox TM, Wang L, et al. Risk of adverse outcomes associated with concomitant use of clopidogrel and proton pump inhibitors following acute coronary syndrome. JAMA. 2009; 301:937–944.

54. Bhatt DL, Cryer BL, Contant CF, et al. Clopidogrel with or without omeprazole in coronary artery disease. N Engl J Med. 2010; 363:1909–1917.

55. Malhotra K, Katsanos AH, Bilal M, et al. Cerebrovascular outcomes with proton pump inhibitors and thienopyridines: a systematic review and meta-analysis. Stroke. 2018; 49:312–318.

56. Sukhovershin RA, Cooke JP. How may proton pump inhibitors impair cardiovascular health? Am J Cardiovasc Drugs. 2016; 16:153–161.

57. Menzies IB, Mendelson DA, Kates SL, et al. The impact of comorbidity on perioperative outcomes of hip fractures in a geriatric fracture model. Geriatr Orthop Surg Rehabil. 2012; 3:129–134.

58. Roche JJ, Wenn RT, Sahota O, et al. Effect of comorbidities and postoperative complications on mortality after hip fracture in elderly people: prospective observational cohort study. BMJ. 2005; 331:1374.

59. Chiang CH, Liu CJ, Chen PJ, et al. Hip fracture and risk of acute myocardial infarction: a nationwide study. J Bone Miner Res. 2013; 28:404–411.

60. Dharmarajan TS, Banik P. Hip fracture. Risk factors, preoperative assessment, and postoperative management. Postgrad Med. 2006; 119:31–38.

61. Durand C, Willett KC, Desilets AR. Proton pump inhibitor use in hospitalized patients: is overutilization becoming a problem? Clin Med Insights Gastroenterol. 2012; 5:65–76.

62. Ngamruengphong S, Leontiadis GI, Radhi S, et al. Proton pump inhibitors and risk of fracture: a systematic review and meta-analysis of observational studies. Am J Gastroenterol. 2011; 106:1209–1218. quiz 19.

63. McGowan B, Bennett K, Barry M. Prescribing of anti-osteoporotic therapies following the use of proton pump inhibitors in general practice. Pharmacoepidemiol Drug Saf. 2010; 19:763–769.

64. Fournier MR, Targownik LE, Leslie WD. Proton pump inhibitors, osteoporosis, and osteoporosis-related fractures. Maturitas. 2009; 64:9–13.