Use of proton pump inhibitors is associated with fractures in young adults: a population-based study

Abstract

Summary

Proton pump inhibitors (PPIs) are associated with risk for fracture in osteoporotic adults. In this population-based study, we found a significant association between PPIs and fracture in young adults, with evidence of a dose–response effect. Young adults who use PPIs should be cautioned regarding risk for fracture.

Introduction

Proton pump inhibitors (PPIs) are associated with fracture in adults with osteoporosis. Because PPI therapy may interfere with bone accrual and attainment of peak bone mineral density, we studied the association between use of PPIs and fracture in children and young adults.

Methods

We conducted a population-based, case–control study nested within records from general medical practices from 1994 to 2013. Participants were 4–29 years old with ≥1 year of follow-up who lacked chronic conditions associated with use of long-term acid suppression. Cases of fracture were defined as the first incident fracture at any site. Using incidence density sampling, cases were matched with up to five controls by age, sex, medical practice, and start of follow-up. PPI exposure was defined as 180 or more cumulative doses of PPIs. Conditional logistic regression was used to estimate the odds ratio and confidence interval for use of PPIs and fracture.

Results

We identified 124,799 cases and 605,643 controls. The adjusted odds ratio for the risk of fracture associated with PPI exposure was 1.13 (95 % CI 0.92 to 1.39) among children aged <18 years old and 1.39 (95 % CI 1.26 to 1.53) among young adults aged 18–29 years old. In young adults but not children, we observed a dose–response effect with increased total exposure to PPIs (p for trend <0.001).

Conclusions

PPI use was associated with fracture in young adults, but overall evidence did not support a PPI–fracture relationship in children. Young adults who use PPIs should be cautioned regarding potentially increased risk for fracture, even if they lack traditional fracture risk factors.

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References

  1. 1.

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

    CAS  Article  PubMed  Google Scholar 

  2. 2.

    van der Pol RJ, Smits MJ, van Wijk MP, Omari TI, Tabbers MM, Benninga MA (2011) Efficacy of proton-pump inhibitors in children with gastroesophageal reflux disease: a systematic review. Pediatrics 127:925–935

    Article  PubMed  Google Scholar 

  3. 3.

    Chai G, Governale L, McMahon AW, Trinidad JP, Staffa J, Murphy D (2012) Trends of outpatient prescription drug utilization in US children, 2002–2010. Pediatrics 130:23–31

    Article  PubMed  Google Scholar 

  4. 4.

    Jacobson BC, Ferris TG, Shea TL, Mahlis EM, Lee TH, Wang TC (2003) Who is using chronic acid suppression therapy and why? Am J gastroenterol 98:51–58

    Article  PubMed  Google Scholar 

  5. 5.

    Johnell O, Kanis JA (2006) An estimate of the worldwide prevalence and disability associated with osteoporotic fractures. Osteoporos Int 17:1726–1733

    CAS  Article  PubMed  Google Scholar 

  6. 6.

    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

    CAS  Article  PubMed  Google Scholar 

  7. 7.

    Targownik LE, Lix LM, Leung S, Leslie WD (2010) Proton-pump inhibitor use is not associated with osteoporosis or accelerated bone mineral density loss. Gastroenterology 138:896–904

    CAS  Article  PubMed  Google Scholar 

  8. 8.

    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 Central  Article  PubMed  Google Scholar 

  9. 9.

    Targownik LE, Leslie WD, Davison KS, Goltzman D, Jamal SA, Kreiger N, Josse RG, Kaiser SM, Kovacs CS, Prior JC, Zhou W, CaMos Research G (2012) 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 107:1361–1369

    Article  PubMed  Google Scholar 

  10. 10.

    Martin AD, Bailey DA, McKay HA, Whiting S (1997) Bone mineral and calcium accretion during puberty. Am J Clin Nutr 66:611–615

    CAS  PubMed  Google Scholar 

  11. 11.

    Yang YX, Metz DC (2010) Safety of proton pump inhibitor exposure. Gastroenterology 139:1115–1127

    CAS  Article  PubMed  Google Scholar 

  12. 12.

    Lewis JD, Schinnar R, Bilker WB, Wang X, Strom BL (2007) Validation studies of the health improvement network (THIN) database for pharmacoepidemiology research. Pharmacoepidemiol Drug Saf 16:393–401

    Article  PubMed  Google Scholar 

  13. 13.

    Denburg MR, Haynes K, Shults J, Lewis JD, Leonard MB (2011) Validation of The Health Improvement Network (THIN) database for epidemiologic studies of chronic kidney disease. Pharmacoepidemiol Drug Saf 20:1138–1149

    PubMed Central  Article  PubMed  Google Scholar 

  14. 14.

    World Health Organization (2014) The World Health Organization child growth standards. http://www.who.int/childgrowth/en/. Accessed July 24

  15. 15.

    Cooper C, Dennison EM, Leufkens HG, Bishop N, van Staa TP (2004) Epidemiology of childhood fractures in Britain: a study using the general practice research database. J Bone Miner Res 19:1976–1981

    Article  PubMed  Google Scholar 

  16. 16.

    Donaldson LJ, Reckless IP, Scholes S, Mindell JS, Shelton NJ (2008) The epidemiology of fractures in England. J Epidemiol Community Health 62:174–180

    CAS  Article  PubMed  Google Scholar 

  17. 17.

    Hassall E, Kerr W, El-Serag HB (2007) Characteristics of children receiving proton pump inhibitors continuously for up to 11 years duration. J Pediatr 150:262–267, 267 e261

    CAS  Article  PubMed  Google Scholar 

  18. 18.

    Booth N (1994) What are the Read codes? Health Libr Rev 11:177–182

    CAS  Article  PubMed  Google Scholar 

  19. 19.

    Van Staa TP, Abenhaim L, Cooper C, Zhang B, Leufkens HG (2000) The use of a large pharmacoepidemiological database to study exposure to oral corticosteroids and risk of fractures: validation of study population and results. Pharmacoepidemiol Drug Saf 9:359–366

    Article  PubMed  Google Scholar 

  20. 20.

    Lubin JH, Gail MH (1984) Biased selection of controls for case–control analyses of cohort studies. Biometrics 40:63–75

    CAS  Article  PubMed  Google Scholar 

  21. 21.

    Cole TJ, Freeman JV, Preece MA (1998) British 1990 growth reference centiles for weight, height, body mass index and head circumference fitted by maximum penalized likelihood. Stat Med 17:407–429

    CAS  Article  PubMed  Google Scholar 

  22. 22.

    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  Article  PubMed  Google Scholar 

  23. 23.

    Loder RT, O’Donnell PW, Feinberg JR (2006) Epidemiology and mechanisms of femur fractures in children. J Pediatr Orthop 26:561–566

    Article  PubMed  Google Scholar 

  24. 24.

    Liu EH, Alqahtani S, Alsaaran RN, Ho ES, Zuker RM, Borschel GH (2014) A prospective study of pediatric hand fractures and review of the literature. Pediatr Emerg Care 30:299–304

    Article  PubMed  Google Scholar 

  25. 25.

    Palvanen M, Kannus P, Parkkari J, Pitkajarvi T, Pasanen M, Vuori I, Jarvinen M (2000) The injury mechanisms of osteoporotic upper extremity fractures among older adults: a controlled study of 287 consecutive patients and their 108 controls. Osteoporos Int: J Established Result Coop Between Eur Found Osteoporos Natl Osteoporos Found USA 11:822–831

    CAS  Article  Google Scholar 

  26. 26.

    Lam JR, Schneider JL, Zhao W, Corley DA (2013) Proton pump inhibitor and histamine 2 receptor antagonist use and vitamin B12 deficiency. JAMA 310:2435–2442

    CAS  Article  PubMed  Google Scholar 

  27. 27.

    Recker RR (1985) Calcium absorption and achlorhydria. N Engl J Med 313:70–73

    CAS  Article  PubMed  Google Scholar 

  28. 28.

    Merriman NA, Putt ME, Metz DC, Yang YX (2010) Hip fracture risk in patients with a diagnosis of pernicious anemia. Gastroenterology 138:1330–1337

    PubMed Central  Article  PubMed  Google Scholar 

  29. 29.

    Chonan O, Takahashi R, Yasui H, Watanuki M (1998) Effect of L-lactic acid on calcium absorption in rats fed omeprazole. J Nutr Sci Vitaminol (Tokyo) 44:473–481

    CAS  Article  Google Scholar 

  30. 30.

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

    CAS  PubMed  Google Scholar 

  31. 31.

    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

    Article  PubMed  Google Scholar 

  32. 32.

    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

    CAS  Article  PubMed  Google Scholar 

  33. 33.

    Keller J, Schinke T (2013) The role of the gastrointestinal tract in calcium homeostasis and bone remodeling. Osteoporos Int 24:2737–2748

    CAS  Article  PubMed  Google Scholar 

  34. 34.

    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  Article  PubMed  Google Scholar 

  35. 35.

    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  Article  PubMed  Google Scholar 

  36. 36.

    Wren TA, Shepherd JA, Kalkwarf HJ, Zemel BS, Lappe JM, Oberfield S, Dorey FJ, Winer KK, Gilsanz V (2012) Racial disparity in fracture risk between white and nonwhite children in the United States. J Pediatr 161:1035–1040

    PubMed Central  Article  PubMed  Google Scholar 

  37. 37.

    Heidelbaugh JJ, Goldberg KL, Inadomi JM (2009) Overutilization of proton pump inhibitors: a review of cost-effectiveness and risk [corrected]. Am J Gastroenterol 104(Suppl 2):S27–S32

    CAS  Article  PubMed  Google Scholar 

  38. 38.

    El-Serag HB, Richardson P, Pilgrim P, Gilger MA (2007) Determinants of gastroesophageal reflux disease in adults with a history of childhood gastroesophageal reflux disease. Clin Gastroenterol Hepatol 5:696–701

    Article  PubMed  Google Scholar 

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Conflicts of interest

None.

Funding

Daniel Freedberg was funded by the National Center for Advancing Translational Sciences (NIH KL2TR000081); Michelle Denburg was funded by the NIH (K23 DK093556) and a Nephcure Foundation–American Society of Nephrology Research Grant; Mary Leonard was funded by the NIH (K24DK076808). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH or other organizations.

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Correspondence to D. E. Freedberg.

Electronic supplementary material

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Supplementary Table 1

Fracture type within the study, by age and sex. (DOCX 27 kb)

Supplementary Table 2

Fracture type within the study, by age and PPI exposure. (DOCX 26 kb)

Supplementary Table 3

Conditional logistic regression model for the relationship between proton pump inhibitors and fracture, by age. (DOCX 23 kb)

Supplementary Table 4

Conditional logistic regression model for the relationship between acid suppression and fracture, by age. (DOCX 23 kb)

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Freedberg, D.E., Haynes, K., Denburg, M.R. et al. Use of proton pump inhibitors is associated with fractures in young adults: a population-based study. Osteoporos Int 26, 2501–2507 (2015). https://doi.org/10.1007/s00198-015-3168-0

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Keywords

  • Acid suppression medications
  • Bone mineral density
  • Fracture
  • Histamine-2 receptor antagonists
  • Osteoporosis
  • Outcomes research
  • Pediatrics
  • Pharmacoepidemiology
  • Proton pump inhibitors