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Gastroesophageal reflux disease with proton pump inhibitor use is associated with an increased risk of osteoporosis: a nationwide population-based analysis

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Abstract

Summary

Gastroesophageal reflux disease (GERD) with proton pump inhibitor (PPI) use is associated with an increased risk of osteoporosis. The risk of hip fracture is not increased in GERD patients with PPI use.

Introduction

The relationship between GERD with PPI treatment and the risk of osteoporosis is unclear. We aimed to determine the risk of developing osteoporosis in patients diagnosed with GERD.

Methods

Patients diagnosed with GERD and received PPI treatment between 2000 and 2010 were identified from the Longitudinal Health Insurance Database as the study cohort (n = 10,620), which was frequency matched with the comparison cohort (n = 20,738) sampled from the general population according to age, sex, index year, and comorbidities. Both cohorts were followed until the end of 2011. The risk of osteoporosis was evaluated in both groups by using Cox proportional hazards regression models.

Results

The GERD patients with PPI treatment had a greater incidence (31.4 vs 20.7 per 1000 person-year; crude hazard ratio [cHR] 1.51; 95 % confidence interval [CI] 1.40–1.63) and a higher risk (adjusted HR [aHR] 1.50; 95 % CI 1.39–1.62) of osteoporosis than that of the comparison cohort. However, the overall incidence of hip fracture was not different between the GERD with PPI use and the control cohorts (aHR 0.79; 95 % CI 0.53–1.18).

Conclusion

GERD with PPI use is associated with an increased risk of osteoporosis. The findings of our study do not support an increased risk of hip fracture in GERD patients treated with a PPI.

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Abbreviations

GERD:

Gastroesophageal reflux disease

PPI:

Proton pump inhibitor

aHR:

Adjusted hazard ratio

CI:

Confidence interval

NHIRD:

National Health Insurance Research Database

LHID2000:

Longitudinal Health Insurance Database 2000

NHI:

National Health Insurance

ICD-9-CM:

International Classification of Diseases, Ninth Revision, Clinical Modification

BNHI:

Bureau of National Health Insurance

GABA:

Gamma-aminobutyric acid

References

  1. Rachner T, Khosla S, Hofbauer L (2011) New horizons in osteoporosis. Lancet 377:1276–1287

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Dawson-Hughes B, Looker AC, Tosteson AN, Johansson H, Kanis JA, Melton LJ 3rd (2010) The potential impact of new National Osteoporosis Foundation guidance on treatment patterns. Osteoporos Int 21:41–52

    Article  CAS  PubMed  Google Scholar 

  3. Kinsella K, Wan H (2009) International Population Reports, p 95/09–1, An aging world: 2008. US Census Bureau, US Government Printing Office, Washington, DC

    Google Scholar 

  4. Xia WB, He SL, Xu L, Liu AM, Jiang Y, Li M, Wang O, Xing XP, Sun Y, Cummings SR (2012) Rapidly increasing rates of hip fracture in Beijing, China. J Bone Miner Res 27:125–129

    Article  PubMed  Google Scholar 

  5. Vakil N, van Zanten SV, Kahrlas P, Dent J, Jones R (2006) The Montrel definition and classification of gastroesophageal reflux disease: a global evidence-based consensus. Am J Gastroenterol 101:1900–1920

    Article  PubMed  Google Scholar 

  6. Jung HK (2011) Epidemiology of gastroesophageal reflux disease in Asia: a systemic review. J Neurogastroenterol Motil 17:14–27

    Article  PubMed  PubMed Central  Google Scholar 

  7. Bredenoord AJ, Pandolfino JE, Amout AJPM (2013) Gastro-oesophageal reflux disease. Lancet 381:1933–1942

    Article  PubMed  Google Scholar 

  8. Souza RF, Huo X, Mittal V, Schuler CM, Carmack SW, Zhang HY, Zhang X, Yu C, Hormi-Carver K, Genta RM, Spechler SJ (2009) Gastroesophageal reflux might cause esophagitis through a cytokine-mediated mechanisms rather than caustic acid injury. Gastroenterology 137:1776–1784

    Article  CAS  PubMed  Google Scholar 

  9. Oh TY, Lee JS, Ahn BO, Cho H, Kim WB, Kim YB, Surh YJ, Cho SW, Lee KM, Hahm KB (2001) Oxidative stress is more important than acid in the pathogenesis of reflux oesophagitis in rats. Gut 49:364–371

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Dent J, El-Serag HB, Wallander MA, Johnsson S (2005) Epidemiology of gastro-oesophageal reflux disease: a systemic review. Gut 54:710–717

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Lim SL, Goh WT, Lee JM, Ng TP, Ho KY, Community Medicine GI Study Group (2005) Changing prevalence of gastroesophageal reflux with changing time: longitudinal study in an Asian population. J Gastroenterol Hepatol 20:995–1001

    Article  PubMed  Google Scholar 

  12. Wong WM, Lai KC, Lam KF, Hui WM, Hu WH, Lam CL, Xia HH, Huang JQ, Chan CK, Lam SK, Wong BC (2003) Prevalence, clinical spectrum and health care utilization of gastro-oesophageal reflux disease in a Chinese population: a population-based study. Aliment Pharmacol Ther 18:595–604

    Article  CAS  PubMed  Google Scholar 

  13. Chen M, Xiong I, Chen H, Xu A, He L, Hu P (2005) Prevalence, risk factors and impact of gastroesophageal reflux disease symptoms: a population-based study in South China. Scand J Gastroenterol 40:759–767

    Article  PubMed  Google Scholar 

  14. 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

    Article  PubMed  PubMed Central  Google Scholar 

  15. 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

    Article  CAS  PubMed  Google Scholar 

  16. 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

    Article  CAS  PubMed  Google Scholar 

  17. Database NHIR. Taiwan, http://nhird.nhri.org.tw/en/Background.html (cited in 2015)

  18. Siris ES, Adler R, Bilezikian J, Bolognese M, Dawson-Hughes B, Favus MJ, Harris ST, Jan de Beur SM, Khosla S, Lane NE, Lindsay R, Nana AD, Orwoll ES, Saag K, Silverman S, Watts NB (2014) The clinical diagnosis of osteoporosis: a position statement from the National Bone Health Alliance Working Group. Osteoporos Int 25:1439–1443

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Ford AC, Forman D, Reynolds PD, Cooper BT, Moayyedi P (2005) Ethnicity, gender, and socioeconomic status as risk factors for esophagitis and Barrett’s esophagus. Am J Epidemiol 162:454–460

    Article  PubMed  Google Scholar 

  20. Menon S, Jayasena H, Nightingale P, Trudgill NJ (2011) Influence of age and sex on endoscopic findings of gastrooesophageal reflux disease: an endoscopy database study. Eur J Gastroenterol Hepatol 23:389–395

    Article  PubMed  Google Scholar 

  21. Achem SR, DeVault KR (2014) Gastroesophageal reflux disease and the elderly. Gastroenterol Clin N Am 43:147–160

    Article  Google Scholar 

  22. Sossalla S, Schotola H, Schmitto J, Toischer K, Sihns C, Schworer H, Hasenfuss G, Maier L, Schillinger W (2011) Effects of different proton pump inhibitors on cardiac contractility in isolated human failing myocardium. J Cardiovasc Surg 52:437–444

    CAS  Google Scholar 

  23. Khinchi P, Saha S, Saraf SA, Kaithwas G (2014) Combination therapy of gamma-aminobutyric acid derivative promotes proton pump inhibitor based healing of reflux esophagitis in animal model. Pharmacol Rep 66:165–168

    Article  CAS  PubMed  Google Scholar 

  24. Hall SD, Prokic EJ, McAllister CJ, Ronnqvist KC, Williams AC, Yamawaki N, Witton C, Woodhall GL, Stanford IM (2014) GABA-mediated changes in inter-hemispheric beta frequency activity in early-stage Parkinson’s disease. Neuroscience 281:68–76

    Article  CAS  PubMed Central  Google Scholar 

  25. Sung HY, Park JW, Kim JS (2014) The frequency and severity of gastrointestinal symptoms in patients with early Parkinson’s disease. J Mov Disord 7:7–12

    Article  PubMed  PubMed Central  Google Scholar 

  26. Treiman DM (2001) GABAergic mechanisms in epilepsy. Epilepsia 42(suppl 3):8–12

  27. Zhang J, Cui PL, Lv D, Yao SW, Xu YQ, Yang ZX (2011) Gastroesophageal reflux in cirrhotic patients without esophageal varices. World J Gastroenterol 17:1753–1758

    Article  PubMed  PubMed Central  Google Scholar 

  28. Giorgio M, Trinei M, Migliaccio E, Pelicci PG (2007) Hydrogen peroxide: a metabolic by-product or a common mediator of ageing signals? Nat Mol Cell Biol 8:722–728

    Article  CAS  Google Scholar 

  29. Armas LAG, Recker RR (2012) Pathophysiology of osteoporosis. Endocrinol Metab Clin N Am 41:475–486

    Article  CAS  Google Scholar 

  30. Ilic K, Obradovic N, Vujasinovic-Stupar N (2013) The relationship among hypertension, antihypertensive medications, and osteoporosis: a narrative review. Calcif Tissue Int 92:217–227

    Article  CAS  PubMed  Google Scholar 

  31. Bagger YZ, Rasmussen HB, Alexandersen P, Werge T, Christiansen C, Tanko LB, PERF study group (2007) Links between cardiovascular disease and osteoporosis in postmenopausal women: serum lipids or atherosclerosis per se? Osteoporos Int 18:505–512

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Pirih F, Lu J, Ye F, Bezouglaia O, Atti E, Ascenzi MG, Tetradis S, Demer L, Aghaloo T, Tintut Y (2012) Adverse effects of hyperlipidemia on bone regeneration and strength. JBMR 27:309–318

    Article  CAS  Google Scholar 

  33. Nakchbandi IA, Osteoporosis and fractures in liver disease (2014) Relevance, pathogenesis and therapeutic implications. World J Gastroenterol 20:9427–9438

    PubMed  PubMed Central  Google Scholar 

  34. Weinstein RS (2012) Glucocorticoid-induced osteoporosis and osteonecrosis. Endocinol Metab Clin N Am 41:595–611

    Article  Google Scholar 

  35. Pack AM, Morrell MJ (2004) Epilepsy and bone health in adults. Epilepsy Behav 5(suppl 2):S24–S29

  36. Hill DD, Cauley JA, Sheu Y, Bunker CH, Patrick AL, Baker CE, Beckles GLA, Wheeler VW, Zmuda JM (2008) Correlates of bone mineral density in men of African ancestry: the Tobago Bone Health Study. Osteoporos Int 19:227–234

    Article  CAS  PubMed  Google Scholar 

  37. 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 Study. Osteoporos Int 24:1161–1168

    Article  CAS  PubMed  Google Scholar 

  38. Hinson AM, Wilkerson BM, Rothman-Fitts I, Rggs AT, Stack BC, Bodenner DL (2015) Hyperparathyroidism associated with long-term proton pump inhibitors independent of concurrent bisphosphonate therapy in elderly adults. J Am Geriatr Soc 63:2070–2073

    Article  PubMed  Google Scholar 

  39. Soloman DH, Diem SJ, Ruppert K, Lian YJ, Liu CC, Wohlfart A, Greendale GA, Finkelstein JS (2015) Bone mineral density changes among women initiating proton pump inhibitors or H2 receptor antagonists: a Swan cohort study. JBMR 30:232–239

    Article  Google Scholar 

  40. Gray SL, LaCroix AZ, Larson J, Robbins J, Cauley JA, Manson JE, Chen Z (2010) Proton pump inhibitors use, hip fracture, and changes in bone mineral density in postmenopausal women. Arch Intern Med 170:765–771

    Article  PubMed  PubMed Central  Google Scholar 

  41. Kanis JA, Borgstrom F, De Laet C, Johansson H, Johnell O, Jonsson B, Oden A, Zethraeus N, Pfleger B, Khaltaev N (2005) Assessment of fracture risk. Osteoporos Int 16:581–589

    Article  PubMed  Google Scholar 

  42. Armour KJ, Armour KE, van’t Hof RJ, Reid DM, Wei XQ, Liew FY, Ralston SH (2001) Activation of the inducible nitric oxide synthase pathway contributes to inflammation-induced osteoporosis by suppressing bone formation and causing osteoblast apoptosis. Arthritis Rheum 44:2790–2796

    Article  CAS  PubMed  Google Scholar 

  43. Sertorio JT (2013) Proton pump inhibitors and nitric oxide mechanisms in type 2 diabetes. Diabetologia 56:2763–2764

    Article  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

This study is supported in part by Taiwan Ministry of Health and Welfare Clinical Trial and Research Center of Excellence (MOHW105-TDU-B-212-133019), China Medical University Hospital, Academia Sinica Taiwan Biobank Stroke Biosignature Project (BM10501010037), NRPB Stroke Clinical Trial Consortium (MOST 104-2325-B-039 -005), Tseng-Lien Lin Foundation, Taichung, Taiwan, Taiwan Brain Disease Foundation, Taipei, Taiwan, and Katsuzo and Kiyo Aoshima Memorial Funds, Japan; and CMU under the Aim for Top University Plan of the Ministry of Education, Taiwan.

Author information

Authors and Affiliations

  1. Digestive Disease Center, Show-Chwan Memorial Hospital, Changhua, Taiwan

    C.-H. Chen

  2. Department of Food Science and Technology, Hungkuang University, Taichung, Taiwan

    C.-H. Chen

  3. Meiho University of Technology, Pingtung, Taiwan

    C.-H. Chen

  4. Management Office for Health Data, China Medical University Hospital, Taichung, Taiwan

    C.-L. Lin

  5. College of Medicine, China Medical University, Taichung, Taiwan

    C.-L. Lin

  6. Graduate Institute of Clinical Medical Science, School of Medicine, College of Medicine, China Medical University, No. 2, Yuh-Der Road, Taichung, 40447, Taiwan

    C.-H. Kao

  7. Department of Nuclear Medicine and PET Center, China Medical University Hospital, Taichung, Taiwan

    C.-H. Kao

Authors
  1. C.-H. Chen
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  3. C.-H. Kao
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Corresponding author

Correspondence to C.-H. Kao.

Ethics declarations

Compliance with ethical standards

The NHIRD encrypts patient personal information to protect privacy and provides researchers with anonymous identification numbers associated with relevant claims information, including sex, date of birth, medical services received, and prescriptions. Therefore, patient consent is not required to access the NHIRD. This study was approved to fulfill the condition for exemption by the Institutional Review Board (IRB) of China Medical University (CMUH-104-REC2-115). The IRB also specifically waived the consent requirement.

Conflicts of interest

None.

Funding

The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. No additional external funding was received for this study.

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Chen, CH., Lin, CL. & Kao, CH. 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 (2016). https://doi.org/10.1007/s00198-016-3510-1

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  • DOI: https://doi.org/10.1007/s00198-016-3510-1

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