Skip to main content

Advertisement

SpringerLink
Log in

Proton Pump Inhibitors, Histamine H2 Receptor Antagonists, and Other Antacid Medications and the Risk of Fracture

  • Published:
Calcified Tissue International Aims and scope Submit manuscript

Abstract

We studied the effect of proton pump inhibitors, histamine H2 receptor antagonists, and other types of antacid drugs on fracture risk. All cases were subjects with any fracture sustained during the year 2000 (n = 124,655). For each case, three controls (n = 373,962) matched on age and gender were randomly drawn from the background population. The primary exposure variables were use of proton pump inhibitors, histamine H2 antagonists, and other antacid drugs. Adjustments were made for several confounders, including diagnosis of an ulcer, nonsteroidal anti-inflammatory drug use, use of histamine H1 antagonists, stomach resection, previous fracture, and use of corticosteroids. The effect of dose was examined by stratifying for cumulated dose (defined daily dose). Use of proton pump inhibitors was associated with an increase in fracture risk for use within the last year [odds ratio (OR) = 1.18, 95% confidence interval (CI) 1.12–1.43 for overall fracture risk; OR = 1.45, 95% CI 1.28–1.65 for hip fractures; and OR = 1.60, 95% CI 1.25–2.04 for spine fractures). Histamine H2 antagonists were associated with a decreased fracture risk if they had been used within the last year (OR = 0.88, 95% CI 0.82–0.95 for any fracture, OR = 0.69, 95% CI 0.57–0.84 for hip fractures). Other antacids were not associated with overall fracture risk but were associated with hip and spine fractures. Proton pump inhibitors appeared to be associated with a limited increase in fracture risk, in contrast to histamine H 2 antagonists, which seemed to be associated with a small decrease in fracture risk. In all cases, the changes in risk estimates were small and the clinical significance was limited.

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

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Farina C, Gagliardi S (2002) Selective inhibition of osteoclast vacuolar H+-ATPase. Curr Pharm Des 8:2033–2048

    Article  PubMed  CAS  Google Scholar 

  2. Sahara T, Itoh K, Debari K, et al. (2003) Specific biological functions of vacuolar-type H+-ATPase and lysosomal cysteine proteinase, cathepsin K, in osteoclasts. Anat Rec A Discov Mol Cell Evol Biol 270:152–161

    Article  PubMed  CAS  Google Scholar 

  3. Sasaki T (1996) Recent advances in the ultrastructural assessment of osteoclastic resorptive functions. Microsc Res Tech 33:182–191

    Article  PubMed  CAS  Google Scholar 

  4. Shibata T, Amano H, Yamada S, et al. (2000) Mechanisms of proton transport in isolated rat osteoclasts attached to bone. J Med Dent Sci 47:177–185

    PubMed  CAS  Google Scholar 

  5. Gagliardi S, Nadler G, Consolandi E, et al. (1998) 5-(5,6-Dichloro-2-indolyl)-2-methoxy-2,4-pentadienamides: novel and selective inhibitors of the vacuolar H+-ATPase of osteoclasts with bone antiresorptive activity. J Med Chem 41:1568–1573

    Article  PubMed  CAS  Google Scholar 

  6. Rzeszutek K, Sarraf F, Davies JE (2003) Proton pump inhibitors control osteoclastic resorption of calcium phosphate implants and stimulate increased local reparative bone growth. J Craniofac Surg 14:301–307

    Article  PubMed  CAS  Google Scholar 

  7. Sundquist K, Lakkakorpi P, Wallmark B, et al. (1990) Inhibition of osteoclast proton transport by bafilomycin A1 abolishes bone resorption. Biochem Biophys Res Commun 168:309–313

    Article  PubMed  CAS  Google Scholar 

  8. Visentin L, Dodds RA, Valente M, et al. (2000) A selective inhibitor of the osteoclastic V-H+-ATPase prevents bone loss in both thyroparathyroidectomized and ovariectomized rats. J Clin Invest 106:309–318

    Article  PubMed  CAS  Google Scholar 

  9. Xu J, Feng HT, Wang C, et al. (2003) Effects of bafilomycin A1: an inhibitor of vacuolar H+-ATPases on endocytosis and apoptosis in RAW cells and RAW cell-derived osteoclasts. J Cell Biochem 88:1256–1264

    Article  PubMed  CAS  Google Scholar 

  10. Grisso JA, Kelsey JL, O’Brien LA, et al. (1997) Risk factors for hip fracture in men. Hip Fracture Study Group. Am J Epidemiol 145:786–793

    PubMed  CAS  Google Scholar 

  11. Adachi Y, Shiota E, Matsumata T, et al. (1998) Bone mineral density in patients taking H2-receptor antagonist. Calcif Tissue Int 62:283–285

    Article  PubMed  CAS  Google Scholar 

  12. Wacholder S, McLaughlin JK, Silverman DT, et al. (1992) Selection of controls in case-control studies. I. Principles. Am J Epidemiol 135:1019–1028

    PubMed  CAS  Google Scholar 

  13. Vestergaard P, Emborg C, Støving RK, et al. (2002) Fractures in patients with anorexia nervosa, bulimia nervosa, and other eating disorders - a nation-wide register study. Int J Eat Disord 32:301–308

    Article  PubMed  Google Scholar 

  14. Vestergaard P, Mosekilde L (2002) Fracture risk in patients with celiac disease, Crohn’s disease, and ulcerative colitis: a nation-wide follow-up study in 16,416 patients in Denmark. Am J Epidemiol 156:1–10

    Article  PubMed  Google Scholar 

  15. Vestergaard P, Rejnmark L, Mosekilde L (2005) Fracture risk associated with systemic and topical corticosteroids. J Intern Med 257:374–384

    Article  PubMed  CAS  Google Scholar 

  16. Vestergaard P, Rejnmark L, Mosekilde L (2004) Fracture risk associated with use of anti-epileptic drugs. Epilepsia 45:1330–1337

    Article  PubMed  CAS  Google Scholar 

  17. Klotzbuecher CM, Ross PD, Landsman PB, et al. (2000) Patients with prior fractures have an increased risk of future fractures: a summary of the litterature and statistical synthesis. J Bone Miner Res 15:721–739

    Article  PubMed  CAS  Google Scholar 

  18. Charlson ME, Pompei P, Ales KL, et al. (1987) A method of classifying prognostic comorbidity in longitudinal studies: development and validation. J Chron Dis 40:373–383

    Article  PubMed  CAS  Google Scholar 

  19. Kanis JA, Johansson H, Johnell O, et al. (2005) Alcohol intake as a risk factor for fracture. Osteoporosis Int 16:737–742

    Article  Google Scholar 

  20. Andersen TF, Madsen M, Jørgensen J, et al. (1999) The Danish National Hospital Register. Dan Med Bull 46:263–268

    PubMed  CAS  Google Scholar 

  21. Munk-Jørgensen P, Mortensen PB (1997) The Danish Psychiatric Central Register. Dan Med Bull 44:82–84

    PubMed  Google Scholar 

  22. Mosbech J, Jørgensen J, Madsen M, et al. (1995) The Danish National Patient Register: evaluation of data quality [in Danish]. Ugeskr Læger 157:3741–3745

    PubMed  CAS  Google Scholar 

  23. Nielsen GL, Sørensen HT, Zhou W, et al. (1997) The pharmaco-epidemiologic prescription database of north Jutland. Int J Risk Saf Med 10:203–205

    Google Scholar 

  24. Vestergaard P, Mollerup CL, Frøkjær VG, et al. (2000) Cohort study of risk of fracture before and after surgery for primary hyperparathyroidism. BMJ 321:598–602

    Article  PubMed  CAS  Google Scholar 

  25. Yamaura K, Yonekawa T, Nakamura T, et al. (2003) The histamine H2-receptor antagonist, cimetidine, inhibits the articular osteopenia in rats with adjuvant-induced arthritis by suppressing the osteoclast differentiation induced by histamine. J Pharmacol Sci 92:43–49

    Article  PubMed  CAS  Google Scholar 

  26. Lesclous P, Guez D, Baroukh B, et al. (2004) Histamine participates in the early phase of trabecular bone loss in ovariectomized rats. Bone 34:91–99

    Article  PubMed  CAS  Google Scholar 

  27. Lesclous P, Guez D, Saffar JL (2002) Short-term prevention of osteoclastic resorption and osteopenia in ovariectomized rats treated with the H2 receptor antagonist cimetidine. Bone 30:131–136

    Article  PubMed  CAS  Google Scholar 

  28. Dobigny C, Saffar JL (1997) H1 and H2 histamine receptors modulate osteoclastic resorption by different pathways: evidence obtained by using receptor antagonists in a rat synchronized resorption model. J Cell Physiol 173:10–18

    Article  PubMed  CAS  Google Scholar 

  29. Mattsson JP, Vaananen K, Wallmark B, et al. (1991) Omeprazole and bafilomycin, two proton pump inhibitors: differentiation of their effects on gastric, kidney and bone H+-translocating ATPases. Biochim Biophys Acta 1065:261–268

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  31. Tran TM, Van den NA, Hendriks JJ, et al. (1998) Effects of a proton-pump inhibitor in cystic fibrosis. Acta Paediatr 87:553–558

    Article  PubMed  CAS  Google Scholar 

  32. Persson P, Gagnemo-Persson R, Chen D, et al. (1993) Gastrectomy causes bone loss in the rat: is lack of gastric acid responsible? Scand J Gastroenterol 28:301–306

    PubMed  CAS  Google Scholar 

  33. Hoidrup S, Grønbæk M, Gottschau A, et al. (1999) Alcohol intake, beverage preference, and risk of hip fracture in men and women. Am J Epidemiol 149:993–1001

    PubMed  CAS  Google Scholar 

Download references

Acknowledgments

Danmarks Statistik (Statistics Denmark) is acknowledged for the help without which this project would not have been possible. Research Librarian Ms. Edith Clausen is acknowledged for invaluable help with the references. The Danish Medical Research Council granted financial support (grant 22-04-0495).

Author information

Authors and Affiliations

  1. The Osteoporosis Clinic, Aarhus Amtssygehus, Aarhus University Hospital, Tage Hansens Gade 2, DK-8000, Aarhus C, Denmark

    P. Vestergaard

  2. Department of Endocrinology and Metabolism C, Aarhus Amtssygehus, Aarhus University Hospital, Tage Hansens Gade 2, DK-8000, Aarhus C, Denmark

    L. Rejnmark & L. Mosekilde

Authors
  1. P. Vestergaard
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. L. Rejnmark
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. L. Mosekilde
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to P. Vestergaard.

Rights and permissions

Reprints and permissions

About this article

Cite this article

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 79, 76–83 (2006). https://doi.org/10.1007/s00223-006-0021-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00223-006-0021-7

Keywords

Search

Navigation