Current Gastroenterology Reports

, Volume 12, Issue 6, pp 448–457 | Cite as

Association of Long-Term Proton Pump Inhibitor Therapy with Bone Fractures and Effects on Absorption of Calcium, Vitamin B12, Iron, and Magnesium

Article

Abstract

Proton pump inhibitors (PPI) are one of the most widely used classes of drugs. PPIs have a very favorable safety profile, and it is unusual for a patient to stop them because of side effects. However, with increasing numbers of patients chronically taking PPIs for gastroesophageal reflux disease and other common, persistent conditions, the long-term potential adverse effects are receiving increasing attention. An insufficiently studied area receiving much attention is the long-term effect of chronic acid suppression on the absorption of vitamins and nutrients. This increased attention results from the reported potential adverse effect of chronic PPI treatment leading to an increased occurrence of bone fractures. Interest in this area has led to examination of the effects of PPIs on calcium absorption/metabolism and numerous cohort, case-control, and prospective studies of their ability to affect bone density and cause bone fractures. In this article, these studies are systematically examined, as are studies of the effects of chronic PPI use on absorption of VB12, iron, and magnesium. Studies in each area have led to differing conclusions, but when examined systematically, consistent results of several studies support the conclusion that long-term adverse effects on these processes can have important clinical implications.

Keywords

Proton pump inhibitor PPI Acid suppression H+K+ATPase inhibitor Omeprazole Lansoprazole Rabeprazole Pantoprazole Esomeprazole Hip fractures Vitamin B12 Cobalamin Iron deficiency anemia Hypomagnesemia Hypocalcemia Osteoporosis Zollinger-Ellison syndrome 

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    Lahner E, Annibale B, Delle Fave G: Systematic review: impaired drug absorption related to the co-administration of antisecretory therapy. Aliment Pharmacol Ther 2009, 29:1219–1229.CrossRefPubMedGoogle Scholar
  2. 2.
    Jensen RT: Consequences of long-term proton pump blockade: Highlighting insights from studies of patients with gastrinomas. Basic Clin Pharmacol Toxicol 2006, 98:4–19.CrossRefPubMedGoogle Scholar
  3. 3.
    McColl KE: Effect of proton pump inhibitors on vitamins and iron. Am J Gastroenterol 2009, 104(Suppl 2):S5–S9.CrossRefPubMedGoogle Scholar
  4. 4.
    • Lodato F, Azzaroli F, Turco L, et al.: Adverse effects of proton pump inhibitors. Best Pract Res Clin Gastroenterol 2010, 24:193–201. This article is a recent general review of all adverse effects of PPIs, including the absorption of vitamins and nutrients and possible effects on bone fractures.Google Scholar
  5. 5.
    Moayyedi P, Cranney A: Hip fracture and proton pump inhibitor therapy: balancing the evidence for benefit and harm. Am J Gastroenterol 2008, 103:2428–2431.CrossRefPubMedGoogle Scholar
  6. 6.
    Yang YX, Lewis JD, Epstein S, Metz DC: Long-term proton pump inhibitor therapy and risk of hip fracture. JAMA 2006, 296:2947–2953.CrossRefPubMedGoogle Scholar
  7. 7.
    Ali T, Roberts DN, Tierney WM: Long-term safety concerns with proton pump inhibitors. Am J Med 2009, 122:896–903.CrossRefPubMedGoogle Scholar
  8. 8.
    Thomson AB, Sauve MD, Kassam N, Kamitakahara H: Safety of the long-term use of proton pump inhibitors. World J Gastroenterol 2010, 16:2323–2330.CrossRefPubMedGoogle Scholar
  9. 9.
    Studies link PPIs to increased risk of bacterial infection, bone fracture. Today in Medicine May 21, 2010:1–4.Google Scholar
  10. 10.
    Targownik LE: Another bad break for proton-pump inhibitors? Nat Rev Rheumatol 2009, 5:478–480.CrossRefPubMedGoogle Scholar
  11. 11.
    Kirkpantur A, Altun B, Arici M, Turgan C: Proton pump inhibitor omeprazole use is associated with low bone mineral density in maintenance haemodialysis patients. Int J Clin Pract 2009, 63:261–268.CrossRefPubMedGoogle Scholar
  12. 12.
    Targownik LE, Lix LM, Leung S, Leslie WD: Proton-pump inhibitor use is not associated with osteoporosis or accelerated bone mineral density loss. Gastroenterology 2010, 138:896–904.CrossRefPubMedGoogle Scholar
  13. 13.
    Insogna KL: The effect of proton pump-inhibiting drugs on mineral metabolism. Am J Gastroenterol 2009, 104(Suppl 2):S2–S4.CrossRefPubMedGoogle Scholar
  14. 14.
    •• 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. This article describes a recent prospective study demonstrating that PPI use is associated with increased occurrence of bone fractures.Google Scholar
  15. 15.
    Kaye JA, Jick H: Proton pump inhibitor use and risk of hip fractures in patients without major risk factors. Pharmacotherapy 2008, 28:951–959.CrossRefPubMedGoogle Scholar
  16. 16.
    den Elzen WP, Groeneveld Y, de Ruijter W, et al.: Long-term use of proton pump inhibitors and vitamin B12 status in elderly individuals. Aliment Pharmacol Ther 2008, 27:491–497.CrossRefGoogle Scholar
  17. 17.
    Valuck RJ, Ruscin JM: A case-control study on adverse effects: H2 blocker or proton pump inhibitor use and risk of vitamin B12 deficiency in older adults. J Clin Epidemiol 2004, 57:422–428.CrossRefPubMedGoogle Scholar
  18. 18.
    Termanini B, Gibril F, Sutliff VE III, et al.: Effect of long-term gastric acid suppressive therapy on serum vitamin B 12 levels in patients with Zollinger-Ellison syndrome. Am J Med 1998, 104:422–430.CrossRefPubMedGoogle Scholar
  19. 19.
    Nand S, Tanvetyanon T: Proton pump inhibitors and iron deficiency: is the connection real? South Med J 2004, 97:799.CrossRefPubMedGoogle Scholar
  20. 20.
    Sharma VR, Brannon MA, Carloss EA: Effect of omeprazole on oral iron replacement in patients with iron deficiency anemia. South Med J 2004, 97:887–889.CrossRefPubMedGoogle Scholar
  21. 21.
    Stewart CA, Termanini B, Sutliff VE, et al.: Assessment of the risk of iron malabsorption in patients with Zollinger-Ellison syndrome treated with long-term gastric acid antisecretory therapy. Aliment Pharmacol Ther 1998, 12:83–98.CrossRefPubMedGoogle Scholar
  22. 22.
    Festen HP: Intrinsic factor secretion and cobalamin absorption. Physiology and pathophysiology in the gastrointestinal tract. Scand J Gastroenterol 1991, 26:1–7.CrossRefGoogle Scholar
  23. 23.
    Dutta SK: Editorial: vitamin B 12 malabsorption and omeprazole therapy. J Am Coll Nutr 1994, 13:544–545.PubMedGoogle Scholar
  24. 24.
    Koop H: Review article: metabolic consequences of long-term inhibition of acid secretion by omeprazole. Aliment Pharmacol Ther 1992, 6:399–406.CrossRefPubMedGoogle Scholar
  25. 25.
    Steinberg WM, King CE, Toskes PP: Malabsorption of protein-bound cobalamin but not unbound cobalamin during cimetidine administration. Dig Dis Sci 1980, 25:188–191.CrossRefPubMedGoogle Scholar
  26. 26.
    • Rozgony NR, Fang C, Kuczmarski MF, Bob H: Vitamin B(12) deficiency is linked with long-term use of proton pump inhibitors in institutionalized older adults: could a cyanocobalamin nasal spray be beneficial? J Nutr Elder 2010, 29:87–99. A recent prospective study demonstrated a marked increase of VB 12 deficiency in elderly institutionalized participants using chronic PPIs and demonstrated the effectiveness of a VB 12 nasal spray.Google Scholar
  27. 27.
    Dharmarajan TS, Kanagala MR, Murakonda P, et al.: Do acid-lowering agents affect vitamin B12 status in older adults? J Am Med Dir Assoc 2008, 9:162–167.CrossRefPubMedGoogle Scholar
  28. 28.
    Hirschowitz BI, Worthington J, Mohnen J: Vitamin B12 deficiency in hypersecretors during long-term acid suppression with proton pump inhibitors. Aliment Pharmacol Ther 2008, 27:1110–1121.CrossRefPubMedGoogle Scholar
  29. 29.
    Norton JA, Fraker DL, Alexander HR, et al.: Surgery to cure the Zollinger-Ellison syndrome. N Engl J Med 1999, 341:635–644.CrossRefPubMedGoogle Scholar
  30. 30.
    Gibril F, Jensen RT: Zollinger-Ellison syndrome revisited: diagnosis, biologic markers, associated inherited disorders, and acid hypersecretion. Curr Gastroenterol Rep 2004, 6:454–463.CrossRefPubMedGoogle Scholar
  31. 31.
    Metz DC, Jensen RT: Gastrointestinal neuroendocrine tumors: pancreatic endocrine tumors. Gastroenterology 2008, 135:1469–1492.CrossRefPubMedGoogle Scholar
  32. 32.
    Force RW, Meeker AD, Cady PS, et al.: Ambulatory care increased vitamin B12 requirement associated with chronic acid suppression therapy. Ann Pharmacother 2003, 37:490–493.CrossRefPubMedGoogle Scholar
  33. 33.
    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.CrossRefPubMedGoogle Scholar
  34. 34.
    Chonan O, Takahashi R, Yasui H, Watanuki M: Effect of L-lactic acid on calcium absorption in rats fed omeprazole. J Nutr Sci Vitaminol (Tokyo) 1998, 44:473–481.Google Scholar
  35. 35.
    O'Connell MB, Madden DM, Murray AM, et al.: Effects of proton pump inhibitors on calcium carbonate absorption in women: a randomized crossover trial. Am J Med 2005, 118:778–781.CrossRefPubMedGoogle Scholar
  36. 36.
    Sipponen P, Harkonen M: Hypochlorhydric stomach: a risk condition for calcium malabsorption and osteoporosis? Scand J Gastroenterol 2010, 45:133–138.CrossRefPubMedGoogle Scholar
  37. 37.
    Yu EW, Blackwell T, Ensrud KE, et al.: Acid-suppressive medications and risk of bone loss and fracture in older adults. Calcif Tissue Int 2008, 83:251–259.CrossRefPubMedGoogle Scholar
  38. 38.
    Wright MJ, Sullivan RR, Gaffney-Stomberg E, et al.: Inhibiting gastric acid production does not affect intestinal calcium absorption in young healthy individuals: a randomized, crossover controlled clinical trial. J Bone Miner Res 2010 (Epub ahead of print).Google Scholar
  39. 39.
    Wright MJ, Proctor DD, Insogna KL, Kerstetter JE: Proton pump-inhibiting drugs, calcium homeostasis, and bone health. Nutr Rev 2008, 66:103–108.CrossRefPubMedGoogle Scholar
  40. 40.
    Tuukkanen J, Vaananen HK: Omeprazole, a specific inhibitor of H + -K + -ATPase, inhibits bone resorption in vitro. Calcif Tissue Int 1986, 38:123–125.CrossRefPubMedGoogle Scholar
  41. 41.
    Sheraly AR, Lickorish D, Sarraf F, Davies JE: Use of gastrointestinal proton pump inhibitors to regulate osteoclast-mediated resorption of calcium phosphate cements in vivo. Curr Drug Deliv 2009, 6:192–198.CrossRefPubMedGoogle Scholar
  42. 42.
    Yang YX: Proton pump inhibitor therapy and osteoporosis. Curr Drug Saf 2008, 3:204–209.CrossRefPubMedGoogle Scholar
  43. 43.
    Johnson DA: Safety of proton pump inhibitors: current evidence for osteoporosis and interaction with antiplatelet agents. Curr Gastroenterol Rep 2010, 12:167–174.CrossRefPubMedGoogle Scholar
  44. 44.
    Cote GA, Howden CW: Potential adverse effects of proton pump inhibitors. Curr Gastroenterol Rep 2008, 10:208–214.CrossRefPubMedGoogle Scholar
  45. 45.
    Laine L: Proton pump inhibitors and bone fractures? Am J Gastroenterol 2009, 104:S21–S26.CrossRefPubMedGoogle Scholar
  46. 46.
    Moayyedi P, CAG Clinical Affairs Committee: Hip fracture and proton pump inhibitor therapy: position statement. Can J Gastroenterol 2008, 22:855–858.PubMedGoogle Scholar
  47. 47.
    Corley DA: Proton pump inhibitor, H2 antagonists, and risk of hip fracture: a large population-based study [abstract]. Gastroenterology 2009, 136:A70.CrossRefGoogle Scholar
  48. 48.
    •• Roux C, Briot K, Gossec L, et al.: Increase in vertebral fracture risk in postmenopausal women using omeprazole. Calcif Tissue Int 2009, 84:13–19. This article describes the only prospective study examining the effects of chronic PPI use on bone fractures, demonstrating a threefold increase in risk of vertebral fractures with chronic PPI use in postmenopausal females.Google Scholar
  49. 49.
    Targownik LE, Lix LM, Metge CJ, et al.: Use of proton pump inhibitors and risk of osteoporosis-related fractures. CMAJ 2008, 179:319–326.PubMedGoogle Scholar
  50. 50.
    Recker RR: Calcium absorption and achlorhydria. N Engl J Med 1985, 313:70–73.CrossRefPubMedGoogle Scholar
  51. 51.
    Graziani G, Como G, Badalamenti S, et al.: Effect of gastric acid secretion on intestinal phosphate and calcium absorption in normal subjects. Nephrol Dial Transplant 1995, 10:1376–1380.PubMedGoogle Scholar
  52. 52.
    Bo-Linn GW, Davis GR, Buddrus DJ, et al.: An evaluation of the importance of gastric acid secretion in the absorption of dietary calcium. J Clin Invest 1984, 73:640–647.CrossRefPubMedGoogle Scholar
  53. 53.
    Serfaty-Lacrosniere C, Wood RJ, Voytko D, et al.: Hypochlorhydria from short-term omeprazole treatment does not inhibit intestinal absorption of calcium, phosphorus, magnesium or zinc from food in humans. J Am Coll Nutr 1995, 14:364–368.PubMedGoogle Scholar
  54. 54.
    Knox TA, Kassarjian Z, Dawson-Hughes B, et al.: Calcium absorption in elderly subjects on high- and low-fiber diets: effect of gastric acidity. Am J Clin Nutr 1991, 53:1480–1486.PubMedGoogle Scholar
  55. 55.
    Heaney RP, Smith KT, Recker RR, Hinders SM: Meal effects on calcium absorption. Am J Clin Nutr 1989, 49:372–376.PubMedGoogle Scholar
  56. 56.
    Mizunashi K, Furukawa Y, Katano K, Abe K: Effect of omeprazole, an inhibitor of H+, K(+)-ATPase, on bone resorption in humans. Calcif Tissue Int 1993, 53:21–25.CrossRefPubMedGoogle Scholar
  57. 57.
    Cui GL, Syversen U, Zhao CM, et al.: Long-term omeprazole treatment suppresses body weight gain and bone mineralization in young male rats. Scand J Gastroenterol 2001, 36:1011–1015.CrossRefPubMedGoogle Scholar
  58. 58.
    Tolia V, Boyer K: Long-term proton pump inhibitor use in children: a retrospective review of safety. Dig Dis Sci 2008, 53:385–393.CrossRefPubMedGoogle Scholar
  59. 59.
    Tucker KL, Hannan MT, Qiao N, et al.: Low plasma vitamin B12 is associated with lower BMD: the Framingham Osteoporosis Study. J Bone Miner Res 2005, 20:152–158.CrossRefPubMedGoogle Scholar
  60. 60.
    Morris MS, Jacques PF, Selhub J: Relation between homocysteine and B-vitamin status indicators and bone mineral density in older Americans. Bone 2005, 37:234–242.CrossRefPubMedGoogle Scholar
  61. 61.
    Miret S, Simpson RJ, McKie AT: Physiology and molecular biology of dietary iron absorption. Annu Rev Nutr 2003, 23:283–301.CrossRefPubMedGoogle Scholar
  62. 62.
    Koop H, Bachem MG: Serum iron, ferritin, and vitamin B 12 during prolonged omeprazole therapy. J Clin Gastroenterol 1992, 14:288–292.CrossRefPubMedGoogle Scholar
  63. 63.
    • Hutchinson C, Geissler CA, Powell JJ, Bomford A: Proton pump inhibitors suppress absorption of dietary non-haem iron in hereditary haemochromatosis. Gut 2007, 56:1291–1295. This article describes a well-done recent study demonstrating that PPIs can decrease the absorption of iron in patients with primary hemochromatosis and that its chronic use can decrease the frequency of phlebotomies needed to maintain body iron stores at correct levels.CrossRefPubMedGoogle Scholar
  64. 64.
    Epstein M, McGrath S, Law F: Proton-pump inhibitors and hypomagnesemic hypoparathyroidism. N Engl J Med 2006, 355:1834–1836.CrossRefPubMedGoogle Scholar
  65. 65.
    Cundy T, Dissanayake A: Severe hypomagnesaemia in long-term users of proton-pump inhibitors. Clin Endocrinol (Oxf) 2008, 69:338–341.CrossRefGoogle Scholar
  66. 66.
    Kuipers MT, Thang HD, Arntzenius AB: Hypomagnesaemia due to use of proton pump inhibitors—a review. Neth J Med 2009, 67:169–172.PubMedGoogle Scholar
  67. 67.
    Shabajee N, Lamb EJ, Sturgess I, Sumathipala RW: Omeprazole and refractory hypomagnesaemia. BMJ 2008, 337:a425.CrossRefPubMedGoogle Scholar
  68. 68.
    • Mackay JD, Bladon PT: Hypomagnesaemia due to proton-pump inhibitor therapy: a clinical case series. QJM 2010, 103:387–395. This recent report of the characteristics of 10 cases of PPI-induced hypomagnesemia emphasizes its refractory nature, severity of manifestations, and disappearance when the PPI is stopped.CrossRefPubMedGoogle Scholar
  69. 69.
    Hoorn EJ , van der Hoek J, de Man RA, et al.: A case series of proton pump inhibitor-induced hypomagnesemia. Am J Kidney Dis 2010, 56:112–116.CrossRefPubMedGoogle Scholar
  70. 70.
    Francois M, Lévy-Bohbot N, Caron J, Durlach V: Chronic use of proton-pump inhibitors associated with giardiasis: a rare cause of hypomagnesemic hypoparathyroidism? [in French]. Ann Endocrinol (Paris) 2008, 69:446–448.Google Scholar
  71. 71.
    Broeren MA, Geerdink EA, Vader HL, van den Wall Bake AW: Hypomagnesemia induced by several proton-pump inhibitors. Ann Intern Med 2009, 151:755–756.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC (outside the USA) 2010

Authors and Affiliations

  1. 1.Department of Medicine and Bioregulatory Science, Graduate School of Medical ScienceKyushu UniversityFukuokaJapan
  2. 2.Digestive Diseases Branch, National Institutes of Diabetes and Digestive and Kidney DiseasesNational Institutes of HealthBethesdaUSA

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