Proton pump inhibitors and their effect on the bone

Česká verzia

Authors: Markéta Ječmenová; Radek Kroupa
Authors place of work: Interní gastroenterologická klinika LF MU a FN Brno
Published in the journal: Vnitř Lék 2016; 62(2): 139-146
Category: Reviews

Summary

Introduction:
The proton pump inhibitors are commonly used drugs for the treatment of the digestive disorders. Many patients require long-term maintenance therapy. The prolonged acid inhibition is considered to be safe, but recently, the attention has been paid to the possible effects on the bone metabolism and the higher incidence of the fractures in patients using the PPIs.

The aim of this work is to give a complex overview on the topic and analyse the source of information about the increased risk of the fractures.

Results:
Several epidemiological studies describe the incidence of the fractures in the patients with PPIs. Further articles, mainly describing the effect of the bisphosphonate therapy for the osteoporosis, also track the PPI effects. The studies dealing with the articles on densitometry targeting on the effect of the PPIs on the bone metabolism are rare.

Conclusion:
It is not possible to unequivocally determinate the risks of the long term PPI therapy on bone based on the existing studies due to the heterogenous populations, multimorbidity of the patients and the concurrent medication. Untill now, no study has evaluated the incidence of the risk events based on the indication of the long-term therapy. Routine monitoring of the bone parameters during the PPI therapy is not recommended. The safety of the long-term PPI therapy should be based on the clear indication of the prescription.

Key words:
bisphosphonates – bone – calcium – fracture – proton pump inhibitors – osteoporosis

Zdroje

1. Khan M, Santana J, Donnellan C et al. Medical treatments in the short term management of reflux oesophagitis. Cochrane Database Syst Rev 2007; (2):CD003244.

2. Chubineh S, Birk J. Proton pump inhibitors: the good, the bad, and the unwanted. South Med J 2012; 105(11): 613–618.

3. Martínek J, Lukáš M. Inhibitory protonové pumpy – up to date. Gastroent Hepatol 2011; 65(6): 331–342.

4. Lukáš K, Bureš J, Drahoňovský V et al. Refluxní choroba jícnu. Standardy České gastroenterologické společnosti – aktualizace 2009. Vnitř Lék 2009; 55(10): 967–975.

5. Seifert B, Dítě P, Bureš J et al. Gastroenterologie. Doporučení diagnostické a terapeutické postupy pro všeobecné praktické lékaře. Novelizace 2012. Centrum doporučených postupů pro praktické lékaře – Společnost všeobecného lékařství ČLS JEP: Praha 2012. Dostupné z WWW: http://www.svl.cz/files/files/Doporucene-postupy-2008–2012/Gastro_2012.pdf.

6. Teramura-Grönblad M, Hosia-Randell H, Muurinen S et al. Use of proton-pump inhibitors and their associated risks among frail elderly nursing home residents. Scand J Prim Health Care 2010; 28(3): 154–159.

7. Reeve E, Andrews JM, Wiese MD et al. The Feasibility of a Patient-Centered Deprescribing Process to Reduce Inappropriate Use of Proton Pump Inhibitors. Ann Pharmacother 2015; 49(1): 29–38.

8. Laine L, Ahnen D, McClain C et al. Review article: potential gastrointestinal effects of long-term acid supression with proton pump inhibitors. Aliment Pharmacol Ther 2000; 14(6): 651–668.

9. Chubineh S, Birk J. Proton Pump Inhibitors: The Good, the Bad, and the Unwanted. South Med J 2012; 105(11): 613–618.

10. Brunner G, Creutzfeldt W, Harke U et al. Therapy with omeprazole in patients with peptic ulcerations resistant to extended high-dose ranitidine treatment. Digestion 1988; 39(2): 80–90.

11. Kroupa R, Dolina J. Rizika dlouhodobé antisekreční terapie. Vnitř Lék 2010; 56(2): 115–119.

12. Yang YX. Proton pump inhibitor therapy and osteoporosis. Curr Drug Saf 2008; 3(3): 204–209.

13. Stewart AF, Vignery A, Silvergate A et al. Quntitative bone histomorphometry in humoral hypercalcemia of malignancy: uncoupling of bone cell activity. J Clin Endocrinol Metab 1982; 55(2): 219–227.

14. Mizunashi K, Furakawa Y, Katano K et al. Effect of omeprazole, an inhibitor of H+, K(+)ATPasaxe, on bone resorption in humans. Calcif Tissue Int 1993; 53(1): 21–25.

15. Longo D, Fauci A, Kasper D. Harrison’s Principles of Internal Medicine. Voll. 2. 18th ed. McGraw-Hill 2012: 2444–2457. ISBN 978–0-07174889–6.

16. Sipponen P, Härkönen M. Hypochlorhydric stomach: a risk condition for calcium malabsorption and osteoporosis? Scand J Gastroenterol 2010; 45(2): 133–138.

17. Ayuk J, Gittoes NJ. Contemporary view of the clinical relevance of magnesium homeostasis. Ann Clin Biochem 2014; 51(Pt 2): 179–188.

18. Hess MW, Hoenderop JG, Drenth JP et al. Systematic review: hypomagnesaemia induced by proton pump inhibition. Aliment Pharmacol Ther 2012; 36(5): 405–413.

19. Markovits N, Loebstein R, Halkin H et al. The association of proton pump inhibitors and hypomagnesemia in the community setting. J Clin Pharmacol 2014; 54(8): 889–895.

20. Cundy T, Dissanayake A. Severe hypomagnesaemia in long-term users of proton-pump inhibitors. Clin Endocrinol (Oxf) 2008; 69(2): 338–341.

21. Rude RK, Singer FR, Gruber HE. Skeletal and hormonal effects of magnesium deficiency. J Am Coll Nutr 2009; 28(2): 131–141.

22. Orchard TS, Larson JC, Alghothani N et al. Magnesium intake, bone mineral density, and fractures: results from the Women’s Health Initiative Observational Study. Am J Clin Nutr 2014; 99(4): 926–933.

23. Lewis SJ, Franco S, Young G et al. Altered bowel function and duodenal bacterial overgrowth in patients treated with omeprazole. Aliment Pharmacol Ther 1996; 10(4): 557–561.

24. Ito T, Jenses RT. Association of long term proton pump inhibitor therapy with bone fractures and efects on absorbtion of calcium, vit B12, iron and magnesium. Curr Gastroenterol Rep 2010; 12(6): 448–457.

25. Tuukkanen J, Vaananen HK. Omeprazole, a specific inhibitor of H+K+-ATPase, inhibits bone resorption in vitro. Calcif Tissue Int 1986; 38(2): 123–125.

26. Feng Z, Zeng S, Wang Y et al. Bisphosphonates for the prevention and treatment of osteoporosis in patients with rheumatic diseases: a systematic review and meta-analysis. PLoS One 2013; 8: e80890. Dostupné z DOI: http://dx.doi.org/10.1371/journal.pone.0080890.

27. Knopp-Sihota JA, Cummings GG, Homik J et al. The association between serious upper gastrointestinal bleeding and incident bisphosphonate use: a population-based nested cohort study. BMC Geriatr 2013; 13: 36. Dostupné z DOI: http://dx.doi.org/10.1186/1471–2318–13–36.

28. Miyake K, Kusunoki M, Shinji Y et al. Bisphosphonate increases risk of gastroduodenal ulcer in rheumatoid arthritis patients on long-term nonsteroidal antiinflammatory drug therapy. J Gastroenterol 2009; 44(2): 113–120.

29. Peng YL, Hu HY, Luo JC et al Alendronate, a bisphosphonate, increased upper and lower gastrointestinal bleeding: risk factor analysis from a nationwide population-based study. Osteoporos Int 2014; 25(5): 1617–1623.

30. Ozdil K, Kahraman R, Sahin Aet al. Bone density in proton pump inhibitors users: a prospective study. Rheumatol Int 2013; 33(9): 2255–2260.

31. 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(4): 251–259.

32. Kirkpantur A, Altun B, Arici M et al. Proton pump inhibitor omeprazole use is associated with low bone mineral density in maintenance haemodialysis patients. Int J Clin Pract 2009; 63(2): 261–268.

33. Yang XY, Lewis JD, Epstein S et al. Long-term Proton Pump Inhibitor Therapy and Risk of Hip Fracture. JAMA 2006; 296(24): 2947–2953.

34. Pasina L, Nobili A, Tettamanti M et al. Prevalence and appropriateness of drug prescriptions for peptic ulcer and gastro-esophageal reflux disease in a cohort of hospitalized elderly. Eur J Intern Med 2011; 22(2): 205–210.

35. Hvid-Jensen F, Nielsen RB, Pedersen L et al. Lifestyle factors among proton pump inhibitor users and nonusers: a cross-sectional study in a population-based setting. Clin Epidemiol 2013; 5: 493–499.

36. Teramura-Grönblad M, Hosia-Randell H, Muurinen S et al. Use of proton-pump inhibitors and their associated risks among frail elderly nursing home residents. Scand J Prim Health Care 2010; 28(3): 154–159.

37. Zofková I. Léky indukovaná osteoporóza (Drug induced osteoporosis). Vnitř Lék 2013; 59(1): 59–63.

38. Löhr J, Oliver MR, Frulloni L. Synopsis of recent guidelines on pancreatic exocrine insufficiency. United European Gastroenterol J 2013; 1(2): 79–83.

39. Lodato F, Azzaroli F, Di Girolamo M et al. Proton pump inhibitors in cirrhosis: tradition or evidence based practice? World J Gastroenterol 2008; 14(19): 2980–2985.

40. Dujsíková H, Novotný I, Tomandl J et al. Chronická pankreatitida a skelet (Chronic pancreatitis and the skeleton). Vnitř Lék 2010; 56(7): 656–662.

41. Luxon BA. Bone disorders in chronic liver diseases. Curr Gastroenterol Rep 2011; 13(1): 40–48.

42. Tondapu P, Provost D, Adams-Huet B et al. Comparison of the absorption of calcium carbonate and calcium citrate after Roux-en-Y gastric bypass. Obes Surg 2009; 19(9): 1256–1261.

43. Dawson-Hughes B, Dallal GE, Krall EA et al. A controlled trial of the effect of calcium supplementation on bone density in postmenopausal women. N Engl J Med 1990; 323(13): 878–883.

44. Wang H, Bua P, Capodice J. A comparative study of calcium absorption following a single serving administration of calcium carbonate powder versus calcium citrate tablets in healthy premenopausal women. Food Nutr Res 2014; 58. Dostupné z DOI: http://dx.doi.org/10.3402/fnr.v58.23229.

45. Bainbridge KE, Sowers M, Lin X et al. Risk factors for low bone mineral density and the 6-year rate of bone loss among premenopausal and perimenopausal women. Osteoporos Int 2004; 15(6): 439–446.

46. Cammarota S, Bruzzese D, Sarnelli G et al. Proton pump inhibitors prescribing following the introduction of generic drugs. Eur J Clin Invest 2012; 42(10): 1068–1078.

47. Dent J, El-Serag HB, Wallader MA et al. Epidemiology of gastro-esofageal reflux disease: a systematic review. Gut 2005; 54(5): 710–717.

48. Haastrup P, Paulsen MS, Begtrup LM et al. Strategies for discontinuation of proton pump inhibitors: a systematic review. Fam Pract 2014; 31(6): 625–630.

49. 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(4): 1161–1168.

50. Yu EW, Bauer SR, Bain PA et al. Proton pump inhibitors and risk of fractures: a meta-analysis of 11 international studies. Am J Med 2011; 124(6): 519–526.

51. 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(7): 1209–1218.

52. 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(9): 765–771.

53. Corley DA. Proton pump inhibitor, H2 antagonists, and risk of hip fracture: a large population-based study[abstract] Gastroenterology. 2009; 136(Suppl 1): A70.

54. Roux C, Briot K, Gossec L et al. Increase in vertebral fracture risk in postmenopausal women using omeprazole. Calcif Tissue Int 2009; 84(1): 13–19.

55. 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(2): 76–83.

56. 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(9): 1361–1369.

57. Sharara AI, El-Halabi MM, Ghaith OA et al. Proton pump inhibitors have no measurable effect on calcium and bone metabolism in healthy young males: a prospective matched controlled study. Metabolism 2013; 62(4): 518–526.

58. 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(3): 896–904.

59. Kaye JA, Jick H. Proton pump inhibitor use and risk of hip fractures in patients without major risk factors. Pharmacotherapy 2008; 28(8): 951–959.

60. Targownik LE, Lix LM, Metge CJ et al. Use of proton pump inhibitors and risk of osteoporosis-related fractures. CMAJ 2008; 179(4): 319–326.

61. Prieto-Alhambra D, Pagès-Castellà A, Wallace G et al. Predictors of fracture while on treatment with oral bisphosphonates: a population-based cohort study. J Bone Miner Res 2014; 29(1): 268–274.

62. Itoh S, Sekino Y, Shinomiya K et al. The effects of risedronate administered in combination with a proton pump inhibitor for the treatment of osteoporosis. J Bone Miner Metab 2013; 31(2): 206–211.

63. Roux C, Goldstein JL, Zhou X et al. Vertebral fracture efficacy during risedronate therapy in patients using proton pump inhibitors. Osteoporos Int 2012; 23(1): 277–284.

64. Abrahamsen B, Eiken P, Eastell R. Proton pump inhibitor use and the antifracture efficacy of alendronate. Arch Intern Med 2011; 171(11): 998–1004.

65. De Vries F, Cooper AL, Cockle SM et al. Fracture risk in patients receiving acid-suppressant medication alone and in combination with bisphosphonates. Osteoporos Int 2009; 20(12): 1989–1998.