Histamine H<sub>2</sub>-receptor Antagonists Therapy and Risk of Hip Fracture: A Meta-analysis_Chinese Journal of Evidence-Based Medicine

Authors：

 FANXiu-de ¹ , YINPan-pan ² , WANGXiao-yun ¹ , CHENZhen ¹ ,  XUJun-wang ¹

1. Department of Gastroenterology, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China;
2. Department of Ultrasonography, the Affiliated Hospital of Jining Medical School, Jining 27200, China;

Corresponding author：

XUJun-wang, Email: xujwdoctor@aliyun.com

Keywords：

Histamine H₂-receptor antagonists; Hip; Fracture; Meta-analysis; Observational study

DOI：

10.7507/1672-2531.20160212

Video：

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Objective To evaluate the association between H₂RA and the risk of hip fracture by performing a meta-analysis. Methods We searched CNKI, PubMed and EMbase from inception to September 19th 2016, to collect case-control studies or cohort studies reporting the risk of hip fracture with H₂RA. Two reviewers independently screened literature, extracted data and assessed the risk of bias of included studies. Then meta-analysis was performed using Stata 13 software. Results Eleven studies involving 206 276 hip fracture cases were included. The result of meta-analysis showed that patients receiving H₂RA therapy had approximately 1.12 times the risk of developing hip fracture compared with nonusers (OR=1.12 95%CI 1.02 to 1.24, P=0.022). Subgroup analyses by interval time indicated that the risk appeared greater with the continuous users (OR=1.11, 95%CI 1.01 to 1.24, P=0.039) whereas the discontinuous users was not significantly associated with hip fracture risk. Conclusion H₂RA therapy may be associated with an increased risk of hip fracture. For patients with intermittent medication, the side effect may disappear by discontinuation of PPI use for at least 30 days, but the study did not find time-effect relationship or dose-effect relationship. Considering the limitations of this study, more rigorous clinical trials evaluating the potential side-effect of H₂RA are needed.

Citation： FANXiu-de, YINPan-pan, WANGXiao-yun, CHENZhen, XUJun-wang. Histamine H₂-receptor Antagonists Therapy and Risk of Hip Fracture: A Meta-analysis. Chinese Journal of Evidence-Based Medicine, 2016, 16(12): 1401-1407. doi: 10.7507/1672-2531.20160212 Copy

1.	Neuman MD, Silber JH, Magaziner JS, et al. Survival and functional outcomes after hip fracture among nursing home residents. JAMA Intern Med, 2014, 174(8):1273-1280.
2.	Si L, Winzenberg TM, Jiang Q, et al. Projection of osteoporosis-related fractures and costs in China:2010-2050. Osteoporos Int, 2015, 26(7):1929-1937.
3.	Freedberg DE, Haynes K, Denburg MR, et al. Use of proton pump inhibitors is associated with fractures in young adults:a population-based study. Osteoporos Int, 2015, 26(10):2501-2507.
4.	van der Hoorn MM, Tett SE, de Vries OJ, et al. The effect of dose and type of proton pump inhibitor use on risk of fractures and osteoporosis treatment in older Australian women:A prospective cohort study. Bone, 2015, 81:675-682.
5.	王小蕾, 王蔚虹, 董欣红. 质子泵抑制剂对骨折风险影响的系统评价. 中国循证医学杂志, 2012, 12(2):216-223.
6.	Eom CS, Jeon CY, Lim JW, et al. Use of acid-suppressive drugs and risk of pneumonia:a systematic review and meta-analysis. CMAJ, 2011, 183(3):310-319.
7.	Kwok CS, Arthur AK, Anibueze CI, et al. Risk of Clostridium difficile infection with acid suppressing drugs and antibiotics:meta-analysis. Am J Gastroenterol, 2012, 107(7):1011-1019.
8.	Yu T, Tang Y, Jiang L, et al. Proton pump inhibitor therapy and its association with spontaneous bacterial peritonitis incidence and mortality:A meta-analysis. Dig Liver Dis, 2016, 48(4):353-359.
9.	Release FN. FDA:Possible Fracture Risk with High Dose, Long-term Use of Proton Pump Inhibitors. Available at:http://www.fda.gov/newsevents/newsroom/pressannouncements/ucm213377.htm.
10.	Yang YX, Lewis JD, Epstein S, et al. Long-term proton pump inhibitor therapy and risk of hip fracture. JAMA, 2006, 296(24):2947-2953.
11.	Khalili H, Huang ES, Jacobson BC, et al. Use of proton pump inhibitors and risk of hip fracture in relation to dietary and lifestyle factors:a prospective cohort study. BMJ, 2012, 344:e372.
12.	Schubert ML, Peura DA. Control of gastric acid secretion in health and disease. Gastroenterology, 2008, 134(7):1842-1860.
13.	Wells GA, Shea BJ, O'Connell D, et al. The Newcastle-Ottawa Scale (NOS) for Assessing the Quality of Non-Randomized Studies in Meta-Analysis. 2000.
14.	Davies HT, Crombie IK, Tavakoli M. When can odds ratios mislead? BMJ, 1998, 316(7136):989-991.
15.	Higgins JP, Thompson SG. Quantifying heterogeneity in a meta-analysis. Stat Med, 2002, 21(11):1539-1558.
16.	Higgins JP, Thompson SG, Deeks JJ, et al. Measuring inconsistency in meta-analyses. BMJ, 2003, 327(7414):557-560.
17.	Schmid CH, Stark PC, Berlin JA, et al. Meta-regression detected associations between heterogeneous treatment effects and study-level, but not patient-level, factors. J Clin Epidemiol, 2004, 57(7):683-697.
18.	Egger M, Davey SG, Schneider M, et al. Bias in meta-analysis detected by a simple, graphical test. BMJ, 1997, 315(7109):629-634.
19.	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.
20.	Grisso JA, Kelsey JL, O'Brien LA, et al. Risk factors for hip fracture in men. Hip Fracture Study Group. Am J Epidemiol, 1997, 145(9):786-793.
21.	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.
22.	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.
23.	Corley DA, Kubo A, Zhao W, et al. Proton pump inhibitors and histamine-2 receptor antagonists are associated with hip fractures among at-risk patients. Gastroenterology, 2010, 139(1):93-101.
24.	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.
25.	Pouwels S, Lalmohamed A, Souverein P, et al. Use of proton pump inhibitors and risk of hip/femur fracture:a population-based case-control study. Osteoporos Int, 2011, 22(3):903-910.
26.	Cea Soriano L, Ruigomez A, Johansson S, et al. Study of the association between hip fracture and acid-suppressive drug use in a UK primary care setting. Pharmacotherapy, 2014, 34(6):570-581.
27.	Grisso JA, Kelsey JL, O'Brien LA, et al. Risk factors for hip fracture in men. Amer J Epidemiol, 1997, 145(9):786-793.
28.	Cooper C, Campion G, Melton LJ, 3rd. Hip fractures in the elderly:a world-wide projection. Osteoporos Int, 1992, 2(6):285-289.
29.	Brown MJ, Mezuk B. Brains, bones, and aging:psychotropic medications and bone health among older adults. Curr Osteoporos Rep, 2012, 10(4):303-311.
30.	Mazzantini M, Di Munno O. Glucocorticoid-induced osteoporosis:2013 update. Reumatismo, 2014, 66(2):144-152.
31.	Leavy B, Michaelsson K, Aberg AC, et al. The Impact of Disease and Drugs on Hip Fracture Risk. Calcif Tissue Int, 2016. In press.
32.	Cai D, Feng W, Jiang Q. Acid-suppressive medications and risk of fracture:an updated meta-analysis. Int J Clin Exp Med, 2015, 8(6):8893-8904.
33.	Graziani G, Badalamenti S, Como G, et al. Calcium and phosphate plasma levels in dialysis patients after dietary Ca-P overload. Role of gastric acid secretion. Nephron, 2002, 91(3):474-479.
34.	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(7):778-781.
35.	Gagnemo-Persson R, Samuelsson A, Hakanson R, et al. Chicken parathyroid hormone gene expression in response to gastrin, omeprazole, ergocalciferol, and restricted food intake. Calcif Tissue Int, 1997, 61(3):210-215.
36.	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.
37.	Uzoigwe OF. Proton pump inhibitors and fracture:do they do what it says on the tin? Osteoporos Int, 2016, 27(4):1671-1672.

1. Neuman MD, Silber JH, Magaziner JS, et al. Survival and functional outcomes after hip fracture among nursing home residents. JAMA Intern Med, 2014, 174(8):1273-1280.
2. Si L, Winzenberg TM, Jiang Q, et al. Projection of osteoporosis-related fractures and costs in China:2010-2050. Osteoporos Int, 2015, 26(7):1929-1937.
3. Freedberg DE, Haynes K, Denburg MR, et al. Use of proton pump inhibitors is associated with fractures in young adults:a population-based study. Osteoporos Int, 2015, 26(10):2501-2507.
4. van der Hoorn MM, Tett SE, de Vries OJ, et al. The effect of dose and type of proton pump inhibitor use on risk of fractures and osteoporosis treatment in older Australian women:A prospective cohort study. Bone, 2015, 81:675-682.
5. 王小蕾, 王蔚虹, 董欣红. 质子泵抑制剂对骨折风险影响的系统评价. 中国循证医学杂志, 2012, 12(2):216-223.
6. Eom CS, Jeon CY, Lim JW, et al. Use of acid-suppressive drugs and risk of pneumonia:a systematic review and meta-analysis. CMAJ, 2011, 183(3):310-319.
7. Kwok CS, Arthur AK, Anibueze CI, et al. Risk of Clostridium difficile infection with acid suppressing drugs and antibiotics:meta-analysis. Am J Gastroenterol, 2012, 107(7):1011-1019.
8. Yu T, Tang Y, Jiang L, et al. Proton pump inhibitor therapy and its association with spontaneous bacterial peritonitis incidence and mortality:A meta-analysis. Dig Liver Dis, 2016, 48(4):353-359.
9. Release FN. FDA:Possible Fracture Risk with High Dose, Long-term Use of Proton Pump Inhibitors. Available at:http://www.fda.gov/newsevents/newsroom/pressannouncements/ucm213377.htm.
10. Yang YX, Lewis JD, Epstein S, et al. Long-term proton pump inhibitor therapy and risk of hip fracture. JAMA, 2006, 296(24):2947-2953.
11. Khalili H, Huang ES, Jacobson BC, et al. Use of proton pump inhibitors and risk of hip fracture in relation to dietary and lifestyle factors:a prospective cohort study. BMJ, 2012, 344:e372.
12. Schubert ML, Peura DA. Control of gastric acid secretion in health and disease. Gastroenterology, 2008, 134(7):1842-1860.
13. Wells GA, Shea BJ, O'Connell D, et al. The Newcastle-Ottawa Scale (NOS) for Assessing the Quality of Non-Randomized Studies in Meta-Analysis. 2000.
14. Davies HT, Crombie IK, Tavakoli M. When can odds ratios mislead? BMJ, 1998, 316(7136):989-991.
15. Higgins JP, Thompson SG. Quantifying heterogeneity in a meta-analysis. Stat Med, 2002, 21(11):1539-1558.
16. Higgins JP, Thompson SG, Deeks JJ, et al. Measuring inconsistency in meta-analyses. BMJ, 2003, 327(7414):557-560.
17. Schmid CH, Stark PC, Berlin JA, et al. Meta-regression detected associations between heterogeneous treatment effects and study-level, but not patient-level, factors. J Clin Epidemiol, 2004, 57(7):683-697.
18. Egger M, Davey SG, Schneider M, et al. Bias in meta-analysis detected by a simple, graphical test. BMJ, 1997, 315(7109):629-634.
19. 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.
20. Grisso JA, Kelsey JL, O'Brien LA, et al. Risk factors for hip fracture in men. Hip Fracture Study Group. Am J Epidemiol, 1997, 145(9):786-793.
21. 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.
22. 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.
23. Corley DA, Kubo A, Zhao W, et al. Proton pump inhibitors and histamine-2 receptor antagonists are associated with hip fractures among at-risk patients. Gastroenterology, 2010, 139(1):93-101.
24. 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.
25. Pouwels S, Lalmohamed A, Souverein P, et al. Use of proton pump inhibitors and risk of hip/femur fracture:a population-based case-control study. Osteoporos Int, 2011, 22(3):903-910.
26. Cea Soriano L, Ruigomez A, Johansson S, et al. Study of the association between hip fracture and acid-suppressive drug use in a UK primary care setting. Pharmacotherapy, 2014, 34(6):570-581.
27. Grisso JA, Kelsey JL, O'Brien LA, et al. Risk factors for hip fracture in men. Amer J Epidemiol, 1997, 145(9):786-793.
28. Cooper C, Campion G, Melton LJ, 3rd. Hip fractures in the elderly:a world-wide projection. Osteoporos Int, 1992, 2(6):285-289.
29. Brown MJ, Mezuk B. Brains, bones, and aging:psychotropic medications and bone health among older adults. Curr Osteoporos Rep, 2012, 10(4):303-311.
30. Mazzantini M, Di Munno O. Glucocorticoid-induced osteoporosis:2013 update. Reumatismo, 2014, 66(2):144-152.
31. Leavy B, Michaelsson K, Aberg AC, et al. The Impact of Disease and Drugs on Hip Fracture Risk. Calcif Tissue Int, 2016. In press.
32. Cai D, Feng W, Jiang Q. Acid-suppressive medications and risk of fracture:an updated meta-analysis. Int J Clin Exp Med, 2015, 8(6):8893-8904.
33. Graziani G, Badalamenti S, Como G, et al. Calcium and phosphate plasma levels in dialysis patients after dietary Ca-P overload. Role of gastric acid secretion. Nephron, 2002, 91(3):474-479.
34. 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(7):778-781.
35. Gagnemo-Persson R, Samuelsson A, Hakanson R, et al. Chicken parathyroid hormone gene expression in response to gastrin, omeprazole, ergocalciferol, and restricted food intake. Calcif Tissue Int, 1997, 61(3):210-215.
36. 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.
37. Uzoigwe OF. Proton pump inhibitors and fracture:do they do what it says on the tin? Osteoporos Int, 2016, 27(4):1671-1672.

Chinese Journal of Evidence-Based Medicine

Histamine H₂-receptor Antagonists Therapy and Risk of Hip Fracture: A Meta-analysis

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Histamine H₂-receptor Antagonists Therapy and Risk of Hip Fracture: A Meta-analysis