Proton Pump Inhibitors and the Risk of Bone Fractures: A Systematic Review_Chinese Journal of Evidence-Based Medicine

Authors：

WANG Xiaolei ,  WANG Weihong , DONG Xinhong

Department of Gastroenterology, Peking University First Hospital, Beijing 100034, China;

Corresponding author：

WANG Weihong, Email: wangweihong@medmail.com.cn

Keywords：

Proton pump inhibitor; Fracture; Hip; Systematic review; Meta-analysis; Cohort study; Case control study

DOI：

10.7507/1672-2531.20120035

Video：

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Objective 　To compare the risk of bone fractures in proton pump inhibitor users and nonusers, so as to evaluate the effects of proton pump inhibitors on the risk of bone fractures.
Methods 　We searched PubMed, MEDLINE and EMbase databases to March 1st 2011 to identify case-control studies or cohort studies evaluating the risk of fracture in proton pump inhibitor users and nonusers. We conducted systematic review and meta-analysis according to the fracture site, duration of exposure, average daily dose and time of last use. Summary odds ratios (OR) and 95% confidence interval (CI) were calculated by RevMan 5.0.25 software. We also calculated and looked for heterogeneity.
Results 　Eleven studies were identified from ten literatures, including seven case-control studies and four cohort studies. In case-control studies, the risk of total fractures increased by 36% in proton pump inhibitor users as compared with nonusers (OR=1.36, 95%CI 1.20 to 1.55). The risk of hip fracture increased by 39% (OR=1.39, 95%CI 1.13 to 1.71). In cohort studies, the risk of total fractures increased by 59% (OR=1.59, 95%CI 1.47 to 1.73). The risk of non-hip fractures increased by 65% (OR=1.65, 95%CI 1.47 to 1.85). As compared with nonusers, fracture risk increased by 41% in current users and by 38% in past users whose last use was at least 1 year ago. There was no significant difference between the two groups.
Conclusion 　Proton pump inhibitors increase the risk of fracture to a certain degree. The effect does not fade away by discontinuation of PPI use for at least one year. Stricter clinical trials are needed to exclude confounding factors.

Citation： WANG Xiaolei,WANG Weihong,DONG Xinhong. Proton Pump Inhibitors and the Risk of Bone Fractures: A Systematic Review. Chinese Journal of Evidence-Based Medicine, 2012, 12(2): 216-223. doi: 10.7507/1672-2531.20120035 Copy

1.	王小蕾, 王蔚虹. 长期服用质子泵抑制剂需要关注的临床问题. 临床药物治疗杂志, 2009, 7(4): 6-11.
2.	Parker M, Johansen A. Hip fracture. BMJ, 2006, 333(7557): 27-30.
3.	Stang A. Critical evaluation of the Newcastle-Ottawa scale for the assessment of the quality of nonrandomized studies in meta-analyses. Eur J Epidemiol, 2010, 25(9): 603-605.
4.	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.
5.	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.
6.	Abrahamsen B, Eiken P, Eastell R. Proton pump inhibitor use and the antifracture efficacy of alendronate. Arch Intern Med, 2011, 171(11): 998-1004.
7.	Yamaguchi T, Sugimoto T, Yamauchi M, et al. Multiple vertebral fractures are associated with refractory reflux esophagitis in postmenopausal women. J Bone Miner Metab, 2005, 23(1): 36-40.
8.	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.
9.	Chiu HF, Huang YW, Chang CC, et al. Use of proton pump inhibitors increased the risk of hip fracture: a population-based case-control study. Pharmacoepidemiol Drug Saf, 2010, 19(11): 1131-1136.
10.	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.
11.	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.
12.	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.
13.	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.
14.	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.
15.	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.
16.	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.
17.	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.
18.	Norwegian Institute of Public Health. WHO International Working Group for drug statistics methodology. 2009: Available from: http://www.whocc.no/atcddd/.
19.	麦劲壮, 李何, 方积乾, 等. Meta分析中失安全系数的估计. 循证医学, 2006, 6(5): 297-303.
20.	Sheikh MS, Santa Ana CA, Nicar MJ, et al. Gastrointestinal absorption of calcium from milk and calcium salts. N Engl J Med, 1987, 317(9): 532-536.
21.	James WP, Branch WJ, Southgate DA. Calcium binding by dietary fibre. Lancet, 1978, 1(8065): 638-639.
22.	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.
23.	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.
24.	Yang YX. Proton pump inhibitor therapy and osteoporosis. Curr Drug Saf, 2008, 3(3): 204-209.
25.	Tuukkanen J, Väänänen HK. Omeprazole, a specific inhibitor of H+-K+-ATPase, inhibits bone resorption in vitro. Calcif Tissue Int, 1986, 38(2): 123-125.
26.	Mizunashi K, Furukawa Y, Katano K, et al. Effect of omeprazole, an inhibitor of H+, K+-ATPase, on bone resorption in humans. Calcif Tissue Int, 1993, 53(1): 21-25.
27.	Hyun JJ, Chun HJ, Keum B, et al. Effect of omeprazole on the expression of transcription factors in osteoclasts and osteoblasts. Int J Mol Med, 2010, 26(6): 877-883.
28.	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(4): 364-368.
29.	Kocsis I, Arato A, Bodanszky H, et al. Short-term omeprazole treatment does not influence biochemical parameters of bone turnover in children. Calcif Tissue Int, 2002, 71(2): 129-132.
30.	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.
31.	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.
32.	Cummings SR, Melton LJ 3rd. Epidemiology and osteoporotic fractures. Lancet, 2002, 359(9319): 1761-1767.
33.	Figura N, Gennari L, Merlotti D, et al. Prevalence of Helicobacter pylori infection in male patients with osteoporosis and controls. Dig Dis Sci, 2005, 50(5): 847-852.
34.	Agardh D, Björck S, Agardh CD, et al. Coeliac disease-specific tissue transglutaminase autoantibodies are associated with osteoporosis and related fractures in middle-aged women. Scand J Gastroenterol, 2009, 44(5): 571-578.

1. 王小蕾, 王蔚虹. 长期服用质子泵抑制剂需要关注的临床问题. 临床药物治疗杂志, 2009, 7(4): 6-11.
2. Parker M, Johansen A. Hip fracture. BMJ, 2006, 333(7557): 27-30.
3. Stang A. Critical evaluation of the Newcastle-Ottawa scale for the assessment of the quality of nonrandomized studies in meta-analyses. Eur J Epidemiol, 2010, 25(9): 603-605.
4. 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.
5. 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.
6. Abrahamsen B, Eiken P, Eastell R. Proton pump inhibitor use and the antifracture efficacy of alendronate. Arch Intern Med, 2011, 171(11): 998-1004.
7. Yamaguchi T, Sugimoto T, Yamauchi M, et al. Multiple vertebral fractures are associated with refractory reflux esophagitis in postmenopausal women. J Bone Miner Metab, 2005, 23(1): 36-40.
8. 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.
9. Chiu HF, Huang YW, Chang CC, et al. Use of proton pump inhibitors increased the risk of hip fracture: a population-based case-control study. Pharmacoepidemiol Drug Saf, 2010, 19(11): 1131-1136.
10. 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.
11. 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.
12. 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.
13. 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.
14. 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.
15. 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.
16. 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.
17. 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.
18. Norwegian Institute of Public Health. WHO International Working Group for drug statistics methodology. 2009: Available from: http://www.whocc.no/atcddd/.
19. 麦劲壮, 李何, 方积乾, 等. Meta分析中失安全系数的估计. 循证医学, 2006, 6(5): 297-303.
20. Sheikh MS, Santa Ana CA, Nicar MJ, et al. Gastrointestinal absorption of calcium from milk and calcium salts. N Engl J Med, 1987, 317(9): 532-536.
21. James WP, Branch WJ, Southgate DA. Calcium binding by dietary fibre. Lancet, 1978, 1(8065): 638-639.
22. 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.
23. 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.
24. Yang YX. Proton pump inhibitor therapy and osteoporosis. Curr Drug Saf, 2008, 3(3): 204-209.
25. Tuukkanen J, Väänänen HK. Omeprazole, a specific inhibitor of H+-K+-ATPase, inhibits bone resorption in vitro. Calcif Tissue Int, 1986, 38(2): 123-125.
26. Mizunashi K, Furukawa Y, Katano K, et al. Effect of omeprazole, an inhibitor of H+, K+-ATPase, on bone resorption in humans. Calcif Tissue Int, 1993, 53(1): 21-25.
27. Hyun JJ, Chun HJ, Keum B, et al. Effect of omeprazole on the expression of transcription factors in osteoclasts and osteoblasts. Int J Mol Med, 2010, 26(6): 877-883.
28. 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(4): 364-368.
29. Kocsis I, Arato A, Bodanszky H, et al. Short-term omeprazole treatment does not influence biochemical parameters of bone turnover in children. Calcif Tissue Int, 2002, 71(2): 129-132.
30. 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.
31. 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.
32. Cummings SR, Melton LJ 3rd. Epidemiology and osteoporotic fractures. Lancet, 2002, 359(9319): 1761-1767.
33. Figura N, Gennari L, Merlotti D, et al. Prevalence of Helicobacter pylori infection in male patients with osteoporosis and controls. Dig Dis Sci, 2005, 50(5): 847-852.
34. Agardh D, Björck S, Agardh CD, et al. Coeliac disease-specific tissue transglutaminase autoantibodies are associated with osteoporosis and related fractures in middle-aged women. Scand J Gastroenterol, 2009, 44(5): 571-578.

Chinese Journal of Evidence-Based Medicine

Proton Pump Inhibitors and the Risk of Bone Fractures: A Systematic Review

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