Association between acid suppressive drug use and fracture risk in children and adolescents: a meta-analysis_Chinese Journal of Evidence-Based Medicine

Authors：

YE Xixia ¹ , CHEN Mingming ² , SHAO Jie ² , LUO Xinru ² , YE Lei ² , ZHANG Yaqin ¹ ,  CAO Wenting ²

1. Department of Child Health, Hainan Women and Children Medical Center, Haikou 570206, P. R. China;
2. International School of Public Health and One Health, Hainan Medical College, Haikou 571199, P. R. China;

Corresponding author：

CAO Wenting, Email: hy0208040@hainmc.edu.cn

Keywords：

Acid suppressive drug; Fractures; Children; Adolescents; Meta-analysis; Cohort study; Case-control study

DOI：

10.7507/1672-2531.202211085

Video：

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Objective To systematically review the association between acid suppressive drug use and fracture risk in children and adolescents. Methods The PubMed, Web of Science, EMbase, Cochrane Library, CNKI and WanFang Data databases were electronically searched to collect observational studies on the association between acid suppressive drug use and fracture risk in children and adolescents from inception to October 1, 2022. Two reviewers independently screened literature, extracted data and assessed the risk of bias of the included studies. Meta-analysis was then performed by using R4.1.2 software. Results A total of 6 studies involving 1 886 423 children and adolescents were included. Meta-analysis results showed that the use of proton pump inhibitors (PPIs) increased the risk of fracture (RR=1.19, 95%CI 1.10 to 1.29, P<0.01), whereas the use of histamine H2 receptor antagonists (H2RAs) did not increase the risk of fracture (P>0.05). Subgroup analysis showed that PPIs use increased risk of fracture in the lower limb and other sites (P<0.05). Conclusion Current evidence shows that PPIs can increase fracture risk in children and adolescents, but no association has been found between the use of H2RAs and increased fracture risk in this group. Due to the limited quality and quantity of the included studies, more high quality studies are needed to verify the above conclusion.

Citation： YE Xixia, CHEN Mingming, SHAO Jie, LUO Xinru, YE Lei, ZHANG Yaqin, CAO Wenting. Association between acid suppressive drug use and fracture risk in children and adolescents: a meta-analysis. Chinese Journal of Evidence-Based Medicine, 2023, 23(7): 802-806. doi: 10.7507/1672-2531.202211085 Copy

1.	Khawaja M, Thakker J, Kherallah R, et al. Antacid therapy in coronary artery disease and heart failure: proton pump inhibitors vs. H2 receptor blockers. Cardiovasc Drugs Ther, 2022, (6): 1-9.
2.	Khan S, Mohammad A, O'Rourke KP. An audit of the frequency of proton pump inhibitor (PPI) prescription in rheumatoid arthritis (RA) patients taking non-steroidal anti-inflammatory drugs (NSAIDs). Ir J Med Sci, 2014, 183(4): 685-686.
3.	Rückert-Eheberg IM, Nolde M, Ahn N, et al. Who gets prescriptions for proton pump inhibitors and why? A drug-utilization study with claims data in Bavaria, Germany, 2010-2018. Eur J Clin Pharmacol, 2022, 78(4): 657-667.
4.	Lespessailles E, Toumi H. Proton pump inhibitors and bone health: an update narrative review. Int J Mol Sci, 2022, 23(18): 10733.
5.	Hoffmann F, Glaeske G, Schmiemann G. Increased prescribing of proton pump inhibitors in ambulatory care over the years 2005-2013. Z Gastroenterol, 2015, 53(2): 95-100.
6.	Singh A, Kirby DF, Cresci GA. Response to comment on 'proton pump inhibitors. Risks and rewards and emerging consequences to the gut microbiome'. Nutr Clin Pract, 2019, 34(1): 173.
7.	Poly TN, Islam MM, Yang HC, et al. Proton pump inhibitors and risk of hip fracture: a meta-analysis of observational studies. Osteoporos Int, 2019, 30(1): 103-114.
8.	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.
9.	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.
10.	Kwok CS, Yeong JK, Loke YK. Meta-analysis: risk of fractures with acid-suppressing medication. Bone, 2011, 48(4): 768-776.
11.	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.
12.	Davies HT, Crombie IK, Tavakoli M. When can odds ratios mislead. BMJ, 1998, 316(7136): 989-991.
13.	Wang YH, Wintzell V, Ludvigsson JF, et al. Association between proton pump inhibitor use and risk of fracture in children. JAMA Pediatr, 2020, 174(6): 543-551.
14.	Fleishman N, Richardson T, Attard T. The clinical characteristics of fractures in pediatric patients exposed to proton pump inhibitors. J Pediatr Gastroenterol Nutr, 2020, 70(6): 815-819.
15.	Wagner K, Wagner S, Susi A, et al. Prematurity does not increase early childhood fracture risk. J Pediatr, 2019, 207: 148-153.
16.	Malchodi L, Wagner K, Susi A, et al. Early acid suppression therapy exposure and fracture in young children. Pediatrics, 2019, 144(1): e20182625.
17.	Fleishman NR, Richardson T, Attard TM. A multicenter cohort analysis of fractures in histamine-2-receptor antagonist treated pediatric patients. Curr Med Res Opin, 2022, 38(4): 565-570.
18.	Freedberg DE, Lamousé-Smith ES, Lightdale JR, et al. Use of acid suppression medication is associated with risk for C. difficile infection in infants and children:a population-based study. Clin Infect Dis, 2015, 61(6): 912-917.
19.	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.
20.	Colin-Jones DG. The role and limitations of H2-receptor antagonists in the treatment of gastro-oesophageal reflux disease. Aliment Pharmacol Ther, 1995, 9(Suppl 1): 9-14.
21.	Schuler A. Risks versus benefits of long-term proton pump inhibitor therapy in the elderly. Geriatr Nurs, 2007, 28(4): 225-229.
22.	Takasugi S, Shioyama M, Kitade M, et al. Effects of proton pump inhibitor administration and intake of a combination of yogurt and galactooligosaccharides on bone and mineral metabolism in rats. Nutrients, 2016, 8(10): 653.
23.	Yang YX. Proton pump inhibitor therapy and osteoporosis. Curr Drug Saf, 2008, 3(3): 204-209.
24.	Maléth J, Hegyi P. Long-term proton pump inhibitor therapy and osteoporosis. Is there a real danger? Orv Hetil, 2013, 154(26): 1005-1009.
25.	He T, Jin X, Koh YS, et al. The association of homocysteine, folate, vitamin B12, and vitamin B6 with fracture incidence in older adults: a systematic review and meta-analysis. Ann Transl Med, 2021, 9(14): 1143.
26.	Freedberg DE, Kim LS, Yang YX. The risks and benefits of long-term use of proton pump inhibitors: expert review and best practice advice from the American Gastroenterological Association. Gastroenterology, 2017, 152(4): 706-715.
27.	Rosanoff A, Dai Q, Shapses SA. Essential nutrient interactions: does low or suboptimal magnesium status interact with vitamin D and/or calcium status. Adv Nutr, 2016, 7(1): 25-43.
28.	Vinke P, Wesselink E, van Orten-Luiten W, et al. The use of proton pump inhibitors may increase symptoms of muscle function loss in patients with chronic illnesses. Int J Mol Sci, 2020, 21(1): 323.
29.	Cea Soriano L, Ruigómez 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.
30.	范修德, 尹盼盼, 王小云, 等. H2受体拮抗剂对髋部骨折风险影响的Meta分析. 中国循证医学杂志, 2016, 16(12): 1401-1407.

1. Khawaja M, Thakker J, Kherallah R, et al. Antacid therapy in coronary artery disease and heart failure: proton pump inhibitors vs. H2 receptor blockers. Cardiovasc Drugs Ther, 2022, (6): 1-9.
2. Khan S, Mohammad A, O'Rourke KP. An audit of the frequency of proton pump inhibitor (PPI) prescription in rheumatoid arthritis (RA) patients taking non-steroidal anti-inflammatory drugs (NSAIDs). Ir J Med Sci, 2014, 183(4): 685-686.
3. Rückert-Eheberg IM, Nolde M, Ahn N, et al. Who gets prescriptions for proton pump inhibitors and why? A drug-utilization study with claims data in Bavaria, Germany, 2010-2018. Eur J Clin Pharmacol, 2022, 78(4): 657-667.
4. Lespessailles E, Toumi H. Proton pump inhibitors and bone health: an update narrative review. Int J Mol Sci, 2022, 23(18): 10733.
5. Hoffmann F, Glaeske G, Schmiemann G. Increased prescribing of proton pump inhibitors in ambulatory care over the years 2005-2013. Z Gastroenterol, 2015, 53(2): 95-100.
6. Singh A, Kirby DF, Cresci GA. Response to comment on 'proton pump inhibitors. Risks and rewards and emerging consequences to the gut microbiome'. Nutr Clin Pract, 2019, 34(1): 173.
7. Poly TN, Islam MM, Yang HC, et al. Proton pump inhibitors and risk of hip fracture: a meta-analysis of observational studies. Osteoporos Int, 2019, 30(1): 103-114.
8. 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.
9. 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.
10. Kwok CS, Yeong JK, Loke YK. Meta-analysis: risk of fractures with acid-suppressing medication. Bone, 2011, 48(4): 768-776.
11. 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.
12. Davies HT, Crombie IK, Tavakoli M. When can odds ratios mislead. BMJ, 1998, 316(7136): 989-991.
13. Wang YH, Wintzell V, Ludvigsson JF, et al. Association between proton pump inhibitor use and risk of fracture in children. JAMA Pediatr, 2020, 174(6): 543-551.
14. Fleishman N, Richardson T, Attard T. The clinical characteristics of fractures in pediatric patients exposed to proton pump inhibitors. J Pediatr Gastroenterol Nutr, 2020, 70(6): 815-819.
15. Wagner K, Wagner S, Susi A, et al. Prematurity does not increase early childhood fracture risk. J Pediatr, 2019, 207: 148-153.
16. Malchodi L, Wagner K, Susi A, et al. Early acid suppression therapy exposure and fracture in young children. Pediatrics, 2019, 144(1): e20182625.
17. Fleishman NR, Richardson T, Attard TM. A multicenter cohort analysis of fractures in histamine-2-receptor antagonist treated pediatric patients. Curr Med Res Opin, 2022, 38(4): 565-570.
18. Freedberg DE, Lamousé-Smith ES, Lightdale JR, et al. Use of acid suppression medication is associated with risk for C. difficile infection in infants and children:a population-based study. Clin Infect Dis, 2015, 61(6): 912-917.
19. 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.
20. Colin-Jones DG. The role and limitations of H2-receptor antagonists in the treatment of gastro-oesophageal reflux disease. Aliment Pharmacol Ther, 1995, 9(Suppl 1): 9-14.
21. Schuler A. Risks versus benefits of long-term proton pump inhibitor therapy in the elderly. Geriatr Nurs, 2007, 28(4): 225-229.
22. Takasugi S, Shioyama M, Kitade M, et al. Effects of proton pump inhibitor administration and intake of a combination of yogurt and galactooligosaccharides on bone and mineral metabolism in rats. Nutrients, 2016, 8(10): 653.
23. Yang YX. Proton pump inhibitor therapy and osteoporosis. Curr Drug Saf, 2008, 3(3): 204-209.
24. Maléth J, Hegyi P. Long-term proton pump inhibitor therapy and osteoporosis. Is there a real danger? Orv Hetil, 2013, 154(26): 1005-1009.
25. He T, Jin X, Koh YS, et al. The association of homocysteine, folate, vitamin B12, and vitamin B6 with fracture incidence in older adults: a systematic review and meta-analysis. Ann Transl Med, 2021, 9(14): 1143.
26. Freedberg DE, Kim LS, Yang YX. The risks and benefits of long-term use of proton pump inhibitors: expert review and best practice advice from the American Gastroenterological Association. Gastroenterology, 2017, 152(4): 706-715.
27. Rosanoff A, Dai Q, Shapses SA. Essential nutrient interactions: does low or suboptimal magnesium status interact with vitamin D and/or calcium status. Adv Nutr, 2016, 7(1): 25-43.
28. Vinke P, Wesselink E, van Orten-Luiten W, et al. The use of proton pump inhibitors may increase symptoms of muscle function loss in patients with chronic illnesses. Int J Mol Sci, 2020, 21(1): 323.
29. Cea Soriano L, Ruigómez 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.
30. 范修德, 尹盼盼, 王小云, 等. H2受体拮抗剂对髋部骨折风险影响的Meta分析. 中国循证医学杂志, 2016, 16(12): 1401-1407.

Chinese Journal of Evidence-Based Medicine

Association between acid suppressive drug use and fracture risk in children and adolescents: a meta-analysis

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