Skip to main content
Top
Published in: Osteoporosis International 1/2016

01-01-2016 | Original Article

Proton-pump inhibitors and risk of fractures: an update meta-analysis

Authors: B. Zhou, Y. Huang, H. Li, W. Sun, J. Liu

Published in: Osteoporosis International | Issue 1/2016

Login to get access

Abstract

Summary

To identify the relationship between proton-pump inhibitors (PPIs) and the risk of fracture, we conducted an update meta-analysis of observational studies. Results showed that PPI use was associated with a modestly increased risk of hip, spine, and any-site fracture.

Introduction

Many studies have investigated the association of proton-pump inhibitors (PPIs) with fracture risk, but the results have been inconsistent. To evaluate this question, we performed a meta-analysis of relevant observational studies.

Methods

A systematic literature search up to February 2015 was performed in PubMed. We combined relative risks (RRs) for fractures using random-effects models and conducted subgroup and stratified analyses.

Results

Eighteen studies involving a total of 244,109 fracture cases were included in this meta-analysis. Pooled analysis showed that PPI use could moderately increase the risk of hip fracture [RR = 1.26, 95 % confidence intervals (CIs) 1.16–1.36]. There was statistically significant heterogeneity among studies (p < 0.001; I 2 = 71.9 %). After limiting to cohort studies, there was also a moderate increase in hip fracture risk without evidence of study heterogeneity. Pooling revealed that short-term use (<1 year) and longer use (>1 year) were similarly associated with increased risk of hip fracture. Furthermore, a moderately increased risk of spine (RR = 1.58, 95 % CI 1.38–1.82) and any-site fracture (RR = 1.33, 95 % CI 1.15–1.54) was also found among PPI users.

Conclusion

In this update meta-analysis of observational studies, PPI use modestly increased the risk of hip, spine, and any-site fracture, but no evidence of duration effect in subgroup analysis.
Literature
1.
go back to reference Dennison E, Mohamed MA, Cooper C (2006) Epidemiology of osteoporosis. Rheum Dis Clin N Am 32:617–629CrossRef Dennison E, Mohamed MA, Cooper C (2006) Epidemiology of osteoporosis. Rheum Dis Clin N Am 32:617–629CrossRef
2.
go back to reference Osnes EK, Lofthus CM, Meyer HE, Falch JA, Nordsletten L, Cappelen I, Kristiansen IS (2004) Consequences of hip fracture on activities of daily life and residential needs. Osteoporos Int 15:567–574PubMedCrossRef Osnes EK, Lofthus CM, Meyer HE, Falch JA, Nordsletten L, Cappelen I, Kristiansen IS (2004) Consequences of hip fracture on activities of daily life and residential needs. Osteoporos Int 15:567–574PubMedCrossRef
3.
go back to reference Kushner PR, Peura DA (2011) Review of proton pump inhibitors for the initial treatment of heartburn: is there a dose ceiling effect? Adv Ther 28:367–388PubMedCrossRef Kushner PR, Peura DA (2011) Review of proton pump inhibitors for the initial treatment of heartburn: is there a dose ceiling effect? Adv Ther 28:367–388PubMedCrossRef
4.
go back to reference Mönnikes H, Schwan T, van Rensburg C, Straszak A, Theek C, Lühmann R, Sander P, Tholen A (2013) Possible etiology of improvements in both quality of life and overlapping gastroesophageal reflux disease by proton pump inhibitor treatment in a prospective randomized controlled trial. BMC Gastroenterol 13:145PubMedPubMedCentralCrossRef Mönnikes H, Schwan T, van Rensburg C, Straszak A, Theek C, Lühmann R, Sander P, Tholen A (2013) Possible etiology of improvements in both quality of life and overlapping gastroesophageal reflux disease by proton pump inhibitor treatment in a prospective randomized controlled trial. BMC Gastroenterol 13:145PubMedPubMedCentralCrossRef
5.
go back to reference Tsoi KK, Hirai HW, Sung JJ (2013) Meta-analysis: comparison of oral vs. intravenous proton pump inhibitors in patients with peptic ulcer bleeding. Aliment Pharmacol Ther 38:721–728PubMedCrossRef Tsoi KK, Hirai HW, Sung JJ (2013) Meta-analysis: comparison of oral vs. intravenous proton pump inhibitors in patients with peptic ulcer bleeding. Aliment Pharmacol Ther 38:721–728PubMedCrossRef
6.
go back to reference Ye X, Liu H, Wu C, Qin Y, Zang J, Gao Q, Zhang X, He J (2011) Proton pump inhibitors therapy and risk of hip fracture: a systematic review and meta-analysis. Eur J Gastroenterol Hepatol 23:794–800PubMedCrossRef Ye X, Liu H, Wu C, Qin Y, Zang J, Gao Q, Zhang X, He J (2011) Proton pump inhibitors therapy and risk of hip fracture: a systematic review and meta-analysis. Eur J Gastroenterol Hepatol 23:794–800PubMedCrossRef
7.
go back to reference Yu EW, Bauer SR, Bain PA, Bauer DC (2011) Proton pump inhibitors and risk of fractures: a meta-analysis of 11 international studies. Am J Med 124:519–526PubMedPubMedCentralCrossRef Yu EW, Bauer SR, Bain PA, Bauer DC (2011) Proton pump inhibitors and risk of fractures: a meta-analysis of 11 international studies. Am J Med 124:519–526PubMedPubMedCentralCrossRef
8.
go back to reference Eom CS, Park SM, Myung SK, Yun JM, Ahn JS (2011) Use of acid-suppressive drugs and risk of fracture: a meta-analysis of observational studies. Ann Fam Med 9:257–267PubMedPubMedCentralCrossRef Eom CS, Park SM, Myung SK, Yun JM, Ahn JS (2011) Use of acid-suppressive drugs and risk of fracture: a meta-analysis of observational studies. Ann Fam Med 9:257–267PubMedPubMedCentralCrossRef
9.
go back to reference Ngamruengphong S, Leontiadis GI, Radhi S, Dentino A, Nugent K (2011) Proton pump inhibitors and risk of fracture: a systematic review and meta-analysis of observational studies. Am J Gastroenterol 106:1209–1218, quiz 1219 PubMedCrossRef Ngamruengphong S, Leontiadis GI, Radhi S, Dentino A, Nugent K (2011) Proton pump inhibitors and risk of fracture: a systematic review and meta-analysis of observational studies. Am J Gastroenterol 106:1209–1218, quiz 1219 PubMedCrossRef
10.
go back to reference FDA Drug Safety Communication (2010) Possible increased risk of fractures of the hip, wrist, and spine with the use of proton pump inhibitors. U.S. Food and Drug Administration, Rockville FDA Drug Safety Communication (2010) Possible increased risk of fractures of the hip, wrist, and spine with the use of proton pump inhibitors. U.S. Food and Drug Administration, Rockville
11.
go back to reference Moher D, Liberati A, Tetzlaff J, Altman DG (2009) Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. Ann Intern Med 51(264–269):W264CrossRef Moher D, Liberati A, Tetzlaff J, Altman DG (2009) Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. Ann Intern Med 51(264–269):W264CrossRef
13.
14.
go back to reference Higgins JPT, Thompson SG (2002) Quantifying heterogeneity in a meta-analysis. Stat Med 21:1539–1558PubMedCrossRef Higgins JPT, Thompson SG (2002) Quantifying heterogeneity in a meta-analysis. Stat Med 21:1539–1558PubMedCrossRef
16.
go back to reference Yang YX, Lewis JD, Epstein S, Metz DC (2006) Long-term proton pump inhibitor therapy and risk of hip fracture. JAMA 296:2947–2953PubMedCrossRef Yang YX, Lewis JD, Epstein S, Metz DC (2006) Long-term proton pump inhibitor therapy and risk of hip fracture. JAMA 296:2947–2953PubMedCrossRef
17.
go back to reference Vestergaard P, Rejnmark L, Mosekilde L (2006) Proton pump inhibitors, histamine H2 receptor antagonists, and other antacid medications and the risk of fracture. Calcif Tissue Int 79:76–83PubMedCrossRef Vestergaard P, Rejnmark L, Mosekilde L (2006) Proton pump inhibitors, histamine H2 receptor antagonists, and other antacid medications and the risk of fracture. Calcif Tissue Int 79:76–83PubMedCrossRef
18.
go back to reference Targownik LE, Lix LM, Metge CJ, Prior HJ, Leung S, Leslie WD (2008) Use of proton pump inhibitors and risk of osteoporosis-related fractures. CMAJ 179:319–326PubMedPubMedCentralCrossRef Targownik LE, Lix LM, Metge CJ, Prior HJ, Leung S, Leslie WD (2008) Use of proton pump inhibitors and risk of osteoporosis-related fractures. CMAJ 179:319–326PubMedPubMedCentralCrossRef
19.
go back to reference Yu EW, Blackwell T, Ensrud KE, Hillier TA, Lane NE, Orwoll E, Bauer DC (2008) Acid-suppressive medications and risk of bone loss and fracture in older adults. Calcif Tissue Int 83:251–259PubMedPubMedCentralCrossRef Yu EW, Blackwell T, Ensrud KE, Hillier TA, Lane NE, Orwoll E, Bauer DC (2008) Acid-suppressive medications and risk of bone loss and fracture in older adults. Calcif Tissue Int 83:251–259PubMedPubMedCentralCrossRef
20.
go back to reference Roux C, Briot K, Gossec L, Kolta S, Blenk T, Felsenberg D, Reid DM, Eastell R, Glüer CC (2009) Increase in vertebral fracture risk in postmenopausal women using omeprazole. Calcif Tissue Int 84:13–19PubMedCrossRef Roux C, Briot K, Gossec L, Kolta S, Blenk T, Felsenberg D, Reid DM, Eastell R, Glüer CC (2009) Increase in vertebral fracture risk in postmenopausal women using omeprazole. Calcif Tissue Int 84:13–19PubMedCrossRef
21.
go back to reference Corley DA, Kubo A, Zhao W, Quesenberry C (2010) Proton pump inhibitors and histamine-2 receptor antagonists are associated with hip fractures among at-risk patients. Gastroenterology 139:93–101PubMedPubMedCentralCrossRef Corley DA, Kubo A, Zhao W, Quesenberry C (2010) Proton pump inhibitors and histamine-2 receptor antagonists are associated with hip fractures among at-risk patients. Gastroenterology 139:93–101PubMedPubMedCentralCrossRef
22.
go back to reference Gray SL, LaCroix AZ, Larson J, Robbins J, Cauley JA, Manson JE, Chen Z (2010) 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 170:765–771PubMedPubMedCentralCrossRef Gray SL, LaCroix AZ, Larson J, Robbins J, Cauley JA, Manson JE, Chen Z (2010) 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 170:765–771PubMedPubMedCentralCrossRef
23.
go back to reference Chiu HF, Huang YW, Chang CC, Yang CY (2010) Use of proton pump inhibitors increased the risk of hip fracture: a population-based case-control study. Pharmacoepidemiol Drug Saf 19:1131–1136PubMedCrossRef Chiu HF, Huang YW, Chang CC, Yang CY (2010) Use of proton pump inhibitors increased the risk of hip fracture: a population-based case-control study. Pharmacoepidemiol Drug Saf 19:1131–1136PubMedCrossRef
24.
go back to reference Pouwels S, Lalmohamed A, Souverein P, Cooper C, Veldt BJ, Leufkens HG, de Boer A, van Staa T, de Vries F (2011) Use of proton pump inhibitors and risk of hip/femur fracture: a population-based case-control study. Osteoporos Int 22:903–910PubMedPubMedCentralCrossRef Pouwels S, Lalmohamed A, Souverein P, Cooper C, Veldt BJ, Leufkens HG, de Boer A, van Staa T, de Vries F (2011) Use of proton pump inhibitors and risk of hip/femur fracture: a population-based case-control study. Osteoporos Int 22:903–910PubMedPubMedCentralCrossRef
25.
go back to reference Khalili H, Huang ES, Jacobson BC, Camargo CA Jr, Feskanich D, Chan AT (2012) Use of proton pump inhibitors and risk of hip fracture in relation to dietary and lifestyle factors: a prospective cohort study. BMJ 344, e372PubMedPubMedCentralCrossRef Khalili H, Huang ES, Jacobson BC, Camargo CA Jr, Feskanich D, Chan AT (2012) Use of proton pump inhibitors and risk of hip fracture in relation to dietary and lifestyle factors: a prospective cohort study. BMJ 344, e372PubMedPubMedCentralCrossRef
26.
go back to reference Fraser LA, Leslie WD, Targownik LE, Papaioannou A, Adachi JD, CaMos Research Group (2013) The effect of proton pump inhibitors on fracture risk: report from the Canadian Multicenter Osteoporosis Study. Osteoporos Int 24:1161–1168PubMedCrossRef Fraser LA, Leslie WD, Targownik LE, Papaioannou A, Adachi JD, CaMos Research Group (2013) The effect of proton pump inhibitors on fracture risk: report from the Canadian Multicenter Osteoporosis Study. Osteoporos Int 24:1161–1168PubMedCrossRef
27.
go back to reference Reyes C, Formiga F, Coderch M, Hoyo J, Ferriz G, Casanovas J, Monteserín R, Brotons C, Rojas M, Moral I (2013) Use of proton pump inhibitors and risk of fragility hip fracture in a Mediterranean region. Bone 52:557–561PubMedCrossRef Reyes C, Formiga F, Coderch M, Hoyo J, Ferriz G, Casanovas J, Monteserín R, Brotons C, Rojas M, Moral I (2013) Use of proton pump inhibitors and risk of fragility hip fracture in a Mediterranean region. Bone 52:557–561PubMedCrossRef
28.
go back to reference Moberg LM, Nilsson PM, Samsioe G, Borgfeldt C (2014) Use of proton pump inhibitors (PPI) and history of earlier fracture are independent risk factors for fracture in postmenopausal women. The WHILA study. Maturitas 78:310–315PubMedCrossRef Moberg LM, Nilsson PM, Samsioe G, Borgfeldt C (2014) Use of proton pump inhibitors (PPI) and history of earlier fracture are independent risk factors for fracture in postmenopausal women. The WHILA study. Maturitas 78:310–315PubMedCrossRef
29.
go back to reference Cea Soriano L, Ruigómez A, Johansson S, García Rodríguez LA (2014) Study of the association between hip fracture and acid-suppressive drug use in a UK primary care setting. Pharmacotherapy 34:570–581PubMedCrossRef Cea Soriano L, Ruigómez A, Johansson S, García Rodríguez LA (2014) Study of the association between hip fracture and acid-suppressive drug use in a UK primary care setting. Pharmacotherapy 34:570–581PubMedCrossRef
30.
go back to reference Lewis JR, Barre D, Zhu K, Ivey KL, Lim EM, Hughes J, Prince RL (2014) Long-term proton pump inhibitor therapy and falls and fractures in elderly women: a prospective cohort study. J Bone Miner Res 29:2489–2497PubMedCrossRef Lewis JR, Barre D, Zhu K, Ivey KL, Lim EM, Hughes J, Prince RL (2014) Long-term proton pump inhibitor therapy and falls and fractures in elderly women: a prospective cohort study. J Bone Miner Res 29:2489–2497PubMedCrossRef
31.
go back to reference Ding J, Heller DA, Ahern FM, Brown TV (2014) The relationship between proton pump inhibitor adherence and fracture risk in the elderly. Calcif Tissue Int 94:597–607PubMedCrossRef Ding J, Heller DA, Ahern FM, Brown TV (2014) The relationship between proton pump inhibitor adherence and fracture risk in the elderly. Calcif Tissue Int 94:597–607PubMedCrossRef
32.
go back to reference Adams AL, Black MH, Zhang JL, Shi JM, Jacobsen SJ (2014) Proton-pump inhibitor use and hip fractures in men: a population-based case-control study. Ann Epidemiol 24:286–290PubMedCrossRef Adams AL, Black MH, Zhang JL, Shi JM, Jacobsen SJ (2014) Proton-pump inhibitor use and hip fractures in men: a population-based case-control study. Ann Epidemiol 24:286–290PubMedCrossRef
33.
go back to reference Kaye JA, Jick H (2008) Proton pump inhibitor use and risk of hip fractures in patients without major risk factors. Pharmacotherapy 28:951–959PubMedCrossRef Kaye JA, Jick H (2008) Proton pump inhibitor use and risk of hip fractures in patients without major risk factors. Pharmacotherapy 28:951–959PubMedCrossRef
34.
go back to reference de Vries F, Cooper AL, Cockle SM, van Staa TP, Cooper C (2009) Fracture risk in patients receiving acid-suppressant medication alone and in combination with bisphosphonates. Osteoporos Int 20:1989–1998PubMedCrossRef de Vries F, Cooper AL, Cockle SM, van Staa TP, Cooper C (2009) Fracture risk in patients receiving acid-suppressant medication alone and in combination with bisphosphonates. Osteoporos Int 20:1989–1998PubMedCrossRef
35.
go back to reference Abrahamsen B, Vestergaard P (2013) Proton pump inhibitor use and fracture risk—effect modification by histamine H1 receptor blockade. Observational case-control study using National Prescription Data. Bone 57:269–271PubMedCrossRef Abrahamsen B, Vestergaard P (2013) Proton pump inhibitor use and fracture risk—effect modification by histamine H1 receptor blockade. Observational case-control study using National Prescription Data. Bone 57:269–271PubMedCrossRef
36.
go back to reference Mello M, Weideman RA, Little BB, Weideman MW, Cryer B, Brown GR (2012) Proton pump inhibitors increase the incidence of bone fractures in hepatitis C patients. Dig Dis Sci 57:2416–2422PubMedCrossRef Mello M, Weideman RA, Little BB, Weideman MW, Cryer B, Brown GR (2012) Proton pump inhibitors increase the incidence of bone fractures in hepatitis C patients. Dig Dis Sci 57:2416–2422PubMedCrossRef
37.
go back to reference O’Connell MB, Madden DM, Murray AM, Heaney RP, Kerzner LJ (2005) Effects of proton pump inhibitors on calcium carbonate absorption in women: a randomized crossover trial. Am J Med 118:778–781PubMedCrossRef O’Connell MB, Madden DM, Murray AM, Heaney RP, Kerzner LJ (2005) Effects of proton pump inhibitors on calcium carbonate absorption in women: a randomized crossover trial. Am J Med 118:778–781PubMedCrossRef
38.
go back to reference Wright MJ, Sullivan RR, Gaffney-Stomberg E, Caseria DM, O’Brien KO, Proctor DD, Simpson CA, Kerstetter JE, Insogna KL (2010) Inhibiting gastric acid production does not affect intestinal calcium absorption in young, healthy individuals: a randomized, crossover, controlled clinical trial. J Bone Miner Res 25:2205–2211PubMedPubMedCentralCrossRef Wright MJ, Sullivan RR, Gaffney-Stomberg E, Caseria DM, O’Brien KO, Proctor DD, Simpson CA, Kerstetter JE, Insogna KL (2010) Inhibiting gastric acid production does not affect intestinal calcium absorption in young, healthy individuals: a randomized, crossover, controlled clinical trial. J Bone Miner Res 25:2205–2211PubMedPubMedCentralCrossRef
39.
go back to reference Famularo G, Gasbarrone L, Minisola G (2013) Hypomagnesemia and proton-pump inhibitors. Expert Opin Drug Saf 12:709–716PubMedCrossRef Famularo G, Gasbarrone L, Minisola G (2013) Hypomagnesemia and proton-pump inhibitors. Expert Opin Drug Saf 12:709–716PubMedCrossRef
Metadata
Title
Proton-pump inhibitors and risk of fractures: an update meta-analysis
Authors
B. Zhou
Y. Huang
H. Li
W. Sun
J. Liu
Publication date
01-01-2016
Publisher
Springer London
Published in
Osteoporosis International / Issue 1/2016
Print ISSN: 0937-941X
Electronic ISSN: 1433-2965
DOI
https://doi.org/10.1007/s00198-015-3365-x

Other articles of this Issue 1/2016

Osteoporosis International 1/2016 Go to the issue