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.
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.
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.
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.
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.
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Dennison E, Mohamed MA, Cooper C (2006) Epidemiology of osteoporosis. Rheum Dis Clin N Am 32:617–629
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 15:567–574
Kushner PR, Peura DA (2011) Review of proton pump inhibitors for the initial treatment of heartburn: is there a dose ceiling effect? Adv Ther 28:367–388
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 13:145
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 38:721–728
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 23:794–800
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 124:519–526
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 9:257–267
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
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
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):W264
Wells GA, Shea B, O’Connell D, Peterson J, Welch V, Losos M, et al (2012) The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses. http://www.ohri.ca/programs/clinical_epidemiology/oxford.asp
DerSimonian R, Laird N (1986) Meta-analysis in clinical trials. Control Clin Trials 7:177–188
Higgins JPT, Thompson SG (2002) Quantifying heterogeneity in a meta-analysis. Stat Med 21:1539–1558
Egger M, Davey Smith G, Schneider M, Minder C (1997) Bias in meta-analysis detected by a simple, graphical test. BMJ 315:629–634
Yang YX, Lewis JD, Epstein S, Metz DC (2006) Long-term proton pump inhibitor therapy and risk of hip fracture. JAMA 296:2947–2953
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 79:76–83
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 179:319–326
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 83:251–259
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 84:13–19
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 139:93–101
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 170:765–771
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 19:1131–1136
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 22:903–910
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, e372
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 24:1161–1168
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 52:557–561
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 78:310–315
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 34:570–581
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 29:2489–2497
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 94:597–607
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 24:286–290
Kaye JA, Jick H (2008) Proton pump inhibitor use and risk of hip fractures in patients without major risk factors. Pharmacotherapy 28:951–959
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 20:1989–1998
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 57:269–271
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 57:2416–2422
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 118:778–781
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 25:2205–2211
Famularo G, Gasbarrone L, Minisola G (2013) Hypomagnesemia and proton-pump inhibitors. Expert Opin Drug Saf 12:709–716
Conflicts of interest
B. Zhou and Y. Huang contributed equally to this work.
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Zhou, B., Huang, Y., Li, H. et al. Proton-pump inhibitors and risk of fractures: an update meta-analysis. Osteoporos Int 27, 339–347 (2016). https://doi.org/10.1007/s00198-015-3365-x
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