Abstract
In the last decade, epidemiological studies presented inconsistent findings concerning the proton pump inhibitors (PPI) use and the risk of hip fracture. So, this systematic review and meta-analysis were performed with the aim to quantify the risk of hip fracture associated with PPI use. PubMed® and Cochrane Central databases were searched from inception to January 2018. The quality of included studies in meta-analysis was assessed using Newcastle-Ottawa scale. Primary outcome of this study was to assess the risk of hip fracture among PPI user. Secondary outcomes include subgroup analysis based on study design, study quality, duration of PPI use, calcium intake, and geographical region. Sensitivity analysis was also performed. Review Manager (RevMan) was used to perform statistical analysis. This meta-analysis was based on seventeen studies. Pooled risk ratio showed a statistically significant association between PPI use and hip fracture risk (RR 1.26 [95% CI 1.17–1.35], p < 0.00001). Subgroup analysis, based on the study design, showed a highly significant association between PPI use and risk of hip fracture (p < 0.0001). The risk of hip fracture persisted even when stratified by calcium adjustment and the duration of PPI use (p < 0.0001). This meta-analysis suggests that PPI user have a 26% increased risk of hip fracture as compared to non-PPI user. Physicians should take caution in prescribing PPI to patients who are at increased risk of hip fracture.
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References
Everhart JE, Ruhl CE (2009) Burden of digestive diseases in the United States part I: overall and upper gastrointestinal diseases. Gastroenterology 136:376–386
Kahrilas PJ, Shaheen NJ, Vaezi MF (2008) American gastroenterological association medical position statement on the management of gastroesophageal reflux disease. Gastroenterology 135:1383.e1385–1391.e1385
Chan FK, Abraham NS, Scheiman JM, Laine L (2008) Management of patients on nonsteroidal anti-inflammatory drugs: a clinical practice recommendation from the first international working party on gastrointestinal and cardiovascular effects of nonsteroidal anti-inflammatory drugs and anti-platelet agents. Am J Gastroenterol 103:2908–2918
Hoffmann F, Glaeske G, Schmiemann G (2015) Underuse of proton-pump inhibitors in older patients newly starting NSAID treatment. Int J Clin Pract 69:791–795
National Institute for Health and Care Excellence (2014) Gastro-oesophageal reflux disease and dyspepsia in adults: investigation and management. NICE, London
Freedberg DE, Kim LS, Yang YX (2017) The risks and benefits of long-term use of proton pump inhibitors: expert review and best practice advice from the american gastroenterological association. Gastroenterology 152:706–715
Lanza FL, Chan FK, Quigley EM (2009) Guidelines for prevention of NSAID-related ulcer complications. Am J Gastroenterol 104:728–738
Caplan A, Fett N, Rosenbach M, Werth VP, Micheletti RG (2017) Prevention and management of glucocorticoid-induced side effects: a comprehensive review: a review of glucocorticoid pharmacology and bone health. J Am Acad Dermatol 76:1–9
Savarino V, Dulbecco P, de Bortoli N, Ottonello A, Savarino E (2017) The appropriate use of proton pump inhibitors (PPIs): need for a reappraisal. Eur J Intern Med 37:19–24
Aitken M, Kleinrock M (2013) Declining medicine use and costs: for better or worse? A review of the use of medicines in the United States. IMS Health Web. http://www.imshealth.com/cds/ims/Global/Content/Insights/IMS%20Institute%20for%20Healthcare%20Informatics/2012%20U.S.%20Medicines%20U.S.%20Medicines%20. Accessed 24 Feb 2018
Forgacs I, Loganayagam A (2008) Overprescribing proton pump inhibitors. BMJ 336(7634):2–3
Khalili H, Huang ES, Jacobson BC, Camargo CA, 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
Hussain S, Singh A, Habib A, Najmi AK (2017) Proton pump inhibitors use and risk of chronic kidney disease: evidence-based meta-analysis of observational studies. Clin Epidemiol Glob Health. https://doi.org/10.1016/j.cegh.2017.12.008
Hussain S, Singh A, Habib A, Najmi AK (2017) Mp347proton pump inhibitors use and the risk of chronic kidney disease: a systematic review and meta analysis. Nephrol Dial Transplant 32:iii553–iii554
Facts and Statistics. https://www.iofbonehealth.org/facts-statistics. Accessed 24 Feb 2018
Papadimitriou N, Tsilidis KK, Orfanos P, Benetou V, Ntzani EE, Soerjomataram I, Künn-Nelen A, Pettersson-Kymmer U, Eriksson S, Brenner H (2017) Burden of hip fracture using disability-adjusted life-years: a pooled analysis of prospective cohorts in the CHANCES consortium. Lancet Public Health 2:e239–e246
Lenihan CR, Nair SS, Vangala C, Ramanathan V, Montez-Rath ME, Winkelmayer WC (2017) Proton pump inhibitor use and risk of hip fracture in kidney transplant recipients. Am J Kidney Dis 69:595–601
Lin S-M, Yang S-H, Liang C-C, Huang H-K (2018) Proton pump inhibitor use and the risk of osteoporosis and fracture in stroke patients: a population-based cohort study. Osteoporos Int 29:153–162
Pouwels S, Lalmohamed A, Souverein P, Cooper C, Veldt B, Leufkens H, 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 l 22:903–910
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
Vestergaard P, Rejnmark L, Mosekilde L (2006) Proton pump inhibitors, histamine H 2 receptor antagonists, and other antacid medications and the risk of fracture. Calcif Tissue Int 79:76–83
Yang Y-X, Lewis JD, Epstein S, Metz DC (2006) Long-term proton pump inhibitor therapy and risk of hip fracture. JAMA 296:2947–2953
FDA Drug Safety Communication: Possible increased risk of fractures of the hip, wrist, and spine with the use of proton pump inhibitors. http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm213206.htm. Accessed 28 Feb 2018
Wang L, Li M, Cao Y, Han Z, Wang X, Atkinson EJ, Liu H, Amin S (2017) Proton pump inhibitors and the risk for fracture at specific sites: data mining of the FDA adverse event reporting system. Sci Rep 7:5527
Kaye JA, Jick H (2008) Proton pump inhibitor use and risk of hip fractures in patients without major risk factors. Pharmacotherapy 28:951–959
Targownik LE, Goertzen AL, Luo Y, Leslie WD (2017) Long-term proton pump inhibitor use is not associated with changes in bone strength and structure. Am J Gastroenterol 112:95
Moher D, Liberati A, Tetzlaff J, Altman DG, Group P (2009) Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med 6:e1000097
Higgins JP, Altman DG, Gøtzsche PC, Jüni P, Moher D, Oxman AD et al (2011) The Cochrane Collaboration’s tool for assessing risk of bias in randomised trials. BMJ 343:d5928
Singh A, Hussain S, Najmi AK (2017) Number of studies, heterogeneity, generalisability, and the choice of method for meta-analysis. J Neurol Sci 381:347
George BJ, Aban IB (2016) An application of meta-analysis based on DerSimonian and Laird method. J Nucl Cardiol 23:690–692
Egger M, Davey Smith G, Schneider M, Minder C (1997) Bias in meta-analysis detected by a simple, graphical test. BMJ 315:629–634
Review Manager (RevMan) [Computer program] (2014) Version 53 Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration
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
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
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
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
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
Elaine WY, 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
Fraser L, Leslie W, Targownik L, Papaioannou A, Adachi J, Group CR (2013) The effect of proton pump inhibitors on fracture risk: report from the Canadian Multicenter Osteoporosis Study. Osteoporos Int 24:1161–1168
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
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
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
De Vries F, Cooper A, Cockle S, van Staa T-P, Cooper C (2009) Fracture risk in patients receiving acid-suppressant medication alone and in combination with bisphosphonates. Osteoporos Int 20:1989–1998
Lin SC, Koo M, Tsai KW (2014) Association between helicobacter pylori infection and risk of osteoporosis in elderly taiwanese women with upper gastrointestinal diseases: a retrospective patient record review. Gastroenterol Res Pract 2014:814756
Targownik LE, Lix LM, Leung S, Leslie WD (2010) Proton-pump inhibitor use is not associated with osteoporosis or accelerated bone mineral density loss. Gastroenterology 138:896–904
Yang Y-X (2008) Proton pump inhibitor therapy and osteoporosis. Curr Drug Saf 3:204–209
Roux C, Briot K, Gossec L, Kolta S, Blenk T, Felsenberg D, Reid DM, Eastell R, Gluer CC (2009) Increase in vertebral fracture risk in postmenopausal women using omeprazole. Calcif Tissue Int 84:13–19
Targownik LE, Leslie WD, Davison KS et al (2012) The relationship between proton pump inhibitor use and longitudinal change in bone mineral density: a population-based study [corrected] from the Canadian Multicentre Osteoporosis Study (CaMos). Am J Gastroenterol 107:1361–1369
Maggio M, Lauretani F, Ceda GP et al (2013) Use of proton pump inhibitors is associated with lower trabecular bone density in older individuals. Bone 57:437–442
Itoh S, Sekino Y, Shinomiya K, Takeda S (2013) The effects of risedronate administered in combination with a proton pump inhibitor for the treatment of osteoporosis. J Bone Miner Metab 31:206–211
Joo MK, Park JJ, Lee BJ, Kim JH, Yeon JE, Kim JS, Byun KS, Bak YT (2013) The effect of a proton pump inhibitor on bone metabolism in ovariectomized rats. Mol Med Rep 7:1267–1272
Sharara AI, El-Halabi MM, Ghaith OA, Habib RH, Mansour NM, Malli A, El Hajj-Fuleihan G (2013) Proton pump inhibitors have no measurable effect on calcium and bone metabolism in healthy young males: a prospective matched controlled study. Metabolism 62:518–526
Jo Y, Park E, Ahn SB, Jo YK, Son B, Kim SH, Park YS, Kim HJ (2015) A proton pump inhibitor’s effect on bone metabolism mediated by osteoclast action in old age: a prospective randomized study. Gut Liver 9:607–614
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
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
Recker RR (1985) Calcium absorption and achlorhydria. N Engl J Med 313:70–73
Mizunashi K, Furukawa Y, Katano K, Abe K (1993) Effect of omeprazole, an inhibitor of H+, K+-ATPase, on bone resorption in humans. Calcif Tissue Int 53:21–25
Costa-Rodrigues J, Reis S, Teixeira S, Lopes S, Fernandes MH (2013) Dose-dependent inhibitory effects of proton pump inhibitors on human osteoclastic and osteoblastic cell activity. FEBS J 280:5052–5064
Rümenapf G, Schwille P, Erben R, Schreiber M, Berge B, Fries W, Schmiedl A, Koroma S, Hohenberger W (1998) Gastric fundectomy in the rat: effects on mineral and bone metabolism, with emphasis on the gastrin–calcitonin–parathyroid hormone–vitamin D axis. Calcif Tissue Int 63:433–441
Mattsson JP, Väänänen K, Wallmark B, Lorentzon P (1991) Omeprazole and bafilomycin, two proton pump inhibitors: differentiation of their effects on gastric, kidney and bone H+-translocating ATPases. Biochim Biophys Acta 1065:261–268
Tuukkanen J, Koivukangas A, Jämsä T, Sundquist K, Mackay C, Marks S (2000) Mineral density and bone strength are dissociated in long bones of rat osteopetrotic mutations. J Bone Miner Res 15:1905–1911
McLean RR, Jacques PF, Selhub J, Tucker KL, Samelson EJ, Broe KE, Hannan MT, Cupples LA, Kiel DP (2004) Homocysteine as a predictive factor for hip fracture in older persons. N Engl J Med 350:2042–2049
van Staa T-P, de Vries F, Leufkens HG (2006) Gastric acid-suppressive agents and risk of Clostridium difficile-associated disease. JAMA 295:2599
Acknowledgements
First author (Salman Hussain) are grateful to Sun Pharmaceuticals, India, for providing assistance for this project under the joint collaboration for PhD programme with School of Pharmaceutical Education and Research (SPER), Jamia Hamdard, New Delhi, India. Authors are thankful to Dr. Mohd Vaseem Ismail, Assistant Professor at Jamia Hamdard, New Delhi, India for providing his statistical inputs during the manuscript preparation.
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SH and AKN designed the study. SH and ANS searched databases and performed the selection of the studies; SH and MSH completed the data extraction; SH and AH performed the quality assessment of the included studies; SH and ANS wrote the manuscript; SH analyzed and interpreted the data. All authors have reviewed and revised the draft critically for intellectual content. All authors give final approval of the version to be submitted in journal.
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Hussain, S., Siddiqui, A.N., Habib, A. et al. Proton pump inhibitors’ use and risk of hip fracture: a systematic review and meta-analysis. Rheumatol Int 38, 1999–2014 (2018). https://doi.org/10.1007/s00296-018-4142-x
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DOI: https://doi.org/10.1007/s00296-018-4142-x