Skip to main content
Erschienen in: Journal of General Internal Medicine 2/2019

03.12.2018 | Review Paper

A Systematic Review and Meta-analysis of the Association Between Vitamin K Antagonist Use and Fracture

verfasst von: Wendy Fiordellisi, MD, MS, Katherine White, MD, MME, Marin Schweizer, PhD

Erschienen in: Journal of General Internal Medicine | Ausgabe 2/2019

Einloggen, um Zugang zu erhalten

Abstract

Background

Vitamin K antagonist (VKA) anticoagulant use is suspected to increase the risk of bone fracture through inhibition of vitamin K–dependent cofactors of bone formation, an effect not seen with non-vitamin K antagonist oral anticoagulants (NOACs). The purpose of our systematic review and meta-analysis is to investigate the association between VKA use and fracture.

Methods

We searched PubMed, EMBASE, and Cochrane Library for studies analyzing fracture in adults using VKAs versus controls. Two authors independently reviewed articles. We assessed for risk of bias using the Newcastle-Ottawa Quality Assessment Scale and the Cochrane Risk of Bias Tool and calculated pooled effects using random effects models.

Results

We included 23 articles (22 observational studies and 1 randomized controlled trial), studying 1,121,582 subjects. There was no increased odds of fracture in VKA users versus controls (pooled OR 1.01, 95% CI 0.89, 1.14) or in VKA users versus NOAC users (pooled OR 0.95, 95% CI 0.78, 1.15). Subjects using a VKA for 1 year or longer did not have increased odds of fracture (pooled OR 1.07, 95% CI 0.90, 1.27). Compared to controls, there was increased odds of fracture in women (pooled OR 1.11, 95% CI 1.02, 1.21) and older VKA users (≥ 65) (pooled OR 1.07, 95% CI 1.01, 1.14).

Discussion

We found no increase in odds of fracture in VKA users versus controls or NOAC users. There was a small increase in odds of fracture among female and elderly VKA users, which may not be clinically important when accounting for other considerations in choosing an anticoagulant. Our findings suggest that, when anticoagulation is necessary, fracture risk should not be a major consideration in choice of an agent. Future studies directly comparing VKA to NOAC users and studies with longer duration of VKA use may be needed.
Anhänge
Nur mit Berechtigung zugänglich
Literatur
2.
Zurück zum Zitat Kavukcuoglu NB, Patterson-Buckendahl P, Mann AB. Effect of osteocalcin deficiency on the nanomechanics and chemistry of mouse bones. J Mech Behav Biomed Mater. 2009;2(4):348–54.CrossRef Kavukcuoglu NB, Patterson-Buckendahl P, Mann AB. Effect of osteocalcin deficiency on the nanomechanics and chemistry of mouse bones. J Mech Behav Biomed Mater. 2009;2(4):348–54.CrossRef
3.
Zurück zum Zitat Rey-Sanchez P, Lavado-Garcia JM, Canal-Macias ML, Rodriguez-Dominguez MT, Bote-Mohedano JL, Pedrera-Zamorano JD. Ultrasound bone mass in patients undergoing chronic therapy with oral anticoagulants. J Bone Miner Metab. 2011;29(5):546–51.CrossRef Rey-Sanchez P, Lavado-Garcia JM, Canal-Macias ML, Rodriguez-Dominguez MT, Bote-Mohedano JL, Pedrera-Zamorano JD. Ultrasound bone mass in patients undergoing chronic therapy with oral anticoagulants. J Bone Miner Metab. 2011;29(5):546–51.CrossRef
4.
Zurück zum Zitat Sugiyama T, Takaki T, Sakanaka K, Sadamaru H, Mori K, Kato Y, et al. Warfarin-induced impairment of cortical bone material quality and compensatory adaptation of cortical bone structure to mechanical stimuli. J Endocrinol. 2007;194(1):213–22.CrossRef Sugiyama T, Takaki T, Sakanaka K, Sadamaru H, Mori K, Kato Y, et al. Warfarin-induced impairment of cortical bone material quality and compensatory adaptation of cortical bone structure to mechanical stimuli. J Endocrinol. 2007;194(1):213–22.CrossRef
5.
Zurück zum Zitat Sugiyama T, Kawai S. Carboxylation of osteocalcin may be related to bone quality: a possible mechanism of bone fracture prevention by vitamin K. J Bone Miner Metab. 2001;19(3):146–9.CrossRef Sugiyama T, Kawai S. Carboxylation of osteocalcin may be related to bone quality: a possible mechanism of bone fracture prevention by vitamin K. J Bone Miner Metab. 2001;19(3):146–9.CrossRef
6.
Zurück zum Zitat Caraballo PJ, Gabriel SE, Castro MR, Atkinson EJ, Melton Iii LJ. Changes in bone density after exposure to oral anticoagulants: A meta-analysis. Osteoporos Int. 1999;9(5):441–8.CrossRef Caraballo PJ, Gabriel SE, Castro MR, Atkinson EJ, Melton Iii LJ. Changes in bone density after exposure to oral anticoagulants: A meta-analysis. Osteoporos Int. 1999;9(5):441–8.CrossRef
7.
Zurück zum Zitat Veronese N, Bano G, Bertozzo G, Granziera S, Solmi M, Manzato E, et al. Vitamin K antagonists’ use and fracture risk: results from a systematic review and meta-analysis. J Thromb Haemost. 2015;13(9):1665–75.CrossRef Veronese N, Bano G, Bertozzo G, Granziera S, Solmi M, Manzato E, et al. Vitamin K antagonists’ use and fracture risk: results from a systematic review and meta-analysis. J Thromb Haemost. 2015;13(9):1665–75.CrossRef
8.
Zurück zum Zitat Stroup DF, Berlin JA, Morton SC, Olkin I, Williamson GD, Renni D, et al. Meta-analysis of observational studies in epidemiology. JAMA. 2000;283:2008–12.CrossRef Stroup DF, Berlin JA, Morton SC, Olkin I, Williamson GD, Renni D, et al. Meta-analysis of observational studies in epidemiology. JAMA. 2000;283:2008–12.CrossRef
9.
Zurück zum Zitat Moher D, Liberati A, Tetzlaff J, Altman DG. Preferred Reporting Items for Systematic Reviews and Meta-Analyses: The PRISMA Statement. J Clin Epidemiol. 2009;62(10):1006–12.CrossRef Moher D, Liberati A, Tetzlaff J, Altman DG. Preferred Reporting Items for Systematic Reviews and Meta-Analyses: The PRISMA Statement. J Clin Epidemiol. 2009;62(10):1006–12.CrossRef
11.
Zurück zum Zitat Higgins JPT, Altman DG, Gøtzsche PC, Jüni P, Moher D, Oxman AD, et al. The Cochrane Collaboration’s tool for assessing risk of bias in randomised trials. BMJ. 2011;343. Higgins JPT, Altman DG, Gøtzsche PC, Jüni P, Moher D, Oxman AD, et al. The Cochrane Collaboration’s tool for assessing risk of bias in randomised trials. BMJ. 2011;343.
12.
Zurück zum Zitat Review Manager. 5.3 ed. Copenhagen: The Nordic Cochrane Center, The Cochrane Collaboration; 2011. Review Manager. 5.3 ed. Copenhagen: The Nordic Cochrane Center, The Cochrane Collaboration; 2011.
13.
Zurück zum Zitat Sheskin D. Handbook of parametric and nonparametric statistical procedures. 5th ed: Boca Raton: Chapman & Hall/CRC Press; 2011. Sheskin D. Handbook of parametric and nonparametric statistical procedures. 5th ed: Boca Raton: Chapman & Hall/CRC Press; 2011.
14.
Zurück zum Zitat Higgins JPT, Thompson SG. Quantifying heterogeneity in a meta-analysis. Stat Med. 2002;21(11):1539–58.CrossRef Higgins JPT, Thompson SG. Quantifying heterogeneity in a meta-analysis. Stat Med. 2002;21(11):1539–58.CrossRef
15.
Zurück zum Zitat Harbord RM, Egger M, Sterne JA. A modified test for small-study effects in meta-analyses of controlled trials with binary endpoints. Stat Med. 2006;25(20):3443–57.CrossRef Harbord RM, Egger M, Sterne JA. A modified test for small-study effects in meta-analyses of controlled trials with binary endpoints. Stat Med. 2006;25(20):3443–57.CrossRef
16.
Zurück zum Zitat Bhattacharya B, Maung A, Schuster K, Davis KA. The older they are the harder they fall: Injury patterns and outcomes by age after ground level falls. Injury. 2016;47(9):1955–9.CrossRef Bhattacharya B, Maung A, Schuster K, Davis KA. The older they are the harder they fall: Injury patterns and outcomes by age after ground level falls. Injury. 2016;47(9):1955–9.CrossRef
17.
Zurück zum Zitat Boltz MM, Podany AB, Hollenbeak CS, Armen SB. Injuries and outcomes associated with traumatic falls in the elderly population on oral anticoagulant therapy. Injury. 2015;46(9):1765–71.CrossRef Boltz MM, Podany AB, Hollenbeak CS, Armen SB. Injuries and outcomes associated with traumatic falls in the elderly population on oral anticoagulant therapy. Injury. 2015;46(9):1765–71.CrossRef
18.
Zurück zum Zitat Chiang CH, Liu CJ, Chen PJ, Huang CC, Hsu CY, Chen ZY, et al. Hip fracture and risk of acute myocardial infarction: A nationwide study. J Bone Miner Res. 2013;28(2):404–11.CrossRef Chiang CH, Liu CJ, Chen PJ, Huang CC, Hsu CY, Chen ZY, et al. Hip fracture and risk of acute myocardial infarction: A nationwide study. J Bone Miner Res. 2013;28(2):404–11.CrossRef
19.
Zurück zum Zitat Drozdinsky G, Cohen J, Shohat Z, Shiber-Ofer S, Grossman A. Is warfarin usage a risk factor for osteoporotic fractures? A cohort study in the emergency department. Australas Med J. 2017;10(4):329–34.CrossRef Drozdinsky G, Cohen J, Shohat Z, Shiber-Ofer S, Grossman A. Is warfarin usage a risk factor for osteoporotic fractures? A cohort study in the emergency department. Australas Med J. 2017;10(4):329–34.CrossRef
20.
Zurück zum Zitat Fusaro M, Tripepi G, Noale M, Plebani M, Zaninotto M, Piccoli A, et al. Prevalence of vertebral fractures, vascular calcifications, and mortality in warfarin treated hemodialysis patients. Curr Vasc Pharmacol. 2015;13(2):248–58.CrossRef Fusaro M, Tripepi G, Noale M, Plebani M, Zaninotto M, Piccoli A, et al. Prevalence of vertebral fractures, vascular calcifications, and mortality in warfarin treated hemodialysis patients. Curr Vasc Pharmacol. 2015;13(2):248–58.CrossRef
21.
Zurück zum Zitat Gage BF, Birman-Deych E, Radford MJ, Nilasena DS, Binder EF. Risk of osteoporotic fracture in elderly patients taking warfarin: results from the National Registry of Atrial Fibrillation 2. Arch Intern Med. 2006;166(2):241–6.CrossRef Gage BF, Birman-Deych E, Radford MJ, Nilasena DS, Binder EF. Risk of osteoporotic fracture in elderly patients taking warfarin: results from the National Registry of Atrial Fibrillation 2. Arch Intern Med. 2006;166(2):241–6.CrossRef
22.
Zurück zum Zitat Jamal SA, Browner WS, Bauer DC, Cummings SR. Warfarin use and risk for osteoporosis in elderly women. Study of Osteoporotic Fractures Research Group. Ann Intern Med. 1998;128(10):829–32.CrossRef Jamal SA, Browner WS, Bauer DC, Cummings SR. Warfarin use and risk for osteoporosis in elderly women. Study of Osteoporotic Fractures Research Group. Ann Intern Med. 1998;128(10):829–32.CrossRef
23.
Zurück zum Zitat Lai HC, Chien WC, Chung CH, Lee WL, Wu TJ, Wang KY, et al. Atrial fibrillation, CHA2DS2-VASc score, antithrombotics and risk of non-traffic-, non-cancer-related bone fractures: A population-based cohort study. Eur J Intern Med. 2015;26(10):798–806.CrossRef Lai HC, Chien WC, Chung CH, Lee WL, Wu TJ, Wang KY, et al. Atrial fibrillation, CHA2DS2-VASc score, antithrombotics and risk of non-traffic-, non-cancer-related bone fractures: A population-based cohort study. Eur J Intern Med. 2015;26(10):798–806.CrossRef
24.
Zurück zum Zitat Lau WC, Chan EW, Cheung CL, Sing CW, Man KK, Lip GY, et al. Association Between Dabigatran vs Warfarin and Risk of Osteoporotic Fractures Among Patients With Nonvalvular Atrial Fibrillation. JAMA. 2017;317(11):1151–8.CrossRef Lau WC, Chan EW, Cheung CL, Sing CW, Man KK, Lip GY, et al. Association Between Dabigatran vs Warfarin and Risk of Osteoporotic Fractures Among Patients With Nonvalvular Atrial Fibrillation. JAMA. 2017;317(11):1151–8.CrossRef
25.
Zurück zum Zitat Lucenteforte E, Bettiol A, Lombardi N, Mugelli A, Vannacci A. Risk of bone fractures among users of oral anticoagulants: An administrative database cohort study. Eur J Intern Med. 2017;44:e30-e1.CrossRef Lucenteforte E, Bettiol A, Lombardi N, Mugelli A, Vannacci A. Risk of bone fractures among users of oral anticoagulants: An administrative database cohort study. Eur J Intern Med. 2017;44:e30-e1.CrossRef
26.
Zurück zum Zitat Lyons KJ, Majumdar SR, Ezekowitz JA. The unrecognized burden of osteoporosis-related vertebral fractures in patients with heart failure. Circ Heart Fail. 2011;4(4):419–24.CrossRef Lyons KJ, Majumdar SR, Ezekowitz JA. The unrecognized burden of osteoporosis-related vertebral fractures in patients with heart failure. Circ Heart Fail. 2011;4(4):419–24.CrossRef
27.
Zurück zum Zitat Misra D, Zhang Y, Peloquin C, Choi HK, Kiel DP, Neogi T. Incident long-term warfarin use and risk of osteoporotic fractures: propensity-score matched cohort of elders with new onset atrial fibrillation. Osteoporos Int. 2014;25(6):1677–84.CrossRef Misra D, Zhang Y, Peloquin C, Choi HK, Kiel DP, Neogi T. Incident long-term warfarin use and risk of osteoporotic fractures: propensity-score matched cohort of elders with new onset atrial fibrillation. Osteoporos Int. 2014;25(6):1677–84.CrossRef
28.
Zurück zum Zitat Norby FL, Bengtson LGS, Lutsey PL, Chen LY, MacLehose RF, Chamberlain AM, et al. Comparative effectiveness of rivaroxaban versus warfarin or dabigatran for the treatment of patients with non-valvular atrial fibrillation. BMC Cardiovasc Disord. 2017;17(1). Norby FL, Bengtson LGS, Lutsey PL, Chen LY, MacLehose RF, Chamberlain AM, et al. Comparative effectiveness of rivaroxaban versus warfarin or dabigatran for the treatment of patients with non-valvular atrial fibrillation. BMC Cardiovasc Disord. 2017;17(1).
29.
Zurück zum Zitat Ogura-Tomomatsu H, Asano K, Tomomatsu K, Miyata J, Ohmori N, Kodama M, et al. Predictors of osteoporosis and vertebral fractures in patients presenting with moderate-to-severe chronic obstructive lung disease. Copd. 2012;9(4):332–7.CrossRef Ogura-Tomomatsu H, Asano K, Tomomatsu K, Miyata J, Ohmori N, Kodama M, et al. Predictors of osteoporosis and vertebral fractures in patients presenting with moderate-to-severe chronic obstructive lung disease. Copd. 2012;9(4):332–7.CrossRef
30.
Zurück zum Zitat Pieracci FM, Eachempati SR, Shou J, Hydo LJ, Barie PS. Use of long-term anticoagulation is associated with traumatic intracranial hemorrhage and subsequent mortality in elderly patients hospitalized after falls: analysis of the New York State Administrative Database. J Trauma. 2007;63(3):519–24.CrossRef Pieracci FM, Eachempati SR, Shou J, Hydo LJ, Barie PS. Use of long-term anticoagulation is associated with traumatic intracranial hemorrhage and subsequent mortality in elderly patients hospitalized after falls: analysis of the New York State Administrative Database. J Trauma. 2007;63(3):519–24.CrossRef
31.
Zurück zum Zitat Pilon D, Castilloux AM, Dorais M, LeLorier J. Oral anticoagulants and the risk of osteoporotic fractures among elderly. Pharmacoepidemiol Drug Saf. 2004;13(5):289–94.CrossRef Pilon D, Castilloux AM, Dorais M, LeLorier J. Oral anticoagulants and the risk of osteoporotic fractures among elderly. Pharmacoepidemiol Drug Saf. 2004;13(5):289–94.CrossRef
32.
Zurück zum Zitat Rejnmark L, Vestergaard P, Mosekilde L. Fracture risk in users of oral anticoagulants: A nationwide case-control study. Int J Cardiol. 2007;118(3):338–44.CrossRef Rejnmark L, Vestergaard P, Mosekilde L. Fracture risk in users of oral anticoagulants: A nationwide case-control study. Int J Cardiol. 2007;118(3):338–44.CrossRef
33.
Zurück zum Zitat Sato Y, Honda Y, Jun I. Long-term oral anticoagulation therapy and the risk of hip fracture in patients with previous hemispheric infarction and nonrheumatic atrial fibrillation. Cerebrovasc Dis. 2010;29(1):73–8.CrossRef Sato Y, Honda Y, Jun I. Long-term oral anticoagulation therapy and the risk of hip fracture in patients with previous hemispheric infarction and nonrheumatic atrial fibrillation. Cerebrovasc Dis. 2010;29(1):73–8.CrossRef
34.
Zurück zum Zitat Steffel J, Giugliano RP, Braunwald E, Murphy SA, Mercuri M, Choi Y, et al. Edoxaban Versus Warfarin in Atrial Fibrillation Patients at Risk of Falling: ENGAGE AF-TIMI 48 Analysis. J Am Coll Cardiol. 2016;68(11):1169–78.CrossRef Steffel J, Giugliano RP, Braunwald E, Murphy SA, Mercuri M, Choi Y, et al. Edoxaban Versus Warfarin in Atrial Fibrillation Patients at Risk of Falling: ENGAGE AF-TIMI 48 Analysis. J Am Coll Cardiol. 2016;68(11):1169–78.CrossRef
35.
Zurück zum Zitat van Diepen S, Majumdar SR, Bakal JA, McAlister FA, Ezekowitz JA. Heart Failure Is a Risk Factor for Orthopedic Fracture. A Population-Based Analysis of 16,294 Patients. Circulation. 2008;118(19):1946–52.CrossRef van Diepen S, Majumdar SR, Bakal JA, McAlister FA, Ezekowitz JA. Heart Failure Is a Risk Factor for Orthopedic Fracture. A Population-Based Analysis of 16,294 Patients. Circulation. 2008;118(19):1946–52.CrossRef
36.
Zurück zum Zitat Wallace ER, Siscovick DS, Sitlani CM, Dublin S, Mitchell P, Robbins JA, et al. Incident atrial fibrillation and the risk of fracture in the cardiovascular health study. Osteoporos Int. 2017;28(2):719–25.CrossRef Wallace ER, Siscovick DS, Sitlani CM, Dublin S, Mitchell P, Robbins JA, et al. Incident atrial fibrillation and the risk of fracture in the cardiovascular health study. Osteoporos Int. 2017;28(2):719–25.CrossRef
37.
Zurück zum Zitat Wang SH, Chang YS, Liu CJ, Lai CC, Chen WS, Chen TJ, et al. Association of systemic lupus erythematosus with a higher risk of cervical but not trochanteric hip fracture: A nationwide population-based study. Arthritis Care Res. 2013;65(10):1674–81. Wang SH, Chang YS, Liu CJ, Lai CC, Chen WS, Chen TJ, et al. Association of systemic lupus erythematosus with a higher risk of cervical but not trochanteric hip fracture: A nationwide population-based study. Arthritis Care Res. 2013;65(10):1674–81.
38.
Zurück zum Zitat Woo C, Chang LL, Ewing SK, Bauer DC. Single-point assessment of warfarin use and risk of osteoporosis in elderly men. J Am Geriatr Soc. 2008;56(7):1171–6.CrossRef Woo C, Chang LL, Ewing SK, Bauer DC. Single-point assessment of warfarin use and risk of osteoporosis in elderly men. J Am Geriatr Soc. 2008;56(7):1171–6.CrossRef
39.
Zurück zum Zitat Chai-Adisaksopha C, Hillis C, Isayama T, Lim W, Iorio A, Crowther M. Mortality outcomes in patients receiving direct oral anticoagulants: a systematic review and meta-analysis of randomized controlled trials. J Thromb Haemost. 2015;13(11):2012–20.CrossRef Chai-Adisaksopha C, Hillis C, Isayama T, Lim W, Iorio A, Crowther M. Mortality outcomes in patients receiving direct oral anticoagulants: a systematic review and meta-analysis of randomized controlled trials. J Thromb Haemost. 2015;13(11):2012–20.CrossRef
40.
Zurück zum Zitat Sugiyama T, Kugimiya F, Kono S, Kim YT, Oda H. Warfarin use and fracture risk: an evidence-based mechanistic insight. Osteoporos Int. 2015;26(3):1231–2.CrossRef Sugiyama T, Kugimiya F, Kono S, Kim YT, Oda H. Warfarin use and fracture risk: an evidence-based mechanistic insight. Osteoporos Int. 2015;26(3):1231–2.CrossRef
41.
Zurück zum Zitat Guyatt GH, Oxman AD, Kunz R, Falck-Ytter Y, Vist GE, Liberati A, et al. Going from evidence to recommendations. BMJ. 2008;336(7652):1049–51.CrossRef Guyatt GH, Oxman AD, Kunz R, Falck-Ytter Y, Vist GE, Liberati A, et al. Going from evidence to recommendations. BMJ. 2008;336(7652):1049–51.CrossRef
42.
Zurück zum Zitat Beaubrun AC, Kilpatrick RD, Freburger JK, Bradbury BD, Wang L, Brookhart MA. Temporal trends in fracture rates and postdischarge outcomes among hemodialysis patients. J Am Soc Nephrol. 2013;24(9):1461–9.CrossRef Beaubrun AC, Kilpatrick RD, Freburger JK, Bradbury BD, Wang L, Brookhart MA. Temporal trends in fracture rates and postdischarge outcomes among hemodialysis patients. J Am Soc Nephrol. 2013;24(9):1461–9.CrossRef
43.
Zurück zum Zitat Jadoul M, Albert JM, Akiba T, Akizawa T, Arab L, Bragg-Gresham JL, et al. Incidence and risk factors for hip or other bone fractures among hemodialysis patients in the Dialysis Outcomes and Practice Patterns Study. Kidney Int. 2006;70(7):1358–66.CrossRef Jadoul M, Albert JM, Akiba T, Akizawa T, Arab L, Bragg-Gresham JL, et al. Incidence and risk factors for hip or other bone fractures among hemodialysis patients in the Dialysis Outcomes and Practice Patterns Study. Kidney Int. 2006;70(7):1358–66.CrossRef
Metadaten
Titel
A Systematic Review and Meta-analysis of the Association Between Vitamin K Antagonist Use and Fracture
verfasst von
Wendy Fiordellisi, MD, MS
Katherine White, MD, MME
Marin Schweizer, PhD
Publikationsdatum
03.12.2018
Verlag
Springer US
Erschienen in
Journal of General Internal Medicine / Ausgabe 2/2019
Print ISSN: 0884-8734
Elektronische ISSN: 1525-1497
DOI
https://doi.org/10.1007/s11606-018-4758-2

Weitere Artikel der Ausgabe 2/2019

Journal of General Internal Medicine 2/2019 Zur Ausgabe

Leitlinien kompakt für die Innere Medizin

Mit medbee Pocketcards sicher entscheiden.

Seit 2022 gehört die medbee GmbH zum Springer Medizin Verlag

Update Innere Medizin

Bestellen Sie unseren Fach-Newsletter und bleiben Sie gut informiert.