International Orthopaedics

, Volume 42, Issue 7, pp 1469–1478 | Cite as

Nationwide study on the risk of unprovoked venous thromboembolism in non-traumatic osteonecrosis of femoral head

  • Pei-Hsun Sung
  • Hsin-Ju Chiang
  • Yao-Hsu Yang
  • John Y. Chiang
  • Chi-Jen Chen
  • Hon-Kan Yip
  • Mel S. Lee
Original Paper



Endothelial dysfunction is a risk factor for osteonecrosis of femoral head (ONFH) and venous thromboembolism (VTE) [defined as deep venous thrombosis (DVT) or pulmonary embolism (PE)]. However, the risk of unprovoked VTE in non-traumatic ONFH patients remains unclear.


We investigated the relationship between ONFH and VTE using Taiwan National Health Insurance Research Database (NHIRD). Between 1997 and 2010, a total of 1514 non-traumatic ONFH patients were identified from 1,000,000 general populations after excluding initially concomitant diagnoses of DVT and PE, and subjects undergoing lower limb surgery within one year since enrollment. The comparison group (n = 15,140) without ONFH was set up by matching study cohort with age, gender, income and urbanization in a 1:10 ratio. Subjects diagnosed with VTE within one year after surgery were also excluded.


The patients with non-traumatic ONFH had significantly higher frequency of unprovoked VTE, including DVT, than general population (1.19 vs. 0.5%, p < 0.0007), whereas the frequency of PE was similar between these two groups (p = 0.4922). The cumulative incidence of VTE and DVT was also remarkably higher in the ONFH than non-ONFH group (all p < 0.001). After adjusting for age, gender, medications and comorbidities with multivariate analysis, the ONFH patients had a 2.3-fold increase in risk of DVT compared with non-ONFH counterparts (95% CI 1.28 to 4.13, p = 0.0053). Apart from ONFH, age > 65 years and hypertension were also identified as risk factors for DVT occurrence.


The incidence and risk of unprovoked VTE were significantly increased in the non-traumatic ONFH population.


Osteonecrosis of femoral head Venous thromboembolism (VTE) Deep venous thrombosis (DVT) Population-based cohort study Endothelial dysfunction 



Avascular necrosis


Osteonecrosis of femoral head


Nitic oxide


Venous thromboembolic events


Deep vein thrombosis


Pulmonary embolism


National Health Insurance Research Database


National Health Research Institute


Renin-angiotensin-aldosterone system



We would like to thank Institute of Occupational Medicine and Industrial Hygiene, College of Public Health, National Taiwan University, Taiwan for data acquisition. We also thank Health Information and Epidemiology Laboratory of Chang Gung Memorial Hospital, Chia-yi Branch, Taiwan (CLRPG6G0041) for the comments and assistance in data analysis. In addition, this study was supported by a grant from Chia-yi Chang Gung Memorial Hospital, and based on the National Health Insurance Research Database offered by the Bureau of National Health Insurance, Department of Health, Taiwan. We analyzed and interpreted the retrieved data for academic purpose, and therefore the viewpoint is not represented by the Bureau of National Health Insurance, Department of Health, or National Health Research Institutes.

Author contributions

P.H.S and H.J.C. participated in the design of the study, data acquisition, and analysis as well as drafting the manuscript. Y.H.Y and C.J.C. were responsible for the data acquisition and troubleshooting. J.Y.C. and H.K.Y. participated in data analysis, and interpretation. M.S.L. conceived of the study, participated in its design and coordination, and helped to draft the manuscript. All authors read and approved the final manuscript.

Compliance with ethical standards

Conflict of interest

This article is the sole work of the authors. All authors report no conflict of interest.

Ethical review committee statement

This study was approved by the Ethics Institutional Review Board of Chang Gung Memorial Hospital (No. 201600738B1).


  1. 1.
    DiGiovanni CW, Patel A, Calfee R et al (2007) Osteonecrosis in the foot. J Am Acad Orthop Surg 15:208–217CrossRefPubMedGoogle Scholar
  2. 2.
    Lafforgue P (2006) Pathophysiology and natural history of avascular necrosis of bone. Joint Bone Spine 73:500–507. CrossRefPubMedGoogle Scholar
  3. 3.
    Mont MA, Hungerford DS (1995) Non-traumatic avascular necrosis of the femoral head. J Bone Joint Surg Am 77:459–474CrossRefPubMedGoogle Scholar
  4. 4.
    Agarwala S, Jain D, Joshi VR et al (2005) Efficacy of alendronate, a bisphosphonate, in the treatment of AVN of the hip. A prospective open-label study. Rheumatology 44:352–359. CrossRefPubMedGoogle Scholar
  5. 5.
    Wang CJ, Wang FS, Huang CC et al (2005) Treatment for osteonecrosis of the femoral head: comparison of extracorporeal shock waves with core decompression and bone-grafting. J Bone Joint Surg Am 87:2380–2387. CrossRefPubMedGoogle Scholar
  6. 6.
    Gangji V, Hauzeur J-P (2005) Treatment of osteonecrosis of the femoral head with implantation of autologous bone-marrow cells. J Bone Joint Surg Am:106–112Google Scholar
  7. 7.
    Lieberman JR, Conduah A, Urist MR (2004) Treatment of osteonecrosis of the femoral head with core decompression and human bone morphogenetic protein. Clin Orthop Relat Res:139–145Google Scholar
  8. 8.
    Myers TG, Cui Q, Kuskowski M et al (2006) Outcomes of total and unicompartmental knee arthroplasty for secondary and spontaneous osteonecrosis of the knee. J Bone Joint Surg Am 88(Suppl 3):76–82. PubMedGoogle Scholar
  9. 9.
    Woo SB, Hellstein JW, Kalmar JR (2006) Systemic review: bisphosphonates and osteonecrosis of the jaws. Ann Intern Med 144:753–761CrossRefPubMedGoogle Scholar
  10. 10.
    Chao YC, Wang SJ, Chu HC et al (2003) Investigation of alcohol metabolizing enzyme genes in Chinese alcoholics with avascular necrosis of hip joint, pancreatitis and cirrhosis of the liver. Alcohol Alcohol 38:431–436CrossRefPubMedGoogle Scholar
  11. 11.
    Juery P (2007) Avascular necrosis after a steroid injection. CMAJ 176:814. CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Mankin HJ (1992) Nontraumatic necrosis of bone (osteonecrosis). N Engl J Med 326:1473–1479. CrossRefPubMedGoogle Scholar
  13. 13.
    Chang CC, Greenspan A, Gershwin ME (1993) Osteonecrosis: current perspectives on pathogenesis and treatment. Semin Arthritis Rheum 23:47–69CrossRefPubMedGoogle Scholar
  14. 14.
    Chim SM, Tickner J, Chow ST et al (2013) Angiogenic factors in bone local environment. Cytokine Growth Factor Rev 24:297–310. CrossRefPubMedGoogle Scholar
  15. 15.
    Kerachian MA, Harvey EJ, Cournoyer D et al (2006) Avascular necrosis of the femoral head: vascular hypotheses. Endothelium 13:237–244. CrossRefPubMedGoogle Scholar
  16. 16.
    Camporesi EM, Vezzani G, Bosco G et al (2010) Hyperbaric oxygen therapy in femoral head necrosis. J Arthroplast 25:118–123. CrossRefGoogle Scholar
  17. 17.
    Wolberg AS, Rosendaal FR, Weitz JI et al (2015) Venous thrombosis. Nat Rev Dis Primers 1:15006. CrossRefPubMedGoogle Scholar
  18. 18.
    Hill JM, Zalos G, Halcox JP et al (2003) Circulating endothelial progenitor cells, vascular function, and cardiovascular risk. N Engl J Med 348:593–600. CrossRefPubMedGoogle Scholar
  19. 19.
    Deanfield JE, Halcox JP, Rabelink TJ (2007) Endothelial function and dysfunction testing and clinical relevance. Circulation 115:1285–1295PubMedGoogle Scholar
  20. 20.
    Marti CN, Gheorghiade M, Kalogeropoulos AP et al (2012) Endothelial dysfunction, arterial stiffness, and heart failure. J Am Coll Cardiol 60:1455–1469. CrossRefPubMedGoogle Scholar
  21. 21.
    Gresele P, Momi S, Migliacci R (2010) Endothelium, venous thromboembolism and ischaemic cardiovascular events. Thromb Haemost 103:56–61. CrossRefPubMedGoogle Scholar
  22. 22.
    Migliacci R, Becattini C, Pesavento R et al (2007) Endothelial dysfunction in patients with spontaneous venous thromboembolism. Haematologica 92:812–818CrossRefPubMedGoogle Scholar
  23. 23.
    Cheng T-M (2009) Taiwan’s National Health Insurance system: high value for the dollar. In: Okma KGH, Crivelli L (eds) Six countries, six reform models: the health reform experience of Israel, the Netherlands, New Zealand, Singapore, Switzerland and Taiwan. World Scientific, New Jersey, pp 71–204Google Scholar
  24. 24.
    (2010) Venous thromboembolism: reducing the risk of venous thromboembolism (deep vein thrombosis and pulmonary embolism) in patients admitted to hospital. National Clinical Guideline Centre-Acute and Chronic Conditions., LondonGoogle Scholar
  25. 25.
    Rackwitz L, Eden L, Reppenhagen S et al (2012) Stem cell- and growth factor-based regenerative therapies for avascular necrosis of the femoral head. Stem Cell Res Ther 3:7. CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    (2012) Venous thromboembolic diseases: the management of venous thromboembolic diseases and the role of thrombophilia testing. National Clinical Guideline Centre., LondonGoogle Scholar
  27. 27.
    Ceriello A, Quagliaro L, Piconi L et al (2004) Effect of postprandial hypertriglyceridemia and hyperglycemia on circulating adhesion molecules and oxidative stress generation and the possible role of simvastatin treatment. Diabetes 53:701–710CrossRefPubMedGoogle Scholar
  28. 28.
    Brotman DJ, Deitcher SR, Lip GY et al (2004) Virchow’s triad revisited. South Med J 97:213–214. CrossRefPubMedGoogle Scholar
  29. 29.
    Luo RB, Lin T, Zhong HM et al (2014) Evidence for using alendronate to treat adult avascular necrosis of the femoral head: a systematic review. Med Sci Monit 20:2439–2447. CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Gao F, Sun W, Li Z et al (2015) High-energy extracorporeal shock wave for early stage osteonecrosis of the femoral head: a single-center case series. Evid Based Complement Alternat Med 2015:468090. PubMedPubMedCentralGoogle Scholar
  31. 31.
    Wang CJ, Cheng JH, Huang CC et al (2015) Extracorporeal shockwave therapy for avascular necrosis of femoral head. Int J Surg 24:184–187. CrossRefPubMedGoogle Scholar
  32. 32.
    Wassmann S, Laufs U, Baumer AT et al (2001) HMG-CoA reductase inhibitors improve endothelial dysfunction in normocholesterolemic hypertension via reduced production of reactive oxygen species. Hypertension 37:1450–1457CrossRefPubMedGoogle Scholar
  33. 33.
    Ceriello A, Assaloni R, Da Ros R et al (2005) Effect of atorvastatin and irbesartan, alone and in combination, on postprandial endothelial dysfunction, oxidative stress, and inflammation in type 2 diabetic patients. Circulation 111:2518–2524. CrossRefPubMedGoogle Scholar
  34. 34.
    Ferrario CM, Strawn WB (2006) Role of the renin-angiotensin-aldosterone system and proinflammatory mediators in cardiovascular disease. Am J Cardiol 98:121–128. CrossRefPubMedGoogle Scholar
  35. 35.
    Fowkes FJ, Price JF, Fowkes FG (2003) Incidence of diagnosed deep vein thrombosis in the general population: systematic review. Eur J Vasc Endovasc Surg 25:1–5CrossRefPubMedGoogle Scholar
  36. 36.
    Silverstein MD, Heit JA, Mohr DN et al (1998) Trends in the incidence of deep vein thrombosis and pulmonary embolism: a 25-year population-based study. Arch Intern Med 158:585–593CrossRefPubMedGoogle Scholar
  37. 37.
    Schmidt M, Christiansen CF, Horvath-Puho E et al (2011) Non-steroidal anti-inflammatory drug use and risk of venous thromboembolism. J Thromb Haemost 9:1326–1333. CrossRefPubMedGoogle Scholar
  38. 38.
    Ungprasert P, Srivali N, Wijarnpreecha K et al (2015) Non-steroidal anti-inflammatory drugs and risk of venous thromboembolism: a systematic review and meta-analysis. Rheumatology 54:736–742. CrossRefPubMedGoogle Scholar
  39. 39.
    Johannesdottir SA, Horvath-Puho E, Dekkers OM et al (2013) Use of glucocorticoids and risk of venous thromboembolism: a nationwide population-based case-control study. JAMA Intern Med 173:743–752. CrossRefPubMedGoogle Scholar
  40. 40.
    Barritt DW, Jordan SC (1960) Anticoagulant drugs in the treatment of pulmonary embolism. A controlled trial. Lancet 1:1309–1312CrossRefPubMedGoogle Scholar
  41. 41.
    Konstantinides SV, Torbicki A, Agnelli G, et al. (2014) 2014 ESC guidelines on the diagnosis and management of acute pulmonary embolism. Eur Heart J 35:3033-3069, 3069a-3069k.

Copyright information

© SICOT aisbl 2018

Authors and Affiliations

  • Pei-Hsun Sung
    • 1
  • Hsin-Ju Chiang
    • 2
    • 3
  • Yao-Hsu Yang
    • 4
    • 5
    • 6
    • 7
  • John Y. Chiang
    • 8
    • 9
  • Chi-Jen Chen
    • 5
  • Hon-Kan Yip
    • 1
    • 10
    • 11
    • 12
  • Mel S. Lee
    • 13
  1. 1.Division of Cardiology, Department of Internal MedicineKaohsiung Chang Gung Memorial Hospital and Chang Gung University College of MedicineKaohsiung cityTaiwan, Republic of China
  2. 2.Department of Obstetrics and GynecologyKaohsiung Chang Gung Memorial Hospital and Chang Gung University College of MedicineKaohsiungTaiwan
  3. 3.Chung Shan Medical University School of MedicineTaichungTaiwan
  4. 4.Department of Traditional Chinese MedicineChiayi Chang Gung Memorial HospitalChiayiTaiwan
  5. 5.Health Information and Epidemiology Laboratory of Chang Gung Memorial HospitalChiayiTaiwan
  6. 6.School of MedicineChang Gung UniversityTaoyuanTaiwan
  7. 7.Institute of Occupational Medicine and Industrial HygieneNational Taiwan University College of Public HealthTaipeiTaiwan
  8. 8.Department of Computer Science and EngineeringNational Sun Yat-sen UniversityKaohsiungTaiwan
  9. 9.Department of Healthcare Administration and Medical InformaticsKaohsiung Medical UniversityKaohsiungTaiwan
  10. 10.Institute for Translational Research in Biomedicine, Center for Shockwave Medicine and Tissue EngineeringKaohsiung Chang Gung Memorial HospitalKaohsiungTaiwan
  11. 11.Department of Medical ResearchChina Medical University Hospital, China Medical UniversityTaichungTaiwan
  12. 12.Department of NursingAsia UniversityTaichungTaiwan
  13. 13.Department of OrthopedicsKaohsiung Chang Gung Memorial Hospital and Chang Gung University College of MedicineKaohsiung cityTaiwan, Republic of China

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