Osteonecrosis (ON) of the femoral head is the cause of as many as 10% of total hip replacements done in the United States and Europe.5,23 Osteonecrosis is a well-known complication of femoral neck fractures,4,18,28 and additionally, it is seen in association with several nontraumatic conditions. Nationwide epidemiologic studies on nontraumatic ON of the femoral head have been done in Japan. The incidence rate was estimated to be 24 cases per 1,000,000 inhabitants. The proportion of patients with different risk factors was estimated. Approximately 30–50% of patients used corticosteroids, 25–30% of patients abused alcohol, and 20–40% of patients had idiopathic ON.16 These results are similar to those in the United States reported by Jacobs.18
In the early 1990s, a hypercoagulable state first was suggested as a risk factor for ON.19 Since then, several reports on the occurrence of hemostatic disorders in patients with ON of the femoral head have been published, however, with conflicting results.9–11 Thrombophilia and especially factor V Leiden have been implicated as a potential cause of juvenile idiopathic ON of the hip, Legg-Calvé-Perthes disease, in several studies.1,8,12 However, data from other studies have provided no evidence of a role of factor V Leiden or the prothrombin gene mutation in Legg-Calvé-Perthes disease.14,17,20
Resistance to activated protein C (APC) is the most common genetic defect observed in patients with thrombosis, particularly in those with familial thrombosis.6,22,27,29,31 The genotype of APC resistance has been shown to be based on a mutation in factor V (factor V Leiden).2 In the general population the frequency of factor V Leiden varies between 1% and 10% depending on the geographic location.26 The population in southern Sweden, where this study was done, has a frequency of 10%, which is one of the highest frequencies in the world.30 A mutation in the prothrombin gene, the substitution of G for A at nucleotide position 20210, which results in increased plasma prothrombin levels, also has been reported to be associated with the occurrence of venous thrombosis.25 The frequency of the prothrombin 20210A gene mutation is 1–4% in the general population.7
As stated previously, previous studies have not shown a definite correlation between ON of the femoral head and factor V Leiden or the prothrombin 20210A gene mutation. However, we empirically found a high frequency of factor V Leiden in adult patients with ON of the femoral head. Therefore, this study was done to determine whether nontraumatic ON of the femoral head is associated with an increased frequency of factor V Leiden or the prothrombin 20210A gene mutation, and if so, whether these patients have an increased risk of venous thromboembolic complications.
MATERIALS AND METHODS
The local ethics committee approved the study design and written informed consent was obtained from all participants.
In the diagnosis register at our department, 137 patients were identified with nontraumatic ON of the femoral head, treated between 1987 and 2001. Of these 137 patients, 18 were deceased when this study was initiated in 1999. A letter was sent to 119 patients inviting them to participate in the study. Sixty-eight patients accepted. Among the remaining 51 patients, 18 patients did not participate because of poor general health and 33 patients did not participate because they had moved to another area, or for unspecified reasons.
Records from all patients diagnosed with nontraumatic ON of the hip were reviewed and patients included in the study had an interview, clinical examination, and blood sampling. A history on the use of corticosteroid medication, alcohol consumption, exposure to hyperbaric conditions, known hemoglobinopathies, trauma, deep venous thrombosis and pulmonary embolism was taken for each patient by interview. An etiologic factor for ON was identified for each patient. To be classified as having corticosteroid-induced ON, patients had to have taken continuous corticosteroid medication for at least 2 months before experiencing symptoms from the hip. To be classified as having alcohol-induced ON, patients had to have an estimated regular alcohol consumption of more than 400 mL per week before experiencing symptoms from the hip. In patients with no obvious underlying etiologic factor the disease was classified as idiopathic.
Factor V Leiden and the prothrombin 20210A gene mutation were identified as described previously.25,31
Two hundred eighty-two healthy volunteers from southern Sweden were used as the control group for estimation of the frequency of factor V Leiden and the prothrombin 20210A gene mutation in the general population.15,30
To verify the diagnosis of ON, radiographs and MRI scans, if available, were reviewed by two radiologists. Radiographic findings were classified according to the Pittsburgh classification, proposed by Plakseychuk et al24 Consensus on the radiologic diagnosis between the two examiners was set as inclusion criteria for the study. In patients who had several radiologic examinations of the hip or pelvis or both the first examination showing signs of ON was used for classification.
The odds ratios and 95% confidence intervals (CI) for the presence of genetic aberrations and thromboembolic events were calculated according to Kirkwood.21
Sixty-eight adult patients (29 males, 39 females) with ON of the femoral head were included in the study. The mean age at diagnosis was 62 years (SD, 13 years) compared with the mean age of 64 years (SD, 16 years) among the 69 patients (23 males, 46 females) not participating. Based on data from the interview and clinical examination, 35 patients were diagnosed with idiopathic ON, 23 patients were diagnosed with corticosteroid-induced ON, and five patients were diagnosed with alcohol-induced ON (Table 1). Indications for corticosteroid therapy in patients with corticosteroid-induced ON are given in Table 2. At the interview and when reviewing the patient records, five patients had evidence of trauma before having ON develop, although they had been diagnosed with nontraumatic ON of the femoral head. None of the patients with traumatic ON of the femoral head had bilateral disease. Bilateral disease, however, was observed in five patients with corticosteroid-induced ON, in five patients with alcohol-induced ON, and in 11 patients with idiopathic ON.
In the current study, 11 of 63 patients with nontraumatic ON (17%) had factor V Leiden or the prothrombin 20210A gene mutation or both (Table 1). All of these patients were heterozygous for the gene mutations. The frequencies of factor V Leiden and the prothrombin 20210A gene mutation were significantly higher in patients with idiopathic ON than in control subjects or other etiologic groups. Among the 35 patients with idiopathic ON 11 gene mutations were seen in 10 patients (29%): eight factor V Leiden and three prothrombin 20210A gene mutations. This is more than twice the frequency found among 282 healthy volunteers with 32 factor V Leiden and five prothrombin 20210A gene mutations seen in 37 patients (13%) (odds ratio, 2.7; 95% CI, 1.2–5.8).15,30 Factor V Leiden and the prothrombin 20210A gene mutation also were significantly more common in patients with idiopathic ON compared with patients with corticosteroid-induced or alcohol-induced ON (odds ratio, 10.8; 95% CI, 1.4–84). Therefore, all mutations except one were seen in the 35 patients with idiopathic ON. The exception was one patient with factor V Leiden among the 23 patients with corticosteroid-induced ON.
The frequency of factor V Leiden and the prothrombin 20210A mutation among the patients with ON secondary to alcohol abuse or corticosteroid medication was not significantly different from the frequency seen among the 282 healthy volunteers (odds ratio, 4.1; 95% CI, 0.5–30.9.)
The clinical diagnosis was confirmed in all patients by review of plain radiographs of the hip and pelvis, which were available for all patients included in the study, and MRI scans, which were available for nine patients. No obvious connection between gene mutations or etiologic factors and radiologic classification of the ON lesions was observed (Table 3).
Four of the 11 patients (36%) with a gene mutation had a thromboembolic event compared with four of 52 patients (8%) without a gene mutation (Table 4). Among the 63 patients with nontraumatic ON of the femoral head, 10 episodes of thromboembolic complications (seven events of deep venous thrombosis and three events of pulmonary embolism) occurred in eight patients. Six of the 35 patients in the idiopathic group (17%) (95% CI, 8–31) had a history of thromboembolic events when they were interviewed at a mean age of 64 years. This frequency is higher than the accumulated rate of 4% (95% CI, 2.1–4.4) reported by Hansson et al13 in a population of Swedish men who were 67 years old. Although the patients with idiopathic ON only comprised approximately ½ of the patients in the study, eight of 10 thromboembolic events occurred in six patients with idiopathic ON. Furthermore, four of these six patients had a gene mutation compared with none of the patients with thromboembolic events in the corticosteroid and alcohol group (Table 4).
In the early 1990s, a hypercoagulable state first was suggested as a risk factor for ON.19 Since then, several reports on the occurrence of hemostatic disorders in adults with ON of the femoral head 9–11 and in children with Legg-Calvé-Perthes disease have been published showing contradictory results.1,8,12,14,17,20 Based on our empirical observation of a high frequency of factor V Leiden gene mutations among adult patients with ON of the femoral head, this study was done to determine whether ON of the femoral head in adults is associated with factor V Leiden or the prothrombin 20210A gene mutation. We also investigated whether patients with adult onset of ON of the femoral head have a higher frequency of thromboembolic events compared with the general population.
Of the 137 identified patients with nontraumatic ON of the femoral head in our diagnosis register, 69 patients could not or did not want to participate in the study. Among the nonparticipants, 18 patients were deceased, 18 patients had poor general health, and 33 patients did not want to participate because they had moved to another area or for unspecified reasons. Mean age, distribution of etiologic factors, and gender distribution among patients included in the study and among nonparticipants were comparable. However, it is not possible to exclude other, unknown biases based on the fact that only approximately ½ of the eligible patients participated in the study.
The distribution of etiologic factors varies among studies.3,16,18
Although the association between corticosteroid medication and ON of the femoral head generally is accepted, it is difficult to define exact criteria for corticosteroid-induced ON of the femoral head. In this study all patients with corticosteroid-induced ON had been taking continuous corticosteroid medication for more than 2 months. Two patients had taken low-dose corticosteroid medication for less than 7 days because of allergic reactions. These two patients were assigned to the idiopathic group and did not have a gene mutation. Based on these findings and because the exact dose of corticosteroid could not be determined from the interview and review of the charts, the criteria for corticosteroid-induced ON was set as greater than 2 months of continuous corticosteroid use.
Alcohol-induced ON may be underestimated because of the difficulties identifying patients who abuse alcohol. The criteria for alcohol-induced ON has been assigned to 400 mL per week based on the data by Hirota et al,16 who reported a clear increase in risk of having ON of the femoral head for alcohol consumption greater than 400 mL per week.
Concerning the radiologic examinations, interobserver and intraobserver differences were not evaluated in this study because the radiologic diagnosis of ON of the femoral head is a routine procedure and because sufficient radiologic material was available for each participant, often showing the evolution of the ON lesions during several months or years.
Thrombophilia has been suggested as a cause of nontraumatic ON of the femoral head in several studies, none of which has shown a significant increase of factor V Leiden or the prothrombin 20210A gene mutation.9–11 Glueck et al 10,11 showed evidence for different types of inherited thrombophilia and hypofibrinolysis in 83% of patients with idiopathic ON of the hip. However, they 9,11 did not find a significantly increased incidence of resistance to activated protein C or the prothrombin gene mutation in patients with ON of the femoral head.
In contrast to our findings, Glueck et al 9 reported that the frequency of coagulation disorders did not differ significantly between patients with idiopathic and steroid-induced ON. However, the findings in these studies should be judged with caution because they are based on few patients with mutations in the secondary groups.
A possible explanation for the difference between our study and previous studies might be the small numbers of patients included in previous studies. Furthermore, our study was based on consecutive cases from a defined geographic area, whereas the studies of Glueck et al 9–11 were based on a cohort of referred patients.
In addition, variations in the overall frequency of factor V Leiden or the prothrombin 20210A gene mutation with geographic localization may play a significant role. In populations with a low background prevalence of factor V Leiden or the prothrombin 20210A gene mutation, these genetic aberrations probably play a secondary role as causes of ON compared with other, more prevalent, etiologic factors. However, in populations with a higher prevalence of factor V Leiden and the prothrombin 20210A gene mutation, the impact of these mutations as etiologic factors may increase in proportion to their prevalence.
Several studies have shown a significant increase of deep venous thrombosis among patients with factor V Leiden and the prothrombin 20210A gene mutation.15,25,29,30 Therefore, factor V Leiden and the prothrombin 20210A gene mutation might, because of the associated hypercoagulable state, increase the risk of thrombosis in the small vessels of the femoral head, which subsequently leads to partial or total infarction. This is supported by our findings of an increased frequency of thromboembolic events among patients with idiopathic ON, indicating a hypercoagulable state in these patients.
This is, to our knowledge, the first study to show a significant association between idiopathic ON of the femoral head in adults and the presence of factor V Leiden or the prothrombin 20210A gene mutation or both. However, the result of this study applies to a population with a high frequency of factor V Leiden gene mutation and may not apply to populations with a low frequency of the mutation. We also found that patients with idiopathic ON of the femoral head had an increased frequency of thromboembolic events compared with other etiologic groups and with the frequency in the general population.
We thank Dr. Inga Redlund-Johnell for reviewing patient radiographs.
1. Arruda VR, Belangero WD, Ozelo MC, et al. Inherited risk factors for thrombophilia among children with Legg-Calvé-Perthes disease. J Pediatr Orthop
2. Bertina RM, Koeleman BPC, Koster T, et al. Mutation in blood coagulation factor V associated with resistance to activated protein C. Nature
3. Castro FP Jr, Harris MB. Differences in age, laterality, and Steinberg stage at initial presentation in patients with steroid-induced, alcohol-induced, and idiopathic femoral head osteonecrosis. J Arthroplasty
4. Coleman SS, Compere CL. Femoral neck fractures: Pathogenesis of avascular necrosis, nonunion and late degenerative changes. Clin Orthop
5. Coventry MB, Beckenbaugh RD, Nolan DR, et al. 2012 total hip arthroplasties: A study of postoperative course and early complications. J Bone Joint Surg
6. Dahlbäck B, Carlsson M, Svensson PJ. Familial thrombophilia due to a previously unrecognized mechanism characterized by poor anticoagulant response to activated protein C: Prediction of a cofactor to activated protein C. Proc Natl Acad Sci USA
7. Emmerich J, Rosendaal FR, Cattaneo M, et al. Combined effect of factor V Leiden and prothrombin 20210A on the risk of venous thromboembolism: Pooled analysis of 8 case-control studies including 2310 cases and 3204 controls. Thromb Haemost
8. Glueck CJ, Brandt G, Gruppo R, et al. Resistance to activated protein C and Legg-Perthes disease. Clin Orthop
9. Glueck CJ, Freiberg RA, Fontaine RN, et al. Hypofibrinolysis, thrombophilia, osteonecrosis. Clin Orthop
10. Glueck CJ, Freiberg R, Gruppo R, et al. Thrombophilia and Hypofibrinolysis: Reversible Pathogenetic Etiologies of Osteonecrosis. In Urbaniak JR, Jones Jr JP (eds). Osteonecrosis: Etiology Diagnosis and Treatment. Rosemont, IL, American Academy of Orthopaedic Surgeons 105-110, 1997.
11. Glueck CJ, Freiberg R, Tracy T, et al. Thrombophilia and hypofibrinolysis: Pathophysiologies of osteonecrosis. Clin Orthop
12. Gruppo R, Glueck CJ, Wall E, et al. Legg-Perthes disease in three siblings, two heterozygous and one homozygous for the factor V Leiden mutation. J Pediatr
13. Hansson PO, Welin L, Tibblin G, et al. Deep vein thrombosis and pulmonary embolism in the general population: ‘The study of men born in 1913’. Arch Intern Med
14. Hayek S, Kenet G, Lubetsky A, et al. Does thrombophilia play an aetiological role in Legg-Calve-Perthes disease? J Bone Joint Surg
15. Hillarp A, Zöller B, Svensson PJ, et al. The 20210A allele of the prothrombin gene is a common risk factor among Swedish outpatients with verified deep venous thrombosis. Thromb Haemost
16. Hirota Y, Hotokebuchi T, Sugioka Y. Idiopathic Osteonecrosis of the Femoral Head: Nationwide Epidemiologic Studies in Japan. In Urbaniak JR, Jones Jr JP (eds). Osteonecrosis: Etiology Diagnosis and Treatment. Rosemont, IL, American Academy of Orthopaedic Surgeons 51-58, 1997.
17. Hresko MT, McDougall PA, Gorlin JB, et al. Prospective reevaluation of the association between thrombotic diathesis and Legg-Perthes disease. J Bone Joint Surg
18. Jacobs B. Epidemiology of traumatic and nontraumatic osteonecrosis. Clin Orthop
19. Jones JP Jr. Intravascular coagulation and osteonecrosis. Clin Orthop
20. Kealey WDC, Mayne EE, McDonald W, et al. The role of coagulation abnormalities in the development of Pertheś disease. J Bone Joint Surg
21. Kirkwood BR. Cohort and Case-Control Studies. In Kirkwood BR (ed). Essentials of Medical Statistics. Oxford, Blackwell Scientific Publications 177-183, 1988.
22. Koster T, Rosendaal FR, de Ronde H, et al. Venous thrombosis due to poor anticoagulant response to activated protein C: Leiden thrombophilia study. Lancet
23. Mankin HJ. Nontraumatic necrosis of bone (osteonecrosis). N Engl J Med
24. Plakseychuk AY, Shah M, Varitimidis SE, et al. Classification of osteonecrosis of the femoral head: Reliability, reproducibility, and prognostic value. Clin Orthop
25. Poort SR, Rosendaal FR, Reitsma PH, et al. A common genetic variation in the 3-untranslated region of the prothrombin gene is associated with elevated plasma prothrombin levels and an increase in venous thrombosis. Blood
26. Rees DC, Cox M, Clegg JB. World distribution of factor V Leiden. Lancet
27. Rosendaal FR. Risk factors for venous thrombosis: Prevalence, risk, and interaction. Semin Hematol
28. Sevitt S. Avascular necrosis and revascularisation of the femoral head after intracapsular fractures: A combined arteriographic and histological necropsy study. J Bone Joint Surg
29. Svensson PJ, Dahlbäck B. Resistance to activated protein C as a basis for venous thrombosis. N Engl J Med
30. Svensson PJ, Zöller B, Mattiasson I, et al. The factor VR506Q mutation causing APC resistance is highly prevalent amongst unselected outpatients with clinically suspected deep venous thrombosis. J Intern Med
© 2004 Lippincott Williams & Wilkins, Inc.
31. Zöller B, Svensson PJ, He X, et al. Identification of the same factor V gene mutation in 47 out of 50 thrombosis-prone families with inherited resistance to activated protein C. J Clin Invest