Introduction

Spontaneous osteonecrosis of the femoral condyles has been recognised since 1968, when it was first described by Ahlbäck et al. [2]. The knee is the second most common location for osteonecrosis, although osteonecrosis is 10 times more common in the femoral head [20]. Osteonecrosis of the knee is most commonly found in the medial femoral condyle, but it can also occur in the lateral femoral condyle and in the tibia plateau [6]. Osteonecrosis of the knee is the cause of 1% of knee arthroplasties performed in Sweden [24].

Traditionally, osteonecrosis of the knee has been divided into spontaneous or primary, which occurs in the elderly patient without associated risk factors, and atraumatic or secondary osteonecrosis seen predominantly in the young patient in association with corticosteroid medication or alcohol abuse [19].

In the early 1990s, disturbed blood supply and a hypercoagulable state were suggested as risk factors for osteonecrosis [14]. Although the pathogenesis of osteonecrosis of the knee remains unknown, an impairment of the blood supply to the knee has been suggested as a potential cause, possibly due to injury to the vessel wall as well as venous occlusion [27].

At present, it is thought that patients with idiopathic osteonecrosis of the hip most likely have some type of coagulation abnormality that has not been identified [16]. Thrombophilia, an increased tendency to form thrombi, commonly caused by factor V Leiden and the prothrombin 20210A gene mutation, has been implicated as a potential pathogenic factor of non-traumatic osteonecrosis of the hip [9]. Resistance to activated protein C (APC) is the most common genetic defect observed in patients with thrombosis, particularly in those with familial thrombosis [25]. The genotype of APC resistance has been shown to be based on the mutation of Arg to Gln in factor V at position 506 (factor V Leiden) [5]. The risk of thrombosis due to APC resistance is increased approximately 5- to 10-fold in the heterozygous state, and about 50- to 100-fold in the homozygous state [29]. In the general population, the frequency of factor V Leiden varies between 1% and 10% depending on the geographic location [23]. The population in southern Sweden, where this study was performed, has a frequency of 10%, which is one of the highest frequencies in the world [26].

A mutation in the prothrombin gene, the substitution of G for A at nucleotide position 20210, which results in increased plasma prothrombin levels, has also been reported to be associated with the occurrence of venous thrombosis [22]. The frequency of the prothrombin 20210A gene mutation is 6%–12% in patients with deep venous thrombosis compared with 1%–4% in the general population [7].

As thrombophilia has been suggested as a cause of osteonecrosis of the hip, abnormalities in the thrombotic pathway are a likely cause of osteonecrosis of the knee. However, to our knowledge, no studies have provided evidence of a role of thrombophilia in this condition. The current study investigated the association of factor V Leiden and the prothrombin 20210A gene mutation with osteonecrosis of the knee.

Patients and methods

A series of consecutive patients with osteonecrosis of the knee diagnosed between 1998 and 2002 at our institute and without a history of knee trauma or surgery to the knee prior to their osteonecrosis were prospectively enrolled in this study. Forty-four patients were invited to participate in the study: 38 enrolled, and 6 declined. At diagnosis, all patients underwent a complete clinical and radiographic evaluation and blood sampling. In the clinical evaluation, special attention was paid to corticosteroid medication, alcohol abuse, and history of thromboembolic events. An aetiological factor for the osteonecrosis was identified for each patient. To be classified as having a corticosteroid-induced osteonecrosis, patients had to have been taking continuous corticosteroid medication of more than 20 mg/day of prednisone for a minimum of 2 months [9] prior to symptoms arising in the knee. To be classified as having an alcohol-induced osteonecrosis, patients had to have had an estimated regular alcohol consumption of more than 400 ml per week [12] prior to symptoms arising in the knee. In patients with no obvious underlying aetiology, the disease was classified as primary osteonecrosis.

To verify the diagnosis of osteonecrosis and to discover asymptomatic osteonecrosis in the contralateral knee, radiographs and MRI scans were reviewed by two radiologists for findings in accordance with osteonecrosis of the knee. Both knees were examined by plain X-rays in all patients. MRI scans were available for 21 patients and bilateral MRI for 15 of them. The location of the osteonecrosis was noted as well as other pathological findings.

Factor V Leiden and the prothrombin 20210A gene mutation were identified as previously described [22, 29]. The control group comprised 282 healthy volunteers, 180 men and 102 women, mean age 59±12 years (range 34–86 years), with no history of thrombosis and from the same geographic area as the study subjects [11, 26]. The control group was used for estimation of the frequency of factor V Leiden and the prothrombin 20210A gene mutation in the general population.

Furthermore, analysis of the blood group and a basic coagulation profile including haemoglobin concentration, platelets, prothrombin time and activated partial thromboplastin time were done.

The local Ethics Committee approved the study design, and written informed consent was obtained from all patients.

Statistical analysis

The odds ratios and 95% confidence intervals (CI) for the genetic aberrations were calculated according to Kirkwood [15].

Results

Thirty-eight patients (13 men and 25 women) with osteonecrosis of the knee were included in the study. Mean age at diagnosis was 67 years (range 26–88 years), lower (p =0.057; t-test) in men (61 years, range 26–78 years) than in women (70 years, range 38–88 years). Based on data from interviews and clinical examinations, the 38 patients were assigned to aetiological groups. Corticosteroid-induced osteonecrosis was found in 1 man and 3 women treated for inflammatory bowel disease, asthma, rheumatoid arthritis and polymyalgia rheumatica. The mean age in these four patients was 51 years (range 38–68 years). Two men, aged 58 and 59 years, were diagnosed with alcohol-induced osteonecrosis. In 32 patients, 10 men and 22 women, mean age 70 years (range 26–88 years), no aetiological factor could be found, and they were diagnosed with primary osteonecrosis.

A total of 52 osteonecrotic lesions were found in the 38 patients (Table 1). In primary osteonecrosis the majority of osteonecrotic lesions were seen in the medial femoral compartment, whereas corticosteroid-induced lesions showed multiple condylar involvement affecting the femoral and tibial condyles as well as the patella. Five patients had bilateral osteonecrosis of the knee, verified by MRI, and data on aetiology, multifocality, symptomatology and coagulation disorders for these patients are given in Table 2. Two patients, one with primary and one with corticosteroid-induced osteonecrosis of the knee, had been diagnosed with additional non-traumatic osteonecrosis of the femoral head.

Table 1 Location and aetiology of osteonecrosis in the knee: number of lesions
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Table 2 Bilateral osteonecrosis of the knee
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In the current study 12 of 38 patients (32%) had factor V Leiden or the prothrombin 20210A gene mutation or both (Table 3). All patients were heterozygous for the gene mutations. This frequency is significantly higher than the frequency found among 282 healthy volunteers from the same geographic area, with 32 factor V Leiden and 5 prothrombin 20210A gene mutations in 37 volunteers [11, 26] (odds ratio 3.1, 95%CI 1.4–6.6).

Table 3 Aetiologic groups and occurrence of factor V Leiden and prothrombin 20210A gene mutation: number of patients (men; women)
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Haemoglobin concentration, platelets, prothrombin time and activated partial thromboplastin time were within normal limits in all patients. The frequency of different blood groups among the 38 patients with osteonecrosis did not differ from the general population.

Five patients in the study had a history of deep venous thrombosis or pulmonary embolism, and one of them had factor V Leiden, while one had both gene mutations. The latter patient suffered a deep venous thrombosis after a knee arthroplasty, whereas thromboembolic events in the other four patients were not related to surgery.

Discussion

We evaluated the association between factor V Leiden and the prothrombin 20210A gene mutation and osteonecrosis of the knee in 38 consecutive patients. Results of the current study showed a significant increase in the prevalence of factor V Leiden and the prothrombin 20210A gene mutation among patients with osteonecrosis of the knee in comparison with healthy volunteers.

Since our material comprised consecutive patients diagnosed with osteonecrosis of the knee, no selection bias is thought to exist, and the material represents a true sample of patients with osteonecrosis of the knee in a southern Swedish population.

The distribution of aetiological factors varies among different studies [1, 19, 20, 21]. Our material showed a high frequency of primary osteonecrosis of the knee compared with very few secondary osteonecroses. These results are comparable to the findings of Aglietti et al. [1] reporting on a series of 91 patients with idiopathic osteonecrosis of the knee, average age 66 years. In this series 3 patients had been on steroid medication, and 1 patient had been diagnosed with alcohol abuse. However, in a study by Mont et al. [19], including only patients less than 55 years of age, 123 of 136 patients (90%) with a mean age of 36 years had a history of corticosteroid medication. In a second study, comprising 30 patients operated on with total knee arthroplasty for osteonecrosis and with a mean age of 54 years, Mont et al. [21] found 22 corticosteroid-induced osteonecroses and 8 primary osteonecroses.

It is possible that we have underestimated the incidence of alcohol-induced osteonecrosis due to the difficulties of identifying alcohol abuse.

Although the pathogenesis of osteonecrosis is unknown, vascular insufficiency with damage to the microcirculation resulting in bone ischaemia and subsequent necrosis has been suggested as a pathogenic factor. This vascular insufficiency might be caused by microfractures [17, 28] of osteoporotic subchondral bone, leading to the passage of fluid through the articular cartilage into the subchondral bone and to increased bone marrow pressure and deterioration of the microcirculation, or by a venous occlusion induced by a hypercoagulable state. A hypercoagulable state has been suggested as a factor behind osteonecrosis of the hip in adults [9] and in children in some [4, 8] but not all studies [10, 13]. No previous studies have provided evidence of a hypercoagulable state in osteonecrosis of the knee. However, increased intraosseous pressure and venous stasis, a probable result of disturbed microcirculation, have been found by Uchio et al. [27]. They used venography to show venous stasis in the bone marrow and increased intraosseous pressure within the medullary canal, indicating an injury to a vessel or venous occlusion, but they were not able to find actual thrombi. Venous occlusion has also been suggested as a cause of osteonecrosis in general [18] and of osteonecrosis of the knee by Arnoldi et al. [3], who suggested that obstruction of venous drainage could lead to increased intraosseous pressure and consequent necrosis of the bone. In addition, several studies have shown a hypercoagulable state and a significant increase of venous thrombosis among patients with factor V Leiden and the prothrombin 20210A gene mutation [11, 22, 25, 26]. The hypercoagulable state induced by these gene mutations might increase the risk of thrombosis in the small vessels around the knee or in the bone marrow.

This is, to our knowledge, the first study to show a significant association between osteonecrosis of the knee and the presence of factor V Leiden and the prothrombin 20210A gene mutation or both. In a population with a high prevalence of these mutations, our results suggest that these genetic aberrations might outnumber previously accepted aetiological factors such as corticosteroid medication or alcohol abuse as causative agents for osteonecrosis of the knee.