Background
Osteonecrosis (ON) is often secondary to high-dose, long-term steroids or alcoholism, with primary (idiopathic) ON defined when known secondary etiologies are ruled-out [
1]. The development of primary ON appears to follow a sequence of events initiated by familial or acquired thrombophilia [
2‐
4], venous occlusion causing osseous venous outflow obstruction, leading to increased intraosseous venous pressure, reduced arterial flow, ischemia, bone infarction and eventual joint collapse [
3‐
7]. Venous occlusion is the initiating event in experimental models of ON [
8], and enoxaparin can prevent steroid induced ON [
9]. Heritable or acquired thrombophilia-hypofibrinolysis alone, or augmented by testosterone therapy (TT) [
9,
10] or clomiphene given to raise testosterone (in men) [
10] are thought to lead to thrombotic venous occlusion and thence to osteonecrosis [
3,
5‐
7]. In the current report, our specific aim was to describe the association of familial thrombophilia (Factor V Leiden heterozygosity), acquired thrombophilia (lupus anticoagulant, high anticardiolipin [ACLA] antibody IgM), and hypofibrinolysis (4G4G homozygosity for the plasminogen activator inhibitor −1 mutation) with hip and jaw ON, and the interaction of TT with familial thrombophilia in ON.
Discussion
Arthralgia of the hips [
19] and knees [
20] is a very common complaint in the outpatient setting, often requiring diagnostic imaging studies [
21‐
23]. Primary ON [
6] is not a common cause of arthralgia [
24], and the diagnosis and therapy of ON remains poorly understood by many clinicians. While the prevalence of early-stage (pre-joint collapse) primary ON appears to be relatively low [
25], it is important to diagnose, because, as we have shown, treatment with long-term anticoagulation in patients with familial or acquired thrombophilia-hypofibrinolysis and with primary ON (Ficat [
13] stage I-II, pre-joint collapse) often results in complete symptomatic relief and long-term joint preservation of both knees [
7] and hips [
26], and may ameliorate osteonecrosis of the jaw [
27]. The major clinical barrier to reaching this therapeutic benefit is the lack of awareness of the association between thrombophilia- hypofibrinolysis with primary ON [
1,
3,
14,
28‐
31] which we are addressing in the current report.
There appear to be etiologic associations between factor V Leiden heterozygosity [
3,
28,
32], hyperhomocysteinemia [
33], high ACLA IgM [
34], high Factor VIII [
35], hetero-homozygosity for the T786C eNOS mutation [
14] and primary ON. ON, particularly multifocal, occurs in patients with the antiphospholipid antibody syndrome [
36]. Exogenous testosterone therapy (TT) in patients with familial or acquired thrombophilia-hypofibrinolysis promotes development of ON [
32,
37] of the femoral head [
32] and jaw [
10].
In patients with early stage primary-idiopathic ON, before segmental collapse of hips or knees has occurred (Ficat [
13] stage I or II), with a heritable thrombophilia or hypofibrinolysis, anticoagulation therapy of at least 1 year has been shown to arrest progression of ON and lead to clinically significant pain relief [
7,
26,
38,
39]. We have previously [
26] reported that long term anticoagulation (4 to 16 years) stops progression of idiopathic hip ON associated with familial thrombophilia (5 patients with Factor V Leiden Heterozygotes and 1 patient with resistance to activated protein C). On 4–16 years anticoagulation, 9 hips in these 6 patients, 8 originally Ficat II, 1 Ficat 1 remained unchanged [
26] in contrast to untreated ON Ficat stage II where 50–80% of hips progress to collapse (Ficat III-IV) within 2 years of diagnosis [
40,
41]. Left untreated, ON of the hip inevitably leads to irreversible segmental or total joint collapse [
41] (i.e., Ficat III- IV) requiring joint replacement, typically within 2 years of initial diagnosis [
40‐
45].
There were no clinically significant bleeding episodes [
26]. Long term anticoagulation initiated in Ficat I II idiopathic hip in patients heterozygous for the Factor V Leiden mutation may change the natural history of the disease [
26].
Long term anticoagulation is also effective in thrombophilic patients with early (pre-collapse) primary ON of the knee [
7]. In 6 patients with knee osteonecrosis, all 6 with thrombophilia, 4 with concurrent hypofibrinolysis, we determined prospectively whether anticoagulation with Enoxaparin could prevent collapse, progression to osteoarthritis, ameliorate pain, and restore function [
7]. The 6 patients were treated with Enoxaparin (40–60 mg/day for ≥ 3 months) as mandated by an FDA-approved protocol. In post-Enoxaparin prospective follow-up, patients were reassessed clinically every 4–6 months and X-rayed every year. The 6 patients had follow-up for 15.1, 7.5, 3.9, 2.25, 2, and 1 years [
7]. None progressed to joint collapse or severe osteoarthritis; 4 became and remained asymptomatic at 2, 3.9, 7.5, and 15.1 year follow-up [
7]. Thrombophilic-hypofibrinoytic patients with knee ON treated with Enoxaparin have had no collapse or progression to severe osteoarthritis; and most have had resolution of pain and restoration of full function [
7].
In the jaw, when left untreated, ON leads to progressive tooth loss with failure to heal, jaw bone cavitation, and chronic pain syndromes [
10,
16]. Paralleling the patient in our current report, we have previously reported a very similar case of primary ON of the jaw in a 55 year old Caucasian man [
10]. He also had FVL heterozygosity, and rapid progression of disease 6 months after starting TT gel 50 mg/day, with development of high serum T (963 ng/dl, laboratory upper limit [
46] 800 ng/dl) and high estradiol (50 pg/ml, laboratory UNL 42.6 pg/ml). As in our current patient, the development of jaw ON appeared soon (6 months) after initiation of TT therapy [
10], which then interacted with the patient’s familial and acquired thrombophilia and familial hypofibrinolysis, promoting and worsening the jaw ON [
18,
32]. We have previously reported in a pilot study, that warfarin therapy in patients with both Factor V Leiden heterozygosity and osteonecrosis of the jaw was effective in reducing jaw pain [
27].
In patients with thrombophilia-hypofibrinolysis and thrombotic events on TT, continuation of TT, even with adequate concurrent anticoagulation, leads to repetitive thrombotic events [
47].
When the thrombus-promoting TT therapy is stopped, and anticoagulation started, we speculate that venous outflow is restored, increased venous pressure in the bone is reduced, facilitating increased arterial flow, reducing osseous ischemia [
7,
26]. This is accompanied, as in our current case of jaw ON, by reduction of symptoms, and, in longer term anticoagulation studies, by stopping and reversing osteonecrosis [
7,
26]. It is relevant that experimental models of ON have shown venous occlusion to be the initiating event [
8,
48], and that treatment with enoxaparin in experimental animals has the potential to prevent steroid-associated ON [
48]. Giving TT to mice hetero-and homozygous for the Factor V Leiden mutation [
49,
50] and also having experimental antiphospholipid syndrome [
50], and using animal models of venous occlusion and ON [
8,
48] would allow basic science studies of the relationship of TT and thrombophilia to ON [
18].
Historically, in adults with primary ON of weight bearing joints, the most common treatments include invasive forms of secondary and tertiary prevention, including core decompression [
51] with or without stem cell infusion [
52], vascularized fibular graft [
53], and ultimately total joint replacement [
54]. Hence, new diagnoses of ON, initially made by the radiologist and confirmed by the orthopedic or dental surgeon or clinician [
55], rarely undergo a rigorous workup for thrombophilia or hypofibrinolysis [
5]. This represents a clinically important missed-opportunity as many patients may be inadequately treated for their joint pain [
56] while thrombophilia-hypofibrinolysis, a treatable [
7,
26] causative etiology of primary ON (Ficat Stages I-II), goes unaddressed [
5].
Acknowledgements
Not applicable.