Case report: primary osteonecrosis associated with thrombophilia-hypofibrinolysis and worsened by testosterone therapy

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.

Studies were carried out following a protocol approved by the Institutional Review Board with signed informed consent.

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].

Primary ON is often caused by underlying familial and acquired thrombophilia and hypofibrinolysis, and can be worsened by TT or testosterone-elevating clomiphene. In patients with primary ON, it is important for diagnostic and therapeutic reasons to determine whether thrombophilia-hypofibrinolysis are present, and whether TT is being used. To stop progression of early primary ON at Ficat Stage I or II before joint collapse in patients with thrombophilia-hypofibrinolysis, discontinuing TT is essential and may slow or stop progression of the ON. Initiating anticoagulation may stop progression of ON in thrombophilic patients without joint collapse and without progression to jaw cavitation, thus, avoiding the usual natural history of untreated ON, which is total joint replacement within 2 years of initial diagnosis, and in the jaw, chronic pain syndrome with jaw cavitation and recurrent supra-infection.