warfarin and Osteonecrosis

Osteonecrosis is a relatively common comorbidity in systemic lupus erythematosus (SLE), but avascular necrosis in multiple sites is unusual. Multifocal osteonecrosis is defined as osteonecrotic lesions affecting three or more separate anatomic sites. We report a case of a 24-year-old woman diagnosed with SLE when she presented with mucocutaneous, haematological and mild renal manifestations. Initially, she was treated with prednisone and hydroxychloroquine and her condition remained stable. Two years later, she developed severe bilateral pretibial ulcers intractable to immunosuppressive therapy and broad-spectrum antibiotics. MRI of both legs disclosed osteonecrosis of the distal tibia, proximal tibia, distal fibula and talus bilaterally. She had elevated anticardiolipin antibodies for which she was treated with chronic anticoagulation resulting in complete healing of the leg ulcers and no further episodes of osteonecrosis. In addition to this case, we review the demographic, clinical and pharmacological features of 14 cases reported in the literature.

Topics: Adult; Antibodies, Anticardiolipin; Anticoagulants; Antiphospholipid Syndrome; Female; Fibula; Humans; Leg Ulcer; Lupus Erythematosus, Systemic; Magnetic Resonance Imaging; Osteonecrosis; Talus; Tibia; Warfarin; Young Adult

We describe that high-dose methylprednisolone (20 mg/kg) can induce multifocal osteonecrosis (ON) in conjunction with thrombocytopenia, hypofibrinogenemia, and hyperlipemia. Detailed clinical and laboratory evaluations of coagulation system are recommended in those patients who develop manifestations of an abnormal lipid metabolism shortly after high-dose corticosteroid therapy. Moreover, we investigated the effects of the combination treatment with an anticoagulant (warfarin) plus a lipid-lowering agent (probucol) on prevention of steroid-induced osteonecrosis (ON) in this animal model. The incidence of ON in warfarin plus probucol (5%) was significantly lower than that observed in the control group (70%) (p <0.0001). Our results experimentally showed that the combined use of an anticoagulant and a lipid-lowering agent helps prevent steroid-induced ON in rabbits.

Topics: Animals; Anticholesteremic Agents; Anticoagulants; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Therapy, Combination; Glucocorticoids; Humans; Hyperlipidemias; Methylprednisolone; Osteonecrosis; Probucol; Rabbits; Thrombocytopenia; Warfarin

In a preliminary pilot study of 30 treatments in 26 patients with osteonecrosis of the jaws and chronic disabling facial pain, our specific aim was to determine whether, to what degree, and how safely therapy of hypofibrinolysis and thrombophilia would ameliorate the chronic pain associated with osteonecrosis of the mandible and maxilla.. Thrombophilia was treated with Coumadin (DuPont) in 10 patients; hypofibrinolysis was treated with Winstrol (Sanofi-Winthrop) in 20 patients, including 4 who had mixed thrombophilia and hypofibrinolysis and had previously been treated with Coumadin. The initial treatment period was targeted to be 4 months. Each patient was asked to keep a daily written pain-relief numeric rating score and side-effects diary and to provide a summary pain-relief numeric rating score and side effects compilation for the total treatment period.. There were 4 men and 22 women in the study group; their mean age was 49 +/- 11 years. The mean onset of their osteonecrosis pain was at age 45 +/- 12 years, and the mean duration of their facial pain prior to therapy was 4.5 +/- 4.2 years. Ten patients had one or more thrombophilic traits (there were two patients with protein C deficiency, five with resistance to activated protein C and/or the mutant Factor V Leiden gene, and four with high anticardiolipin antibodies). The 10 patients who were thrombophilic were treated with Coumadin (the international normalized ratio was targeted to 2.5-3.0) for 22 +/- 9 weeks. By self-reported pain-relief numeric rating scores, 6 of the 10 patients with thrombophilia (60%) had > or = 40% pain relief, 2 (20%) had no change, and 2 (20%) had increased pain (30% and 80% worse). Nine of the 10 patients with thrombophilia (90%) had no Coumadin-related side effects; 1 patient (10%) stopped Coumadin therapy (after 28 weeks) because of nosebleeds. Winstrol (6 mg per day) was used for 16 +/- 9 weeks in 20 patients with hypofibrinolysis, some of whom had one or more hypofibrinolytic traits (10 had high levels of plasminogen activator/inhibitor activity, usually accompanied by low stimulated tissue plasminogen activator activity; 13 had high Lp[a] lipoprotein). Of these 20 patients with hypofibrinolysis, 9 patients (45%) had > or = 40% pain relief, 3 patients (15%) had 20% to 30% relief, 5 patients (25%) had no improvement, and 3 patients (15%) had increased pain (30% worse, 60% worse, and 70% worse). Six of the 20 patients with hypofibrinolysis (30%) had no Winstrol-related side effects, while 14 (70%) had side effects that could be attributed to Winstrol, including weight gain, peripheral edema, increased facial and body hair, and acne--all of which were reversed within 6 weeks of stopping Winstrol therapy.. We postulate that thrombophilia and hypofibrinolysis lead to impaired venous circulation and venous hypertension of the mandible/maxilla with subsequent development of osteonecrosis and chronic facial pain. In many patients, facial pain can be ameliorated by treating the pathogenetic coagulation defects with Coumadin or Winstrol. Large, double-blind, placebo-controlled crossover studies will be required in the future to validate these preliminary results and to determine whether pain relief with Coumadin or Winstrol justifies the risks and side effects associated with these medications, especially for long-term use, in osteonecrosis of the jaws.

Topics: Adult; Aged; Anabolic Agents; Anticoagulants; Blood Coagulation Disorders; Facial Pain; Female; Fibrinolysis; Humans; Jaw Diseases; Male; Middle Aged; Osteonecrosis; Pilot Projects; Stanozolol; Thrombophilia; Warfarin

Both abnormal lipid metabolisms and coagulopathy have been suggested to be associated with the development of steroid-induced osteonecrosis (ON). We examined plasma risk factors for development of steroid-induced ON in rabbits after prophylaxis with a lipid-lowering agent and/or an anticoagulant.. Seventy adult male rabbits were injected intramuscularly once with 20 mg/kg methylprednisolone acetate. Fifty-five rabbits received prophylaxis with probucol (a lipid-lowering agent; n = 20) or warfarin (an anticoagulant; n = 14) or both (n = 21). Probucol and warfarin were administered beginning 1 to 2 weeks prior to steroid injection. Two weeks after steroid injection, the bilateral femora and humeri were examined histopathologically for the presence of ON. Based on a logistic regression model, laboratory variables before steroid injection were assessed to determine whether they demonstrated any association with the risk of ON.. Twenty-one rabbits developed ON. In the univariate analyses, significant positive associations were observed between plasma concentrations of triglyceride and low-density lipoprotein and the risk of development of ON. In the multivariate model, only the plasma triglyceride level suggested a positive association. Even after adjusting for probucol and warfarin use, the plasma triglyceride level was still suggested to be a predictor for development of ON. Rabbits with higher baseline triglyceride levels had a more pronounced triglyceride increase in their response to steroids.. Our study suggests that, after prophylaxis with probucol and/or warfarin, plasma triglyceride level is associated with the development of steroid-induced ON in rabbits.

Topics: Adrenal Cortex Hormones; Animals; Anticholesteremic Agents; Anticoagulants; Biomarkers; Chemoprevention; Disease Models, Animal; Fatty Acids, Nonesterified; Lipoproteins, LDL; Male; Methylprednisolone; Methylprednisolone Acetate; Odds Ratio; Osteonecrosis; Probucol; Rabbits; Risk Factors; Triglycerides; Warfarin

To investigate the effects of combination treatment with an anticoagulant (warfarin) plus a lipid-lowering agent (probucol) on the prevention of steroid-induced osteonecrosis (ON) in rabbits.. Adult male Japanese white rabbits were injected once intramuscularly with 20 mg/kg of methylprednisolone acetate into the right gluteus medius muscle. The rabbits were then divided into 4 groups and treated as follows: one group received warfarin plus probucol (WP; n = 25), one received probucol alone (PA; n = 30), one received warfarin alone (WA; n = 26), and one received no treatment (nonprophylactic [NP]; n = 20). Two weeks after the steroid injection, the femora and humeri were examined histopathologically for the presence of ON. The sizes of the bone marrow fat cells were examined morphologically. Hematologic examinations were performed before and after the steroid injection.. The incidence of ON in the WP group (5%) was significantly lower than that observed in the NP group (70%). While the incidence rates of ON in the PA (38%) and WA (33%) groups were also significantly lower than that in the NP group, they were significantly higher than that observed in the WP group. The sizes of the bone marrow fat cells in both the WP (53.5 +/- 4.1 microm) and the PA (52.0 +/- 5.0 microm) groups were significantly smaller than those in the NP group (60.0 +/- 4.0 microm). We also observed a prolongation of the prothrombin time and a reduction in the plasma lipid levels in the WP group during the study.. This study experimentally confirmed that the combined use of an anticoagulant and a lipid-lowering agent helps prevent steroid-induced ON in rabbits.

Topics: Adipocytes; Animals; Anticholesteremic Agents; Anticoagulants; Bone Marrow; Drug Therapy, Combination; Glucocorticoids; Injections, Intramuscular; Lipids; Male; Methylprednisolone; Osteonecrosis; Probucol; Rabbits; Warfarin

We succeeded in developing a novel rabbit model of nonsteroid and nontraumatic osteonecrosis (ON) by use of a single- and low-dose lipopolysaccharide (LPS) injection. This model is simple and highly reproducible for the frequent development of multifocal and widespread ON lesions. Male adult Japanese white rabbits intravenously injected with a single injection of 10 microg/kg body weight of LPS were histopathologically examined in the early phase (3 [n = 3], 5 [n = 3], and 24 h [n = 3]) and at 4 weeks (n = 22). Seventy-seven percent of the rabbits developed multifocal ON 4 weeks after LPS injection. ON was also observed in the femoral and humeral condyle. The average percentage of necrotic area/total area examined was 86.7 +/- 29.1% and 78.8 +/- 16.7% in the proximal one third of both the femoral and humeral bones, respectively. Organized thrombi in the intraosseous small-sized arteries and arterioles were frequently seen in and around the necrotic tissues. In the early phase, LPS treatment prominently induced thrombocytopenia, hyperlipidemia, and increased plasma levels of plasminogen activator inhibitor-1 (PAI-1). The plasma level of PAI-1 was significantly higher in the rabbits with ON than in those without ON (p < 0.01). The immunohistochemical expression of tissue factor was exaggerated in monocytes/macrophages and adipocytes in both the femoral and humeral bones of the LPS-treated rabbits. Histologically, marrow necrosis and fibrin thrombi could be observed at 24 h. In addition, pretreatment with an anticoagulant, warfarin potassium, significantly decreased the incidence of LPS-induced ON (33%, n = 9, p < 0.05) associated with elongation of prothrombin time. The results of our study show that a single administration of low-dose lipopolysaccharide induces multifocal and widespread ON characterized by the pathophysiological participation of hypercoagulability in ON development. Therefore, this model would be useful for elucidating the pathogenesis of nonsteroid ON in humans especially inflammatory hypercoagulability-induced as well as for developing preventive and therapeutic strategies.

Topics: Animals; Body Weight; Dose-Response Relationship, Drug; Femur; Immunohistochemistry; Lipopolysaccharides; Male; Osteonecrosis; Rabbits; Warfarin

We describe a 36-year-old man with familial protein S deficiency and homozygosity to the methylene tetrahydrofolate reductase (MTHFR) thermolabile variant who had a stroke followed by an episode of idiopathic osteonecrosis that was successfully managed by surgical core decompression. The patient's symptomatic thrombophilia, as well as that of several of his first-degree relatives who also had thrombotic events, raises the possibility that the thrombophilia was a contributing factor to the development of his osteonecrosis.

Topics: Adult; Anticoagulants; Femur Head; Folic Acid; Humans; Hyperhomocysteinemia; Magnetic Resonance Imaging; Male; Osteonecrosis; Paresis; Pedigree; Protein S Deficiency; Radiography; Stroke; Thromboembolism; Thrombophilia; Warfarin

Topics: Anticoagulants; Blood Coagulation Disorders; Facial Pain; Fibrinolysis; Humans; International Normalized Ratio; Jaw Diseases; Neuralgia; Osteonecrosis; Thrombophilia; Warfarin

In 31 patients with osteonecrosis (primarily of the hip), 74% had 1 or more primary coagulation disorders. In 18 patients, 15 (83%) who had coagulation disorders, the osteonecrosis was initially identified as idiopathic and was not associated with known underlying drugs (glucocorticoids) or diseases (alcoholism, sickle cell disease, Gaucher's disease). In 13 patients, 8 (62 %) who had coagulation disorders, the osteonecrosis was initially identified as secondary, and was associated with glucocorticoids in 12 patients, and with alcoholism in 1. The coagulation disorders included thrombhophilia (increased tendency to intravascular thrombosis) and hypofibrinolysis (reduced ability to lyse thrombi). Of the 18 patients initially thought to have idiopathic osteonecrosis, thrombophilia alone was found in 12% (resistance to activated protein C in 6%, low protein C in 6%), hypofibrinolysis alone was found in 50% (high lipoprotein(a) in 44%, low stimulated tissue plasminogen activator activity was found in 6%), and mixed thrombophilia hypofibrinolysis was found in 22%. Resistance to activated protein C was more common in these 18 patients than in healthy controls (11% versus 0%), as was high lipoprotein(a) (67% versus 20%). Of the 13 patients with secondary osteonecrosis, thrombophilia alone was found in 8% (low protein C), hypofibrinolysis alone was found in 30% (high Lp(a) in 15%, low tissue plasminogen activator activity in 15%), and mixed thrombophilia hypofibrinolysis was found in 23%. Low tissue plasminogen activator activity was more common in the 13 patients with secondary osteonecrosis than in controls (27% versus 7%), as was low protein C (23% versus 0%). In aggregate, these findings lead us to the speculation that primary, heritable thrombophilia or hypofibrinolysis causes thrombotic venous occlusion in the head of the femur, leading to venous hypertension and hypoxic death of bone (osteonecrosis).

Topics: Adult; Aged; Anticoagulants; Blood Coagulation; Female; Femur Head Necrosis; Fibrinolysis; Glucocorticoids; Humans; Lipoprotein(a); Male; Middle Aged; Osteonecrosis; Protein C; Risk Factors; Thrombosis; Tissue Plasminogen Activator; Warfarin