Familial Thrombophilia Is Associated With Primary Multifocal Osteonecrosis: A Case-Control Study of 40 Patients.

To characterize pathoetiologic associations of heritable thrombophilia-hypofibrinolysis with idiopathic (primary) multifocal osteonecrosis (ON) (≥3 ON anatomic sites), we prospectively studied 28 women and 12 men with primary multifocal ON compared with 27 women and 24 men with primary nonmultifocal ON (<3 sites) and 110 healthy controls without ON. The 40 cases with primary multifocal ON differed from controls for 3 familial thrombophilias: Factor V Leiden heterozygosity (6 of 40 [15%] vs 2 of 109 [2%], P=.002), G20210A prothrombin gene heterozygosity (6 of 40 [15%] vs 3 of 110 [3%], P=.011), and high (>150%) Factor VIII (8 of 40 [20%] vs 7 of 103 [7%], P=.031). These case-control familial coagulation differences paralleled those in 51 concurrently evaluated cases with primary nonmulti-focal ON, 7 of 51 (14%) of whom had Factor V Leiden heterozygosity vs 2% of controls (P=.005) and 14 of 44 (32%) of whom had high Factor VIII vs 7 of 103 (7%) of controls (P=.0002). Recognition of familial thrombophilia as a common pathoetiology of primary multifocal ON provides an opportunity for early anticoagulation (before joint collapse), allowing both prophylaxis and therapy aimed at relieving pain and slowing or stopping progression of the disease to joint collapse. [Orthopedics. 2023;46(3):164-168.].

Long-term Anticoagulation Prevents Progression of Stages I and II Primary Osteonecrosis of the Hip in Patients With Familial Thrombophilia.

The authors prospectively assessed long-term anticoagulation outcomes (≥3 years) for 9 patients meeting 4 inclusion criteria: pretreatment Ficat stage I or II primary hip osteonecrosis (ON), factor V Leiden or prothrombin G20210A heterozygosity, no contraindication to anticoagulation, and 90-day participation in an initial enoxaparin 60 mg/d protocol. The primary endpoint was prevention of hip collapse (Ficat stage III or IV). The secondary endpoint was pain relief. After 90 days of enoxaparin 60 mg/d, anticoagulation was continued for 8 patients: 4 receiving warfarin (international normalized ratio targeted to 2 to 2.5; 11.5, 13, 14.5, and 21 years), 1 receiving enoxaparin 120 mg/d (11.5 years), and 3 receiving novel oral anticoagulants (5, 6, and 8 years). Radiographs were obtained before treatment; at 3 to 4, 6 to 8, and 12 to 14 months; and then annually. By selection, 8 patients had factor V Leiden heterozygosity and 1 had prothrombin G202010A heterozygosity. Of their 13 hips (Ficat I or II at entry), 12 remained Ficat I or II after 12±5 years (range, 5.5-21 years) of continuous anticoagulation and follow-up; 1 hip radiographically normalized. None of the 13 hips progressed to collapse (Ficat III or IV). Six patients became symptom free after the first 3 months of receiving enoxaparin, 1 after 6 months of anticoagulation, and 1 after 10 months of anticoagulation; all 8 patients remained symptom free with anticoagulation. Anticoagulation for primary hip ON before hip collapse in patients with familial thrombophilia may change the natural history of ON because most untreated patients with ON have joint collapse and total joint replacement within 2 years of original symptoms. [Orthopedics. 2020;43(4):e208-e214.].

T786C Mutation in the Endothelial Nitric Oxide Synthase Gene in Patients With Primary Osteonecrosis.

Mutations in the T786C endothelial nitric oxide synthase gene (eNOS) are associated with osteonecrosis and Prinzmetal's angina. Nitric oxide is necessary for bone health and ameliorates Prinzmetal's angina. This study compared mutations of T786C eNOS in 146 patients with primary osteonecrosis, 114 patients with Prinzmetal's angina, and 83 normal control subjects. Patients with osteonecrosis had more mutant eNOS alleles than control subjects (42% vs 22%, respectively; P<.0001) but had the same number of mutant alleles as patients with Prinzmetal's angina (42% vs 41%, respectively; P=.7), who in turn had more mutant eNOS alleles than control subjects (41% vs 22%, respectively; P=.0001). Of 146 patients with primary osteonecrosis, 65 (45%) had none of the 5 thrombophilias (Factor V Leiden heterozygosity, high levels of Factors VIII and XI, anticardiolipin antibody immunoglobulin M, and homocysteine) that otherwise distinguished patients with osteonecrosis from control subjects (P<.05). No associations were found between eNOS hetero-homozygosity and the 5 major thrombophilias in primary osteonecrosis. Of the 65 patients who had osteonecrosis but no major thrombophilias, for 41 (28% of the total sample of 146), eNOS hetero-homozygosity was the only abnormality. Normalization of nitric oxide levels with l-arginine 9 g/d or l-citrulline 800 mg/d, both of which relieve vasospastic angina in Prinzmetal's angina, which has the same eNOS genotype as primary osteonecrosis, may slow or stop the progression of osteonecrosis. Placebo-controlled trials of patients with primary osteonecrosis who are hetero-homozygous for the T786C eNOS mutation and have no major thrombophilias are needed to assess the safety and efficacy of this treatment. [Orthopedics. 2017; 40(5):e898-e903.].

Venous Thromboembolism After Knee Arthroscopy in Undiagnosed Familial Thrombophilia.

Venous thromboembolism is uncommon after knee arthroscopy, and there are no guidelines for thromboprophylaxis in elective routine knee arthroscopy. Preoperative evaluation of common thrombophilias should provide guidance for postarthroscopy thromboprophylaxis in otherwise healthy patients who are at high risk for venous thromboembolism. This study assessed 10 patients with venous thromboembolism after total hip or knee arthroplasty. Patients were assessed if venous thromboembolism occurred within 6 months after knee arthroscopy (n=10) or total hip or knee arthroplasty (n=21). This study assessed gene mutations (factor V Leiden, prothrombin G20210A, plasminogen activator inhibitor, methylenetetrahydrofolate reductase) and serologic thrombophilias (high levels of factors VIII and XI, homocysteine, anticardiolipin immunoglobulin G and immunoglobulin M antibodies, and lupus anticoagulant; low antigenic protein C, S, and free S; and antithrombin III deficiency). The same coagulation data were obtained for normal subjects (n=110). The major thrombophilias in the arthroscopy group were factor V Leiden heterozygosity (40%), high factor VIII level (50%), and high homocysteine (30%). The respective values in control subjects were 2% (P=.0004), 7% (P=.0011), and 5% (P=.02). When the arthroscopy group was compared with the 21 patients who had venous thromboembolism after total hip or knee arthroplasty, the sole difference was factor V Leiden heterozygosity, which was 40% vs 0%, respectively (P=.007). Although venous thromboembolism after knee arthroscopy is uncommon, to identify high-risk patients and guide postoperative thromboprophylaxis, the authors suggest routine preoperative measurement of 3 common familial thrombophilias: factor V Leiden, factor VIII, and homocysteine. [Orthopedics. 2016; 39(6):e1052-e1057.].

Testosterone Therapy Can Interact With Thrombophilia, Leading to Osteonecrosis.

Although this effect is not widely recognized, testosterone therapy can interact with thrombophilia, causing osteonecrosis. In 12 men and 4 women who had idiopathic osteonecrosis a median of 6 months after the onset of testosterone therapy, the authors examined the interaction between testosterone therapy and previously undiagnosed thrombophilia. The authors hypothesized that patients who had osteonecrosis after starting testosterone therapy were more likely than 110 normal control subjects or 48 patients who had osteonecrosis and were not receiving testosterone therapy to have thrombophilia. Measures of thrombophilia included Factor V Leiden, prothrombin, PAI-1 gene mutations, Factor VIII, Factor XI, anticardiolipin antibody immunoglobulin G or immunoglobulin M, and homocysteine values. In 10 cases, osteonecrosis occurred 6 months or less after the onset of testosterone therapy, and in all 16 cases, it occurred after a median of 6 months of testosterone therapy. Of the 16 cases, 5 (31%) were Factor V Leiden heterozygotes vs 2 of 109 (2%) healthy control subjects (P=.0003) and 4 of 48 patients who had osteonecrosis and were not receiving testosterone therapy (P=.04). Of the 16 cases, 4 (25%) had high (>150%) Factor VIII levels vs 7 of 103 (7%) healthy control subjects (P=.04), and 3 (19%) had high (>150%) Factor XI levels vs 3 of 101 (3%) healthy control subjects (P=.03). Of the 16 patients with osteonecrosis, 14 (88%) had at least 1 abnormal procoagulant value (of the 8 measured) vs 47 of 110 (43%) healthy control subjects (P=.0009). Of the 5 men whose serum estradiol level was measured while they were receiving testosterone therapy, this level was high (≥42.6 pg/mL) in 4. When testosterone therapy is given to patients with thrombophilia, they are at increased risk for osteonecrosis.

Long term anticoagulation (4-16 years) stops progression of idiopathic hip osteonecrosis associated with familial thrombophilia.

In 6 patients with familial thrombophilia (5 Factor V (FV) Leiden heterozygotes, 1 with resistance to activated protein C (RAPC)), we prospectively assessed whether continuous longterm (4-16 years) anticoagulation would prevent progression of idiopathic osteonecrosis (ON), ameliorate pain, and facilitate functional recovery. Four men and 2 women (9 hips, 8 Ficat stage II, 1 stage I) were anticoagulated with enoxaparin (60 mg/day) for 3 months and subsequently with Coumadin, Xarelto, or Pradaxa, warranted by ≥2 prior thrombotic events. Anticoagulation was continued for 4, 4, 9, 13, 13, and 16 years, with serial clinical and X-ray follow-up. On 4-16-years anticoagulation, 9 hips in the 6 patients (8 originally Ficat II, 1 Ficat I) remained unchanged, contrasted to untreated ON Ficat stage II, where 50%-80% of hips progress to collapse (Ficat stages III-IV) within 2 years after diagnosis. Within 3, 3, 3, 9, and 16 months after starting anticoagulation, 5 patients became pain-free and remained asymptomatic throughout follow-up; the 6th patient required Percocet for pain. There were no significant bleeding episodes. Long term (4-16 years) anticoagulation initiated in Ficat stages I-II of idiopathic hip ON in patients with FV-RAPC changes the natural history of ON, stopping progression, resolving pain, and restoring function.

Medical treatment of osteonecrosis of the knee associated with thrombophilia-hypofibrinolysis.

In 6 patients with stage II knee osteonecrosis, all 6 with thrombophilia and 4 with concurrent hypofibrinolysis, the authors prospectively determined whether anticoagulation with enoxaparin could prevent collapse and progression to osteoarthritis, ameliorate pain, and restore function. The 6 patients were treated with enoxaparin (40 to 60 mg/d for 3 or more months) as mandated by a US Food and Drug Administration-approved protocol. In post-enoxaparin prospective follow-up, patients were reassessed clinically every 4 to 6 months, and radiographs were obtained every year. The 6 patients followed up at 15.1, 7.5, 3.9, 2.25, 2, and 1 year, respectively. None progressed to joint collapse or severe osteoarthritis. Four became and remained asymptomatic at 2-, 3.9-, 7.5-, and 15.1-year follow-up, respectively. A fifth patient did not progress to collapse or severe osteoarthritis but had residual pain at 2.25-year follow-up. The sixth patient had no symptomatic benefit on enoxaparin but improved on rivaroxaban at 1-year follow-up. Two patients had recurrences of knee pain 1 and 4 years after their initial treatment with enoxaparin. One resolved after a second course of enoxaparin, and the other, with a second recurrence 1 year after the second course, resolved after a third course. Pretreatment, all 6 patients required canes, crutches, or wheelchairs, but after enoxaparin, no patient required them, and walking was unrestricted. Thrombophilia-hypofibrinolysis contributes to the pathogenesis of knee osteonecrosis. Thrombophilic-hypofibrinolytic patients with stage II knee osteonecrosis treated with enoxaparin have had no collapse or progression to severe osteoarthritis, and most have had resolution of pain and restoration of full function. This represents a major improvement compared with the natural history of untreated spontaneous knee osteonecrosis.

The role of the factor V Leiden mutation in osteonecrosis of the hip.

We examined the hypothesis that the factor V Leiden (FVL) and G20101A prothrombin gene mutations are commonly associated with hip osteonecrosis. We prospectively evaluated 244 consecutively referred adults with osteonecrosis (ON), 161 idiopathic and 83 secondary. Cases (n = 244) did not differ from 104 normal controls by race. Of the 244 patients, 23 (9.4%) were FVL heterozygotes versus 2 of 104 controls (1.9%), P = .013, risk ratio (RR) = 4.90, 95% confidence interval (CI) 1.18 to 20.4. Of the 161 patients with idiopathic ON, 15 (9.3%) were FVL heterozygotes versus 2 of 104 normal controls (1.9%), P = .017, RR = 4.84, 95% CI 1.13 to 20.8. Of the 83 patients with secondary ON, 8 (9.6%) FVL heterozygotes versus 2 of 104 normal controls (1.9%), P = .024, RR = 5.01, 95% CI 1.09 to 23.0. Prothrombin gene heterozygosity in normal controls (2.9%) did not differ from ON cases (3.4%), P = 1.0. The thrombophilic FVL mutation is commonly associated with and may be pathoetiologic for hip osteonecrosis.

Total hip arthroplasty with ceramic-on-ceramic bearing failure from third-body wear.

This article describes a new mechanism of failure of a ceramic-on-ceramic total hip arthroplasty (THA) due to fretting corrosion and failure of the Morse taper. A 46-year-old man with hip osteonecrosis underwent THA in 2006. A ceramic-on-ceramic, un-cemented THA with a titanium femoral component and metal-on-ceramic Morse taper was implanted. Two years postoperatively, he presented with swelling in his groin and a painless medial thigh mass. The thigh mass was diagnosed as an abscess. Incision and drainage was performed and resulted in a sinus tract that continuously drained copious amounts of seropurulent fluid. Two months later, the patient underwent irrigation, debridement, and explantation of his hip. Frozen sections showed no signs of infection. There was dramatic visible wear of the Morse taper and pieces of metal embedded in the ceramic. Permanent sections showed chronic inflammation and foreign body reaction. He subsequently underwent an uneventful re-implantation with a metal-on-highly-cross-linked-polyethylene THA. In this case, failure of the morse taper led to metal debris, which reacted with the ceramic and caused dramatic third-body wear. The thigh mass, which appeared to be an infection, proved to be a massive foreign body granuloma. Malfunction of the morse taper as reported in this case represents a possible failure mechanism of a ceramic-on-ceramic THA.

Thrombophilia, hypofibrinolysis, the eNOS T-786C polymorphism, and multifocal osteonecrosis.

BACKGROUND: We examined the hypothesis that thrombophilia, hypofibrinolysis, and the endothelial nitric oxide synthase (eNOS) T-786C polymorphism are common, potentially treatable, and similar pathophysiologic causes of multifocal (three sites or more) and unifocal (single-site) osteonecrosis. METHODS: We prospectively evaluated twenty-six consecutively referred adults with multifocal osteonecrosis, who included thirteen with idiopathic multifocal osteonecrosis and thirteen with secondary multifocal osteonecrosis (resulting from steroid therapy in ten and alcoholism in three). We compared these patients with race, sex, and age-matched normal control subjects and with patients with idiopathic unifocal and secondary unifocal osteonecrosis, respectively. Using polymerase chain reaction and serologic measures, we studied thrombophilic and hypofibrinolytic mutations and the eNOS T-786C polymorphism. RESULTS: The total number of polymerase chain reaction and serologic thrombophilic-hypofibrinolytic abnormalities and the eNOS T-786C polymorphism did not differ between patients with idiopathic (p > 0.5) or secondary (p > 0.5) multifocal and unifocal osteonecrosis. The frequency of low free protein-S levels (<66%) in patients with secondary multifocal osteonecrosis (four of eleven patients) was higher than that in the control subjects (one of fifty-nine) (risk ratio = 21.5; 95% confidence interval, 2.6 to 174; p = 0.0016, Benjamini-Hochberg adjusted p [Bp] = 0.004). Factor-V Leiden heterozygosity was present in two of thirteen patients with secondary multifocal osteonecrosis compared with none of sixty-four control subjects (p = 0.027, Bp = 0.008). For eleven patients with secondary multifocal osteonecrosis, the eNOS T-786C polymorphism was present in nine of twenty-two alleles compared with eight of forty-four alleles in twenty-two normal control subjects (risk ratio = 2.3; 95% confidence interval, 1.0 to 5.0; p = 0.047, Bp = 0.016). The frequency of homocystinemia (>13.5 mumol/L) was higher in patients with idiopathic multifocal osteonecrosis (two of thirteen patients) than in normal controls (none of fifty-one) (p = 0.039, Bp = 0.004). A high level of factor VIII (>150%) was seen in four of eight patients with idiopathic multifocal osteonecrosis and in seven of forty-eight normal controls (risk ratio = 3.4; 95% confidence interval, 1.3 to 9.1; p = 0.04, Bp = 0.008). The eNOS T-786C mutant allele was present in seven of twelve alleles in the six patients with idiopathic multifocal osteonecrosis who were tested, compared with twenty-five of 108 alleles in fifty-four control subjects (risk ratio = 2.5; 95% confidence interval, 1.4 to 4.5; p = 0.015, Bp = 0.008). CONCLUSIONS: Limited by the small numbers of patients with multifocal osteonecrosis, this exploratory study suggested that thrombophilia was associated with both idiopathic multifocal osteonecrosis and secondary multifocal osteonecrosis, as was the eNOS T-786C polymorphism. Multifocal and unifocal osteonecrosis are similarly associated with thrombophilia, hypofibrinolysis, and the eNOS T-786C polymorphism, which are potentially treatable pathophysiologic conditions, requiring further study.

Heritable thrombophilia-hypofibrinolysis and osteonecrosis of the femoral head.

We hypothesized that inherited thrombophilia and hypofibrinolysis were risk factors for osteonecrosis of the femoral head. We compared measures of thrombophilia and hypofibrinolysis in referred new adult patients with idiopathic osteonecrosis (n = 71) or secondary osteonecrosis (n = 62) with the same measures in sex- and race-matched healthy control subjects. Heritable thrombophilic Factor VIII and hypofibrinolytic Lp(a) were more frequently high in the 71 patients with idiopathic osteonecrosis than in control subjects. High Factor VIII, Factor V Leiden heterozygosity, and resistance to activated protein C, all heritable thrombophilias, were more frequently present in the 62 patients with secondary osteonecrosis than in control subjects. Our data suggest inherited thrombophilia and hypofibrinolysis are risk factors for both idiopathic and secondary osteonecrosis of the head of the femur.

Association between the T-786C eNOS polymorphism and idiopathic osteonecrosis of the head of the femur.

BACKGROUND: Nitric oxide regulates bone turnover by osteoblasts and osteoclasts. Nitric oxide production is impaired by the T-786C eNOS single nucleotide polymorphism, with a substitution of the nucleotide thymine by cytosine at a locus 786 base pairs upstream of the eNOS gene. This leads to vasoconstriction, platelet aggregation, reduced angiogenesis, and reduced bone formation, all of which may be associated with osteonecrosis of the hip. We studied relationships between the T-786C eNOS polymorphism and idiopathic and secondary necrosis of the head of the femur in order to better understand the pathophysiology of osteonecrosis. METHODS: With use of polymerase chain reaction methodology, the T-786C eNOS polymorphism was compared in ninety-five patients with femoral head necrosis (including thirty-six nonsmokers with idiopathic necrosis and fifty-nine patients with secondary necrosis) and seventy-two healthy normal adult controls. RESULTS: Homozygosity for the mutant eNOS allele (TT) was present in eight (22%) of thirty-six patients with idiopathic osteonecrosis as compared with one (3%) of thirty-six race, gender, and age-matched controls; heterozygosity (TC) was present in nineteen patients (53%) as compared with ten controls (28%); and the wild-type normal genotype (CC) was present in nine patients (25%) as compared with twenty-five controls (69%) (p = 0.0004). Logistic regression revealed that the T-786C eNOS mutant allele was positively associated with idiopathic osteonecrosis of the femoral head (odds ratio, 6.0; 95% confidence interval, 2.51 to 14.4). The fifty-nine patients with secondary osteonecrosis did not differ from fifty-two race, gender, and age-matched controls in terms of the distribution of the T-786C eNOS polymorphism (p = 0.19) or in terms of mutant allele frequency (30% compared with 21%; p = 0.15). The thirty-six patients with idiopathic osteonecrosis differed from the fifty-nine patients with secondary osteonecrosis in that they were more likely to have mutant eNOS genotypes (p = 0.033) and to have a higher mutant T allele frequency (49% compared with 30%; p = 0.009). CONCLUSIONS: The T-786C eNOS polymorphism and resultant reduction of nitric oxide production is associated with, and may contribute to, the pathogenesis of idiopathic osteonecrosis of the femoral head. LEVEL OF EVIDENCE: Prognostic Level III. See Instructions to Authors for a complete description of levels of evidence.

Thumb abduction strength measurement in carpal tunnel syndrome.

PURPOSE: The strength of thumb abduction and index finger flexion was measured with a load cell mounted on a custom-made device. The resulting ratio (thumb-index ratio, or TIR) was used to diagnose carpal tunnel syndrome (CTS) and was compared with the gold standard (electrodiagnostic studies). The ratio was used as an internal control in each subject. METHODS: Sixty-one patients (80 hands) with a clinically and electrodiagnostically confirmed diagnosis of idiopathic CTS and a control group of 51 asymptomatic volunteers (102 hands) were evaluated. The strength of thumb abduction and index finger flexion was measured in standardized fashion in each hand three times, and the mean was taken to calculate TIR. RESULTS: Thumb-index ratio was statistically significant in differentiating between a CTS patient and a normal control. A TIR of 0.51 had a 98% specificity and a 92% positive predictive value for diagnosing CTS. Thumb-index ratio greater than 0.51 was neither sensitive nor specific for diagnosis of CTS. Twenty-four (30%) hands in the investigational group had a TIR < or =0.51 compared with 1 hand (1%) in the control group. There was a significant difference in the TIR between hands with a motor amplitude of < or =4.0 mV and those with an amplitude >4.0 mV. CONCLUSIONS: Most patients with CTS do not appear to have notable weakness of thumb abduction strength. A TIR < or =0.51 had high specificity for differentiating between CTS and controls. However, the performance of this device needs to be evaluated in a general population of patients who present with signs and symptoms of CTS before it would be clinically applicable.

Enoxaparin prevents progression of stages I and II osteonecrosis of the hip.

UNLABELLED: In a prospective pilot study, we hypothesized that enoxaparin (60 mg/day for 12 weeks) would prevent progression of Stages I and II osteonecrosis of the hip associated with thrombophilia or hypofibrinolysis or both over > or = 108 weeks of followup versus untreated historic controls, with different treatment responses in primary versus corticosteroid-associated secondary osteonecrosis. Patients with one or more thrombophilic-hypofibrinolytic disorder and Ficat Stages I or II osteonecrosis of at least one hip were included. A blinded committee interpreted anteroposterior and frog-leg lateral radiographs at entry in the study and every 36 weeks to > or = 108 weeks. Maintenance of the disease at Stages I and II versus progression of the osteonecrosis to Stages III and IV requiring total hip replacement was the major end point. Sixteen patients had primary osteonecrosis (25 hips; 13 Stage I, 12 Stage II), and 12 had secondary osteonecrosis (15 hips; five Stage I, 10 Stage II). With no Enoxaparin-related complications, 19 of 20 hips (95%) with primary osteonecrosis were unchanged from Stages I and II osteonecrosis at > or = 108 weeks; 12 of 15 hips (80%) with secondary osteonecrosis progressed to Stages III and IV osteonecrosis. In primary osteonecrosis at > or = 108 weeks, survival of 95% hips, or 76% (19/25 hips, based on intent to treat), compared favorably with untreated historical controls (approximately 20% 2-year survival), comparable to 20% survival in secondary hip osteonecrosis. Enoxaparin may prevent progression of primary hip osteonecrosis, decreasing the incidence of total hip replacement. LEVEL OF EVIDENCE: Therapeutic study, II-1 (prospective cohort study).

Role of thrombosis in osteonecrosis.

We think that osteonecrosis, to a large degree, develops because of familial and acquired thrombophilia and hypofibrinolysis causing venous thrombosis in the femoral head. We postulate that venous thrombosis leads to increased intraosseus venous pressure, reduced arterial flow, and hypoxic bone death. Many studies suggest that familial and acquired thrombophilia and hypofibrinolysis may play an important etiologic role in adults with osteonecrosis of the hip and jaw and in children with Legg-Perthes disease (pediatric osteonecrosis). We have limited pilot data in adults with osteonecrosis associated with familial thrombophilia and hypofibrinolysis that suggest that 12 weeks of therapy with enoxaparin, if started early (Ficat stages I/II) before femoral head collapse (Ficat stages III/IV), may interrupt the progression of osteonecrosis of the hip. Placebo-controlled trials with a 2-year follow-up or longer in adults will be required to assess the promise of the pilot anticoagulant studies in osteonecrosis.