Comprehensive analysis of pivotal biomarkers, immune cell infiltration and therapeutic drugs for steroid-induced osteonecrosis of the femoral head.

Steroid-induced osteonecrosis of the femoral head (SONFH) is a progressive disease that leads to an increased disability rate. This study aimed to ascertain biomarkers, infiltrating immune cells, and therapeutic drugs for SONFH. The gene expression profile of the GSE123568 dataset was downloaded from the Gene Expression Omnibus (GEO) database. The differentially expressed genes (DEGs) were identified using the NetworkAnalyst platform. Functional enrichment, protein-protein interaction network (PPI), and module analyses were performed using Metascape tools. An immune cell abundance identifier was used to explore immune cell infiltration. Furthermore, hub genes were identified based on maximal clique centrality (MCC) evaluation using cytoHubba application and confirmed by qRT-PCR using clinical samples. Finally, the L1000 platform was used to determine potential drugs for SONFH treatment. The SONFH mouse model was used to determine the therapeutic effects of aspirin. In total, 429 DEGs were identified in SONFH samples. Functional enrichment analysis showed that these DEGs were enriched in myeloid leukocyte activation and osteoclast differentiation processes. A set of nine immune cell types was confirmed to be markedly different between the SONFH and control samples. All 10 hub genes were significantly highly expressed in the serum of SONFH patients, as shown by qRT-PCR. Finally, the therapeutic effect of aspirin on SONFH was examined in animal experiments. Taken together, our data revealed the hub genes and infiltrating immune cells in SONFH, and we also screened potential drugs for use in SONFH treatment.

Astragaloside IV ameliorates steroid-induced osteonecrosis of the femoral head by repolarizing the phenotype of pro-inflammatory macrophages.

Osteonecrosis of the femoral head (ON-FH) is a common complication of steroid use. Pro-inflammatory macrophages play a crucial role in the apoptosis of osteocytes. The objective of the study was to evaluate a plant extract astragaloside IV (AS-IV) in treating ON-FN. Bone-marrow-derived macrophages (BMDMs) were treated with lipopolysaccharides (LPS), IFN-γ or IL-4 to induce M1 and M2-like phenotypes. Quantitative real-time PCR and Western blot were used to examine M1 and M2 phenotypic markers. Flow cytometry was used to analyze MHC II, CD206, F4/80, and CD11b levels and cell apoptosis. Glucocorticoid was used to induce ON-FN in mice. TNF-α and IL-1ß levels in femoral head were determined using enzyme-linked immunosorbent assay. AS-IV repolarized macrophages from M1 to M2 phenotypes. Culture medium from AS-IV treated M1 macrophages induced less cell apoptosis osteocytes compared to that from untreated M1 macrophages. In ON-FH mice, the ratio of M1 macrophages was decreased in the femoral head by AS-IV, concomitant with a decrease in TNF-α and IL-1ß levels. AS-IV is effective in alleviating ON-FH through its effects in repolarizing macrophages from M1-like phenotype to M2-like phenotype, promoting survival of osteocytes, reducing arthritic symptoms, and decreasing inflammatory cytokines.

The Role of Immune Regulatory Cells in Nontraumatic Osteonecrosis of the Femoral Head: A Retrospective Clinical Study.

The immunologic factors have been implicated in the pathogenesis of osteonecrosis. We aimed to investigate the potential role of immune regulatory cells in the development of osteonecrosis of femoral head (ONFH). Sixty-seven patients diagnosed with ONFH and fifty-eight age-, height-, and weight-matched healthy subjects were included in this retrospective study between September 2015 and September 2018. The flow cytometry was used to test the count, percentage, and ratio of T and B lymphocyte subsets in peripheral blood. The T and B lymphocyte levels were compared among different ARCO stages, CJFH types, and etiology groups. The total lymphocyte count, CD3+T cells, Ts cells (CD3+CD8+), B-1 cell count, and B-1 cells (CD5+CD19+) were significantly higher in the patients with ONFH than those in the control subjects. The percentage of T lymphocytes in the patients with ARCO IV stage was significantly smaller than that in the ONFH patients with ARCO II and III stages. The percentage of inhibitory T lymphocytes in patients with CJFH type L3 was significantly smaller than that in the patients with types L1 and L2. In terms of the different ONFH etiologies, the total lymphocyte count and Ts cells (CD3+CD8+) were significantly lower in the ONFH patients induced by excessive alcohol intake than those in the idiopathic ONFH patients. Our results seem to indicate that immune regulatory cells, such as T and B lymphocytes, play an important role in the pathogenesis of ONFH. The development and progression of ONFH may be associated with immune system imbalance.

Correlational analysis between neutrophil granulocyte levels and osteonecrosis of the femoral head.

BACKGROUND: The correlation between peripheral blood neutrophil level and osteonecrosis of the femoral head (ONFH) has not been extensively studied. Thus, we aimed to investigate the correlation between neutrophil level in the peripheral blood (neutrophil granulocyte) and ONFH. METHODS: A total of 984 cases of ONFH and femoral neck fractures (non-ONFH) diagnosed at the Department of Orthopedics at our institution between January 1, 2011 and December 31, 2016 were retrospectively reviewed. The ONFH and non-ONFH groups comprised 488 and 496 cases, respectively. Basic information and peripheral blood cell levels of the two groups were compared. RESULTS: The patients' mean age was 59.89 ± 17.06 years (range: 38-82 years). There were 457 male and 527 female patients, with a male-to-female ratio of 1:1.15. We found that neutrophil granulocyte levels and percentage of neutrophil granulocytes were significantly different between the ONFH and non-ONFH groups. Multimodal regression analysis showed that the percentage of neutrophil granulocytes was an independent protective factor against ONFH. CONCLUSIONS: The factors influencing ONFH are neutrophil granulocyte levels and percentage of neutrophil granulocytes. Percentage of neutrophil granulocytes has a significant correlation with aseptic femoral head necrosis, providing a new perspective and direction for further study of femoral head necrosis.

Osteonecrosis of the femoral head: genetic basis.

PURPOSE: Genetic factors and hereditary forms of osteonecrosis of the femoral head (ONFH) have been elucidated through genetic association studies. The significance of these cases is that they suggest an alternative hypothesis to the development of the disease. This review presents a summary of single nucleotide polymorphisms (SNPs) and other genetic mutation variations found in association with ONFH, including our recent identification of a novel mutation in the transient receptor potential vanilloid 4 (TRPV4) gene in association with inherited ONFH. The purpose of this review is to consolidate and categorize genetic linkages according to physiological pathways. METHODS: A systematic review of literature from PubMed and Google Scholar was undertaken with a focus on genetic linkages and hereditary case studies of the disease. Recent genetic analysis studies published after 2007 were the focus of genetic linkages in non-hereditary cases. RESULTS: The summary of these genetic findings identifies biological processes believed to be involved in the development of ONFH, which include circulation, steroid metabolism, immunity, and the regulation of bone formation. CONCLUSION: Taken together, these associations may lead to new pathways of bone repair and remodeling while opening new avenues for therapeutic targets. Knowledge of genetic variations could help identify individuals considered to be at higher risk of developing ONFH and prevent the multiple hit effect.

Antiphospholipid score is a novel risk factor for idiopathic osteonecrosis of the femoral head in patients with systemic lupus erythematosus.

OBJECTIVE: Idiopathic osteonecrosis of the femoral head (ION) is a common complication of SLE associated with CS therapy. Although the pathogenesis of ION involves local bone ischaemia favoured by thrombophilia, the involvement of aPL in lupus ION remains to be elucidated. We have previously reported the aPL score (aPL-S) as a quantitative marker of aPL and the development of thrombotic events in autoimmune diseases. The aim of this study was to identify the impact of aPL on the development of ION using aPL-S. METHODS: This was a single-centre retrospective study comprising 88 consecutive SLE patients who underwent MRI of the hip joints from January 2000 to March 2017. Baseline characteristics, pharmacotherapy and total hip arthroplasty performed during follow-up were evaluated. RESULTS: The presence of ION was confirmed by MRI scan in 38 patients (43.1%). Male gender, positivity of any aPL, aPL-S, high aPL-S (≥30) and high dose of CS were identified as risk factors for ION by univariate analysis. Multivariate analysis revealed high aPL-S (odds ratio 5.12, 95% CI 1.18-29.79) and use of high-dose CS (odds ratio 10.25, 95% CI 3.00-48.38) as independent variables. Kaplan-Meier analysis showed that patients with high aPL-S received total hip arthroplasty more frequently than those without aPL (P = 0.010). CONCLUSIONS: We newly identified high aPL-S as an important risk factor for ION development in SLE, suggesting the involvement of aPL-induced coagulopathy in the pathophysiology of lupus ION.

Th17 and IL-17 exhibit higher levels in osteonecrosis of the femoral head and have a positive correlation with severity of pain.

OBJECTIVE: Synovitis associated with osteonecrosis of the femoral head (ONFH) is responsible for several clinical symptoms. However, the mechanisms underlying synovitis and the inflammatory environment remain unclear. This study analyzed the proinflammatory mediation expression of IL-17 and Th17, which perform key functions in regulating inflammatory processes in the inflamed synovium and peripheral blood in ONFH. METHODS: Synovial fluid from the hips of 23 patients and 5 controls was collected during surgery, and peripheral blood samples were obtained from 34 patients and 9 controls. The expression of IL-17 in the synovium was detected by immunohistochemistry, and the levels of Th17 and IL-17 in the blood were measured by flow cytometry and ELISA. Pain assessment was performed for all the patients and controls. RESULTS: An inflamed synovium was characterized by increased leukocyte infiltration and IL-17 expression in comparison with the control. Preoperative levels of Th17 and IL-17 were significantly higher in the peripheral blood of the ONFH group than those in the controls. The symptoms were also positively correlated with the Th17 levels of the ONFH patients. CONCLUSION: Th17 cells were recruited to an inflamed synovium, and inflammatory cytokine IL-17 was expressed at an increased level in the hip synovium of ONFH patients, which possibly contributed to clinical syndrome development. Overall, this study will help in identifying new therapeutic strategies for ONFH, especially the targeting of IL-17 to decrease inflammation and pain. < p > < /p >.

Hip Osteonecrosis Is Associated with Increased Plasma IL-33 Level.

The recently discovered IL-33 as an IL-1 cytokine family member has been proved to be specifically released from osteonecrotic bones. We aimed to investigate the potential role of IL-33 in the development of osteonecrosis of femoral head (ONFH). Forty patients diagnosed with ONFH and forty age-, sex-, and body mass index- (BMI-) matched healthy subjects were included in this prospective study between March 2016 and September 2016. A commercially available ELISA kit was used to test the level of plasma IL-33. The IL-33 levels were compared among different ARCO stages, CJFH types, and etiology groups. Plasma IL-33 levels were significantly higher in the ONFH patients than that in the control subjects. The levels of IL-33 did not differ significantly among the ONFH patients with different ARCO stages. The IL-33 levels of patients with CJFH type L3 were significantly higher than that of patients with types L1 and L2. No significant differences were observed in IL-33 levels between steroid-induced, alcohol-induced, and idiopathic patients. Our findings seem to indicate that IL-33 effects may be detrimental during ONFH, which appeared to be associated with the prognosis of ONFH. The IL-33 deserves particular attention in the pathogenesis of ONFH.

Necrotic Bone Stimulates Proinflammatory Responses in Macrophages through the Activation of Toll-Like Receptor 4.

In Legg-Calvé-Perthes disease, loss of blood supply results in ischemic osteonecrosis of the femoral head (ONFH). Generally, macrophages play important roles in inflammatory responses to tissue necrosis, but their role in ONFH is not known. The purpose of this study was to determine the macrophage-inflammatory responses after ONFH and the receptor mechanisms involved in sensing the necrotic bone, using a piglet model of Legg-Calvé-Perthes disease. Induction of ONFH resulted in increased numbers of CD14+ macrophages in the fibrovascular repair tissue compared with normal, as determined by immunohistochemistry. Quantitative real-time PCR analysis of macrophages isolated by laser capture microdissection showed significantly increased expression of proinflammatory cytokines IL-1ß, tumor necrosis factor-α, and IL-6 in ONFH compared with normal. Because Toll-like receptors (TLRs) mediate macrophage-inflammatory responses in other inflammatory conditions, we determined their gene expression in macrophages and found significantly increased levels of TLR4 but not TLR2 and TLR9 in ONFH. Mechanistically, in vitro, bone marrow-derived macrophages treated with necrotic bone showed increased extracellular signal-regulated kinases 1/2 and Iκ kinase-α phosphorylation, increased proliferation, migration, and inflammatory cytokine expression, which were blocked by TLR4 inhibitor, TAK242, and by TLR4 ablation in macrophages using the clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein-9 nuclease method. In conclusion, necrotic bone stimulates macrophage-inflammatory responses through TLR4 activation.

Repairing defect and preventing collapse of femoral head in a steroid-induced osteonecrotic of femoral head animal model using strontium-doped calcium polyphosphate combined BM-MNCs.

We investigated the synergism between strontium-doped calcium polyphosphate (SCPP) and autologous bone marrow mononuclear cells (BM-MNCs) in treating osteonecrosis of the femoral head (ONFH). ONFH was confirmed histopathologically at 2 weeks after methylprednisolone acetate injection and the rabbits were treated with morselized autogenous cancellous compacted bone graft (group I), SCPP combined with BM-MNCs (group II), and calcium polyphosphate (group III), respectively. The amount of newly formed bone in group II increased dramatically by 4, 8, and 12 weeks and much more than that in group III (P<0.05). VEGF expression in group I was significantly higher than in group II (P=0.023), and its expression in group II was significantly higher than in group III (P=0.017). At 12 weeks, group II had articular cartilage collapse and group III had joint-space narrowing. The mean histological and radiological scores for repaired defects in group II were significantly higher than those in group III (P=0.000) but lower than those in group I (P=0.000). The implantation of a combination of SCPP and BM-MNCs enhances VEGF expression and promotes osteogenesis, which may improve angiogenesis and allow incorporation and remodeling into new trabecular bone without mechanical weakening.

A higher frequency of peripheral blood activated B cells in patients with non-traumatic osteonecrosis of the femoral head.

OBJECTIVES: B cells play important roles in inflammatory diseases. This study was aimed at examining the frequency of different subsets of B cells in patients with non-traumatic osteonecrosis of the femoral head (NONFH). METHODS: The percentages of the different subsets of circulating B cells in 28 patients with steroid-related, alcohol-related, or idiopathic NONFH and 10 healthy controls (HC) were examined by flow cytometry. The concentrations of serum C-reactive protein (CRP), fibrinogen (FIB), immunoglobulins, cytokines and blood erythrocyte sedimentation rate (ESR) were measured. RESULTS: In comparison with those in the HC, significantly higher percentages of CD27-, CD86+, CD95+, and CD27+CD95+CD19+ but lower CD27+CD19+ B cells were detected in the patients. The percentages of CD86+, CD95+, and CD27+CD95+CD19+ B cells in each group of the patients were significantly higher than those in the HC. The levels of serum IL-17A and IFN-γ in steroid group and serum TNF-α in alcoholic group were significantly higher than those in the HC. The percentages of CD86+CD19+ B cells were positively associated with the degrees of femoral head collapse in both steroid and alcoholic groups of patients and the levels of serum TNF-α were positively associated with the degrees of femoral head collapse in the alcoholic NONFH patients. CONCLUSIONS: These data suggest a higher frequency of CD86+CD19+ activated B cells and elevated levels of serum TNF-α may be associated with the development of NONFH.

Immune response associated with Toll-like receptor 4 signaling pathway leads to steroid-induced femoral head osteonecrosis.

BACKGROUND: Femoral head osteonecrosis is frequently observed in patients treated with excessive corticosteroids. The objective of the current study was to establish a rat model to investigate the disruption of immune response in steroid-induced femoral head osteonecrosis via Toll-like receptor 4 (TLR4) signaling pathway. METHODS: Male SD rats were divided into the treatment group (group A) and the model group (group B) consisting of 24 rats each, and were injected intramuscularly with 20 mg/kg methylprednisolone (MP) for 8 weeks, once a week. The rats in group A were injected intravenously with 7.5 mg/kg TAK242 before each MP administration. A control group (group N) consisted of 12 rats were received saline injection. All animals were sacrificed 8, 10 and 12 weeks from the first MP injection, respectively. Histopathological analysis was performed and the concentration of tartrate-resistant acid phosphatase (TRAP) in serum was tested. The signaling molecules including TLR4, MyD88, NF-κB p65 and MCP-1 were detected by immunohistochemistry, quantitative real-time PCR and Western blot. RESULTS: Femoral head osteonecrosis was observed in the model rats, and the concentration of TRAP and positive staining of all signaling molecules increased significantly in group B compared with that in group A and group N. Compare with the control group, the mRNA expressions and protein levels of all signaling molecules were enhanced significantly in group B, but no significant in group A. CONCLUSIONS: Corticosteroids can induce femoral head osteonecrosis by disturbing the immune response via TLR4 signaling pathway. These findings suggest that the disruption of immune response play a role in the pathogenesis of osteonecrosis.

Elevations in D-dimer and C-reactive protein are associated with the development of osteonecrosis of the hip in HIV-infected adults.

BACKGROUND: A high incidence of nontraumatic osteonecrosis has been reported in HIV-infected patients. We investigated the levels of D-dimer and C-reactive protein (CRP) in a cohort of HIV-infected adults with and without osteonecrosis of the femoral head. METHODS: Forty-three HIV-infected patients with osteonecrosis of the femoral head and a comparison group of 50 HIV-infected patients with negative MRI of the hips and for whom serial plasma samples were available were included. D-dimer and CRP levels were measured prior to and at the time of diagnosis for osteonecrosis patients, at the time of negative MRI of the hips for controls, and at least 6 months later for both groups. RESULTS: Biomarker levels were elevated at the time of diagnosis in the osteonecrosis cohort compared with controls. Median D-dimer value was 0.32 µg/ml in the osteonecrosis group compared with less than 0.22 µg/ml in the control group (P = 0.016). For CRP, the corresponding values were 2.52 mg/l and 1.23 mg/l (P = 0.003). Postdiagnosis, D-dimer and CRP levels were also elevated in the osteonecrosis patients compared with controls. Linear regression demonstrated a rise in D-dimer levels from prediagnosis to diagnosis in the osteonecrosis patients whereas CRP levels did not change significantly over time. CONCLUSION: Compared to controls, patients who developed osteonecrosis had elevated levels of D-dimer and CRP at diagnosis. D-dimer levels increased whereas CRP levels did not change significantly from prediagnosis to diagnosis. These data suggest that patients with higher levels of inflammation are at an increased risk of osteonecrosis.

Intravenous transplantation of allogeneic bone marrow mesenchymal stem cells and its directional migration to the necrotic femoral head.

In this study, we investigated the feasibility and safety of intravenous transplantation of allogeneic bone marrow mesenchymal stem cells (MSCs) for femoral head repair, and observed the migration and distribution of MSCs in hosts. MSCs were labeled with green fluorescent protein (GFP) in vitro and injected into nude mice via vena caudalis, and the distribution of MSCs was dynamically monitored at 0, 6, 24, 48, 72 and 96 h after transplantation. Two weeks after the establishment of a rabbit model of femoral head necrosis, GFP labeled MSCs were injected into these rabbits via ear vein, immunological rejection and graft versus host disease were observed and necrotic and normal femoral heads, bone marrows, lungs, and livers were harvested at 2, 4 and 6 w after transplantation. The sections of these tissues were observed under fluorescent microscope. More than 70 % MSCs were successfully labeled with GFP at 72 h after labeling. MSCs were uniformly distributed in multiple organs and tissues including brain, lungs, heart, kidneys, intestine and bilateral hip joints of nude mice. In rabbits, at 6 w after intravenous transplantation, GFP labeled MSCs were noted in the lungs, liver, bone marrow and normal and necrotic femoral heads of rabbits, and the number of MSCs in bone marrow was higher than that in the, femoral head, liver and lungs. Furthermore, the number of MSCs peaked at 6 w after transplantation. Moreover, no immunological rejection and graft versus host disease were found after transplantation in rabbits. Our results revealed intravenously implanted MSCs could migrate into the femoral head of hosts, and especially migrate directionally and survive in the necrotic femoral heads. Thus, it is feasible and safe to treat femoral head necrosis by intravenous transplantation of allogeneic MSCs.

Femoral head osteonecrosis can be caused by disruption of the systemic immune response via the toll-like receptor 4 signalling pathway.

OBJECTIVES: Osteonecrosis of the femoral head is observed in patients treated with steroids. However, the pathogenesis of femoral head osteonecrosis remains unclear. We established a rat model with femoral head osteonecrosis by injecting lipopolysaccharide (LPS) and steroid, and assessed the consequences of this on femoral head histology, the systemic immune response and lipid synthesis. METHODS: Male Wistar rats were injected intravenously on days 0 and 1 with 2 mg/kg LPS and intramuscularly with 20 mg/kg methylprednisolone on days 3, 4 and 5. The animals were sacrificed 1, 2, 3 or 4 weeks after the last methylprednisolone injection. Histopathological and biochemical analyses were performed every week. RESULTS: Osteonecrosis of the femoral head was observed in the rats. The plasma triglyceride concentrations had decreased significantly by weeks 2 and 3. The total plasma cholesterol concentrations had increased significantly by week 1 but then decreased significantly by week 4. The plasma concentrations of IL-1beta, IL-2, IL-4, IL-6, IL-10, GM-CSF, IFN-gamma and TNF-alpha had increased significantly by week 1. These cytokines can all be induced by toll-like receptor 4 (TLR4) signalling. CONCLUSIONS: LPS and methylprednisolone induced osteonecrosis of the femoral head in rats and this was associated with a disruption of the innate immune system and lipid synthesis. These findings suggest that the TLR4 signalling pathway plays an important role in the pathogenesis of femoral head osteonecrosis.

Immunologic factors in the pathogenesis of osteonecrosis.

Osteonecrosis is a disease in which death of cellular elements of bone occurs as a result of diminished arterial blood supply. The pathogenetic mechanisms of osteonecrosis remain unresolved. Extravascular pressure and subsequent tamponade of the arterial vessels or an intravascular thrombosis have been suggested. Immunologic factors may also play an important role. In autoimmune disorders, small vessel vasculitis or other disease-associated features, as well as antiphospholipid antibodies, have been involved in the development of osteonecrosis.

Osteonecrosis of the femoral head of laboratory animals: the lessons learned from a comparative study of osteonecrosis in man and experimental animals.

Animal models of osteonecrosis of the femoral head are indispensable to the understanding of successful treatment modalities for avascular necrosis of the femoral head in adults and in children with Legg-Calvé-Perthes disease. Many of these models adequately reflect the current "vascular deprivation" theory regarding the etiology of the disease. In addition to spontaneous occurrence, surgical- and corticosteroid-induced models are suitable, common experimental ones. Osteonecrosis of spontaneously hypertensive rats appears to be due to defective bone formation and compression of the arteries entering the femoral head at its lateral facets by daily weight-bearing loads. Successful modeling of surgical-induced femoral capital necrosis can be a challenge in animals with a dual epiphyseal blood supply. High doses of corticosteroids are a pivotal risk factor in the development of osteonecrosis. The pathogenesis of corticosteroid-induced osteonecrosis likely resides in reduced blood flow. Steroids may reduce blood flow by numerous mechanisms, including marrow adipocytic hypertrophy leading to sinusoidal compression, venous stasis and, eventually, obstruction of the arteries, and arterial occlusion by fat emboli and lipid-loaded fibrin-platelet thrombi. Other, less common varieties of osteonecrosis include those secondary to endotoxin-induced disseminated intravascular coagulation, immune reactions, immoderately low or high temperatures, and high-impact-related injuries. Common to these diverse forms of osteonecrosis are fibrin thrombi clogging arterioles and small arteries.

Procoagulants and osteonecrosis.

OBJECTIVE: To study the relationship between hypofibrinolysis, thrombophilia, and osteonecrosis. We evaluated the frequency of abnormal concentrations of 9 coagulation factors in patients diagnosed with osteonecrosis. METHODS: Blood samples were drawn from 45 patients diagnosed with osteonecrosis. Etiologic associations included systemic lupus erythematosus (n = 9), inflammatory bowel disease (n = 1), corticosteroid therapy (n = 20), or history of heavy alcohol (n = 4) or tobacco (n = 3) use. No associated risk factors were identified in 5 patients; these individuals were labeled "idiopathic." The patient cohort was matched to a similarly studied cohort of 40 healthy individuals without documented osteonecrosis. The following factors were analyzed: plasminogen activator inhibitor (PAI-Fx), stimulated tissue plasminogen activator, lipoprotein (a), resistance to activated protein C, anticardiolipin antibodies (aCL IgG, IgM), protein C, protein S (free), and homocysteine. RESULTS: Thirty-seven of the 45 patients (82.2%) with osteonecrosis were found to have at least one coagulopathy, versus 30% of controls (p < 0.0001). Twenty-one patients (46.7%) were identified with 2 or more abnormal test results versus 2.5% of controls (p < 0.0001). Patients were more likely than controls to have high levels of the hypofibrinolytic plasminogen activator inhibitor activity (42% vs 3%; p < 0.0001), and high anticardiolipin antibody IgG (34% vs 10%; p = 0.008). At least one coagulation factor abnormality was detected in all 5 idiopathic patients; elevated aCL IgG and PAI-Fx were evident in 4 patients. CONCLUSION: This study revealed a high incidence of thrombophilic and hypofibrinolytic coagulation abnormalities in patients with osteonecrosis. These findings have major implications for the diagnosis as well as the treatment of this disease. Since some of these abnormalities may be the result of autosomal dominant disorders, it may be possible to detect individuals at risk for development of this disease.

Histological appearance of the intra-osseous vessels of the femoral head in aseptic osteonecrosis of the hip, with or without antiphospholipid antibodies.

UNLABELLED: It has been suggested that in some patients non-traumatic aseptic osteonecrosis of the hip (AOH) could be the result of the intra-osseous thrombosis. Antiphospholipid antibodies (APL) have been associated with venous and arterial occlusive events and the association between AOH and APL syndrome has been reported. OBJECTIVES: To compare bone vessels of the femoral head in patients operated on for AOH with or without APL. PATIENTS: Twenty patients (mean age 47 yrs) with AOH were included: in eight patients APL (IgG-ELISA) were negative (< 8 GPL units), in nine patients APL were doubtful (8-15 GPL units), and in three patients APL were positive (> 15 GPL units). METHODS: Bone vessels were examined: arteriosclerotic lesions, i.e. fibrosis or thickening of the media and rupture of the internal elastic lamina, thrombosis or vasculitis were sought in the femoral heads after total hip replacement or core decompression. RESULTS: Bone vessel lesions were the same in the three groups.

No link between avascular necrosis of the femoral head and antiphospholipid antibodies.

The rate of occurrence of antiphospholipid antibodies was compared in 47 patients with avascular necrosis of the femoral head and in 47 controls matched on age and sex. Antiphospholipid antibodies were looked for using three techniques in each patient, namely the VDRL test, an ELISA for anticardiolipin, and a circulating anticoagulant detection procedure involving three different tests. The VDRL and the tests for circulating anticoagulants were negative in all the patients and controls. No significant between-group difference was found for the ELISA, which was positive in three patients and two controls.