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Objective: Osteonecrosis (ON), which can lead to physical disability, is a common complication of systemic lupus erythematosus (SLE). The purpose of this study was to determine the prevalence of ON and identify possible risk factors in Chinese SLE patients., Methods: SLE patients who fulfilled the 1997 American College of Rheumatology SLE classification criteria were recruited from the Peking Union Medical College Hospital. The chi-square test (χ 2 test) and multivariate regression analyses were used to evaluate risk factors. The Cox proportional-hazards model was used to construct the survival curves and estimate the simultaneous effects of prognostic factors on survival., Results: We consecutively enrolled 1,158 patients, of which 88 patients (7.6%) developed ON. Among ON patients, 57.1% of patients had isolated femoral head necrosis and 42.9% had multiple joint involvement. The mean age of ON patients (24.62 ± 8.89 years) was significantly younger than SLE patients without ON (27.23 ± 10.16 years, p  = 0.09). The ON group presented with a much longer disease course (10.68 ± 5.97 years, p  < 0.001) and increased incidence of arthritis, kidney, and central nervous system (CNS) involvement (65.9% [ p  < 0.05], 57.6% [ p  < 0.05], and 16.5% [ p  < 0.05], respectively, in the ON group). ON patients were more likely to be treated with glucocorticoid (GC) and to receive a high dose of prednisolone at the initial stage of SLE ( p  < 0.05). The percentage of patients who received hydroxychloroquine was much higher in the control group ( p  < 0.001). Cox regression analysis suggested that CNS involvement and GC therapy were two independent risk factors for ON in SLE patients. The presence of anti-phospholipid antibodies (aPLs) was a risk factor for multiple joint necrosis (odds ratio: 6.28, p  = 0.009)., Conclusions: ON remains a serious and irreversible complication in SLE. In addition to glucocorticoid therapy, we found that CNS system involvement was a risk factor for ON, while the administration of hydroxychloroquine was a protective factor. The clinical characteristics of multiple site ON patients were distinct from isolated femoral head necrosis patients. The presence of aPLs was a risk factor for multiple site osteonecrosis.

The relationship between the appearance of bone metabolism disorders and the onset of steroid-induced osteonecrosis remains unclear. We studied the time course of calcium, phosphorus, osteocalcin, alkaline phosphatase, and mineral density of bone tissue in the subchondral bone of the femoral head of rabbits injected with steroids and attempted to precisely determine the time when disorders in bone metabolism started in animals with steroid-induced osteonecrosis. We detected bone metabolism disorders involved in the early pathogenesis of steroid-induced osteonecrosis, which were the cause, but not the result of this condition.

Background: Systemic lupus erythematosus is a multi-organ inflammatory autoimmune disease; immune complexes are part of the pathogenesis, but not entirely responsible. Trisomy X is the most common female chromosomal abnormality and the role of an additional X chromosome in the development of systemic lupus erythematosus is well recognized. However, the potential complications and optimal management of childhood lupus with trisomy X remain unclear. Herein, we describe a case of childhood-onset systemic lupus erythematosus associated with severe bone complications presumably secondary to trisomy X., Case Presentation: A 16-year-old Japanese girl was diagnosed with childhood-onset systemic lupus erythematosus and trisomy X. A chromosomal abnormality (47, XXX) was incidentally identified on bone marrow examination initially done to determine the cause of pancytopenia. She had a persistent headache, fever　for six days, diffuse hair loss, mucosal ulcers, butterfly eruptions, and palmar erythema. Furthermore, thrombocytopenia, anemia, and erythrocyte fragmentation were detected, suggesting secondary thrombotic microangiopathy. She was initially treated with intravenous methylprednisolone pulse therapy and prescribed monthly cyclophosphamide for severe disease activity, prednisolone, mycophenolate mofetil, and hydroxychloroquine as remission maintenance drugs. She developed generalized extremity pain that had been worsening throughout the disease. Extremity magnetic resonance imaging performed 12 months after the treatment onset revealed multifocal avascular necrosis, and dual-energy X-ray absorptiometry revealed further decreased bone mineral density. High plasma levels of factor VIII were detected by additional tests for coagulation functions, and we suspected the possibility that factor VIII might cause avascular necrosis due to thrombosis. Currently, she is being treated with prednisolone and MMF for SLE. However, her extremity pain has not been managed effectively even under the administration of non-steroidal anti-inflammatory drugs and pregabalin., Conclusions: An additional X chromosome has been reported to be associated with factor VIII and osteoporosis. Additionally, elevated plasma levels of FVIII is the risk factors for thrombosis, which leads to the risk of avascular necrosis. Patients with systemic lupus erythematosus complicated by trisomy X might be at a higher risk of avascular necrosis and osteoporosis that can also manifest in childhood systemic lupus erythematosus.

Purpose: Early diagnosis is crucial to increase the chances of conservation treatment for patients with steroid-induced osteonecrosis of the femoral head (SIONFH). This study aimed to identify serum peptides as potential biomarkers to diagnose SIONFH., Experimental Design: The serum proteome of 32 SIONFH patients and 24 healthy controls are analyzed using magnetic bead-based weak cation exchange (MB-WCX) and matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF-MS). Next, candidate biomarkers are identified using liquid chromatography-electrospray ionization-tandem mass spectrometry (LC-ESI-MS/MS). Candidate biomarkers are then validated using ELISA and western blotting., Results: 39 peaks are identified and the expression fold changes of seven peaks in the two groups are greater than 1.5. Three peaks (m/z: 1077.84 Da; m/z: 1061.78 Da; m/z: 1099.56 Da) tend to be upregulated, while four peaks (m/z: 3973.92 Da; m/z: 7766.53 Da; m/z: 3957.31 Da; m/z: 4212.02 Da) tend to be down-regulated in SIONFH patients. The peak for a 1077.84 Da peptide is identified as Isoform 1 of the Fibrinogen alpha chain precursor (FGA). ELISAs and western blot analyses reveal that the expression of FGA is significantly higher in SIONFH patients than healthy controls., Conclusion and Clinical Relevance: FGA is overexpressed in SIONFH patients, and thus, is a novel potential biomarker for SIONFH., (© 2020 Wiley-VCH GmbH.)

Traumatic osteonecrosis of femoral head (TONFH) is a common orthopedic disease caused by physical injury in hip. However, the unclear pathogenesis mechanism of TONFH and lacking of simple noninvasive early diagnosis method cause the necessity of hip replacement for most patients with TONFH. In this study, we aimed to identify circulating microRNAs (miRNAs) by integrated bioinformatics analyses as potential biomarker of TONFH. mRNA expression profiles were downloaded from the Gene Expression Omnibus database. Then we combined two miRNA screen methods: Weighted gene co-expression network analysis and fold change based differentially expressed miRNAs analysis. As a result, we identified 14 key miRNAs as potential biomarkers for TONFH. Besides, 302 target genes of these miRNAs were obtained and the miRNA-mRNA interaction network was constructed. Furthermore, the results of Kyoto Encyclopedia of Gene and Genome pathway analysis, Gene Ontology function analysis, protein-protein interaction (PPI) network analysis and PPI network module analysis showed close correlation between these 14 key miRNAs and TONFH. Then we established receiver operating characteristic curves and identified 6-miRNA signature with highly diagnosis value including miR-93-5p (area under the curve [AUC] = 0.93), miR-1324 (AUC = 0.92), miR-4666a-3p (AUC = 0.92), miR-5011-3p (AUC = 0.92), and miR-320a (AUC = 0.89), miR-185-5p (AUC = 0.89). Finally, the results of quantitative real-time polymerase chain reaction confirmed the significantly higher expression of miR-93-5p and miR-320a in the serum of patients with ONFH. These circulating miRNAs could serve as candidate early diagnosis markers and potential treatment targets of TONFH., (© 2020 Wiley Periodicals, Inc.)

Recently, the role of microRNAs (miRs) in human diseases has been verified. This study was determined to explore the protective effects of microRNA-26a (miR-26a) in steroid-induced osteonecrosis of the femoral head (SONFH) with the involvement of enhancer of zeste homologue 2 (EZH2).Femoral head (FH) samples from SONFH patients and patients with femoral neck fracture were collected, and rat SONFH models were established by Escherichia coli endotoxin combining with large dose steroid pulse assay. The hemorheology, blood lipid, inflammatory factors, and pathologic changes were measured by a series of experiments. Moreover, the detection of osteoblasts, osteoclasts, miR-26a expression, EZH2 expression, osteoprotegerin (OPG) and osteoprotegerin ligand (OPGL), and the apoptosis of osteocytes were conducted. The target relation between miR-26a and EZH2 was clarified by bioinformatics and dual-luciferase reporter gene assay.MiR-26a was poorly expressed, while EZH2 was highly expressed in SONFH, and the elevation of miR-26a could repress EZH2 expression. Elevated miR-26a and reduced EZH2 were able to decelerate the apoptosis of osteocytes, increase osteoblasts, and decrease osteoclasts, resulting in a repression of SONFH progression. Additionally, EZH2 was a target gene of miR-26a. Furthermore, the elevation of EZH2 could reverse the repression of SONFH progression that is induced by elevated miR-26a.We found that up-regulation of miR-26a and knockdown of EZH2 could suppress the development of SONFH, which would contribute to the therapy of SONFH.

Bone diseases represent an increasing health burden worldwide, and basic research remains necessary to better understand the complexity of these pathologies and to improve and expand existing prevention and treatment approaches. In the present study, 216 bone samples from the caput femoris and collum femoris of 108 patients with degenerative or dysplastic coxarthrosis, hip fracture, or osteonecrosis were evaluated for the proportion of trabecular bone (TB) and expression of parathyroid hormone (PTH) type 1 receptor (PTH1R), osteoprotegerin (OPG), and receptor activator of nuclear factor kappa-B ligand (RANKL). Serum levels of PTH, OPG, soluble RANKL (sRANKL), alkaline phosphatase (AP), osteocalcin, total procollagen type-1 intact N-terminal propeptide (TP1NP), tartrate-resistant acid phosphatase type 5b (TRAP5b), sclerostin, and C-telopeptide of type-1 collagen (ICTP) were also determined. Age was positively correlated with serum levels of PTH, OPG, and sclerostin but negatively associated with TB and sRANKL. Women exhibited less TB, lower sclerostin and ICTP, and higher TRAP5b. Impaired kidney function was associated with shorter bone decalcification time, less TB, lower sRANKL, and higher serum PTH, OPG, and sclerostin. Furthermore, correlations were observed between bone PTH1R and OPG expression and between serum PTH, OPG, and AP. There were also positive correlations between serum OPG and TP1NP; serum OPG and sclerostin; serum AP, osteocalcin, and TRAP5b; and serum sclerostin and ICTP. Serum OPG was negatively associated with sRANKL. In summary, clear relationships between specific bone metabolism markers were observed, and distinct influences of age, sex, and kidney function, thus underscoring their suitability as diagnostic or prognostic markers., Competing Interests: The authors have declared that no competing interests exist.

Objective: To test whether patients with spontaneous osteonecrosis of the knee (SONK) are characterized by abnormal levels of thrombophilia-associated factors., Design: Twenty-five patients with SONK were recruited. Inclusion criteria were (1) age >40 years, (2) acute onset knee pain not precipitated by trauma, and (3) MRI findings consistent with SONK. Exclusion criteria were (1) history of cancer and chemotherapy and (2) factors associated with secondary osteonecrosis. Blood tests included 13 thrombophilia-associated factors that were either heritable mutations or acquired factors. Descriptive statistics included medians, ranges, means, and standard deviations. Mann-Whitney test was used to compare thrombophilia-associated factor levels between the sexes. Spearman's rank test was used to test correlations between smoking status and each thrombophilia-associated factor. Level of significance was set at 0.05., Results: Median patient age was 62 years (range, 44-77 years). There were 16 (64%) men. Thirteen (52%) patients had thrombophilia-associated factor abnormalities of which 9 were elevated fibrinogen but this was less than 1 standard deviation above norm threshold. Other findings were 3 patients with marginally decreased antithrombin below norm threshold, low protein S Ag in only 1 patient, and factor V Leiden mutation heterozygosity in 2 patients, which was not higher than normal population prevalence. Thrombophilia-associated factors neither differed between sexes ( P = nonsignificant) nor correlated with smoking status ( P = nonsignificant)., Conclusion: Thrombophilia-associated factor abnormalities in patients with SONK were minimal. Therefore, clinical workup and treatment strategy in this disease should focus on addressing alternative etiologies leading to abnormal subchondral bone metabolism with focal osteopenia.

Objective To detect serum levels of interleukin-10 (IL-10) and transforming growth factor-β1 (TGF-β1) in patients with systemic lupus erythematosus (SLE) with bone damage, and analyze their clinical significance. Methods The study included 56 patients with SLE. Serum IL-10 and TGF-β1 levels were detected by ELISA. The clinical data of 56 patients were retrospectively analyzed, mainly recording the cases of osteoporosis and osteonecrosis. According to different bone mass, they were divided into normal bone mass group (14 cases), reduced bone mass group (26 cases) and osteoporosis group (16 cases). According to whether or not there was osteonecrosis, the patients were divided into: no osteonecrosis group (49 cases) and osteonecrosis group (7 cases). SPSS18.0 software was used for statistical analysis. Kolmogorov-smirnov t test whether the data is normally distributed. The measurement data of normal distribution are analyzed by the two-tailed t test. For the measurement data of non-normal distribution, mann-whitney U test was used to analyze. Results Compared to the SLE patients with normal bone mass, SLE patients complicated with osteoporosis lowly expressed TGF-β1 and highly expressed IL-10. The serum level of IL-10 was higher in SLE patients with osteonecrosis than that in SLE patients without osteonecrosis. No difference was found in the TGF-β1 between two groups. Conclusion TGF-β1 level is reduced but IL-10 level is elevated in SLE patients with osteoporosis. Serum IL-10 levels in SLE patients with osteonecrosis are higher than that in those without osteonecrosis.

Aim: Osteonecrosis (ON), also known as avascular necrosis, is an important cause of physical disability in rheumatic disease. When this condition affects multiple structures, disability is increased. The purpose of this study was to describe the clinical characteristics of Korean patients with multifocal ON associated with rheumatic disease and to compare them with those of previously reported cases., Methods: We reviewed the clinical characteristics of eight Korean patients with multifocal ON, defined by the involvement of three or more anatomic sites, associated with rheumatic disease in a single referral academic hospital, and compared them with those of 19 similar cases previously reported in the literature., Results: All eight patients were female, with median age of 26 years. All had underlying systemic lupus erythematosus (SLE) and had been using corticosteroids. The most common site affected by ON was the knee joint. However, in contrast to our patients, the previous reported cases had other rheumatic diseases such as myositis, scleroderma and antiphospholipid syndrome. In comparison between Korean multifocal ON patients with SLE and those of previous reports, shoulder joint involvement was higher in previous reports. Common features in patients from both groups were knee joint involvement and prevalent use of corticosteroids., Conclusion: Our findings indicate that multifocal ON is common in young SLE patients who have been using corticosteroids and the most commonly involved site is the knee., (© 2017 Asia Pacific League of Associations for Rheumatology and John Wiley & Sons Australia, Ltd.)

Avascular necrosis of the femoral head (ANFH) is an a frequently occurring orthopaedic disease with high morbidity. Traditional Chinese Medicine (TCM) Yuanshi Shengmai Chenggu Tablet is a valid prescription for treating steroid-induced femoral head necrosis. However, there are rare investigations about the serum protein marker expression after the acting of drugs on hormone and TCM. In the present study, we aimed to systematically discover and validate the serum biomarkers expression difference in patients with steroid-induced avascular necrosis of femoral head (SANFH) after taking Yuanshi Shengmai Chenggu Tablets (SANFH-TCM), so as to reveal the action mechanism of TCM from the molecular level by using isobaric tags for relative and absolute quantification (iTRAQ) with multiple reaction monitoring quantification. Significant differences in fibrinogen alpha, fibrinogen beta, fibrinogen gamma, fibronectin, C-reactive protein, apolipoprotein A, apolipoprotein D, and apolipoprotein E were found among SANFH, SANFH-TCM, and healthy controls. Therefore, our study proposes potential biomarkers for SANFH diagnosis and for the prognosis of femoral head necrosis after Traditional Chinese Medicine treatment.

Background: The pathophysiology of sickle cell disease (SCD) and the variability of its clinical expression remain not fully understood, whether within or between different SCD genotypes. Recent studies have reported associations between lipid levels and several SCD complications. If lipid levels have been previously described as low in sickle cell anemia (SCA), few data have been provided for sickle cell SC disease (SCC). We designed our epidemiological study to isolate lipid levels and profiles by genotype in Guadeloupian cohorts of SCA and SCC adult patients, at steady state. We compared SCD lipid levels with those of the Guadeloupian general population (GGP), and analyzed potential associations between lipid levels and SCD complications (vaso-occlusive crises, acute chest syndrome and osteonecrosis)., Methods: Lipids, apolipoproteins, biological variables and anthropometric evaluation, were collected at steady state from medical files for 62 SCC and 97 SCA adult patients. Clinical SCD complications were collected from the clinical files. Analysis was conducted by genotype for all variables., Results: Different SCC and SCA lipid profiles, both distinct from their GGP's, were identified. Compared to SCC and GGP, higher triglyceride (TG) levels were observed in SCA patients, independent of hydroxyurea, hemolysis, gender, age, body mass index (BMI), abdominal obesity and clinical nutritional status. Our survey highlights also subsequent anthropometrical phenotypes, with an over-representation of abdominal obesity with normal BMI in SCA patients, and affecting almost exclusively females in both genotypes. Moreover, more frequent positive history of acute chest syndrome (ACS) was observed in SCA patients with TG level higher than 1.50 g/l, and of osteonecrosis in SCC patients having non high-density lipoprotein-cholesterol level (Non HDL-C) higher than 1.30 g/l., Conclusions: This study reveals that SCA and SCC patients exhibit distinct lipid profiles and suggests that high TG and Non HDL-C levels are associated with past histories of ACS and osteonecrosis in SCA and SCC patients, respectively.

Background: The objective of this study was to investigate the protective effects of molecular hydrogen, a novel and selective antioxidant, on steroid-induced osteonecrosis (ON) in a rabbit model., Methods: Sixty rabbits were randomly divided into two groups (model group and hydrogen group). Osteonecrosis was induced according to an established protocol of steroid-induced ON. Rabbits in the hydrogen group were treated with intraperitoneal injections of molecular hydrogen at 10 ml/kg body weight for seven consecutive days. Plasma levels of total cholesterol, triglycerides, soluble thrombomodulin(sTM), glutathione(GSH) and malondialdehyde(MDA) were measured before and after steroid administration. The presence or absence of ON was examined histopathologically. Oxidative injury and vascular injury were assessed in vivo by immunohistochemical staining of 8-hydoxy-2-deoxyguanosine(8-OHdG) and MDA, and ink artery infusion angiography. The terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assays were performed to measure apoptosis., Results: The incidence of steroid-induced ON was significantly lower in hydrogen group (28.6%) than that in model group (68.0%). No statistically differences were observed on the levels of total cholesterol and triglycerides. Oxidative injury, vascular injury and apoptosis were attenuated in the hydrogen group compared with those in the model group in vivo., Conclusions: These results suggested that molecular hydrogen prevents steroid-induced osteonecrosis in rabbits by suppressing oxidative injury, vascular injury and apoptosis.

We describe thrombosis, deep venous thrombosis (DVT) pulmonary embolism (PE; n = 9) and hip-knee osteonecrosis (n = 5) that developed after testosterone therapy (median 11 months) in 14 previously healthy patients (13 men and 1 woman; 13 Caucasian and 1 African American), with no antecedent thrombosis and previously undiagnosed thrombophilia-hypofibrinolysis. Of the 14 patients, 3 were found to be factor V Leiden heterozygotes, 3 had high factor VIII, 3 had plasminogen activator inhibitor 1 4G4G homozygosity, 2 had high factor XI, 2 had high homocysteine, 1 had low antithrombin III, 1 had the lupus anticoagulant, 1 had high anticardiolipin antibody Immunoglobulin G, and 1 had no clotting abnormalities. In 4 men with thrombophilia, DVT-PE recurred when testosterone was continued despite therapeutic international normalized ratio on warfarin. In 60 men on testosterone, 20 (33%) had high estradiol (E2 >42.6 pg/mL). When exogenous testosterone is aromatized to E2, and E2-induced thrombophilia is superimposed on thrombophilia-hypofibrinolysis, thrombosis occurs. The DVT-PE and osteonecrosis after starting testosterone are associated with previously undiagnosed thrombophilia-hypofibrinolysis. Thrombophilia should be ruled out before administration of exogenous testosterone.

Objective: The aim of this study was to examine the role of coenzyme Q10 (CoQ10) in the prevention of steroid-induced osteonecrosis of the femoral head (ONFH) in rats., Methods: The study included 20 Sprague-Dawley rats injected once with 20 mg/kg of methylprednisolone acetate into the right gluteus medius muscle to induce osteonecrosis. Animals were divided into two equal groups; Group 1 received no prophylaxis (control group) and the Group 2 received CoQ10. Hematological examinations were performed before steroid injection (0 weeks) and at 4 weeks after steroid injection. Femoral heads were examined histologically to evaluate osteonecrosis., Results: Changes in blood glutathione (GSH) and malondialdehyde (MDA) concentrations were less significant in the CoQ10 group. The incidence of histologic changes consistent with early osteonecrosis was lower in the CoQ10 group (2 of 10; 20%) than the control group (7 of 10; 70%)., Conclusion: Coenzyme Q10 may be useful as a preventing agent in steroid-induced ONFH. Inhibited oxidative stress is a possible mechanism for this effect.

Multifocal or multiple osteonecrosis (ON), defined by the involvement of 3 or more anatomic sites, is unusual, being observed in only 3%-10% of patients diagnosed with ON. We report the clinical characteristics of a cohort of 29 patients with multifocal ON from a single center and evaluate the prevalence of associated prothrombotic abnormalities in 26 of these patients. We conducted a retrospective study of all patients diagnosed with multifocal ON evaluated in our institution during the last 20 years. We recorded clinical manifestations and underlying diagnoses. A wide thrombophilic profile was performed, including antithrombin, protein C, protein S, lupus anticoagulant, anticardiolipin antibodies, activated protein C resistance, factor V Leiden, mutation G-20210-A of the prothrombin gene, and factor VIII. Coagulation test results were compared with those in a healthy control group and a group of patients with history of lower-extremity deep venous thrombosis. The mean age of the patients was 49.2 ± 15 years (range, 28-81 yr). The mean number of ON localizations per patient was 5.2 ± 2.3 (range, 3-11). Hips were the most commonly affected joint (82%), followed by knees (58%), shoulders (37%), and ankles (13%). Most patients had an underlying disease process, and 12 of 25 (48%) patients had coagulation test abnormalities. The most common alterations were high factor VIII levels and antiphospholipid antibody (aPL) positivity in 24% and 20% of cases, respectively. These abnormalities were more prevalent in patients with multifocal ON compared with patients in the control groups. Sixty-one percent of patients had a history of corticosteroid treatment. Patients with coagulation abnormalities had a higher number of ON localizations per patient (6.5 ± 2.7 vs. 3.88 ± 0.8; p = 0.002) and a higher prevalence of atypical ON localizations (25% vs. 0%; p = 0.05). In conclusion, in the present cohort of patients with multifocal ON, 48% of the patients had at least 1 prothrombotic factor, especially high levels of factor VIII and aPL. These findings have major implications for the diagnosis and treatment of multifocal ON and clearly indicate the need to perform a thrombophilic profile in these patients.

Objective: To determine whether levels of cryofibrinogen are increased in non-traumatic osteonecrosis (ON) and could correlate with disease staging., Methods: We prospectively analysed cryofibrinogen levels by immunofixation electrophoresis in 50 patients with non-traumatic ON, 50 healthy volunteers and 8 patients with traumatic ON. Staging of disease involving the femoral heads and the size of necrotic lesions were assessed by the Association Research Circulation Osseous (ARCO) classification system., Results: Mean cryofibrinogen levels in patients with non-traumatic ON were significantly increased relative to healthy controls and to patients with traumatic ON (222.1 ± 20.6, 59.9 ± 5.6 and 52.3 ± 14.9 mg/dl, respectively, P < 0.001). In the non-traumatic ON group, mean cryofibrinogen levels were significantly increased in patients with multifocal ON compared with patients with mono/bifocal ON (276.5 ± 56.5 and 149.3 ± 15.4 mg/dl, respectively, P = 0.03). There were no significant differences in cryofibrinogen levels observed with respect to the size of the necrotic lesions involving the femoral heads. Moreover, cryofibrinogen levels in patients with ON of the femoral heads classified according to the stage of disease were not significantly different between patients with stage 1/2 and patients with stage 3 ON (179.2 ± 31.3 vs 204.1 ± 29.0 mg/dl, respectively; P = 0.813)., Conclusion: Cryofibrinogen levels are increased in non-traumatic ON and, more importantly, in multifocal ON. The fact that cryofibrinogen levels are not correlated with the size of lesions and the stage of disease could imply systemic rather than local involvement characterizing the pathogenesis of ON.

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.

The objective of this study was to investigate in vivo effects of lipoic acid (LA) in preventing steroid-induced osteonecrosis and the possible pathway in a rabbit model. Sixty rabbits were divided into 2 groups: rabbits were intraperitoneally injected with LA aqueous solution at 36 mg/kg of body weight per day for 4 weeks in Group A and rabbits were injected with physiologic saline (PS) as a control in Group B. At 2 weeks after starting treatment, they were intramuscularly injected once with 20 mg/kg of methylprednisolone acetate (MPSL). The femora were histopathologically examined for the presence of osteonecrosis. The plasma levels of total cholesterol (TC), low-density lipoprotein (LDL), high-density lipoprotein (HDL), glutathione (GSH), endothelin (ET) and malondialdehyde (MDA) were assayed at 2 weeks after the injection of MPSL. The incidence of osteonecrosis was significantly higher in Group B (73.1%) than in Group A (20.8%). The GSH level was higher in Group A than in Group B after the LA injection. The plasma MDA and ET levels were lower in Group A than in Group B at 2 weeks after the MPSL administration. Lipoic acid can prevent the development of steroid-induced osteonecrosis in rabbits. Inhibited oxidative stress and amendment of vascular endothelial dysfunction is a possible mechanism for this effect.

Background: To investigate the relationship between chemokines and cytokines and osteonecrosis in Gaucher disease, we conducted multiplex assays in a cohort of 100 adult patients., Methods: Mean age was 45 years (18-86); 92 Gaucher patients received imiglucerase (median duration 8 years (2-18)). Forty-three had experienced osteonecrosis (ON), and eight had ON despite enzyme therapy. Serum cytokines/chemokines were determined by fluorimetric bead arrays in samples from Gaucher patients and healthy volunteers (10 males and 10 females). Intra-assay and inter-assay coefficients of variation were 2%-9.8% and 5.6%-15%, respectively., Results: VEGF and CCL5/RANTES did not differ between Gaucher and control samples. Concentrations of CCL3/MIP-1α, CCL4/MIP-1β, CCL2/MCP-1, CXCL8/IL-8, IL-1ra and CCL18/PARC were elevated in Gaucher patients (p<0.05 for each). Median CCL4/MIP-1β, CXCL8/IL-8, CCL5/RANTES and CCL18/PARC concentrations were greater in the 43 osteonecrosis patients (88.6 pg/mL, 30.5 pg/mL, 89.6 ng/mL and 434 ng/mL, respectively) compared with the 57 patients who had no evidence of osteonecrosis (medians of 59.4, 13.3, 62.7 and 283, respectively, p<0.05). Moreover, the eight patients with ON despite imiglucerase had median concentrations of CCL3/MIP-1α, CCL4/MIP-1β, CXCL8/IL-8, CCL5/RANTES and CCL18/PARC (73.2, 120.9, 36.3 pg/mL, 105 and 767 ng/mL, respectively), which significantly exceeded the values in 84 patients now free of ON (52.3, 71.2, 16.5 pg/mL, 69.5 and 315 ng/mL, respectively, p<0.05). Treatment exposures were similar., Conclusion: Numerous serum cytokines are elevated in Gaucher disease. CCL18/PARC, CCL3/MIP-1α, CCL4/MIP-1β, CCL5/RANTES and CXCL8/IL-8 are potential biomarkers of osteonecrosis and may allow prediction of this disabling complication., (Copyright © 2010 Elsevier Inc. All rights reserved.)

Purpose: the purpose of this retrospective study was to examine the possibility of utilizing serum C-terminal telopeptide cross-link of type I collagen (s-CTX) and serum osteocalcin (s-OC) as risk markers for oral bisphosphonate-related osteonecrosis of the jaws (BRONJ)., Patients and Methods: the s-CTX values and the s-OC values were measured from 23 patients (one male, 22 females) diagnosed with BRONJ using clinical and radiographic examinations. The two biochemical markers were evaluated during a regular checkup for osteoporosis management. For the control group of s-CTX study, s-CTX values were obtained from 61 independently recruited postmenopausal women who have been on bisphosphonate therapy for >6 months. The s-CTX values of the ONJ group and the control group were compared. Because of retrospective nature of this study, the control group for s-OC study could not be established. A single sample t-test was performed for the s-OC value from the ONJ group., Result: twenty-three ONJ patients had taken alendronate for osteoporosis treatment, and the s-CTX testing results were low levels of 10-192 pg/ml (mean: 93.2 ± 49.4 pg/ml). Mean of s-CTX of the control (n=61) was 125 ± 85.7 pg/ml. The duration of BP therapy ranged between 1 and 10 years (4.82 ± 2.6). The s-OC level was estimated between 0.2 and 5.4 ng/ml (1.91 ± 1.51 ng/ml). The mean s-CTX value of the control group was higher but without significance (P=0.12). The s-OC values of the ONJ group were significantly lower than the lowest value of the reference range (P<0.001)., Conclusion: as a result of the s-CTX and s-OC testings at the diagnosis of BRONJ, the values of the two markers were decreased. The decrease of the s-OC values implies a problem during the bone-formation process. Therefore, we can assume that in this patient group, invasive dental surgery contributes to an increase in the risk of BRONJ incidence. This result may imply that, during bisphosphonate therapy, simultaneous consideration of s-CTX showing inhibition of bone resorption and s-OC indicating the degree of bone formation might be a set of risk markers assessing risk prediction for BRONJ before invasive dental surgery.

Objective: To examine whether plasma adiponectin level is correlated with osteonecrosis of the femoral head (ONFH)., Methods: Blood adiponectin level in patients with nontraumatic ONFH (n = 120) was compared with a group of healthy subjects (n = 120). Patients with hip osteoarthritis (OA; n = 30) and traumatic ONFH (n = 45) were included as controls. Potential compounding factors, such as plasma low-density lipoprotein (LDL), high-density lipoprotein (HDL), apolipoprotein A1 (apo A1), apolipoprotein B (apo B), total cholesterol (TC), triglycerides (TG), and C-reactive protein (CRP) were also examined., Results: Patients with nontraumatic ONFH had significantly lower plasma levels of adiponectin than the healthy controls (7.14 ± 3.53 vs 10.93 ± 3.41 μg/ml, respectively; p < 0.001). Adiponectin level was positively correlated with HDL (r = 0.282, p < 0.001) and age (r = 0.145, p = 0.01), yet negatively correlated with body mass index (r = -0.70, p < 0.001), TG (r = -0.55, p<0.001), LDL/HDL ratio (r = -0.173, p = 0.002), and CRP (r = -0.634, p < 0.001). No correlation was seen with LDL (r = -0.017, p = 0.762). A multiple logistic regression analysis revealed that adiponectin level is an independent predictor of the presence of nontraumatic ONFH (p < 0.001, OR 0.676, 95% CI 0.546 to 0.845)., Conclusion: Low adiponectin level is significantly associated with the presence of nontraumatic ONFH. This biomarker may be useful in assessing the potential presence of nontraumatic ONFH.

Atraumatic osteonecrosis has been associated with a variety of clinical conditions including corticosteroid usage, alcoholism, infections, hyperbaric events, storage disorders, marrow-infiltrating diseases, coagulation defects, and some autoimmune diseases. Osteonecrosis due to thrombophilia is an extremely rare condition with only few cases reported previously in the literature. Hormone-replacement therapies cause increased risk of venous thrombosis, probably by causing a synergistic effect with inherited clotting defects. In this article, we report a young female with Turner syndrome, who developed avascular necrosis of the femoral head during treatment with oral estrogen, which was associated with low protein S levels.

Background and Objective: The most common risk factor for bisphosphonate-related osteonecrosis of the jaws (BRONJ) is dentoalveolar surgery. It has been suggested that reduced serum C-terminal telopeptide (CTX) can determine the degree of osteoclast suppression and may predict the development of BRONJ after dentoalveolar surgery. Although there are many radiographic appearances associated with BRONJ, there are little data that describes changes preceding dentoalveolar surgery. The objective of this retrospective study was: 1) to investigate if reduced serum CTX values (i.e., <150 pg/mL) were associated with BRONJ after dentoalveolar surgery; and 2) to determine if specific radiographic changes are associated with teeth that develop BRONJ after extraction., Study Design: A retrospective review of radiographic and/or serum CTX data was performed for 68 patients with a history of bisphosphonate therapy who either underwent dental extraction or were diagnosed with BRONJ in the Department of Oral and Maxillofacial Surgery during the period 2007-2009. Postoperative healing was assessed for 26 patients with reduced serum CTX levels (<150 pg/mL) who either underwent dental extraction or treatment for BRONJ. Preoperative radiographs were evaluated for 55 patients who either healed normally or developed BRONJ after dental extraction., Results: All 26 patients (100%) who had serum CTX levels <150 pg/mL healed successfully after dentoalveolar surgery (20 patients) or after treatment for BRONJ (6 patients). Among the 55 patients who underwent radiographic evaluation, 24 patients (83%) with BRONJ exhibited periodontal ligament (PDL) widening associated with extracted teeth, whereas only 3 patients (11%) who healed normally demonstrated PDL widening., Conclusion: These data suggest that radiographic PDL widening may be a more sensitive indicator than CTX testing in predicting risk of BRONJ. Current guidelines that recommend minimal surgical intervention may need to be revised to include alternative strategies for the elimination or management of this pathology., (Copyright © 2010 Mosby, Inc. All rights reserved.)

Purpose: Osteonecrosis of the jaw is a well-documented side effect of bisphosphonate (BP) use. Attempts have recently been made to predict the development of bisphosphonate-related osteonecrosis of the jaw (BRONJ). We prospectively investigated the predictive value of serum levels of C-terminal telopeptide of collagen I (CTX), bone-specific alkaline phosphatase, and parathyroid hormone for the development of BRONJ., Patients and Methods: Data on the demographics, comorbidities, and BP treatment were collected from 78 patients scheduled for dentoalveolar surgery. Of the 78 patients, 51 had been treated with oral BPs and 27 had been treated with frequent intravenous infusions of BPs. Blood samples for CTX, bone-specific alkaline phosphatase, and parathyroid hormone measurements were taken preoperatively. Surgery was performed conservatively, and antibiotic medications were prescribed for 7 days., Results: Of the 78 patients, 4 patients taking oral BPs (7.8%) and 14 receiving intravenous BPs (51.8%) developed BRONJ. A CTX level less than 150 pg/mL was significantly associated with BRONJ development, with an increased odds ratio of 5.268 (P = .004). The bone-specific alkaline phosphatase levels were significantly lower in patients taking oral BPs who developed BRONJ. The parathyroid hormone levels were similar in patients who did and did not develop BRONJ., Conclusion: The incidence of BRONJ after oral surgery involving bone is greater among patients receiving frequent, intravenous infusions of BPs than among patients taking oral BPs. Although the measurement of serum levels of CTX is not a definitive predictor of the development of BRONJ, it might have an important role in the risk assessment before oral surgery., (Copyright 2010 American Association of Oral and Maxillofacial Surgeons. Published by Elsevier Inc. All rights reserved.)

Asymmetric dimethylarginine (ADMA) is associated with pulmonary hypertension (PHT) in sickle cell disease (SCD). We studied the relationship of ADMA to other SCD-related complications. Plasma ADMA and associated parameters were determined in 52 HbSS/HbSbeta(0)-thalassemia and 24 HbSC/HbSbeta(+)-thalassemia patients. As expected ADMA levels were higher in HbSS/HbSbeta(0)-thalassemia patients with PHT (p=0.018), but also in those with other hemolysis-associated complications such as leg ulcers (p=0.012), cholelithiasis (p=0.008) and priapism (p=0.02) compared with counterparts without these complications. ADMA levels did not differ between patients with and without other disease related complications such as retinopathy and avascular osteonecrosis. Higher ADMA concentrations therefore seem to be associated to the hemolytic phenotype of SCD.

Biochemical markers of bone metabolism have been used in medicine to evaluate and provide treatment to patients with metabolic bone diseases, such as osteoporosis. Serum cross-linked C-telopeptide of type I collagen (CTX) is a marker of osteoclast activity and is used to assess the level of bone resorption. Recently, in oral and maxillofacial surgery, it was proposed that the levels of serum CTX may predict the subsequent risk of developing osteonecrosis of the jaws (ONJ) after oral surgery procedures for patients taking oral bisphosphonates (BPs). The goal of this study was to determine whether this specific serum marker of bone resorption could preoperatively predict the risk of developing ONJ from oral BPs.We hypothesized that there is no clinical correlation between the observed preoperative serum CTX values and the risk of developing ONJ. The authors examine the scientific basis (validity) of the morning fasting serum CTX test in 163 consecutive patients who underwent various oral surgery procedures in the office. The authors also review the laboratory test results and the recommended protocol based on the test values. One hundred sixty-three patients (mean age, 75.9 years) were divided into 2 groups. Group I was the control group that consisted of 109 patients taking oral BPs who did not take the CTX test preoperatively. Group 2 consisted of 54 patients taking BPs and who elected to have the CTX test performed to assess their level of risk of developing ONJ, preoperatively. Both groups of patients were observed for a period of 8 weeks for signs and symptoms of BP-associated ONJ after surgery. The clinical data at 8 weeks and beyond revealed that there was no evidence of BP-associated ONJ in all participants. We conclude that the serum CTX is not a valid preoperative test to accurately assess the level of risk of developing ONJ and is not indicated in the oral surgery patient.

Purpose: The aim of the present study was to correlate the staging of bisphosphonate-related osteonecrosis of the jaws (BRONJ) with serum C-terminal cross-linking telopeptide of type I collagen (CTX), which is under debate as an index of risk prediction. Stage I BRONJ was defined as asymptomatic osteonecrotic bone. Stage II BRONJ includes infection, and stage III includes additional complications such as fracture or extraoral fistulas., Patients and Methods: The serum CTX values of 18 patients (mean age 74 years) who were diagnosed with osteonecrosis of the jaws caused by oral bisphosphonate were investigated., Results: The serum CTX values ranged from 10 to 262 pg/mL (mean 112 +/- 76.1). The mean duration of bisphosphonate therapy was 3.9 years, and 17 of the 18 patients had received once weekly 70 mg aldendronate and 1 patient once weekly 35 mg risedronate. The risk assessment was rated according to the CTX values of the individual patient (minimal risk, more than 150 pg/mL; moderate, 100 to 150 pg/mL; and high, less than 100 pg/mL). Next, the BRONJ scores were calculated according to the number of the BRONJ lesions and their stage. The risk assessment and BRONJ scores were correlated. The result was statistically significant (P = .019)., Conclusions: BRONJ is relatively rare but has been increasingly recognized in our clinic. The usefulness of the serum CTX value as an index of risk prediction continues to be debated. Considering the staging of lesions and the number of lesions, we found a significant correlation between the disease severity and the risk assessment using serum CTX.

Biochemical markers of bone metabolism have been used in medicine to evaluate and provide treatment to patients with metabolic bone diseases, such as osteoporosis. Serum cross-linked C-telopeptide of type I collagen is a marker of osteoclast activity and is used to assess the level of bone resorption. Recently, in oral and maxillofacial surgery, it was proposed that the levels of serum cross-linked C-telopeptide of type I collagen may predict the subsequent risk of developing osteonecrosis of the jaws after oral surgery procedures for patients taking oral bisphosphonates. The astute clinician must critically review the scientific literature and must decide if biochemical markers of bone resorption are of benefit in managing the oral surgery patient on bisphosphonates.

Objective and Design: In this study, we have investigated the relevance of peripheral blood inflammatory CD14(+)CD16(+) monocytes phenotype to patients with aseptic loosening (AL)., Material and Treatment: Immunophenotypes of monocytes were examined among patients with AL (n = 43), patients with mechanical loosening (ML, n = 30), patients with stable implant (SI, n = 16), and patients with osteoarthritis (OA, n = 17) using flow cytometry., Methods: Immunological assay was used to measure TNF-alpha and IL-1 beta levels in both sera and culture media of implant wear stimulated CD14(+)CD16(+) and CD14(++)CD16(-) monocytes. Periprosthetic tissues were collected during surgery for histological assessment., Results: The frequency of CD14(+)CD16(+) monocytes showed significant increase in AL patients than in ML, SI, and OA patients. A positive association was found between the subpopulation of CD14(+)CD16(+) monocytes and plasma TNF-alpha and IL-1 beta level in AL patients. Furthermore, a positive correlation existed between the subpopulation of CD14(+)CD16(+) monocytes and the total histopathology score., Conclusion: The results indicate that CD14(+)CD16(+) monocytes represent a sensitive marker for the disease activity of AL, and may serve as an effective prognostic index to identify total joint replacement recipients who are at increased risk for osteolysis and progression of AL.

Bisphosphonate holiday has been suggested as a treatment modality for oral bisphosphonate-related osteonecrosis; however, there is debate that it can undermine beneficial effects of bisphosphonate therapy. A case successfully treated after bisphosphonate holiday is presented.

Bone turnover markers (BTMs) have become increasingly important in the management of postmenopausal osteoporosis (PMO). In bisphosphonate-treated women with PMO, BTMs can provide early indications of treatment efficacy, are predictors of BMD response and fracture risk reduction, and are potentially useful for monitoring patient compliance. The bone resorption marker serum C-telopeptide cross-link of type 1 collagen (sCTX) has shown high sensitivity and specificity for the detection of increased bone resorption. Recently, sCTX has been singled out as a potential indicator of risk of osteonecrosis of the jaw (ONJ) in patients receiving oral bisphosphonates who require oral surgery. However, whether BTMs are capable of predicting ONJ risk and whether sCTX is usable for this purpose are controversial questions. This article presents an overview of the current literature regarding critical issues affecting the clinical utility of BTMs (including variability and reference ranges) and the current applications of BTMs in PMO management, with a focus on sCTX. Last, the appropriateness of using sCTX to predict ONJ risk in women receiving oral bisphosphonates for PMO is evaluated.

Purpose: To determine whether any abnormality in serum bone markers is related to bisphosphonate-induced osteonecrosis of the jaw., Materials and Methods: We obtained serum bone markers and other relevant endocrine assays on 7 patients with osteonecrosis of the jaws (ONJ). The assays were C-telopeptide, N-telopeptide, bone specific alkaline phosphatase, osteocalcin, intact parathyroid hormone, T3, T4, TSH, and vitamin D 25 hydroxy. Diagnostic criteria for ONJ were those formulated by the American Association of Oral and Maxillofacial Surgeons., Results: Five of our patients were women. Two had metastatic breast cancer and had been treated with zoledronic acid; 1 had also received pamidronate. Three others had osteoporosis and had been treated with daily alendronate. One man had metastatic prostate cancer treated with zoledronic acid. Another man had Gaucher's disease treated with zoledronic acid. All patients had been withdrawn from bisphosphonate for at least 6 months. None was taking or had taken corticosteroids. None of the lesions had shown any significant healing and all were still causing the patients considerable distress, yet the bone markers were within the normal range as measured in our laboratory, except for intact parathyroid hormone, which was slightly elevated in 1 case of metastatic breast cancer (177 pg/mL)., Conclusions: We hypothesize that matrix metalloproteinase 2 (MMP2) is a candidate gene for bisphosphonate-induced ONJ for 3 reasons: 1) MMP2 is associated with bone abnormalities which could be related to ONJ. 2) Bisphosphonates are associated with atrial fibrillation, and MMP2 is the only gene known to be associated with both bone abnormalities and atrial fibrillation. 3) A network of disorders and disease genes linked by known disorder-gene associations indicates that cardiovascular disease and bone disease are closely related, suggesting that a single drug such as bisphosphonate, acting on a single gene, MMP2, could have both bone and cardiovascular side effects different from the osteoclast inhibition that is characteristic of bisphosphonate.

Objective: 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., Methods: 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., Results: 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., Conclusion: 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.

Osteonecrosis of the jaws (ONJ) is an important possible late adverse effect of bisphosphonates. Serum C-terminal cross-linking telopeptide of type I collagen (CTX) can determine bone turnover and can act as a biological marker of bone resorption. We studied this biological marker in 15 patients (Group 1) with bisphosphonate-induced ONJ comparing with a control group of 10 healthy people matched by age and gender. We found no statistically significant relationships in Group 1 either between the serum CTX and the number of areas of exposed bone nor with the size of the osteonecrotic area.

Recently, osteonecrosis of the jaw (ONJ) with bisphosphonates is frequently reported. ONJ due to bisphosphonate is an adverse event in the treatment of breast cancer with bone metastasis. We report a case of ONJ due to bisphosphonates. A 66-year-old woman was admitted to our hospital due to right advanced breast cancer with bone metastasis. She received neo-adjuvant chemotherapy consisting of paclitaxel 70 mg/m2, qw, trastuzumab 2 mg/m2, qw. After chemotherapy, we performed modified mastectomy for local control. Postoperative adjuvant chemotherapy was added with bisphosphonate for bone metastasis of breast cancer. After bisphosphonate was used 14 times, she had a pain and pus-discharge in her lower jaw. The dentists' diagnosis was ONJ. We treated her with antibiotics and local minor curettage. The inflammatory symptoms almost disappeared. In this case, the administration of bisphosphonates was thought to be a major risk factor for ONJ. We think that special precautions for ONJ should be taken in patients administered bisphosphonates for bone metastasis of breast cancer.

Objectives: The pathogenetic mechanisms involved in steroid-induced osteonecrosis are poorly understood. Appropriate experimental models of the human disease are indispensable to the understanding of successful treatment modalities for osteonecrosis., Methods: In the present experiment we devised a novel rabbit model of steroid-induced osteonecrosis by use of two low-dose LPS and three high-dose MPS to investigate the development of osteonecrosis. Thirty eight rabbits were used and tissue assessments were performed on proximal third and distal condyles of femora and humeri obtained 6 weeks after the administration of LPS and MPS. MRI of these regions and intraosseous pressure of proximal femur were obtained at 0 and 6 weeks. Other assessments included serum plasminogen activator/inhibitor ratio, cholesterol level, LDL/HDL ratio, and triglyceride levels at various time points., Results: The study showed that with this osteonecrosis induction protocol there was low animal mortality (6.2%), high rate of osteonecrosis (90%), induction of thrombotic state, and hypercholesterol/lipidemia., Discussion: On the whole, this is a novel modified animal model of steroid associated osteonecrosis and it would be useful for elucidating the pathogenesis of steroid associated osteonecrosis and developing preventive and therapeutic strategies.

We obtained serum bone markers and other relevant endocrine assays on 5 patients with osteonecrosis of the jaw (ONJ). The assays were C-telopeptide, N-telopeptide, bone-specific alkaline phosphatase, osteocalcin, intact parathyroid hormone, T3, T4, TSH, and Vitamin D 25 hydroxy. Diagnostic criteria for ONJ were those formulated by the American Association of Oral and Maxillofacial Surgeons. Four of our patients were women. Two had metastatic breast cancer and had been treated with zoledronic acid; one had also received pamidronate. Two others had osteoporosis and had been treated with daily alendronate. One man had metastatic prostate cancer treated with zoledronic acid. All patients had been withdrawn from bisphosphonate for at least 6 months. None were taking or had taken corticosteroids. None of the lesions had shown any significant healing and all were still causing the patients considerable distress. Yet the bone markers were within the normal range as measured in our laboratory, except for intact parathyroid hormone, which was slightly elevated in one case of metastatic breast cancer (177 pg/mL). Because the jaws have a greater blood supply than other bones, and a high bone turnover rate, bisphosphonates are highly concentrated in the jaws. This anatomic concentration of bisphosphonates might cause bisphosphonate-osteonecrosis to be manifested exclusively in the jaws and is consistent with our finding of normal serum bone markers in ONJ patients.

Osteonecrosis of the femoral head (ONFH) is a skeletal disorder characterized by ischemic deterioration, bone marrow edema and eventually femoral head collapse. The systemic regulation of ONFH in adult patients has not been examined. Serum proteomic is an innovative tool that potentially detects simultaneous expressions of serum proteins in pathological contexts. We compared the serum proteome profiles of 11 adult patients with ONFH (3 females and 8 males) and 11 healthy volunteers (3 females and 8 males). The proteins in the aliquots of sera were subjected to isoelectric focusing, two-dimensional gel electrophoresis and silver staining. The protein spots were matched and quantified using an imaging analysis system. The differentially expressed protein spots were subjected to in-gel trypsin digestion. The peptide mass fingerprints were identified by matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF/TOF) and a bioinformation search. We found that ONFH patients showed significantly higher abundances of kininogen 1 variant, complement factor C3 precursor, and complement factor H and lower levels of antithrombin III chain B, apolipoprotein A--IV precursor, and gelsolin isoform alpha precursor. These proteins of interest were reported to modulate thrombotic/fibrinolytic reactions, oxidative stress, vessel injury, tissue necrosis or cell apoptosis in several tissue types under pathological contexts. Taken together, the occurrence of ONFH was associated with various serum protein expressions. Our high--throughput serum proteomic findings indicated that multiple pathological reactions presumably occurred in ONFH.

We retrospectively reviewed cementless THAs with metal-on-metal bearings in five patients with chronic renal failure and investigated the relations between renal failure and elevated serum cobalt and chromium levels and the side effects of these elevations. Serum cobalt and chromium levels were measured by atomic absorption spectrophotometry at a minimum followup of 2.7 years (mean, 3.9 years; range, 2.7-6.2 years) in five patients with chronic renal failure and in six patients with normal renal function after THA. Mean serum cobalt concentration was 12.5 microg/L in patients with chronic renal failure; this was more than 100-fold higher than in patients with the same prosthesis type and similar followup period, but with no known renal disease. However, the mean serum chromium concentration was 5.1 microg/L, which was within the normal range in all 11 study patients. Side effects related to elevation of serum cobalt or serum chromium concentration were not identified and overall clinical results were good 4 years after surgery. The serum cobalt level was higher in patients with chronic renal failure. Longer followup is necessary to determine any clinical effects.

Objective: The present study employed both static and dynamic imaging modalities to study both intra- and extravascular events attributing to steroid-associated osteonecrosis (ON) using an experimental protocol with a single low-dose lippolysaccharide (LPS) injection and subsequently three injections of high-dose methylprednisolone (MPS)., Methods: Fourteen 28-week-old male New Zealand white rabbits received one intravenous injection of LPS (10 microg/kg). After 24 hours, three injections of 20 mg/kg of MPS were given intramuscularly at a time interval of 24 hours. Additional 6 rabbits were used as controls. Dynamic MRI was performed on bilateral femora for local intraosseous perfusion before and after LPS injection. Blood samples were collected for haematological examinations before and after LPS injection. Bilateral femora were dissected and decalcified for microCT-based microangiography. ON lesion, intravascular thrombus and extravascular marrow fat cell size were examined histopathologically., Results: Intravascular thrombus was observed in all ON rabbits. Extravascular marrow fat cell size was significantly increased in ON rabbits than that of the controls (P < 0.05). Compared to baseline, a significant decrease in ratio of tissue-type-plasminogen-activator/plasminogen-activator inhibitor 1, activated-partial- thromboplatin-time, and a significant increase in ratio of low-density-lipoprotein/high-density-lipoprotein were only found in ON rabbits (P < 0.05). Dynamic MRI showed a significant decrease in the perfusion index 'maximum enhancement' in the ON rabbits (P < 0.05) and microCT-based microangiography showed blocked stem vessels in ON samples. Overall, 93% of the rabbits (13/14) developed ON and no rabbits died throughout the experiment period., Conclusion: Both intra- and extravascular events were found attributing to the steroid-associated ON based on our experimental protocol with a single low-dose LPS injection and subsequent three injections of high-dose MPS. Both high ON incidence and no mortality in rabbits treated with this inductive protocol suggested its effectiveness for future studies on evaluation of therapeutic efficacy of interventions developed for prevention of steroid-associated ON.