Risk of osteonecrosis in systemic lupus erythematosus: An 11-year Chinese single-center cohort study.

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 (χ2 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.

Metabolic Disorders and Mineral Density of the Bone Tissue in the Early Pathogenesis of Osteonecrosis: Study on Rabbits with Steroid-Induced 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.

Identification of potential miRNA biomarkers for traumatic osteonecrosis of femoral head.

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.

Lipid profiles in French West Indies sickle cell disease cohorts, and their general population.

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.

Protective effects of molecular hydrogen on steroid-induced osteonecrosis in rabbits via reducing oxidative stress and apoptosis.

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.

Cryofibrinogen levels are increased in non-traumatic osteonecrosis: a new pathogenic clue to osteonecrosis?

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.

Lipoic acid prevents steroid-induced osteonecrosis in rabbits.

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.

Potential biomarkers of osteonecrosis in Gaucher disease.

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-1ß, CCL2/MCP-1, CXCL8/IL-8, IL-1ra and CCL18/PARC were elevated in Gaucher patients (p<0.05 for each). Median CCL4/MIP-1ß, 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-1ß, 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-1ß, CCL5/RANTES and CXCL8/IL-8 are potential biomarkers of osteonecrosis and may allow prediction of this disabling complication.

Retrospective study of two biochemical markers for the risk assessment of oral bisphosphonate-related osteonecrosis of the jaws: can they be utilized as risk markers?

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.

Childhood-onset systemic lupus erythematosus with trisomy X and the increased risk for bone complications: a case report.

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.

Plasma asymmetric dimethylarginine concentrations in sickle cell disease are related to the hemolytic phenotype.

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.

Serologic bone markers for predicting development of osteonecrosis of the jaw in patients receiving bisphosphonates.

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.

CTX biochemical marker of bone metabolism. Is it a reliable predictor of bisphosphonate-associated osteonecrosis of the jaws after surgery? Part II: a prospective clinical study.

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.

Isoform 1 of Fibrinogen Alpha Chain Precursor is a Potential Biomarker for Steroid-Induced Osteonecrosis of the Femoral Head.

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.

The protective effects of microRNA-26a in steroid-induced osteonecrosis of the femoral head by repressing EZH2.

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.

Expansion of CD14+CD16+ peripheral monocytes among patients with aseptic loosening.

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.

Correlation between serum C-terminal cross-linking telopeptide of type I collagen and staging of oral bisphosphonate-related osteonecrosis of the jaws.

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.

Bisphosphonate-induced osteonecrosis of the jaws, bone markers, and a hypothesized candidate gene.

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.

CTX biochemical marker of bone metabolism. Is it a reliable predictor of bisphosphonate-associated osteonecrosis of the jaws after surgery? Part I: biological concepts with a review of the literature.

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.