Identification of novel drug targets for osteoarthritis by integrating genetics and proteomes from blood.

BACKGROUND: Osteoarthritis (OA) is a degenerative osteoarticular disease, involving genetic predisposition. How the risk variants confer the risk of OA through their effects on proteins remains largely unknown. Therefore, we aimed to discover new and effective drug targets for OA and its subtypes. METHODS: A proteome-wide association study (PWAS) was performed based on OA and its subtypes genome-wide association studies (GWAS) summary datasets and the protein quantitative trait loci (pQTL) data. Subsequently, Mendelian randomization (MR) and colocalization analysis was conducted to estimate the associations between protein and OA risk. The replication analysis was performed in an independent dataset of human plasma pQTL data. RESULTS: The abundance of seven proteins was causally related to OA, two proteins to knee OA and six proteins to hip OA, respectively. We replicated 2 of these proteins using an independent pQTL dataset. With the further support of colocalization, and higher ECM1 level was causally associated with a higher risk of OA and hip OA. Higher PCSK1 level was causally associated with a lower risk of OA. And higher levels of ITIH1, EFEMP1, and ERLEC1 were associated with decreased risk of hip OA. CONCLUSION: Our study provides new insights into the genetic component of protein abundance in OA and a promising therapeutic target for future drug development.

Genetic insights into serum cathepsins as diagnostic and therapeutic targets in knee and hip osteoarthritis.

Osteoarthritis (OA) is a chronic disease due to the deterioration of cartilage structure and function, involving the progressive degradation of the cartilage extracellular matrix. Cathepsins, lysosomal cysteine proteases, play pivotal roles in various biological and pathological processes, particularly in protein degradation. Excess cathepsins levels are reported to contribute to the development of OA. However, the causal relationship between the cathepsin family and knee and hip OA remains uncertain. Therefore, this study utilized bidirectional Mendelian Randomization (MR) analyses to explore this causal association. Our results indicated that elevated serum levels of cathepsin O increase the overall risk of knee OA, while increased serum levels of cathepsin H enhance the risk of hip OA. Conversely, the reverse MR analyses did not reveal a reverse causal relationship between them. In summary, OA in different anatomical locations may genetically result from pathological elevations in different serum cathepsin isoforms, which could be utilized as diagnostic and therapeutic targets in clinical practice.

Circulating cytokines levels and osteoarthritis: A Mendelian randomization study.

BACKGROUND: Previous traditional observational studies have suggested the contribution of several cytokines and growth factors to the development of osteoarthritis (OA). This study aimed to determine the association of circulating cytokine and growth factor levels with OA. METHODS: We used two-sample Mendelian randomization (MR) to explore the causality between circulating cytokine and growth factor levels and OA [including knee or hip OA (K/HOA), knee OA (KOA), and hip OA (HOA)]. Summary level data for circulating cytokine and growth factor levels were sourced from a genome-wide association study (GWAS) involving 8,293 participants of Finnish ancestry. Single-nucleotide polymorphisms related to K/HOA (39,427 cases and 378,169 controls), KOA (24,955 cases and 378,169 controls), and HOA (15,704 cases and 378,169 controls) were obtained from a previous GWAS. The inverse variance weighted (IVW) method was primarily used for our MR analysis. For exposures to only one relevant SNP as IV, we used the Wald ratio as the major method to assess causal effects. We also conducted a series of sensitivity analyses to improve the robustness of the results. RESULTS: Circulating vascular endothelial growth factor levels were suggestively associated with an increased risk of K/HOA (odds ratio (OR) = 1.034; 95 % confidence interval (CI) = 1.013-1.055; P = 0.001), KOA (OR = 1.034; 95 % CI = 1.014-1.065; P = 0.002), and HOA (OR = 1.039; 95 % CI = 1.003-1.067; P = 0.034). Circulating interleukin (IL)-12p70 levels was suggestively associated with K/HOA (OR = 1.047; 95 % CI = 1.018-1.077; P = 0.001), KOA (OR = 1.058; 95 % CI = 1.022-1.095; P = 0.001), and HOA (OR = 1.044; 95 % CI = 1.000-1.091; P = 0.048). Circulating IL-18 levels were suggestively associated with HOA (OR = 1.068; 95 % CI = 1.014-1.125; P = 0.012). However, limited evidence exists to support causal genetic relationships between other circulating cytokines, growth factor levels and K/HOA, KOA, and HOA. CONCLUSIONS: Our MR analysis provides suggestive evidence of causal relationships between circulating cytokines and growth factors levels and OA, providing new insights into the etiology of OA.

Fatty Acid Intake and Polyunsaturated Fatty Acid Biomarkers and Risk of Total Knee or Hip Arthroplasty Among Older Women in the Women's Health Initiative.

OBJECTIVE: The objective was to determine whether baseline fatty acid intake and erythrocyte omega-3 and omega-6 polyunsaturated fatty acids (PUFAs) can predict risk of total hip arthroplasty (THA) and total knee arthroplasty (TKA) in older women. METHODS: This was a prospective analysis of 34,990 women in the Women's Health Initiative. Dietary fatty acids were estimated from food frequency questionnaires. Imputed erythrocyte PUFAs were available in a subcohort of 3,428 women. Arthroplasty (THA and TKA), used as a surrogate of severe osteoarthritis, was identified via linked Medicare data. Cox proportional hazards models were constructed to estimate risk of arthroplasty. RESULTS: Risk of THA was associated with higher intake of arachidonic acid, (multivariable hazard ratio [HR] quartile 4 [Q4] vs Q1: 1.16; 95% confidence interval [CI] 1.01-1.34; P = 0.03) and higher intake of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA; HR Q4 vs Q1: 1.20; 95% CI 1.05-1.39; P = 0.003). There was a linear trend (P = 0.04) for patients to have a higher risk of THA with higher erythrocyte EPA and DHA in body mass index-adjusted models; however, there was no significant difference in patients who had THAs by quartiles of erythrocyte EPA and DHA (P = 0.10). Dietary fatty acids and erythrocyte PUFAs were not significantly associated with risk of TKA. CONCLUSION: Higher baseline intakes of arachidonic acid and EPA and DHA were associated with a modestly higher risk of THA. No association was found between fatty acids and patients who had TKAs. Further research in populations with direct measures of osteoarthritis severity is needed to better understand the importance of PUFAs in modulating osteoarthritis and arthroplasty risk.

Underdiagnosis of primary hyperparathyroidism in patients with osteoarthritis undergoing arthroplasty.

BACKGROUND: Primary hyperparathyroidism (HPT) is commonly underdiagnosed and undertreated. Joint pain is a nonspecific symptom associated with osteoarthritis or primary HPT. We hypothesize that patients treated for osteoarthritis are underdiagnosed with primary HPT. METHODS: Adult patients diagnosed with hip/knee osteoarthritis at the Medical College of Wisconsin from January 2000 to October 2020 were queried. Patients with a calcium level drawn within 1 year of diagnosis of osteoarthritis were included. Patients who had undergone prior parathyroidectomy were excluded. Patients were stratified by serum calcium level, HPT diagnosis, and PTH level. Arthroplasty rates were compared between groups. RESULTS: Of 54,788 patients, 9,967 patients (18.2%) had a high serum calcium level, of whom 1,089 (10.9%) had a diagnosis of HPT. Only 76 (7.0%) patients with HPT underwent parathyroidectomy, 208 (19.1%) underwent knee/hip arthroplasty, and 14 (1.3%) underwent both. Arthroplasty was performed in 1,793 patients without evaluation and/or definitive treatment for HPT. There were higher rates of arthroplasty performed in patients with a high serum calcium level compared with those without (21.2% vs 17.4%, P < .001). CONCLUSION: Patients with high serum calcium levels were more likely to undergo arthroplasty than those with normocalcemia. Hypercalcemia in the setting of hip or knee osteoarthritis should prompt a full evaluation for primary HPT.

Sex Steroids and Osteoarthritis: A Mendelian Randomization Study.

Objective: Sex steroids are thought to contribute to the pathogenesis of osteoarthritis (OA). This study investigated the causal role of sex steroids in site- and sex-specific OA and risk of joint replacement surgery using the Mendelian randomization (MR) method. Methods: Instrumental variables for estradiol, dehydroepiandrosterone sulfate, testosterone (T), and dihydrotestosterone (DHT) were selected. We used the inverse variance weighting (IVW) approach as the main MR method to estimate causal effects based on the summary-level data for OA and joint replacement surgery from genome-wide association studies (GWAS). Results: A positive causal association was observed between serum T level and risks of hip OA (odds ratio [OR]=1.558, 95% confidence interval [CI]: 1.193-2.034; P=0.001) and hip replacement (OR=1.013, 95% CI: 1.008-1.018; P=2.15×10-8). Serum DHT level was also positively associated with the risk of hip replacement (OR=1.011, 95% CI: 1.006-1.015; P=4.03×10-7) and had potential causality with hip OA (OR=1.398, 95% CI: 1.054-1.855; P=0.020). Conclusions: Serum T and DHT levels may play causal roles in the development of hip OA and contribute to the risk of hip replacement, although the underlying mechanisms require further investigation.

Endotypes of primary osteoarthritis identified by plasma metabolomics analysis.

OBJECTIVE: To identify endotypes of osteoarthritis (OA) by a metabolomics analysis. METHODS: Study participants included hip/knee OA patients and controls. Fasting plasma samples were metabolomically profiled. Common factor analysis and K-means clustering were applied to the metabolomics data to identify the endotypes of OA patients. Logistic regression was utilized to identify the most significant metabolites contributing to the endotypes. Clinical and epidemiological factors were examined in relation to the identified OA endotypes. RESULTS: Six hundred and fifteen primary OA patients and 237 controls were included. Among the 186 metabolites measured, 162 passed the quality control analysis. The 615 OA patients were classified in three clusters (A, 66; B, 200; and C, 349). Patients in cluster A had a significantly higher concentration of butyrylcarnitine (C4) than other clusters and controls (all P < 0.0002). Elevated C4 is thought to be related to muscle weakness and wasting. Patients in cluster B had a significantly lower arginine concentration than other clusters and controls (all P < 7.98 × 10-11). Cluster C patients had a significantly lower concentration of lysophosphatidylcholine (with palmitic acid), which is a pro-inflammatory bioactive compound, than other clusters and controls (P < 3.79 × 10-6). Further, cluster A had a higher BMI and prevalence of diabetes than other clusters (all P ≤ 0.0009), and also a higher prevalence of coronary heart disease than cluster C (P = 0.04). Cluster B had a higher prevalence of coronary heart disease than cluster C (P = 0.003) whereas cluster C had a higher prevalence of osteoporosis (P = 0.009). CONCLUSION: Our data suggest three possible clinically actionable endotypes in primary OA: muscle weakness, arginine deficit and low inflammatory OA.

Disentangling Associations Between Serum Muscle Biomarkers and Sarcopenia in the Presence of Pain and Inflammation Among Patients With Osteoarthritis: The SPSS-OK Study.

BACKGROUND/OBJECTIVE: Reduction of muscle markers, such as creatine phosphokinase (CK), in rheumatic diseases and its association with reduced muscle mass may be of clinical importance in osteoarthritis (OA). Considering the complexity of secondary sarcopenia, clarifying the association between muscle markers and sarcopenia and disentangling the involvement of OA-related conditions are of clinical importance. We investigated the association between serum muscle biomarkers and sarcopenia among patients with OA, considering the presence of pain and inflammation. METHODS: Overall, 1425 patients with knee and hip OA scheduled for joint replacement surgery were included in a single-center cross-sectional study from Screening for People Suffering Sarcopenia in Orthopedic cohort of Kobe study. Primary outcome was sarcopenia defined by 2 criteria (the Asian Working Group for Sarcopenia and the European Working Group on Sarcopenia in Older People). Pain and inflammation were measured using the numeric rating scale and serum C-reactive protein (CRP) levels, respectively. Associations between the biomarkers (serum CK, aspartate aminotransferase, alanine aminotransferase) and sarcopenia were examined using logistic regression models. RESULTS: Sarcopenia by the Asian Working Group for Sarcopenia criteria was present in 4.0% of patients. In adjusted analyses, sarcopenia was negatively associated with higher serum CK levels, but not with serum aspartate aminotransferase or alanine aminotransferase levels independent of pain score and serum CRP. Neither pain score nor serum CRP level was associated with sarcopenia. Similar results were found when the European Working Group on Sarcopenia in Older People criteria were used. CONCLUSIONS: Serum CK was associated with sarcopenia, suggesting the potential usefulness for sarcopenia detection regardless of pain or inflammation in OA.

Causal association of adipokines with osteoarthritis: a Mendelian randomization study.

OBJECTIVE: This two-sample Mendelian randomization study aimed to delve into the effects of genetically predicted adipokine levels on OA. METHODS: Summary statistic data for OA originated from a meta-analysis of a genome-wide association study with an overall 50 508 subjects of European ancestry. Publicly available summary data from four genome-wide association studies were exploited to respectively identify instrumental variables of adiponectin, leptin, resistin, chemerin and retinol-blinding protein 4. Subsequently, Mendelian randomization analyses were conducted with inverse variance weighted (IVW), weighted median and Mendelian randomization-Egger regression. Furthermore, sensitivity analyses were then conducted to assess the robustness of our results. RESULTS: The positive causality between genetically predicted leptin level and risk of total OA was indicated by IVW [odds ratio (OR): 2.40, 95% CI: 1.13-5.09] and weighted median (OR: 2.94, 95% CI: 1.23-6.99). In subgroup analyses, evidence of potential harmful effects of higher level of adiponectin (OR: 1.28, 95% CI: 1.01-1.61 using IVW), leptin (OR: 3.44, 95% CI: 1.18-10.03 using IVW) and resistin (OR: 1.18, 95% CI: 1.03-1.36 using IVW) on risk of knee OA were acquired. However, the mentioned effects on risk of hip OA were not statistically significant. Slight evidence was identified supporting causality of chemerin and retinol-blinding protein 4 for OA. The findings of this study were verified by the results from sensitivity analysis. CONCLUSIONS: An association between genetically predicted leptin level and risk of total OA was identified. Furthermore, association of genetically predicted levels of adiponectin, leptin and resistin with risk of knee OA were reported.

Serum fatty acid chain length associates with prevalent symptomatic end-stage osteoarthritis, independent of BMI.

Higher body mass index (BMI) is associated with osteoarthritis (OA) in both weight-bearing and non-weight-bearing joints, suggesting a link between OA and poor metabolic health beyond mechanical loading. This risk may be influenced by systemic factors accompanying BMI. Fluctuations in concentrations of metabolites may mark or even contribute to development of OA. This study explores the association of metabolites with radiographic knee/hip OA prevalence and progression. A 1H-NMR-metabolomics assay was performed on plasma samples of 1564 cases for prevalent OA and 2,125 controls collected from the Rotterdam Study, CHECK, GARP/NORREF and LUMC-arthroplasty cohorts. OA prevalence and 5 to 10 year progression was assessed by means of Kellgren-Lawrence (KL) score and the OARSI-atlas. End-stage knee/hip OA (TJA) was defined as indication for arthroplasty surgery. Controls did not have OA at baseline or follow-up. Principal component analysis of 227 metabolites demonstrated 23 factors, of which 19 remained interpretable after quality-control. Associations of factor scores with OA definitions were investigated with logistic regression. Fatty acids chain length (FALen), which was included in two factors which associated with TJA, was individually associated with both overall OA as well as TJA. Increased Fatty Acid chain Length is associated with OA.

Multi-tissue epigenetic analysis of the osteoarthritis susceptibility locus mapping to the plectin gene PLEC.

OBJECTIVE: In cartilage, the osteoarthritis (OA) associated single nucleotide polymorphism (SNP) rs11780978 correlates with differential expression of PLEC, and with differential methylation of PLEC CpG dinucleotides, forming eQTLs and mQTLs respectively. This implies that methylation links chondrocyte genotype and phenotype, thus driving the functional effect of this genetic risk signal. PLEC encodes plectin, a cytoskeletal protein that enables tissues to respond to mechanical forces. We sought to assess whether these PLEC functional effects were cartilage specific. METHOD: Cartilage, fat pad, synovium and peripheral blood were collected from patients undergoing arthroplasty. PLEC CpGs were analysed for mQTLs and allelic expression imbalance (AEI) was performed to test for eQTLs. Plectin was knocked down in a mesenchymal stem cell (MSC) line using CRISPR/Cas9 and cells phenotyped by RNA-sequencing. RESULTS: mQTLs were discovered in fat pad, synovium and blood. Their effects were however stronger in the joint tissues and of comparable effect between these tissues. We observed AEI in synovium in the same direction as for cartilage and correlations between methylation and PLEC expression. Knocking-down plectin impacted on pathways reported to have a role in OA, including Wnt signalling, glycosaminoglycan biosynthesis and immune regulation. CONCLUSIONS: Synovium is also a target of the rs11780978 OA association functionally operating on PLEC. In fat pad, mQTLs were identified but these did not correlate with PLEC expression, suggesting the functional effect is not joint-wide. Our study highlights interplay between genetic risk, DNA methylation and gene expression in OA, and reveals clear differences between tissues from the same diseased joint.

Is the bone tissue of the femoral neck demineralised in patients with hip fracture?

The aim of this study is to establish the falsifiability of the "osteoporotic hypothesis" for hip fracture, according to which the bone density and mineral composition of bone tissue in patients with hip fracture is poorer than when no such fracture is present, and that this circumstance is relevant to the occurrence of a fracture. The study population consisted of forty patients treated with arthroplasty. Twenty patients with femoral neck fracture and another twenty with hip osteoarthritis received the same diagnostic protocol and the same antibiotic, anaesthetic, surgical and antithrombotic prophylaxis. Levels of calcium (Ca), phosphorus (P) and vitamin D in blood, amongst other values, were determined, and five samples of bone tissue from the proximal femoral metaphysis were obtained and characterised by optical microscopy and microanalytical analysis. No statistically significant differences were observed between the two groups with respect to the trabecular number, area or thickness, or inter-trabecular distance. However, there were differences in the length of the trabeculae, which was greater in the patients with hip osteoarthritis (p = 0.002), but not when the groups were compared by gender. When compared by age, a greater inter-trabecular distance was observed in the patients aged over 75 years (p = 0.036) but there were no differences in the remaining parameters. Serum levels of Ca (p = 0.03), P (p < 0.01) and vitamin D (p < 0.01) were lower in the fracture group. In the quantitative microanalytical analysis, no significant differences were observed in bone levels of Ca or P or in the Ca/P index, nor was there any correlation between serum and levels of bone Ca or P (Ca-0.197:p = 0.314;P-0.274:p = 0.158).Multiple linear regression revealed no correlation between the diagnoses, vitamin D and bone levels of Ca or P. Despite the reduced serum levels of Ca and P in the patients with hip fracture, no correlation was observed with bone levels of Ca and P,which were similar in both groups. There were differences in the organic bone structure, in terms of length and inter-trabecular distance. For patients with osteoporosis, treatment should be aimed at increasing the synthesis of bone trabeculae to reinforce their structure. Nevertheless, no such treatment can prevent falls, and therefore no reduction in hip fractures amongst this population can be assured.

Initial metal ion levels predict risk of elevation in metal on metal total hip arthroplasty.

INTRODUCTION: Screening protocols for asymptomatic patients with metal on metal (MoM) total hip arthroplasty (THA) are evolving. Most surgeons began screening patients around 2010 by obtaining cobalt (Co) and chromium (Cr) metal ion levels. There is currently no data available to guide repeat screening in this familiar clinical scenario. Therefore, the following study evaluated how metal ion levels change after an initial metal ion level in patients with MoM THAs. MATERIALS AND METHODS: 171 consecutive patients (265 hips) underwent primary MoM THA. All patients had at least one Co and Cr ion level draw. 84 patients (136 hips) had 2 ion level draws. Ion levels were divided into elevated levels (⩾4.5 ppb) and normal levels (<4.5 ppb). The probability of an ion level returning elevated after an initial normal level was identified. Additionally, a threshold value was determined that reliably identified every patient that did not subsequently rise above 4.5 ppb. RESULTS: 12 metal ion levels were ⩾4.5 ppb on the first lab draw. On the second draw, all 12 remained ⩾4.5 ppb. Of the 121 hips with initial metal ion levels <4.5 ppb, 5 metal ion levels became ⩾4.5 ppb. Utilising an initial screening cutoff of 3.0 ppb, no patient was identified with a second lab value ⩾4.5 ppb. DISCUSSION: Initial metal ion levels reliably predicted those that would remain elevated or remain normal with a subsequent metal ion level. An initial metal ion level above 3.0 ppb may represent a cutoff at which further workup is necessary.

Good midterm results after Birmingham hip resurfacing and total hip arthroplasty.

The aim of this study is to determine the functional outcome and midterm survival rates of the Birmingham Hip Resurfacing and Birmingham Total Hip Arthroplasty. This retrospective, observational study included 150 surgeries (46 resurfacing procedures and 104 arthroplasty procedures) performed in 127 patients from 2005 to 2012. The Resurfacing and Arthroplasty study groups were evaluated with clinical (Harris Hip Score and Hip Disability and Osteoarthritis Outcome Score) and radiological follow-up. Cobalt and chromium levels were measured via blood samples. No revisions were required in either study group. Femoral stem osteolysis was observed in three patients in the Arthroplasty group. No osteolysis was observed in the Resurfacing group. Significantly higher clinical scores were observed in the Resurfacing group (p=0.04 and p=0.04, respectively). The average level of metal ions were similar in both groups. Both groups showed excellent midterm clinical and radiographic results with 100 percent survival rates. Additional follow-up is required to monitor future changes in blood metal ion levels.

Comprehensive assessment of tissue and serum parameters of bone metabolism in a series of orthopaedic patients.

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.

Outcomes and predictors of treatment failure following two-stage total joint arthroplasty with articulating spacers for evolutive septic arthritis.

BACKGROUND: The treatment strategy for evolutive septic arthritis (SA) with coexistent degenerative joint disease is not well established. The purposes of this study were to 1) investigate treatment outcome and potential risk factors of treatment failure in patients with evolutive SA following two-stage procedure, including insertion of an antibiotic-loaded spacer at the first stage and subsequent implantation of a new prosthesis; and 2) determine the performance of serum erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and Interleukin-6 (IL-6) in predicting persisting infection at second-stage procedure. METHODS: We retrospectively reviewed 74 patients with evolutive SA of hips and knees who underwent a two-stage TJA between 2008 and 2015. The treatment success was defined according to the modified Delphi criteria and Kaplan-Meier survivorship curves were constructed to determine treatment success. A Cox regression model was performed to identify risk factors for treatment failure. Receiver operating characteristic (ROC) curves were generated to determine the prognostic value of ESR, CRP, and IL-6 in predicting persistent infection before second-stage prostheses implantation. RESULTS: Overall, the treatment success rate was 93% for hips and 100% for knees after the first-stage surgery. The treatment success rate was 89% for hips and 84% for knees after second-stage prosthesis implantation with a mean follow-up of 4.7 (range, 2.2 to 10.8) years. Older age (Hazard ratio [HR] [per 10-year increase], 1.20; 95% confidential interval [CI], 1.11 to 1.62), higher preoperative CRP level (HR [per 1-mg/dL increase], 1.15; 95% CI, 1.04 to 1.28) and resistant organism (HR, 13.96; 95% CI, 3.29 to 19.20) were associated with an increased risk of treatment failure. All serologic tests presented limited values in predicting persisting infection, with the area under ROC curve of ESR, CRP, IL-6 and combination of the three markers was 57.8, 61.6, 60.3, and 62.1%, respectively. CONCLUSIONS: Two-stage TJA is an adequate management of infection control in patients with evolutive SA. The three potential risk factors (old age, high preoperative CRP, and resistant organism profile) may predict treatment failure following a two-stage procedure for evolutive SA. Additionally, serum ESR, CRP, and IL-6 had no benefit in predicting persisting infection before second-stage prostheses implantation. These findings may be useful when treating patients with evolutive SA.

Vascular cell adhesion molecule 1 in patients with severe osteoarthritis of the hip : A prospective cross-sectional study.

BACKGROUND: Osteoarthritis (OA) of the hip is a frequent and debilitating joint disease. Only few clinical risk factors for hip OA are established and clinically applicable biomarkers to identify patients at risk are still lacking. The glycoprotein vascular cell adhesion molecule 1 (VCAM-1) is expressed by chondrocytes and synovial tissue and was a predictive marker for development of severe large joint OA in a previous study. OBJECTIVE: It was tested whether increased serum levels of VCAM-1 are prevalent in patients with severe OA of the hips. METHODS: In this prospective, multicenter, cross-sectional study, risk factors of severe hip OA were investigated in patients scheduled for hip joint arthroplasty and 100 patients were randomly selected for validation of VCAM-1 as a potential biomarker for hip OA. Serum samples were analyzed by an enzyme-linked immunosorbent assay and compared with a sex and age-matched control cohort. RESULTS: The groups were similar in age, gender ratio and prevalence of diabetes. Serum concentrations of VCAM-1 were 8% higher in OA patients compared to controls, without reaching statistical significance (818 ng ml-1, 95% confidence interval, CI 746-891 ng ml-1 versus 759 ng m-1, 95% CI 711-807 ng ml-1; P = 0.4839). CONCLUSION: The results of this study show that serum concentrations of VCAM-1 cannot distinguish patients with severe hip OA from age and sex-matched controls.

The role of ADAMTS genes in the end stage of hip osteoarthritis.

PURPOSE: The aim of this study is to investigate which ADAMTS genes play a major role in the development of primary hip osteoarthritis, by comparing the tissue and blood samples in patients with hip osteoarthritis and a control group. MATERIAL AND METHODS: Human articular cartilage was obtained from femoral heads of 15 patients with end stage osteoarthritis undergoing total hip replacement. As the control group, the cartilages was obtained from femoral heads of 15 patients, who did not have osteoarthritis or degenerative changes in hip joint, undergoing hip replacement following the fracture of the femoral neck. After the cartilage samples were taken from the resection materials, the DNA polymorphisms in the patients' cartilage samples were tested by Polymerase Chain Reaction (PCR), the serum levels of aggrecanase genes were analyzed with Enzyme-Linked ImmunoSorbent Assay (ELISA). RESULTS: The level of ADAMTS5 and ADAMTS9 genes were found significantly lower as a result of ELISA analysis degenerative arthritis group than the control group (p < 0,05). ADAMTS 1, 4, 8, 15 were similar between the two groups in ELISA analysis (p > 0,05). As a result of quantitative real time RT-PCR analysis, the level of ADAMTS8 mRNA increased 3.5 fold in hip degenerative arthritis group when compared with femoral neck fractures group. ADAMTS1, ADAMTS4 and ADAMTS5 expression levels in hip degenerative arthritis group were decreased 2.5, 2 and 2.5 fold, respectively. ADAMTS9, 15 were found to be similar between two groups. CONCLUSON: As a result of this study on hip osteoarthritis, the ADAMTS8 levels was found to be significantly higher in the end stage of hip osteoarthritis. Unlike similar studies on knee osteoarthritis, ADAMTS1,4,5 levels were found to be lower.

Metal ion concentrations after metal-on-metal hip arthroplasty are not correlated with habitual physical activity levels.

INTRODUCTION: Metal-on-metal (MoM) hip arthroplasties have shown high clinical failure rates with many patients at risk for a revision and under surveillance for high metal ion concentrations. Implant wear releasing such ions is assumed to be a function of use, i.e. the patient's physical activity. This study aimed to assess whether habitual physical activity levels of MoM patients are correlated with metal ion concentrations and are higher in patients with high (at risk) than in patients with low (safe) metal ion concentrations. METHODS: A cohort study was conducted of patients with any type of MoM hip prosthesis. Metal ion concentrations were determined using ICP-MS. Habitual physical activity of subjects was measured in daily living using an acceleration-based activity monitor. Outcome consisted of quantitative and qualitative activity parameters. RESULTS: In total, 62 patients were included. Mean age at surgery was 60.8 ± 9.3 years and follow-up was 6.3 ± 1.4 years. Cobalt concentrations were highly elevated overall (112.4 ± 137.9 nmol/L) and significantly more in bilateral (184.8 ± 106.5 nmol/L) than in unilateral cases (87.8 ± 139.4 nmol/L). No correlations were found between physical activity parameters and metal ion concentrations. Subgroup analysis of patients with low versus high cobalt concentration showed no significant differences in habitual physical activity. DISCUSSION: No correlation was found between physical activity levels and metal ion concentrations. Implant use by normal habitual activities of daily living seems not to influence metal ion concentrations.

Differences in peri-operative serum inflammatory markers between normoponderal and obese patients undergoing large joint replacement for osteoarthritis-a descriptive study.

PURPOSE: The occurrence, evolution and treatment outcome of osteoarthritis are influenced by a series of factors, including obesity. Assessing how chronic inflammation present in obesity changes the values of peri-operative biological tests could facilitate a clearer interpretation of laboratory examinations for the proper management of possible complications. METHODS: This descriptive study compared biological and clinical factors during the peri-operative period in patients undergoing total hip/knee replacement, in order to identify the special characteristics of the inflammatory status in obese compared to normal weight patients. In the two groups (71 normoponderal, 74 obese), serum levels of fibrinogen, high-sensitivity C-reactive protein (hsCRP), tumour necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) were determined 24 hours pre- and post-operatively. RESULTS: Our results found significant post-operative increases in serum levels of IL-6 and hsCRP in both groups (p = 0.0001), with inter-group differences in pre-operative hsCRP (p = 0.02) and post-operative IL-6 levels (p = 0.013). Interestingly, TNF-alpha levels were much higher in the obese pre-operatively than post-operatively (p = 0.002) and higher than the normoponderals (p = 0.003), decreasing to levels similar to those of the normal weight patients on day two. CONCLUSIONS: Because of its important clinical implications, an appropriate comprehension of the peri-operative changes in a patient's inflammatory status has the potential to influence therapeutic attitude. We failed to observe any significant post-operative differences in the mean values of the markers assessed, except those of IL-6, implying that serum levels of fibrinogen, hsCRP and TNF-alpha within 24 hours after large joint replacements are not influenced by the patient's ponderal status.