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.

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.

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.

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.

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.

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.

Medium- and long-chain acylcarnitines are associated with osteoarthritis severity and arterial stiffness in end-stage osteoarthritis patients: a case-control study.

AIM: Arterial pathology has been suggested to be involved in osteoarthritis (OA). Metabolic profiling enables the determination of low-molecular-weight molecules, which might further explain the pathogenesis of OA and its relationship with cardiovascular diseases (CVD). The aim of this study was to compare the metabolic profile of lipid metabolism-related compounds and arterial stiffness in OA patients and in controls. METHOD: The serum of 70 end-stage OA patients prior to joint replacement surgery and 82 age-matched controls were analyzed by the AbsoluteIDQ™ p180 kit (BIOCRATES Life Sciences AG, Innsbruck, Austria) using the targeted metabolomic approach. Arterial stiffness was assessed by measuring carotid-femoral and carotid-radial pulse wave velocity. Aortic-brachial pulse wave velocity ratio (PWV-ratio) was used as the measure of arterial stiffness gradient. Principal component analysis was performed to analyze the large number of metabolites. RESULTS: The OA patients had decreased levels of C10:1, C10:2, C12, C12:1, C14, C14:2, C14:1-OH, carnitine palmitoyltransferase 1 (CPT1) ratio and total AC/C0 compared with age-matched controls. There was independent association between acylcarnitines and PWV-ratio in the OA patients. Furthermore, acylcarnitines were associated with OA radiographic severity. The component that resembles acylcarnitines was an independent predictor of the PWV-ratio for OA patients. CONCLUSION: We found decreased levels of acylcarnitines in OA patients. Furthermore, medium-and long-chain acylcarnitines associated independently with arterial stiffness and were related to radiographic severity of OA. Thus, acylcarnities might play an important role in the association between OA and CVD.

Comparação clínica, laboratorial e densitométrica de pacientes com coxartrose e com fraturas do colo femoral / Clinical, laboratory and densitometric comparison of patients with coxarthrosis and femoral neck fractures

RESUMO Objetivo: comparar dados clínicos, laboratoriais e densitométricos de pacientes com osteoartrose e com fratura do colo femoral. Métodos: estudo transversal de pacientes com fratura do colo femoral e osteoartrose do quadril, submetidos à artroplastia de quadril. Dados clínicos, laboratoriais e densitométricos foram coletados. Resultados: cinquenta e três pacientes foram incluídos, 22 com fraturas do colo femoral e 31 com osteoartrose. Pacientes com fratura do colo do fêmur apresentaram maior idade do que os pacientes com osteoartrose, tendo valores de IMC, densidade mineral óssea e força de preensão palmar (pacientes sarcopênicos) inferiores, estando mais incapacitados neurologicamente e apresentando um pior escore ASA. Entre os vários parâmetros bioquímicos analisados, diferenças estatisticamente significantes foram encontrados no cálcio sérico total, cálcio ionizado, vitamina D, tiroxina livre, eritrócitos, hemoglobina, hematócrito, glóbulos brancos totais, neutrófilos, linfócitos e creatinina entre os dois grupos. Outros hormônios analisados e parâmetros bioquímicos não diferiram significativamente, apesar de mostrarem tendências entre os dois grupos. Conclusão: pacientes com fraturas do colo do fêmur são mais idosos do que pacientes com osteoartrose, apresentam um menor peso e IMC, são mais debilitados, muitos com anemia e massa óssea reduzida, além de terem uma diminuição significativa no cálcio total, cálcio ionizado, vitamina D e creatinina e um aumento significativo na tiroxina livre.

ABSTRACT Objective: to compare clinical, laboratory and densitometric data from patients with osteoarthrosis and femoral neck fractures. Methods: we conducted a cross-sectional study of patients with femoral neck fracture and hip osteoarthrosis submitted to hip arthroplasty. We collected clinical, laboratory and densitometric data. Results: we included 53 patients, 22 with femoral neck fractures and 31 with osteoarthrosis. Patients with femoral neck fractures were older than patients with osteoarthrosis, with lower BMI values, bone mineral density and palmar grip strength (sarcopenic patients), being more neurologically impaired and presenting a worse ASA score. Among the various biochemical parameters analyzed, we found statistically significant differences in total serum calcium, ionized calcium, vitamin D, free thyroxine, erythrocytes, hemoglobin, hematocrit, total white blood cells, neutrophils, lymphocytes and creatinine between the two groups. Other hormones analyzed and biochemical parameters did not differ significantly, although they showed trends between the two groups. Conclusion: patients with femoral neck fractures are older than patients with osteoarthrosis, have a lower weight and BMI, are more debilitated, many with anemia and reduced bone mass, and have a significant decrease in total calcium, ionized calcium, vitamin D and creatinine and a significant increase in free thyroxine.

Perioperative plasmatic presepsin levels in patients undergoing total hip or knee replacement: a preliminary study.

Presepsin (sCD14-ST) is an emerging biomarker in the diagnosis of sepsis. In the field of orthopaedics, it could be useful in the diagnosis and management of periprosthetic joint infections (PJI). The aim of this study is to define the normal perioperative plasmatic levels of presepsin in patients undergoing primary cementless total hip replacement (THR) or primary cemented total knee replacement (TKR). For this purpose, 50 patients (19 male, 31 female, mean age= 64.04±8.88) were recruited. The patients were divided into two groups: Group A patients underwent cementless THR, whereas Group B patients underwent cemented TKR. On recruitment, anthropometric data, smocking status, osteoarthritis stage according to Kellgren and Lawrence, Harris Hip Score (HHS) for Group A patients and Knee Society Score (KSS) for Group B patients, drugs assumption and comorbidities were recorded. All the patients underwent serial blood tests, including complete blood count, presepsin (PS), C-reactive protein (CRP) and procalcitonin (PCT) 24 hours before arthroplasty (T0) and at 24 (T1), 48 (T2), 72 (T3) and 96 (T4) hours postoperatively. Body temperature (θ) was recorded every six hours in the time lapse T0-T4. Presepsin plasmatic concentration was comparable at baseline in both groups. After surgery, however, a significant increase of presepsin was observed in Group A, whereas in Group B no significant changes of presepsin were recorded. A comparable trend of this biomarker was found in the two groups, i.e. presepsin increased from T0 to T3, when it reached its maximum value, and its decrease started at T4. Finally, presepsin resulted more accurate than CRP in the evaluation of perioperative inflammatory response in patients undergoing THR or TKR. These data will be helpful in defining a reference interval for presepsin in patients with prosthetic joint implants, and a cut-off of this biomarker for the diagnosis of PJI.

Lymphocyte opioid receptors as innovative biomarkers of osteoarthritic pain, for the assessment and risk management of opioid tailored therapy, before hip surgery, to prevent chronic pain and opioid tolerance/addiction development: OpMarkArt (Opioids-Markers-Arthroprosthesis) study protocol for a randomized controlled trial.

BACKGROUND: The incidence of post-surgical chronic pain ranges between 20% and 40% in Europe. Osteoarthritis pain after prosthesis implantation is one of the most severe secondary syndromes, depending not only on surgery but also on organic changes before and after joints replacement. No data are available about risk factors. An excessive inflammatory response plays a central role but a best therapy is not defined yet. It is not clear whether opioid administration could influence post-surgical pain and lead to tolerance or addiction. Interestingly, the immune system, together with the nervous and peptidergic ones, is involved in hypersensibility. The connection across the three biological systems lies in the presence of opioid receptors on immune cells surface. Here, we show a method to analyze whether opioids could modulate lymphocytes, by proposing opioid receptors as biological markers to prevent chronic pain and opioid tolerance or addiction after hip surgery. METHODS/DESIGN: After institutional independent ethics committee approval, 60 patients, in pain and undergoing hip surgery, will be enrolled in a single-blind, randomized, phase IV, pilot study. Pain treatment will be selected inside a class of non-steroidal anti-inflammatory drugs (NAISDs) or paracetamol or a class of opioids, into three medication arms: 25 mg tapentadol twice daily; 75 mg tapentadol twice daily; NSAIDs or paracetamol in accordance with surgeon's custom. For each group, we will collect blood samples before, during and after surgery, to apply molecular analysis. We will perform lymphocyte opioid receptors genes and proteins expression and functional analysis. Data will be statistically analyzed. DISCUSSION: This project has the potential to obtain a personalized diagnostic kit, by considering lymphocyte opioid receptors as biological markers. Starting from a simple blood sample, it will be possible to decide the best therapy for a single patient. Using a noninvasive approach, we expect to fix a daily standard dose and timing, before and after surgery, to bypass hip chronic pain and the insurgence of tolerance or addiction. The analysis of opioid receptors sensitivity will help to identify the best drug administration in each specific case (tailored therapy). TRIAL REGISTRATION: ISRCTN, ISRCTN12559751 . Retrospectively registered on 23 May 2017.

Changes in expression of Wnt signaling pathway inhibitors dickkopf-1 and sclerostin before and after total joint arthroplasty.

The aim is to study how serum concentration of Dickkopf-1 (DKK1) and Sclerostin (SOST) varies in patients before and after undergoing total joint arthroplasty (TJA). A total of 104 patients undergoing TJA were included in this study. Serum DKK1 and SOST were measured at 1 day before and 1, 3, and 5 days after surgery. DKK1 levels were highest at 5 days' postoperation, increasing to 25.17% above preoperation levels (P < .01), while SOST levels were lowest at 3 days' postoperation, falling to 18.71% below preoperation levels (P < .05). Serum levels of DKK1 and SOST showed opposite trends in the days following TJA. Our research describes for the first time the perioperative changes observed in serum DKK1 and SOST levels of osteoarthritis (OA) patients undergoing TJA. Increased DKK1 and decreased SOST levels may help maintain the equilibrium of the WNT pathway in OA patient's postsurgery.

Identification of serological biomarker profiles associated with total joint replacement in osteoarthritis patients.

OBJECTIVE: Establish a biomarker panel associated with all-cause total joint replacement (TJR) through identification of patients with osteoarthritis (OA) who do or do not progress to TJR and investigate effects of nonsteroidal anti-inflammatory drugs (NSAIDs). DESIGN: Serum samples from patients enrolled in phase III trials of tanezumab who experienced TJR (n = 174) or matched patients who did not (n = 321) were analyzed for bone, cartilage, soft tissue, and inflammation markers. Classification and Regression Tree (CART) analysis was used to identify biomarker phenotypes associated with TJR. RESULTS: At baseline, biomarker combinations for patients who did not use NSAIDs before starting tanezumab and used NSAIDs during tanezumab treatment <90 days ("nonNSAID"), identified 77% (95% confidence interval [CI]: 71-84%) of patients who experienced TJR and 77% (95% CI: 65-86%) who did not over a 6-month study period (on average). These biomarker combinations increased odds of identifying patients to remain free of a TJR by 3.3-fold. In patients who used NSAIDs continuously (during screening and ≥90 days during tanezumab treatment), 64% (95% CI: 54-73%) who had TJR and 75% (95% CI: 68-83%) who did not were identified by biomarker combinations different from nonNSAID patients, with an increase in odds of identifying patients to remain free of a TJR by two-fold. CONCLUSIONS: Although validation on other cohorts is necessary, biomarkers may assist in identifying patients who will need TJR. The profiles suggest NSAID use increases importance of bone metabolism in TJR pathology.

The value of serial metal ion levels in following up patients with metal-on-metal hip arthroplasty.

BACKGROUND: The sensitivity of cobalt (Co) and chromium (Cr) ion-levels in detecting poorly performing metal-on-metal hip implants is low. This study proposes that serial changes in ion-levels are a more accurate marker of arthroplasties at risk. METHODS: Serial metal ion-levels and implant data of 285 patients with ASR resurfacing or replacement were studied. Patient and implant characteristics were analysed using univariate and multivariate analyses. RESULTS: 111 (39%) had revision surgery. Time since index surgery (p<0.001), acetabular inclination (p<0.001), their interaction (p<0.001) and femoral head size (p = 0.01) were significant variables. Head size (≤51 mm) had lower Co and Cr levels (p = 0.01). Cr/Co showed marginal decrease over time in the unrevised group and no decrease prerevision. CONCLUSIONS: Repeated measurement of ion-levels were higher in the revision group suggesting that serial measurements rather than absolute values may have a role to play in predicting implant failure.

Serologic and radiographic outcome of total hip arthroplasty with CoCr modular neck at mid-term follow-up.

PURPOSE: The aim of this study is a radiographic evaluation and to determine serologic values of chromium and cobalt in the blood and urine of patients who have been implanted with a Stryker® ABG II Modular Neck and see if there is correlation with the features of prosthesis and patients. METHODS: The study involves the collection of data from patients operated on for total hip model with the ABG II Modular Neck with a minimum follow-up of 1 year. RESULTS: We evaluated 22 patients who underwent implantation of a hip prosthesis with modular neck in CoCr. Of these, the average Cr in the blood was 0.63 µgL-1 (range 0.1-2.15 µgL-1), the average of Co in the blood was 3.50 µgL-1 (range 0.62-7.78 µgL-1), the average Cr in the urine was 1.24 µgL-1 (range 0.48-2.21 µgL-1), and the average Co in urine was 14.22 µgL-1 (range 3.3-31.2 µgL-1). None of these patients had undergone revision surgery. CONCLUSIONS: Our study seems to indicate that the restoration of offset and age are correlated with the release of metal ions, although the correlation is weak and needs better methodological studies and a greater number of patients to confirm this hypothesis. STUDY TYPE: Case series Level of Evidence 4.

Serum and bone pentosidine in patients with low impact hip fractures and in patients with advanced osteoarthritis.

BACKGROUND: Femoral neck fractures are a common occurrence in patients suffering from osteoporosis, while intracapsular hip fracture is rare in cases of osteoarthritis of the hip. Previous histomorphometric studies have emphasized the association between bone microarchitecture and the risk of low-impact fractures in osteoarthritis and osteoporosis patients. However, the strength of bone material is also a function of composition of organic bone matrix. In order to compare tissue material properties in these two clinical conditions, serum and bone pentosidine, a non-enzymatic collagen crosslinking element, was measured in patients who suffered a low-impact fracture, and in patients with advanced osteoarthritis. METHODS: The patient population consisted of 70 patients who underwent hemiarthroplasty surgery for a femoral neck fracture, and 41 patients with advanced hip joint osteoarthritis without a history of low- impact fracture, who were indicated for total hip joint replacement. Pentosidine content was analyzed in bone samples and in serum obtained from fracture and osteoarthritis patients using high performance liquid chromatography. RESULTS: Serum and bone concentrations of pentosidine were higher in subjects with hip fractures compared with osteoarthritis after adjustment for age, sex, weight, serum creatinine, and diabetes. A significant positive correlation was found between bone and serum pentosidine in fractured cases. A comparable relationship was also demonstrated for pentosidine levels in serum and bone relative to differentiation of fracture and osteoarthritis cases. CONCLUSIONS: Serum pentosidine can be considered a potential biomarker for identification of subjects with impaired bone quality and bone strength.