sRANKL Levels Research Articles

A transdiagnostic and diagnostic-specific approach on inflammatory biomarkers in eating disorders: A meta-analysis and systematic review

Eating disorders (EDs) are severe mental illnesses with a multifactorial etiology and a chronic course. Among the biological factors related to pathogenesis and maintenance of EDs, inflammation acquired growing scientific interest. This study aimed to assess the inflammatory profile of EDs, focusing on anorexia nervosa, bulimia nervosa, and including for the first time binge eating disorder. A comprehensive research of existing literature identified 51 eligible studies for meta-analysis, comparing levels of tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), C-reactive protein (CRP), osteoprotegerin (OPG), soluble receptor activator of nuclear factor kappa-B ligand (sRANKL), interleukin-1β (IL-1β), and interleukin-10 (IL-10) between patients with EDs and healthy controls (HCs). The systematic review explored other inflammatory biomarkers of interest, which did not meet the meta-analysis criteria. Results revealed significantly elevated levels of TNF-α, OPG, sRANKL, and IL-1β in patients with EDs compared to HCs. Additionally, the results highlighted the heterogeneity of inflammatory state among patients with EDs, emphasizing the need for further research into the association between inflammatory biomarkers and psychopathological correlates. This approach should transcend categorical diagnoses, enabling more precise subcategorizations of patients.Overall, this study contributed to the understanding of the inflammatory pathways involved in EDs, emphasizing potential implications for diagnosis, staging, and targeted interventions.

Serum levels of soluble receptor activator for nuclear factor kB ligand play a crucial role in the association of osteoprotegerin with coronary artery disease.

Osteoprotegerin (OPG) is a soluble decoy receptor for receptor activator of nuclear factor kB ligand (RANKL), and is implicated in the pathogenesis of atherosclerosis. The aim of the present study was to examine the hypothesis that serum OPG concentrations are increased in patients with stable coronary artery disease (CAD) at different serum levels of soluble RANKL (sRANKL). The study used a case-control design in which consecutively hospitalized individuals were recruited. Fasting blood samples were taken upon admission for serum testing. Participants with previously diagnosed CAD that was asymptomatic or had controlled symptoms constituted the stable CAD group, whereas patients with negative coronary computed tomography angiography results constituted the control non-CAD group. Exclusion criteria included recent acute coronary syndrome, severe heart failure, CAD-complicating autoimmune, blood or thyroid diseases, cancer, elevated temperature with or without infection, severe liver or kidney dysfunction, abnormal calcium metabolism, recent surgery and trauma history. A total of 118 individuals were included in the study. Smoothed plots generated using the recursive method and multivariate models showed that the incidence of stable CAD increased with serum OPG level up to the turning point of 18 pg/ml. This trend was observed at both high [odds ratio (OR), 1.61; 95% confidence interval (CI), 1.04-2.50; P=0.032) and low sRANKL concentrations (OR, 1.52; 95% CI, 1.06-2.17; P=0.022) after adjustment for cardiovascular risk factors. In conclusion, serum OPG levels ≤18 pg/ml are positively associated with stable CAD, regardless of sRANKL levels. In addition, at the same serum OPG level, higher sRANKL levels are associated with a greater incidence of stable CAD compared with lower sRANKL levels. This study identified the relationship between OPG, sRANKL, and stable CAD, and established the reference range for future clinical use.

Biochemical Examination of Plasma Ghrelin Levels in Individuals Afflicted With Chronic Periodontal Disease: A Comparative Study.

This study intended to assess plasma ghrelin levels in individuals with chronic periodontitis and analyze potential associations with bone turnover indicators, serum cytokines, and periodontal parameters. The research contained 80 patients each with 40 individuals with periodontally healthy controls (C) (28 males, 12 females) and 40 chronic periodontitis (CP) patients(29 males, 11 females). The blood samples were analyzed for soluble receptor activator nuclear factor kappa B ligand (sRANKL), interleukin-1 beta (IL-1β), total and acylated ghrelin, tumor necrosis factor-alpha (TNF-α), osteocalcin (OSC) and alkaline phosphatase (ALP), and periodontal parameters were recorded. The CP group had considerably higher plasma concentrations of both acylated and total ghrelin than the C group (p<0.05). Gender-based investigation showed substantial differences only among men in both groups (p<0.05). Hence, no significant modifications were identified in serum sRANKL, TNFα, and ALP levels between the groups. However, there was a notable difference in serum OSC and IL-1β levels in the CP group (p<0.05). Furthermore, total ghrelin/acylated ghrelin and total ghrelin/ALP revealed positive correlations. No significant association was found between symptoms and ghrelin levels. The study findings indicate elevated levels of ghrelin and acylated ghrelin in male CP patients.

Higher Adiponectin Levels in Children and Adolescents with T1D Probably Contribute to the Osteopenic Phenotype through the RANKL/OPG System Activation

Background: Diabetes mellitus is an increasing global health emergency, with serious complications (including osteoporosis). Leptin and adiponectin are among the least-investigated possible contributing factors of T1D low bone mass. Methods: In this case-control cross-sectional analysis, we evaluated 40 pairs of T1D children and adolescents and controls. We evaluated body diameters and skinfolds, leptin, adiponectin, lipids and lipoproteins, bone metabolic markers and DXA parameters of BMD and fat percentage. Results: Leptin levels were comparable between groups and correlated well with body mass parameters. Adiponectin levels were found to be higher in the patient group and correlated with higher levels of HbA1c, triglycerides and s-RANKL. Conclusions: In this study, leptin levels were no different, but adiponectin levels were found to be higher in children and adolescents with T1D and correlated with diabetic metabolic derangement indices and s-RANKL in the patient group. Adiponectin can be considered a surrogate marker of T1D in young patients’ metabolic status and probably contributes to the diabetic low bone mass phenotype via activation of the RANKL/OPG metabolic pathway.

Serum sRAGE, sRANKL and osteoprotegerin in subgroups of rheumatoid arthritis patients: biomarkers associated with iron and disease status

Soluble receptors are important for the balance between ligands and their membrane receptors. Changes in the expression of soluble receptors are associated with human diseases. The aim of this study was to determine the serum levels of sRAGE, sRANKL and OPG in subgroups of rheumatoid arthritis (RA) patients according to the level of CRP and to assess the relationship of these parameters with markers of iron and disease status. The study involved 114 RA patients. The levels of sRAGE, sRANKL and OPG were higher in the subgroup with increased CRP level compared to the subgroup with normal CRP. sRAGE showed a significant positive correlation with sTfR (r = 0.435, p < 0.0001), prohepcidin (r = 0.232, p = 0.04), sRANKL (r = 0.636, p < 0.0001), RF (r = 0.363, p < 0.002), and antiCCP antibodies (r = 0.429, p = 0.003) in the subgroup with normal CRP. Serum sRANKL was positively associated with sRAGE (r = 0.636, p < 0.0001), sTfR (r = 0.513, p < 0.0001), CRP (r = 0.223, p = 0.048), DAS28 (r = 0.269, p = 0.016), RF (r = 0.390, p = 0.001) and antiCCP antibodies (r = 0.445, p = 0.002) also in the subgroup with normal CRP. Serum OPG was positively correlated with ferritin in the subgroup with normal CRP. The association of sRAGE, sRANKL and OPG with markers of iron and disease status in RA suggests a relationship between inflammatory state, osteoclast activation and impaired iron and immune status. Therefore, sRAGE, sRANKL and OPG can be useful markers for the assessment of early pathological changes in RA and can also assist in monitoring of the therapy.

The influence of RANKL/osteoprotegerin on the prognosis of childhood acute lymphoblastic leukemia

Aims: The aim is to investigate the association of the osteoprotegerin (OPG)/ soluble(s) receptor activator nuclear kappa B ligand (RANKL) with the prognosis of children with acute lymphoblastic leukemia (ALL). Methods: Patients with the diagnosis of ALL between the years 2008-2010, were enrolled in the study. Demographic characteristics and complete blood count findings, treatment responses, as well as OPG and sRANKL levels were evaluated on admission and at the end of induction treatment. Results: Mean serum levels of OPG and sRANKL on admission were 38,6 ±19,03 ng/ml and 0,22±0,24 ng/ml, respectively. Whereas, at the end of induction, serum levels were measured as 35,5±40,8 ng/ml for OPG and 0,033±0,056 ng/ml for sRANKL. A statistically significant decrease was determined for sRANKL at the end of induction therapy, compared to admission (p:0,000). Conclusion: In the current research, OPG and sRANKL are increased at diagnosis of childhood B-ALL. Whereas, no significant relationship between the OPG and sRANKL levels and the disease prognosis was determined.

A single-center study of bone mineral density in adult patients with severe hemophilia A in correlation with markers of bone metabolism

Osteopenia and osteoporosis are well-known hemophilia A comorbidities. The pathogenesis of bone turnover alteration resulting in reduced bone mass includes impaired osteoblastic differentiation and disinhibition of RANKL-induced osteoclastogenesis as a result of a low FVIII level. To evaluate the bone mineral density (BMD) in adult patients with severe hemophilia A and assess a possible correlation with the bone remodeling biomarkers OPG/RANKL, CTX-1, osteocalcin, and Vit D. 28 male subjects with severe hemophilia A and 33 age-matched controls were recruited. The biomarkers were tested with the ELISA assay and BMD with DEXA of the lumbar spine (LS) and total hip (TH). The patients had lower LS-BMD (-0.955±0.145 vs. 1.118±0.079, p=0.05) and TH-BMD (-0.840±0.147 vs. 0.951±0.075, p=0.05) than those of the controls. The TH T-scores were -1.41±0.91 vs. 0.4±0.49 (p=0.05) and the LS T-scores -1.16±1.046 vs. 0.14±0.72 (p=0.05). 66.6% of patients under 50 years had osteopenia and 8.3% had osteoporosis. Fifty percent of those over 50 years old had osteopenia and 20% had osteoporosis. We found significantly higher OPG levels (123.69±107.05 vs. 41.98±18.95, p=0.05) than that in controls and lower sRANKL levels (23.49±29.39 vs. 131.32±201.27, p=0.05) and sRANKL/OPG ratio (0.27±0.35 vs. 5.28±10.01, p=0.05) than those in controls. A positive correlation was found between sRANKL and the BMD T-score of lumbar spine (p=0.001) in the patient group. sRANKL level and ratio can be used as predictors of low BMD.

Evaluation of an association between RANKL and OPG with bone disease in people with cystic fibrosis

BackgroundAs people with Cystic Fibrosis (CF) live longer, extra-pulmonary complications such as CF-related bone disease (CFBD) are becoming increasingly important. The etiology of CFBD is poorly understood but is likely multifactorial. Bones undergo continuous remodeling via pathways including RANK (receptor activator of NF-κB)/sRANKL (soluble ligand)/OPG (osteoprotegerin). We sought to examine the association between sRANKL (stimulant of osteoclastogenesis) and OPG levels (inhibitor of osteoclast formation) and CFBD to investigate their potential utility as biomarkers of bone turnover in people with CF. MethodsWe evaluated sRANKL and OPG in plasma from people with CF and healthy controls (HC) and compared levels in those with CF to bone mineral density results. We used univariable and multivariable analysis to account for factors that may impact sRANKL and OPG. ResultsWe found a higher median [IQR] sRANKL 10,896pg/mL [5,781–24,243] CF; 2,406pg.mL [659.50–5,042] HC; p= 0.0009), lower OPG 56.68pg/mL [36.28–124.70] CF; 583.20pg/mL [421.30–675.10] HC; p < 0.0001), and higher RANKL/OPG in people with CF no BD than in HC (p < 0.0001). Furthermore, we found a higher RANKL/OPG ratio 407.50pg/mL [214.40–602.60] CFBD; 177.70pg/mL [131.50–239.70] CF no BD; p = 0.007) in people with CFBD versus CF without bone disease. This difference persisted after adjusting for variables thought to impact bone health. ConclusionsThe current screening recommendations of imaging for CFBD may miss important markers of bone turnover such as the RANKL/OPG ratio. These findings support the investigation of therapies that modulate the RANK/RANKL/OPG pathway as potential therapeutic targets for bone disease in CF.

Decreased level of soluble receptor activator of nuclear factor-κβ ligand (sRANKL) in overweight and obese children.

IntroductionChildhood obesity contributes to the development of cardiovascular diseases. The molecular pathway – receptor activator of nuclear factor-κβ ligand (RANKL), its receptor RANK and osteoprotegerin (OPG) - takes part not only in bone metabolism but is also involved in the atherosclerosis process. RANKL stimulates osteogenic differentiation and calcification of vascular smooth cells. The associations between the OPG-sRANKL system and various cardiovascular risk factors were displayed. We aimed to evaluate the relationships between serum sRANKL (soluble RANKL) levels and the OPG/sRANKL ratio with cardiometabolic risk factors in overweight and obese children.Material and methodsThe study included 70 children with overweight and obesity (mean age 13.0 ± 2.8) and 35 age-matched normal weight, healthy peers as a control group. In all patients, anthropometric measurements and laboratory tests were performed. Additionally, an oral glucose tolerance test (OGTT) was made only in overweight and obese children. Atherogenic and insulin resistance indices were calculated.ResultsOverweight and obese children had lower sRANKL levels compared to the control group (median 276.95 vs 325.90, p=0.011), and consequently a higher OPG/sRANKL ratio (0.02 vs 0.01, p = 0.013). The studied children in the lowest quartile of sRANKL levels had higher body weight, Body Mass Index, waist circumference and increased glucose and insulin levels 60 minutes after OGTT and higher uric acid values compared to children in the highest quartile. In multivariable linear regression analysis sRANKL negatively correlated only with uric acid (β = - 0.508, p = 0.041). No association was found for the OPG/sRANKL ratio.ConclusionExcess fat mass seems to alter the OPG/RANKL ratio mainly by reducing serum sRANKL levels. The correlation between sRANKL and uric acid may suggest a contribution of the OPG-sRANKL system in the cardiometabolic process, but that observation should be confirmed in future studies.

DJ-1 controls T cell differentiation and osteoclastogenesis in rheumatoid arthritis

Herein, we investigated the effect of DJ-1 on helper T cell differentiation, fibroblast-like synoviocyte (FLS) activation, and osteoclastogenesis in rheumatoid arthritis (RA). Serum and synovial fluid (SF) of RA and osteoarthritis (OA) patients were collected, and DJ-1 and H2O2 levels were investigated. CD4+ cells from peripheral blood mononuclear cells (PBMCs) were cultured under type 17 helper T cell (Th17) polarization conditions, and CD4+ T cell differentiation, pro-inflammatory cytokine levels, and soluble receptor activator of nuclear factor kappa-Β ligand (RANKL) were assessed. RA-FLSs were stimulated with 50 μM H2O2, and DJ-1 (10, 50, 100 ng/mL) to evaluate MMP-9, VEGF, TNF-α, and sRANKL production, while RANKL+ FLSs were assessed using flow cytometry. Monocytes were cultured with RANKL or IL-17A with or without DJ-1 and H2O2-pretreated RA-FLS, and tartrate-resistant acid phosphatase (TRAP) staining and RT-qPCR of osteoclast-related genes were performed. The levels of DJ-1 and H2O2 in serum and SF of RA patients were higher than those of OA patients. Under Th17-polarizing conditions, CD4+RANKL+ and CD4+CCR4+CCR6+CXCR3- T cells decreased, whereas CD4+CD25highFoxp3+ T cell increased after DJ-1 administration. Additionally, IL-17A, TNF-α, and sRANKL levels decreased in DJ-1-treated groups. DJ-1 lowered MMP-9, VEGF, TNF-α, and sRANKL levels, and RANKL+ FLS in ROS-stimulated RA-FLS. Both RANKL and IL-17A stimulated osteoclast differentiation, DJ-1 decreased TRAP+ cell count, and the expression levels of TRAP, ATP6v0d2, NFATc1, and CTSK. These findings were also observed in in vitro osteoclastogenesis with DJ-1 pretreated RA-FLS. As DJ-1 regulates Th17/Treg imbalance, pro-inflammatory cytokine production, RA-FLS activation, and osteoclastogenesis, it holds potential for RA therapy.

Could Bone Biomarkers Predict Bone Turnover after Kidney Transplantation?—A Proof-of-Concept Study

Aim: Bone disease after kidney transplant (KT) results from multiple factors, including previous bone and mineral metabolism disturbances and effects of transplant-related medications. New biomolecules have been recently associated with the development and progression of the chronic kidney disease–associated bone and mineral disorder (CKD-MBD). These include sclerostin and the soluble receptor activator of nuclear factor-kB ligand (sRANKL). Methods: To better understand the role of biomarkers in post-transplant bone disease, this study was designed to prospectively evaluate and correlate results from the histomorphometric analysis of bone biopsies after KT with emerging serum biomarkers of the CKD-MBD: sclerostin, Dickkopf-related protein 1 (Dkk-1), sRANKL and osteo-protegerin (OPG). Results: Our data shows a significant increase in plasma levels of bioactive sclerostin after KT accompanied by a significant reduction in plasma levels of Dkk-1, suggesting a promotion of the inhibition of bone formation by osteoblasts through the activation of these inhibitors of the Wnt signaling pathway. In addition, we found a significant increase in plasma levels of free sRANKL after KT accompanied by a significant reduction in plasma levels of its decoy receptor OPG, suggesting an enhanced bone resorption by osteoclasts mediated by this mechanism. Conclusions: Taken together, these results suggest that the loss of bone volume observed after KT could be explain mainly by the inhibition of bone formation mediated by sclerostin accompanied by an enhanced bone resorption mediated by sRANKL.

Serum PTH, PTH1R/ATF4 pathway, and the sRANKL/OPG system in bone as a new link between bone growth, cross-sectional geometry, and strength in young rats with experimental chronic kidney disease.

The progression of chronic kidney disease (CKD) in children is associated with deregulated parathyroid hormone (PTH), growth retardation, and low bone accrual. PTH can cause both catabolic and anabolic impact on bone, and the activating transcription factor 4 (ATF4), a downstream target gene of PTH, is related to its anabolic effect. Osteoprotegerin (OPG) and receptor activator of NF-κB ligand (RANKL) are PTH-dependent cytokines, which may play an important role in the regulation of bone remodeling. This study aimed to evaluate the impact of endogenous PTH and the bone RANKL/OPG system on bone growth, cross-sectional geometry and strength utilizing young, nephrectomized rats. The parameters of cross-sectional geometry were significantly elevated in rats with CKD during the three-month experimental period compared with the controls, and they were strongly associated with serum PTH levels and the expression of parathyroid hormone 1 receptor (PTH1R)/ATF4 genes in bone. Low bone soluble RANKL (sRANKL) levels and sRANKL/OPG ratios were also positively correlated with cross-sectional bone geometry and femoral length. Moreover, the analyzed geometric parameters were strongly related to the biomechanical properties of femoral diaphysis. In summary, the mild increase in endogenous PTH, its anabolic PTH1R/ATF4 axis and PTH-dependent alterations in the bone RANKL/OPG system may be one of the possible mechanisms responsible for the favorable impact on bone growth, cross-sectional geometry and strength in young rats with experimental CKD.

Serum RANKL levels in Chinese patients with ankylosing spondylitis: a meta-analysis

ObjectiveWe aimed to determine the association between serum receptor activator of nuclear factor-kappa B ligand (sRANKL) levels and ankylosing spondylitis (AS) in Chinese patients.MethodsThe PubMed, Cochrane Library, Embase, Chinese Biomedical Database, Web of Science, China National Knowledge Infrastructure, VIP, and Wan Fang databases were searched for studies conducted before October 1, 2020, without language restrictions. STATA version 12.0 and Revman version 5.3 were used to analyze the data. The standard mean differences (SMDs) and corresponding 95% confidence intervals (95% CIs) were calculated.ResultsTwelve clinical case–control studies, including 585 patients with AS and 423 healthy controls, were included. The combined SMD for sRANKL suggested that the sRANKL level was significantly higher in Chinese patients with AS than in healthy controls (SMD: 3.27, 95% CI 2.11–4.43, P < 0.00001). Serum RANKL-related factor osteoprotegerin (OPG) levels (SMD: 0.86, 95% CI 0.09–1.64, P < 0.03) were lower in the Chinese patients with AS than in healthy controls, and the RANKL/OPG ratio (SMD = 1.05, 95% CI 0.64–1.46, P < 0.00001) in Chinese patients with AS was approximately the same as that of healthy controls. Subgroup analysis indicated that patients from North and South China had higher sRANKL levels than controls; the sRANKL levels of patients from South China were higher in the subgroup with a Bath Ankylosing Spondylitis Functional Index (BASFI) of > 4 than those of patients in other subgroups. In terms of duration, patients with AS for > 8 years had higher sRANKL levels than health controls. Other subgroup analyses were conducted by region, language, source of control, age, and Bath Ankylosing Spondylitis Disease Activity Index (BASDAI). In these subgroups, the sRANKL levels were significantly higher in the patients with AS than in healthy controls. The BASFI and BASDAI were sources of heterogeneity.ConclusionsThe sRANKL levels are higher in Chinese patients with AS, especially among those from South China. sRANKL levels may be positively correlated with the pathogenesis of AS among Chinese patients.

Physical activity and Mediterranean diet as potential modulators of osteoprotegerin and soluble RANKL in gBRCA1/2 mutation carriers: results of the lifestyle intervention pilot study LIBRE-1

PurposeEmerging evidence suggests that the progesterone-mediated receptor activator of nuclear factor κB (RANK)/soluble RANK ligand (sRANKL)/osteoprotegerin (OPG) pathway plays an important role in mammary carcinogenesis and is hyperactivated in germline (g)BRCA1/2 mutation carriers. We analyzed the effects of a 3-month intensive lifestyle intervention within the LIBRE-1 study on the serum levels of OPG and sRANKL and hypothesized that the intervention program provides a beneficial impact on the biomarkers by increasing OPG and reducing sRANKL serum concentrations.MethodsSerum levels of OPG and sRANKL of 49 gBRCA1/2 mutation carriers were quantified using enzyme-linked immunosorbent assays. We used previously collected blood samples from participants of the prospective LIBRE-1 study, who were randomized into an intervention group (IG), increasing physical activity and adherence to the Mediterranean diet (MedD) through supervised sessions from study entry to the first study visit after 3 months and a usual-care control group (CG). Differences in biomarker levels before and after the 3-month intervention were tested within and between study groups.ResultsThe lifestyle intervention resulted in a significant increase in OPG for participants in both the IG (q = 0.022) and CG (q = 0.002). sRANKL decreased significantly in the IG (q = 0.0464) and seemed to decrease in the CG (q = 0.5584). An increase in the intake of Omega-3 polyunsaturated fatty acids was significantly associated with an increase in OPG (r = 0.579, q = 0.045). Baseline serum levels of sRANKL were a strong predictor for the change of sRANKL in the course of the intervention (ß-estimate = − 0.70; q = 0.0018). Baseline physical fitness (assessed as VO2peak) might predict the change of OPG in the course of the intervention program (ß-estimate = 0.133 pg/ml/ml/min/kg; p = 0.0319; q = 0.2871).ConclusionFindings from this pilot study seem to confirm our hypothesis by showing an increase in OPG and decrease in sRANKL over a 3-month lifestyle intervention and suggest that increased physical activity and adherence to the MedD are potent modulators of the biomarkers OPG and potentially sRANKL.

Effects of submucosally administered platelet-rich plasma on the rate of tooth movement.

To evaluate the effects of submucosally administered platelet-rich plasma (PRP) on the rate of maxillary canine retraction. Levels of soluble receptor activator of nuclear factor-κb ligand (sRANKL) and osteoprotegerin (OPG) in the gingival crevicular fluid (GCF) were also measured over 2 months. This split-mouth trial involved 20 sites in 10 subjects randomly assigned to PRP (experimental) side and control side. After alignment, the freshly prepared PRP was injected submucosally distal to the experimental side maxillary canine, and retraction was performed using NiTi closed-coil springs (150 g) on 0.019 × 0.025-inch stainless steel wire. The rate of canine movement was assessed using digital model superimposition at 0, 30, and 60 days. The OPG and sRANKL were assayed using enzyme-linked immunosorbent assay from GCF collected at 0, 1, 7, 21, 30, and 60 days. Twenty sites were analyzed using paired t test. The rate of tooth movement increased significantly by 35% on the PRP side compared with the control side in the first month (P = .0001) and by 14% at the end of the second month (P = .015). Using the Mann-Whitney U test, OPG levels were found to be significantly decreased on the 7th (P = .003) and 30th day on the PRP side (P = .01), while sRANKL became detectable by the third week postinjection on the PRP side (P = .069). Submucosal injection of platelet-rich plasma significantly increased tooth movement during the 60-day observation period. Local injection of PRP significantly altered the levels of OPG and sRANKL in GCF.

Assessment of Serum sRANKL, sRANKL/OPG Ratio, and Other Bone Turnover Markers with the Estimated 10-Year Risk of Major and Hip Osteoporotic Fractures in Rheumatoid Arthritis: A Cross-Sectional Study.

Background Fracture risk assessment tool (FRAX) index was developed for estimating of the 10-year risk of major or hip osteoporotic fracture. To date, there is insufficient information regarding the correlation between FRAX and serum bone turnover markers (BTMs), such as soluble ligand of receptor activator of nuclear factor-κB (sRANKL), osteoprotegerin (OPG), and other molecules related with secondary osteoporosis in rheumatoid arthritis (RA). Therefore, this study is aimed at assessing the correlation between the FRAX and serum levels of sRANKL, OPG, sRANKL/OPG ratio, Dickkopf-1 (DKK-1), and sclerostin (SOST) in RA. Methods Cross-sectional study included 156 postmenopausal women with RA. Bone mineral density (BMD) was measured at lumbar spine (L1-L4) and total hip using dual-energy X-ray absorptiometry (DXA). RA patients were divided into (A) RA + osteoporosis and (B) RA without osteoporosis. FRAX scores were calculated including the total hip BMD. Serum sRANKL, OPG, DKK-1, and SOST levels were measured by ELISA. Pearson tests were used for assessing the correlation between serum levels of these molecules and FRAX scores in RA. Results The RA + osteoporosis group had elevated sRANKL levels (p = 0.005), higher sRANKL/OPG ratio (p = 0.017), decreased DKK-1 (p = 0.028), and lower SOST levels (p < 0.001). Low total hip BMD correlated with high sRANKL (p = 0.001) and sRANKL/OPG ratio (p = 0.005). Total hip and lumbar spine BMD correlated with DKK-1 (p = 0.009 and p = 0.05, respectively) and SOST levels (p < 0.001 and p < 0.001, respectively). Higher sRANKL levels and sRANKL/OPG ratio correlated with estimated 10-year risk of a major osteoporotic fractures (p = 0.003 and p = 0.003, respectively) and hip fracture (p = 0.002 and p = 0.006, respectively). High serum SOST levels were associated with a low estimated 10-year risk of a major osteoporotic fracture (p = 0.003) and hip fracture (p = 0.009). Conclusion High sRANKL levels and sRANKL/OPG ratio can be useful to detect a subgroup of RA patients who has an increased 10-year risk of major and hip osteoporotic fractures.

Sclerostin and DKK1 circulating levels associate with low bone turnover in patients with chronic kidney disease Stages 3 and 4.

Background Disordered mineral and bone metabolism is a common complication of chronic kidney disease (CKD). Bone biopsy remains the gold standard tool for evaluating renal osteodystrophy (ROD), but it is an invasive procedure. Despite a growing interest in the ability of newer bone biomarkers to discriminate between different forms of ROD, data on pre-dialysis patients are scarce.MethodsA cross-sectional study was conducted in a cohort of 56 patients with CKD Stages 3 and 4. Participants underwent a transiliac bone biopsy after a course of double tetracycline labelling. Circulating levels of Wnt signalling inhibitors sclerostin and Dickkopf-1 (DKK1), soluble receptor activator of nuclear factor-κB ligand (sRANKL) and osteoprotegerin were measured and correlated with histomorphometric analysis results.ResultsMost patients had abnormal bone histology and low-turnover bone disease was the predominant form of ROD. Characteristics associated with high bone turnover were worse renal function, lower serum calcium and higher intact parathyroid hormone and fibroblast growth factor-23 levels. Patients with low bone turnover, on the other hand, presented with higher sclerostin along with lower DKK1 and sRANKL levels. In the multivariable logistic regression analysis, sclerostin and DKK1 levels were independently associated with low-turnover bone disease.ConclusionsOur results suggest that circulating levels of Wnt signalling inhibitors sclerostin and DKK1 are predictive of low-turnover bone disease in patients not yet on dialysis. Further research is needed to assess the performance of these bone turnover biomarkers, compared with histomorphometric analysis, in the diagnosis and treatment monitoring of ROD.

FETUIN A DEFICIENCY IS ASSOCIATED WITH ARTERIAL DAMAGE IN PEDIATRIC PATIENTS WITH PRIMARY HYPERTENSION

Abstract Objective: Circulating calcification inhibitors: fetuin A (FA) and osteoprotegerin (OPG) together with soluble ligand of the receptor activator of nuclear factor kappa-B (sRANKL) have been linked to vascular calcifications and subclinical arterial damage. The aim of the study was to evaluate the relationship between FA, OPG, sRANKL and arterial damage in children with primary hypertension (PH). Design and method: We performed cross-sectional analysis of FA, OPG, sRANKL, peripheral and central blood pressure (BP), ambulatory blood pressure monitoring (ABPM), parameters of arterial damage including common carotid artery intima media thickness (cIMT), pulse wave velocity (PWV), augmentation index normalized to heart rate of 75 beats per minute (AIx75HR) and ECHO-tracking (ET) analysis of carotid artery stiffness in 60 patients with PH (age: 14.84 ± 3.05 years) and 20 healthy children (age 14.11 ± 2.99 years). Results: Children with PH had significantly higher peripheral and central BP, BP in ABPM, thicker cIMT, higher PWV, and AIx75HR. FA was significantly lower in patients with PH compared to healthy peers (340.57 ± 70.43 vs. 389.19 ± 99.22 [mg/mL], P = 0.019) without differences in OPG, sRANKL, and OPG/sRANKL and OPG/FA ratios. In children with PH, FA level correlated negatively with cIMT Z-score and ET AIx; sRANKL level correlated negatively with ABPM, systolic blood pressure (SBP), SBP load, diastolic BP load, and AIx75HR; OPG/sRANKL ratio correlated positively with SBP load, while OPG/FA ratio correlated positively with ET AIx. In multivariate analysis FA was a significant determinant of cIMT [mm] and cIMT Z-score (beta = -0.208, 95%CI (-0.407 - -0.009), P = 0.041 and beta = -0.224, 95%CI (-0.435 - -0.013), P = 0.038, respectively). Conclusions: In children with PH arterial damage is related to fetuin A deficiency.

Biomarker levels in peri-implant crevicular fluid of healthy implants, untreated and non-surgically treated implants with peri-implantitis.

To compare biomarker levels in peri-implant crevicular fluid (PICF) of healthy implants with levels in PICF of implants with peri-implantitis (before and after non-surgical treatment). Samples were taken from 20 healthy implants (n=17 patients) and from 20 implants with peri-implantitis (n=19 patients) before and 3months after non-surgical treatment using the Airflow Master Piezon® (EMS). A Luminex™ assay was used to evaluate pro-inflammatory and anti-inflammatory cytokines IL-1β, TNF-α, IL-6 and G-CSF, collagen degradation enzyme MMP-8, chemokines MCP-1 & MIP-1α/CCL3, bone markers OPG and sRANKL and interferon-γ. Clinical and radiographical characteristics were assessed. A Mann-Whitney U and Wilcoxon signed-rank test analysed between- and within-group differences. IL-1β and MMP-8 levels were found significantly elevated in implants with peri-implantitis (p=.007; p=<.001, respectively). No difference in levels of TNF-α, IL-6, MCP-1 and MIP-1α/CCL3, OPG and G-CSF between healthy and diseased implants was found. Levels of sRANKL and INF-γ were under the level of detection. None of the biomarker levels improved after non-surgical therapy, and levels of IL-1β and MMP-8 remained high. Implants diagnosed with peri-implantitis have higher levels of IL-1β and MMP-8 in PICF compared to healthy implants. Non-surgical therapy did not influence the inflammatory immune response.

Lumbar spine bone mineral density and trabecular bone score-adjusted FRAX, but not FRAX without bone mineral density, identify subclinical carotid atherosclerosis

PurposeOsteoporosis and atherosclerosis share common risk factors. Aim of this study was to test if FRAX (which is an algorithm that can identify subjects at risk of fracture), without or with BMD values, also adjusted for trabecular bone score (TBS) was able to identify subclinical atherosclerosis, evaluated by measurement of carotid intima media thickness (cIMT ≥ 0.9 mm) as compared to DXA values.MethodsNinety postmenopausal women underwent DXA measurement and cIMT evaluation. For each patient, the FRAX algorithm for major osteoporotic fracture (M) and for hip fracture (H) without BMD was computed, together with FRAX with BMD and TBS-adjusted FRAX. Serum levels of osteoprotegerin, sRANKL, and interleukin-6 were also measured.ResultsThere were no differences in anthropometric parameters and cardiovascular risk factors between subjects with cIMT ≥ 0.9 mm (35% of subjects, group A) compared to those with cIMT < 0.9 mm (group B). The prevalence of osteoporosis and FRAX BMD, TBS-adjusted FRAX both for M and H were higher in group A compared to group B. The best ROC curves to identify subjects with a cIMT ≥ 0.9 mm were: lumbar spine T-score, with a threshold of − 2.5 SD (area under the curve, AUC 0.64; p = 0.02) with a sensibility of 50% and a specificity of 76%; TBS-adjusted FRAX H with a sensibility of 50% and a specificity of 72% (AUC 0.64; p = 0.01 with a threshold of 3%). Interleukin-6 positively correlated with FRAX BMD H and M.ConclusionsFRAX without BMD does not identify subclinical carotid atherosclerosis, while lumbar spine T-score and TBS-adjusted FRAX H similarly detected it with higher specificity for T-score.