OBJECTIVE:To investigate the relative contribution of cartilage and synovial turnover to predict progression in patients with knee or hip osteoarthritis (OA). METHODS:A total of 449 patients with symptomatic knee or hip OA (mean age: 62 yr, 62% women) with a Kellgren-Lawrence (KL) score ≥2 from the prospective KHOALA cohort study were investigated. Progression was defined as a one-point increase in the KL scores from knee or hip radiographs and/or a joint replacement during 5 years follow-up. The association of baseline urinary CTX-II and serum Col 3-4, biochemical markers of cartilage and synovial turnover, respectively, with progression was assessed by multivariable discrete-time survival models. RESULTS:Increased baseline CTX-II levels were associated with an increased risk of knee and/or hip OA progression, patients with levels in the fourth quartile having an odds ratio (OR; 95%CI) of 2.57 (1.57-4.18) compared with subjects with levels in first quartile, after adjustment for demographical and OA clinical variables and KL scores. When analyses were restricted to patients with knee or hip OA progression only, similar findings were obtained with corresponding ORs (95% CI) of 2.36 (1.32-4.21) and 3.39 (1.42-8.11), respectively. There was no significant association of baseline Col 3-4 and the risk of knee or hip progression. CONCLUSIONS:Increased urinary CTX-II, but not Col 3-4, is independently associated with a higher risk of structural progression in patients with knee or hip OA. Cartilage turnover may play a more important role than synovial activity as assessed with Col 3-4 to mediate joint damage in established OA. TRIAL REGISTRATION:ClinicalTrials.gov, http://clinicaltrials.gov, NCT00481338.

OBJECTIVES:To investigate whether serum C1M and C2M, biochemical markers of synovial and cartilage tissue destruction, were associated with progression of joint damage in patients with early arthritis. METHODS:813 early arthritis patients (<6 months of symptoms, 82% with rheumatoid arthritis, 18% undifferentiated arthritis) from the prospective ESPOIR study were followed for 5 years. Radiographic progression was assessed using the van der Heijde Sharp score, and progression was defined as an increase of 1 or 5 unit(s) between baseline and 1 year or 5 years. Associations between baseline C1M and C2M and progression were assessed by logistic regression. RESULTS:Increased baseline continuous serum C1M levels were associated with the risk of progression at 1 year, after adjustment for age, gender and body mass index (BMI). Patients with levels in the highest quartile of C1M had an OR (95% CI) of total joint damage progression of 2.75 (1.70-4.45) compared with patients in the lowest quartile. When disease activity score 28, C reactive protein and anticyclic citrullinated peptide 2 antibodies positivity were included in the model, high C1M remained significantly associated with progression with an OR (95% CI) of 2.12 (1.06-4.23). At 5 years, C1M was significantly associated with the risk of total joint damage progression after adjustment for age, gender and BMI. There was no significant association of C2M with progression at 1 year or 5 years. CONCLUSIONS:High baseline serum C1M, but not C2M, is associated with increased radiographic progression in early arthritis, independently of classical risk factors. C1M, in conjunction with other risk factors, may help identify patients at higher risk of joint damage.

Objective To investigate the association of plasma cartilage acidic protein 1 (CRTAC1), a novel biochemical marker of osteoarthritis (OA), and total joint replacement (TJR) in postmenopausal women. Methods The association of plasma CRTAC1 with the incidence of TJR was investigated in a prospective cohort including 478 postmenopausal women. A total of 38 women underwent a TJR for OA during a median follow-up of 18 years. Every one of the TJR cases were age- and BMI (kg/m 2 )-matched with 2 controls with no TJR from the same cohort. Plasma CRTAC1 was measured before TJR. The association between CRTAC1 and TJR incidence was investigated by conditional logistic regression. Results Increased CRTAC1 was associated with a higher risk of TJR with an odds ratio (OR) of 1.80 (95% CI 1.11-2.92) for 1 SD increase, which remained significant after adjusting for Western Ontario and McMaster Universities Osteoarthritis Index, knee OA baseline severity (Kellgren-Lawrence grade), hip OA, and hip bone mineral density. Urinary crosslinked C-telopeptide of type II collagen (CTX-II) was also associated with a higher risk of TJR with an adjusted OR of 1.83 (95% CI 1.11-3.00). When CRTAC1 and CTX-II were included in the same model, both markers were significantly associated with TJR with similar ORs. Conclusion CRTAC1 is a new risk indicator of TJR for OA in postmenopausal women. Combined with knee and hip OA and CTX-II, it may help to identify subjects at risk for TJR.

Background: In early rheumatoid arthritis (RA), radiographic assessments are insensitive to identify patients at high risk of progression, because the extension of joint damage, especially cartilage degradation, is rather limited. Biochemical markers reflecting dynamic processes of tissue remodeling may be more sensitive to predict progression in early RA, but available data are lacking. Objectives: To investigate whether systemic biochemical markers of matrix-metalloprotease (MMP) driven type I (C1M) and type II (C2M) collagen degradation as indicators of synovial and cartilage tissues remodeling respectively, predict progression of joint damage in a prospective longitudinal cohort of patients with early RA. Crossectional associations of C1M and C2M with demographical variables and classical parameters of disease activity were also investigated. Methods: Patients from the prospective ESPOIR cohort included 813 patients with definitive or probable clinical diagnosis of RA (ACR-EULAR 2010 criteria) or a diagnosis of undifferentiated arthritis (UA) with potential for progression to RA. All patients presented with swelling of two or more joints, 6 weeks to 6 months’ symptom duration and no previous treatment with DMARD or glucocorticoids. Hand and feet radiographs were obtained at baseline and after 1- and 5-year follow-up and scored for bone erosion, joint space narrowing (JSN) and total damage by the modified van der Heijde Sharp (vHS) score. Progression was defined as an increase of 1 or 5 unit(s) in vHS between baseline and 1 or 5 years, respectively. Serum C1M and C2M were measured at baseline using validated ELISAs. The crossectional associations of C1M and C2M with age, BMI, DAS 28 and CRP were analyzed using regression analyses. The association between baseline levels of C1M and C2M and radiological progression over 1 and 5 years was assessed by logistic regression. Results: At baseline, 81 % of patients had a diagnosis of early RA, whereas 19% had UA (median: symptom duration, 4.9 months; DAS28, 5.1; C-reactive protein, 9 mg/L). The extent of radiological joint damage was low (median vHS; erosion: 0, JSN: 1, total: 1.5). C1M was associated with BMI (p<0.05) and men had higher levels than women (+28%, p<0.0001) whereas C2M correlated positively with age (p<0.05). At baseline, serum C1M was highly correlated with DAS28 (r=0.45, p<0.0001) and CRP (r=0.87, p<0.0001), whereas C2M was only slightly associated with both variables (r=0.09 and 0.11, p<0.05, respectively). Mean baseline levels of C1M were significantly increased in patients who had a radiological progression both at year 1 and year 5 compared to subjects with no progression (Figure 1). In contrast C2M levels were similar in patients with progression and non-progression (NS both at 1 and 5 years).Table shows the 1-year and 5 -year odds-ratio (OR) and 95 % CI of radiological progression (increase from baseline in vHS score) for each SD increase of baseline C1M levels after adjustments for age, gender, BMI and diagnosis of RA. After further adjustments for baseline DAS 28, CRP, ACPA positivity and radiological erosion, increased baseline C1M remained significantly associated with progression of bone erosion at year 1 (OR; 95% CI: 1.45; 1.02-2.05 for each SD increased levels). There was no significant association between baseline C2M levels and radiological progression at either 1 or 5 years. Conclusion: Increased baseline serum C1M - but not C2M- is consistently associated with a higher risk of radiographic progression in patients with early RA. Synovial tissue remodeling may be a prominent determinant of progression in the early phase of the disease whereas cartilage turnover is likely to play a minor role at this stage. Serum C1M as a sensitive marker of synovial tissue remodeling could help identifying patients with early RA at higher risk of progression. REFERENCES: NIL. Acknowledgements: NIL. Disclosure of Interests: Patrick Garnero: None declared, Sofie Falkenløve Madsen Employee of Nordic Bioscience, Evelyne Gineyts: None declared, Florent Eymard: None declared, Jérémie Sellam: None declared, Roland Chapurlat: None declared, Anne-Christine Bay-Jensen Share Holder of Nordic Bioscience, Employee of Nordic Bioscience.Figure 1 Table 1Progression ofOdds-ratio (95% CI) of progression for each SD increase of baseline C1MProgression at 1 yearProgression at 5 yearsTotal vHS1.29 (1.10-1.51)1.35 (1.12-1.64)Erosion vHS1.46 (1.19-1.80)1.18 (0.91-1.53)JSN vHS1.23 (1.05-1.44)1.26 (1.05-1.51)

The presented guidelines are an update of the position paper, endorsed by the International Osteoporosis Foundation (IOF), on nomenclature of bone markers published over 2 decades ago. Novel insight into bone biology and pathophysiology of bone disorders has highlighted the increasing relevance of new and known mediators implicated in various aspects of bone metabolism. This updated guideline proposes the nomenclature Bone Status Indices (BSI) as the comprehensive classification rather than bone turnover markers, bone markers, metabolic markers of bone turnover or metabolic markers of bone turnover, that are currently in use for the implicated molecules. On behalf of the IFCC Committee on Bone Metabolism and the Joint IOF Working Group and IFCC Committee on Bone Metabolism, the authors propose standardized nomenclature, abbreviations and measurement units for the bone status indices.

OBJECTIVE:To investigate whether serum Col 3-4, a new biochemical marker of synovial tissue turnover, was associated with progression of joint damage in patients with early arthritis. METHODS:A total of 788 early arthritis patients (<6 months of symptoms, 82% diagnosis of RA, 18% undifferentiated arthritis) from the prospective ESPOIR study were investigated. Progression was defined as an increase of 1 or 5 unit(s) in radiographic van der Heijde modified Sharp score between baseline and 1 or 5 years, respectively. Associations between baseline Col 3-4 and progression were assessed by logistic regression. RESULTS:Each standard deviation increase of baseline Col 3-4 levels was associated with an increased 5-yr total damage progression with an odds ratio (OR, 95% CI) of 1.51 (1.21, 1.88), which remained significant when DAS28, C-reactive protein and anti-citrullinated protein antibodies positivity were included in the model [OR (95% CI): 1.34 (1.01, 1.76)]. Further adjustment for bone erosion did not modify the association. Patients with both Col 3-4 in the highest quintile and bone erosion had a >2-fold higher risk of progression [OR (95% CI): 7.16 (2.31, 22)] than patients with either high Col 3-4 [2.91 (1.79, 4.73)] or bone erosion [2.36 (2.38, 3.70)] alone. Similar associations were observed for prediction of 12 months progression. CONCLUSIONS:Increased serum Col 3-4 is associated with a higher risk of structural progression, independently of major risk factors. Col 3-4 may be useful in association with bone erosion to identify patients with early arthritis at higher risk.

CONTEXT:Spinal-cord injury (SCI) induces bone loss and dramatically increases the risk of fracture. OBJECTIVES:Determine the effects of whole-body vibration (WBV) on areal bone mineral density (aBMD), whole body composition and bone biological parameters in individuals with chronic-state SCI. DESIGN:Randomized study. SETTING:Centre Neurologique PROPARA. PARTICIPANTS:Fourteen subjects were randomly assigned to a WBV or a control group. INTERVENTIONS:WBV (20-45 min, 30-45 Hz, 0.5 g) was performed in verticalized persons twice weekly for 6 months. OUTCOME MEASURES:aBMD was measured by DXA at baseline and 6 months and bone biological parameters at baseline, 1, 3 and 6 months. RESULTS:No significant aBMD change was found in either the WBV or control group after 6 months of follow-up. Similarly, periostin, sclerostin and bone turnover markers remained relatively stable throughout follow-up and no difference in variation was observed within-group and between groups. Except for whole-body fat mass, which showed a significant decrease in the WBV group compared to controls, no difference in changes was observed, whatever the localization for fat and lean body mass. CONCLUSIONS:During the chronic phase, aBMD and bone remodeling reach a new steady state. However, the DXA technique and the bone markers, including sclerostin and periostin, both of which reflect bone cell activity influenced by mechanical strain, showed that the bone tissue of individuals with SCI was insensitive to 6 months of WBV training at the study dose. Nevertheless, results of this preliminary study that was underpowered need to be confirmed and other modalities of WBV may be more effective in improving aBMD of this population. TRIALS REGISTRATION:N°IDRCB:2011-A00224-37.

Purpose: The development of reliable biochemical markers that can improve the identification of patients with osteoarthritis (OA) at high risk for progression and total joint replacement (TJR) is urgently needed. Current markers, including urinary CTX-II, lack sensitivity and specify as a single test. Two recent studies have shown that plasma cartilage acidic protein 1 (CRTAC-1), a cartilage matrix molecule, is strongly associated with the burden and progression of knee, hip and hand OA. These studies, however, relied on complex, costly proteomic analyses which can not be used in large clinical studies and for the management of patients. In addition, these studies did not compare the performance of CRTAC-1 with that of urinary CTX-II, the current most predictive OA biochemical marker. So, the aim of this study was to investigate the association of plasma CRTAC-1 measured by a simple ELISA and the progression to TJR in postmenopausal women.

The objective of this study was to develop a serum biochemical marker of the degradation of type III and IV collagens, as an index of synovium turnover, and evaluate its performance in patients with rheumatoid arthritis (RA). An enzyme-linked immunosorbent assay for serum synovial collagen fragments (Col3-4) was developed using an antibody recognizing a specific sequence from human type III collagen, which shares 70% homology with type IV collagen. Immunohistochemistry was performed to localize Col3-4 and the matrix metalloprotease MMP-9 which is upregulated in RA synovial fibroblasts in the synovial tissue from a RA patient. Serum Col3-4 was measured in patients with RA (n = 66, 73% women, mean age 62 years, median disease activity score 28 with erythrocyte sedimentation rate (DAS28-ESR) 2.6) and in sex and age matched healthy controls (n = 70, 76% women, mean age 59 years). Col3-4 immunoassay demonstrated adequate analytical performances and recognized a circulating neoepitope resulting from the cleavage of type III and IV collagens. In RA synovium tissue, Col3-4 fragments were localized in the lining layer where destructive fibroblasts are present and around blood vessels rich in type IV collagen. MMP-9 colocalized with Col3-4 staining and efficiently released Col3-4 fragments from type III and type IV collagen digestion. Serum Col3-4 was markedly increased in patients with RA (+240% vs controls, p < 0.0001) and correlated with DAS28-ESR (r = 0.53, p < 0.0001). Patients with RA and active disease (DAS28-ESR > 3.2, n = 20) had 896% (p < 0.0001) higher levels than subjects with low activity (n = 46). Serum Col3-4 is a specific and sensitive biochemical marker reflecting MMP- mediated type III and IV collagen degradation from synovial tissue. Serum Col3-4 levels are markedly increased in patients with RA, particularly in those with active disease, suggesting that it may be useful for the clinical investigation of RA.

Background Rheumatoid arthritis (RA) is characterized by synovial tissue (ST) inflammation leading to pain, joint destruction, impaired mobility and ultimately increased morbidity and mortality. These various components of disease etiology can be monitored by pain scores and imaging technologies. Noninvasive assessment of joint tissues metabolism can be performed by measuring serum metabolites of tissue matrix turnover. Specific biochemical markers (BM) of bone and cartilage have been developed, but there is still a lack of a sensitive index of ST metabolism abnormalities, although there are early and key drivers of joint destruction. Objectives To develop a sensitive ELISA-based serum BM of ST turnover (SynHelix) and evaluate its performance in patients with RA. Methods We identified a 11 amino-acid sequence (HELIX-III) within the triple helical portion of type III collagen, a main component of ST matrix which is released during ST turnover and can be measured in the serum. A highly specific rabbit polyclonal antibody raised against the synthetic HELIX-III peptide was produced to develop a competitive ELISA. Specificity of the antibody was evaluated by competitive inhibitions with homologous sequences of type I, IV and XI collagens which are also present in ST, but in minor quantities for the two later. Immunohistochemistry analysis of human ST obtained during hip surgery was performed to investigate in situ localisation of the HELIX-III peptide. ELISA was then used to quantify serum HELIX-III fragments in two samples of patients with low (n= 40, median DAS 28: 2.1) and moderate (n=11, median DAS28: 3.5) RA activity participating in clinical trials. Levels in RA subjects were compared to sex and age-matched healthy controls randomly selected from epidemiological cohorts (n=70). Results The ELISA for SynHelix demonstrated adequate analytical performances with intra and interassay variations below 10 and 15%, respectively; analytical and functional limits of quantification of 0.21 and 2.5 ng/ml, respectively and dilution recovery of human serum ranging from 80 to 108%. Competitive inhibition experiments demonstrated that the antibody does not recognize HELIX-III peptide shortened or elongated by one amino-acid, indicating that immunogenicity is dependent on the presence of a neopitope resulting from the cleavage of the collagen molecule. The antibody does not recognize the homologous sequence of type I collagen, but shows significant immunoreactivity with the homologous sequences of type IV (alpha 5) and type XI (alpha 2) collagens with however a lower affinity than for type III collagen (a 2.2 and 4-fold higher concentration, respectively, is needed to displace 50% of the immune signal). Immunohistochemistry of ST tissue from RA subjects showed increased staining in the interstitial tissue and around vessels which are rich in type IV collagen. Median serum levels of SynHelix were significantly higher in patients with low (p=0027, +17%) and moderate RA activity (+220%, p=00004 vs healthy controls; +164% p=0.16 vs low RA) compared with those in age-matched controls, although CRP did not discriminate RA patients with low and moderate activity (2.2 mg/L for both groups, p=0.90). In RA subjects, serum SynHelix correlates modestly with CRP (r=0.59, p <0.0001), but not with DAS28. Conclusion The new SynHelix ELISA measures precisely circulating degradation fragments of Helix-III peptide-containing collagens. Serum SynHelix levels are already increased in patients with low activity RA, values correlating modestly the degree of systemic inflammation. Larger longitudinal studies are needed to further evaluate the value of SynHelix to predict disease outcome in RA. Disclosure of Interests Patrick Garnero: None declared, Evelyne Gineyts: None declared, Jean-Charles Rousseau: None declared, Hubert MAROTTE: None declared, Roland Chapurlat Consultant of: BMS, abbvie, Lilly, Galapagos, fresenius-Kiabi, novartis.

Abstract BackgroundRheumatoid arthritis (RA) is characterized by synovium inflammation leading to joint destruction. No sensitive serum biochemical marker of synovial tissue activity is currently available. The aims of this study were to develop a new sensitive serum biochemical marker of synovium turnover and evaluate its performance in patients with RA.Methods We developed an enzyme-linked immunosorbent assay to measure synovial collagen fragments in serum (SynCol) using an antibody recognizing a specific 11 amino acid sequence from the triple helical portion of human type III collagen. The specificity of the antibody was evaluated by competitive inhibition with several collagen-related peptides. Immunohistochemistry was performed to localize the SynCol fragments in RA synovium. Serum SynCol was measured in patients with RA (n=66, 73% women, mean age 62 years, median disease activity score 28 (DAS 28) 2.6) participating in randomized clinical trials and in sex and age matched healthy controls (n=70, 76% women, mean age 59 years). ResultsThe SynCol ELISA demonstrated adequate analytical performances. Competitive inhibition experiments showed that the antibody used in the ELISA recognizes a neoepitope resulting from the cleavage of type III collagen molecules and also the homologous sequences of type IV collagen, but does not cross-react with intact type III and IV collagens. Immunohistochemistry of synovial tissue from a RA subject showed staining of SynCol fragments in the lining layer where destructive fibroblasts are localized and around blood vessels which are rich in type IV collagen. SynCol staining co-localized with matrix metalloproteinase 9 (MMP-9) immunostaining. Serum SynCol levels were significantly increased in patients with RA compared to healthy controls (+ 247 %, p <0.0001). In RA patients, circulating SynCol levels correlated with DAS 28 (r=0.66, p <0.0001) and patients with active disease (DAS 28 > 3.2, n=20) had levels which were 888 % (p<0.0001) higher than in those with low activity (n=46). Conclusions The SynCol ELISA is a sensitive and precise assay measuring circulating type III and IV collagen degradation fragments originating from synovial tissue turnover. Serum SynCol levels are markedly increased in patients with RA, particularly in those with active disease. Trial Registration- Role of the ANS Dysregulation in the Persistence of Fatigue in Rheumatoid Arthritis Patients Treated with Anti-TNF (ANSRA) NCT02475486- Bone MicroArchitecture Abatacept (BMA2) NCT02675218- Impact of the Persistence of Inflammation at Doppler Ultrasound Level on the Structural Evolution of Erosion in Rheumatoid Arthritis Treated with Biotherapy. NCT02531061IRB for synovial tissue 2019-A02742-55 (Comité de Protection des Personnes Sud-Méditerranée I

La progression de la destruction articulaire dans la polyarthrite arthrite rhumatoïde (PR) débutante est variable d’un patient à l’autre et elle est difficile à prédire par les facteurs de risque classiques (ACPA, CRP, DAS28, score radiologique). L’objectif de cette étude est d’analyser la valeur prédictive du dosage sérique de Col3-4, un nouveau marqueur biologique de la dégradation des collagènes synoviaux (type III et IV), chez les patients atteints de PR débutante de la cohorte ESPOIR. La concentration sérique de Col 3-4 a été mesurée au temps de base par dosage ELISA (brevet INSERM, reproductibilité intra et inter dosage < 10 et 15 %) chez la totalité des patients de la cohorte ESPOIR disposant d’un prélèvement sérique (n = 788, 82 % de PR, 18 % de patients avec une arthrite indifférenciée, présence de symptômes < 6 mois, naïfs de traitements par DMARDs et corticoïdes). Les associations entre les valeurs de base de Col3-4 et la progression radiologique (score de Sharp/van der Heijde, > 1 unité à 1 an et 5 unités à 5 ans) ont été analysées par régression logistique avant et après ajustement par les facteurs de risque classiques. Au temps de base, Col3-4 était plus élevé chez les PR (p = 0,0001) et chez les patients ACPA positifs (p = 0,0001). Col3-4 était significativement corrélé à la protéine C-réactive (CRP) (p < 0,0001), au DAS28 (p < 0,0001) et très faiblement au score d’érosion (r2 = 0,0081, p = 0,017). Le Tableau 1 montre le risque de progression radiologique à 5 ans pour une augmentation d’un écart-type du Col 3-4 sérique au temps de base. Les patients avec les taux de Col3-4 les plus élevés (5e quintile de la population) avaient un odds-ratio (OR, 95 % CI) de progression du score total à 5 ans de 2,93 (1,79–4,73) par rapport aux autres malades (quintiles 1 à 4) ; ceux présentant une érosion osseuse un OR (95 % CI) de 2,26 (1,38–3,70). Les patients présentant à la fois un Col3-4 élevé et une érosion osseuse avaient un OR (95 %CI) de progression à 5 ans de 7,16 (2,31–22) par rapport à l’ensemble des autres malades. Des résultats similaires ont été observés pour la prédiction de la progression à 1 an et lorsque les analyses étaient limitées aux patients PR. Des taux sériques augmentés de Col3-4 sont associés à un risque élevé de progression structurale à 1 et 5 ans dans la PR débutante, indépendamment des facteurs de risque classiques. En association avec le score radiologique d’érosion, Col 3-4 pourrait être utile pour améliorer l’identification des patients à risque élevé de destruction. L’utilité de cette combinaison pour la prise en charge individuelle de la maladie reste à être testée de manière prospective.

In recent years, markers research has focused on the structural components of cartilage matrix. Specifically, a second generation of degradation markers has been developed against type II collagen neoepitopes generated by specific enzymes. A particular effort has been made to measure the degradation of minor collagens III and X of the cartilage matrix. However, because clinical data, including longitudinal controlled studies, are very scarce, it remains unclear whether they will be useful as an alternative to or in combination with current more established collagen biological markers to assess patients with osteoarthritis (OA). In addition, new approaches using high-throughput technologies allowed to detect new types of markers and improve the knowledge about the metabolic changes linked to OA. The relative advances coming from phenotype research are a first attempt to classify the heterogeneity of OA, and several markers could improve the phenotype characterization. These phenotypes could improve the selection of patients in clinical trials limiting the size of the studies by selecting patients with OA characteristics corresponding to the metabolic pathway targeted by the molecules evaluated. In addition, the inclusion of rapid progressors only in clinical trials would facilitate the demonstration of efficacy of the investigative drug to reduce joint degradation. The combination of selective biochemical markers appears as a promising and cost-effective approach to fulfill this unmet clinical need. Among the various potential roles of biomarkers in OA, their ability to monitor drug efficacy is probably one of the most important, in association with clinical and imaging parameters. Biochemical markers have the unique property to detect changes in joint tissue metabolism within a few weeks.

OBJECTIVE:Identifying objective risk-indicators for total joint replacement (TJR) is useful to enrich population at high risk in OA clinical trials. We investigate the association of urinary CTX-II, a biochemical marker of cartilage breakdown, with the risk of TJR. METHOD:478 postmenopausal women (mean age 65.5 ± 7.5 yr) from the OFELY cohort were studied. CTX-II, serum CTX-I (bone resorption) and PINP (bone formation), were measured at baseline. Association between CTX-II and incidence of TJR was assessed by Cox Hazard Regression. RESULTS:During a median (95%CI) 17.8 (15.0-18.1) years follow-up, 38 women sustained a TJR, including hip (n = 29) or knee (n = 9) replacement. CTX-II -but not CTX-I or PINP- was higher in patients with TJR (+34%, P = 0.001 vs women with no TJR). Increased baseline CTX-II levels were associated with a higher risk of TJR with a Hazard Ratio (HR) (95 CI) of 1.45 (1.13-1.85) per 1 SD increase after adjustment for age, BMI and total hip BMD. CTX-II remained significantly associated with the risk of TJR after further adjustment for total WOMAC, prevalent knee OA (KL ≥ 2) and self-reported hip OA [HR (95 CI): 1.31 (1.01-1.71), P = 0,04]. When women were categorized as low and high CTX-II (lower and above the 95 percentile of healthy premenopausal women, respectively), subjects with high levels had an age-BMI-hip BMD adjusted HR (95 CI) of 3.00 (1.54-5.85) compared to women with low levels which remained significant after further adjustment for WOMAC, knee and/or hip OA [HR (95 CI): 2.45 (1.25-4.89), P = 0.01]. CONCLUSION:CTX-II is an independent risk indicator of TJR in postmenopausal women suggesting that it may be useful to identify subjects at high risk of TJR.

Purpose: Identifying objective risk-factors for total joint replacement (TJR) is useful to enrich population at high risk in osteoarthritis (OA) clinical trials. In this study, we investigated the value of urinary CTX-II, a biochemical marker of cartilage breakdown, to predict TJR in postmenopausal women. Methods: 478 postmenopausal women (mean age 65.5±7.5 yr.) from the OFELY cohort were studied. Urinary CTX-II, serum CTX-I (bone resorption) and PINP (bone formation), were measured at baseline. Total WOMAC, radiological knee OA (KL grade >= 2), clinical hip OA and bone mineral density (BMD, DXA) of the spine and hip were also assessed at baseline. The association between CTX-II, CTX-I, PINP and the incidence of TJR was assessed by Cox Hazard Regression before and after adjustment for confounding variables. Results: During a median (95%CI) 17.8 (15.0-18.1) years follow-up, 38 women sustained a TJR including 29 subjects with total hip replacement (THR) and 9 individuals with total knee replacement (TKR). Urinary CTX-II -but not CTX-I or PINP- was higher in patients with TJR (+34%, p=0.001 vs women with no TJR). Increased baseline CTX-II-but not CTX-I or PINP- was associated with an increased risk of TJR [age-BMI adjusted HR (95% CI): 1.46 (1.14-1.86) per 1 SD increase]. Increased total WOMAC, prevalent knee OA, prevalent self-reported hip OA and increased spine and hip BMD were also significantly associated with the risk of incident TJR. Women with CTX-II levels in the highest quartile had an age-BMI adjusted 2.66 (95% CI: 1.37-5.17) greater risk of TJR than subjects in the lower three quartiles. CTX-II remained a significant predictor of TJR after further adjustment for total WOMAC, prevalent knee OA, self-reported hip OA and spine BMD (HR: 2.10, p=0.037 for levels in the highest quartile). Patients with both hip OA and high CTX-II had a higher risk and likelihood ratio of positive test (LR+) of TJR (HR: 4.71, p=0.001; LR+5.32) than subjects with only one risk factor (HR ; LR+ : 2.62 ; 2.62 for hip OA and 2.66 ; 2.06 for CTX-II). Similarly, patients with both increased CTX-II and higher spine BMD (highest Q), had a higher risk of TJR (HR: 5.43, p<0.002, LR+: 5.01). When the analyses were restricted to patients with THR, similar results were obtained [age-BMI adjusted HR (95%CI): 3.50 (1.69-7.26) for levels in the highest quartile]. Conclusions: Urinary CTX-II is a new independent risk factor of TJR in postmenopausal women. Combination of CTX-II with other risk factors may be useful to identify subjects at high risk for TJR.

Structural damage is a hallmark in RA, spondyloarthropy (SpA) and psoriatric arthritis (PsA). Its progression is difficult to predict and current radiological or inflammatory biological markers lack sensitivity. Biochemical markers of bone, cartilage and synovial tissues provide a dynamic indication of the anabolism and catabolism of joint tissues and can be easily measured by immunoassays. Novel biochemical markers including post-translational modifications of matrix proteins and enzyme-generated neoepitopes with increased tissue and/or biological pathway specificity have been developed. Their evaluation in clinical trials of novel biologic therapies and epidemiological studies indicated that their measurements could be useful to predict progression of structural damage and treatment efficacy, independently of current clinical, radiological and biological indices of disease activity. In this paper we briefly describe the latest developments in biochemical markers and critically analyse the clinical data assessing the utility of established and novel biochemical markers in RA, SpA and PsA.

Bone metabolism is characterized by an intimate cooperation of bone cells including osteoblasts, osteoclasts, and osteocytes in order to maintain bone tissue quantity and the integrity of bone structure. In metabolic bone diseases such as osteoporosis, bone metabolism is altered, leading to bone loss that is often accompanied by changes in the microarchitecture that result in bone fragility and ultimately fracture. The development of serum and urinary assays for biochemical markers, reflecting either enzymatic activities of osteoblasts and osteoclasts or breakdown products of bone tissue, has been very useful for investigating the complex pathways of bone metabolism and their alterations in bone diseases. Novel biological markers have been developed, and studies suggest that they may be valuable research tools for investigating the mechanisms of bone metabolism and assessing the activity of osteocytes, and some of them may be of value for the management of patients with osteoporosis and other bone diseases. In this chapter we will present briefly the established biochemical markers, review the new data on emerging biomarkers, and then discuss their clinical utility in osteoporosis and other metabolic bone diseases.