OA Population Research Articles

AB0780 Identification of Knee OA Phenotypes: A Replication Study Using Data from the Amsterdam Osteoarthritis Cohort

BackgroundWe previously identified 5 clinically relevant phenotypes from a heterogeneous knee OA population (Osteoarthritis Initiative [OAI] cohort), which needs to be replicated for validation.ObjectivesThe present study aims to replicate this...

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

Purpose: 1. To identify patients who will progress to requiring total joint replacement (TJR) amongst a population with moderate-to severe-osteoarthritis (OA) by measuring tissue specific biomarkers in serum thus establishing a panel of prognostic biomarkers that may provide molecular insight into the mechanism and pathology of the progression of OA. 2. Investigate the effect of NSAIDs on the predictive and diagnostic serum profile. Methods: OA patients were randomly selected from clinical trials investigating the anti-NGF therapeutic antibody tanezumab. Serum samples from 240 patients who underwent a TJR (cases) and from 440 control OA patients who did not undergo TJR were used. Control group consisted of ∼2 patients per case matched on: age (<65 or ≥ 65 years), Kellgren-Lawrence (K-L) grade, gender, BMI category (<30 or ≥30 kg/m2), OA severity (severe if both WOMAC Pain and Physical function subscale scores were ≥7 and the Patient Global Assessment score was ≥4 (i.e. Poor or Very Poor), otherwise baseline OA severity was classified as not severe). On the average, the OA population was 62 years old, 80% K-L grade ≥3, females (68%), BMI ∼31 kg/m2, WOMAC pain score of 7. Serum samples were analyzed for bone (Total Osteocalcin, CTX-I, DKK1, SOST), cartilage (C2M, COMP, PIIANP), connective tissue (PINP, ICTP, C1M), synovial tissue (C3M), protease burden (MMP-9) as well as inflammation markers (IL6, hsCRP, VEGF). Classification and Regression Tree analysis was used to identify biomarker phenotypes. Results: For NSAID and non-NSAID users separately, biomarker phenotypes were identified at baseline for patients predisposed for TJR. At baseline, a biomarker combination for patients who used NSAIDs before start of tanezumab clinical trials identified 96% of patients who underwent a TJR and 61% of the patients who did not undergo a TJR. Identification of these biomarker phenotypes lowers the odds of a TJR by 14-fold as compared to not having knowledge of the biomarkers. For patients who did not use NSAIDs, 83% of patients who had a TJR and 63% of the patients who did not undergo a TJR, were identified which lowers the odds of a TJR by 3.6-fold. For patients who used NSAIDs continuously, 84% of patients who had a TJR and 77% of the patients who did not have a TJR, were identified which lowers the odds of a TJR by 4.7-fold. Conclusions: Serological biomarker profiles for predicting TJR were identified irrespective of NSAID use and may assist in identifying those patients whom will need a TJR. The profiles also suggest that NSAID use increases the importance of the role of bone metabolism in TJR pathology. The results need validation on other cohorts, and may finally provide value to patients and payers in selecting the most optimal treatment strategy for moderate-to-severe OA patients.

An OA phenotype may obtain major benefit from bone-acting agents

BackgroundOsteoarthritis (OA) joints display relevant microstructure alterations associated to an increase in remodeling at subchondral bone, which supports its crucial role in OA pathogenesis. Despite this, the treatment of knee OA patients with antiresorptive drugs has given discordant results, suggesting the existence of a particular patient subset with good response to halting high subchondral remodeling. ObjectiveTo identify an OA phenotype that may obtain major benefit from therapy with bone-acting agents. MethodsA systematic review of the literature was performed by searching the Medline and PubMed databases from 1990 to April 2013 using the following keywords: subchondral bone, articular cartilage, and osteoarthritis in various combinations with bone agents, bone mineral density, and scintigraphy. ResultsEarly animal and human studies provided the rationale for the beneficial use of bone agents on OA cartilage damage. Several bone-acting agents have reduced low back pain and likely spondylosis progression. Recently, strontium ranelate has been reported to exert both structural and clinical benefits in knee OA patients with radiological progression. However, other antiresorptives have shown divergent results. Human studies suggest that these contradictory results may be due to the lack of well-defined OA phenotypes and an accurate methodology to recruit and follow up these patients. ConclusionsA particular subset of postmenopausal patients with high remodeling and/or low subchondral bone density may benefit from the treatment with bone-acting agents hindering OA progression. This OA population could be identified with the simultaneous use of subchondral bone dual-energy X-ray absorptiometry and scintigraphy.

SAT0334 Three Trajectories of Activity Limitations in Early Symptomatic Knee Osteoarthritis: a 5-Year Follow-Up Study

BackgroundOsteoarthritis (OA) is a leading cause of activity limitations among older adults. The knee OA population is heterogeneous and is likely to consist of subgroups with distinct trajectories of activity...

The relationship between retinal vessel calibre and knee cartilage and BMLs

BackgroundWhether the increase in vascular disease prevalence and mortality in OA populations is a result of co-occurrence of cardiovascular disease and OA, which are both common in the older population, is due to OA treatments or to the common association with reduced physical activity and/or obesity is unclear. One way to explore this non-invasively is to examine the cross-sectional relationship between changes in retinal microvasculature, which have been shown to be markers of generalized vascular pathology, and knee structural changes in an asymptomatic community-based population.MethodsA community sample of 289 (61% women) aged 50–79 years with no knee symptoms underwent magnetic resonance imaging (MRI) of their dominant knee in 2003. Cartilage volume and bone marrow lesions (BMLs) were determined. All subjects also had retinal photographs taken from which retinal arteriolar and venular diameters were determined and summarized as the central retinal arteriolar equivalent (CRAE) and the central retinal venular equivalent (CRVE).ResultsRetinal venular diameter was significantly wider in subjects with a BML compared with subjects without a BML (mean (SD) 214.2 (2.8) μm versus 207.5 (1.1) μm respectively independent of age, gender and BMI. A trend for decreased medial tibial cartilage with increasing CRAE was also observed (regression coefficient −2.70 μl, 95%CI-5.74, 0.5, p=0.08).ConclusionThese findings suggest that vascular pathology, indicative of inflammatory processes, is associated with early structural knee changes. The role of micro-vascular changes in the pathogenesis of OA warrants further investigation.

294 DIETARY ANTIOXIDANTS AND HIP CARTILAGE VOLUME IN ADULTS WITHOUT CLINICAL HIP OSTEOARTHRITIS

Purpose: Whether the increase in vascular disease prevalence and mortality in OA populations is a result of co-occurrence of cardiovascular disease and OA, which are both common in the older population, is due to OA treatments or to the common association with reduced physical activity and/or obesity is unclear. One way to explore this noninvasively is to examine the relationship between changes in retinal microvasculature, which have been shown to be markers of generalized vascular pathology, and knee structural changes in an asymptomatic community-based population. Methods: A community sample of 289 (61% women) aged 50–79 years with no knee symptoms underwent magnetic resonance imaging (MRI) of their dominant knee in 2003. Cartilage volume and bone marrow lesions (BMLs) were determined. All subjects also had retinal photographs taken from which retinal arteriolar and venular diameters were determined and summarized as the central retinal arteriolar equivalent (CRAE) and the central retinal venular equivalent (CRVE). Results: Retinal venular diameter was significantly wider in subjects with a BML compared with subjects without a BML [mean (SD)] 214.2 (2.8) mm versus 207.5 (1.1) mm respectively independent of age, gender and BMI. A trend for decreased medial tibial cartilage with increasing CRAE was also observed (regression coefficient −2.70ml, 95%CI −5.74, 0.5, p = 0.08). Conclusions: These findings suggest that vascular pathology, indicative of inflammatory processes, is associated with early structural knee changes. The role of micro-vascular changes in the pathogenesis of OA warrants further investigation.

Mutation analysis of candidate genes within the 2q33.3 linkage area for familial early-onset generalised osteoarthritis

In a genome-wide linkage scan of seven families with familial early-onset osteoarthritis (FOA), we mapped a FOA locus to a 5 cM region on chromosome 2q33.3-2q34 with a maximum LOD score of 6.05. To identify causal variants, 17 positional candidate genes and FRZB were sequenced for coding, splice sites, and 5' and 3' untranslated regions. The pathogenicity of possible disease-causing variants was evaluated using predicted effects on protein structure and function, splicing enhancers, degree of conservation and frequency in 790 unrelated subjects from the population-based Rotterdam study scored for the presence of radiographic signs of OA (ROA). Nine novel variants, identified in NRP2, XM_371590, ADAM23, IDH1, PIP5K3 and PTHR2, cosegregated with FOA, of which two were promising. IDH1 Y183C cosegregated in one family, involved a conserved amino-acid change and showed a damaging effect predicted by PolyPhen and SIFT. In the Rotterdam sample, carriers of IDH1 Y183C (0.02) had an increased but insignificant risk for generalised ROA. The second variant, NRP2 c.1938-21T>C cosegregated in three families. In the Rotterdam sample, carriers conferred an increased risk of 2.1 (95% confidence interval, 1.1-4.1, P=0.032) to have generalised ROA. Furthermore, two variants (NRP2 c.1938-21T>C and IDH1 c.933-28C>T) occurred together on the haplotypes segregating with FOA in two out seven families. This haplotype was rare in the Rotterdam sample (0.0013). Two promising variants in or near NRP2 and IDH1 may not be sufficient for the onset of FOA alone but might have a modulating role with FOA. Confirmation in other OA populations is required.

P283 ONE YEAR OAI PILOT DATA: LONG TERM VARIABILITY OF CARTILAGE MORPHOLOGY AS MEASURED BY MRI DESS

twice was evaluated using pairwise differences and linear correlation between pairs of measures. The surface area estimate from automatic segmentation gave a linear correlation coefficient of 0.96 between pairs of estimates on the same knee, and the mean absolute pairwise difference was 2.9%. Conclusions: The cartilage surface area estimate obtained from the automatic cartilage segmentation method can separate healthy populations from OA populations with statistical significance (p = 0.014). Since the method is fully automatic it has full intra-scan reproducibility, and the results show that is also has high inter-scan reproducibility (absolute pairwise difference of 2.9%, linear correlation coefficient of 0.96). Because the method is fully automatic, reproducible and can separate healthy populations from OA populations using the cartilage area estimate obtained from the method, it may be a useful tool in clinical studies using MRI.

P235 dGEMRIC as a function of BMI in an OA population

P235 dGEMRIC as a function of BMI in an OA population