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Background Osteoarthritis (OA) can lead to joint failure and ultimately total joint replacement (TJR). Identifying risk-factors of developing joint failure is of interest for clinicians and researchers. Currently late-stage clinical trial design for evaluating new treatments in OA is evolving with the possible utilization of accelerated approval pathways. This may require outcome studies with longer duration, in which joint failures may qualify as an endpoint. However, TJRs are relatively rare events and are known to be biased by doctor/patient interactions as well as local practice guidelines, and consequently, there is a need for objective non-invasive measures, such as soluble biomarkers (BM), to enrich the population for this outcome. BM may act as important tools in investigating the association between biochemical/pathological processes and risk of joint failure. Degradation of collagens type I and II are known to be involved in OA disease progression, and the biomarkers CTX-I (C-telopeptide of crosslinked collagen type I), a marker of bone degradation, and CTX-II (C-telopeptide of crosslinked collagen type II), a marker of cartilage degradation, may reflect disease progression with clinical relevance for the risk of joint failure. Objectives To evaluate baseline (BL) BM sCTX-I and uCTX-II as predictors of TJR. Methods Data from two clinical trials investigating oral salmon calcitonin (SMC) in OA, NCT00486434 and NCT00704847, was analyzed post-hoc. Data was dichotomized by the bottom and top quartile of the respective BM concentration at BL to compare the number TJRs of the knee or hip in groups with high vs. low sCTX-I or uCTX-II, respectively. For means of visualization, plotted in Kaplan-Meier curves. Cox Proportional Hazard Regression was performed to determine the association of BL sCTX-I and uCTX-II to the incidence of TJR while adjusting for co-variates; age, BMI, and gender. Data from both treatment groups were analyzed. Only the first reported incident was included in the analysis for each subject. Results A total of 68 TJRs of knee or hip were reported, of which 49 were knees and 18 were hips. One patient underwent two TJRs, resulting in 67 subjects with events. Results from the Cox Proportional Hazard Regression adjusted for covariates of age, BMI, and sex (table 1), indicate that high BL sCTX-I compared to low was associated with a 3.4 times higher risk of undergoing an arthroplasty of the knee or hip within a two-year period (p=0.04). High BL uCTX-II compared to low was associated with a 3.1 times higher risk of undergoing a TJR of the knee or hip during the study period (p=0.04), and an 8.9-fold increased risk of undergoing a knee replacement during the study period (p=0.02). TJR events over time in groups of high or low uCTX-II through the study are illustrated in figure 1. Conclusion High levels of sCTX-I and uCTX-II at BL were associated with increased risk of undergoing TJR of the knee or hip during the two year study. Our findings support the role of sCTX-I and uCTX-II as important biomarkers in clinical OA trials evaluating incidence of TJRs. Disclosure of Interests Jonathan Bjerre-Bastos Employee of: I am a full-time employee in Nordic Bioscience, Anne-Christine Bay-Jensen Shareholder of: I own shares of Nordic Bioscience, Employee of: I am a full-time employee in Nordic Bioscience, Morten Karsdal Shareholder of: I own shares of Nordic Bioscience, Employee of: I am a full-time employee in Nordic Bioscience, Inger Byrjalsen Employee of: I am a full-time employee in Nordic Bioscience, Jeppe Ragnar Andersen Shareholder of: Nordic Bioscience, Employee of: Nordic Bioscience, Bente Juel Riis Shareholder of: Yes, I own shares in Nordic Bioscience, Employee of: I am a full-time employee in Nordic Bioscience, Claus Christiansen Shareholder of: Yes, I own shares in Nordic Bioscience, Employee of: I am a full-time employee in Nordic Bioscience, Asger Reinstrup Bihlet Shareholder of: Yes, I own shares in Nordic Bioscience., Employee of: I am a full-time employee in Nordic Bioscience

Background Osteoarthritis (OA) is a heterogeneous disease described by a combination of joint pain, physical disability and radiographic alterations leading to joint failure and total joint replacement (TJR). Commonly used endpoints in OA trials are worsening of pain and joint space narrowing. TJR is normally not considered an endpoint. Age and female gender are considered as major risk factors for developing OA. Objectives We hypothesise that TJR can be used as an endpoint in OA outcome studies within reasonable time frame. To investigate the basis for this hypothesis, we explored the prevalence and incidence of TJR as a reflection of joint failure in the Prospective Epidemiologic Risk Factor (PERF I) study. Methods A total of 5,855 Danish postmenopausal women aged 49–88 enrolled in the Prospective Epidemiologic Risk Factor (PERF I) study during 1999–2001 (baseline). Three, six and twelve year follow-up data from the Danish National registry was collected in end of 2014, including occurrence of TJR, OA and other relevant diagnosis. Also, women where at baseline and in 2014 asked whether they had a TJR or OA. The biomarker C1M was measured in baseline serum samples. The PERF I study was carried out in accordance with ICH-GCP and the study protocol was approved by the local ethics committees. Results There were 798 women that had their first TJR between baseline and 12 year follow-up; giving an incidence proportion of 13.6%. The TJR women were on average 1 year older (p=0.010) and heavier (1.7 kg/cm2, p 40 ng/mL, median) that after baseline underwent there first ever TJR (841). Group 1 is as described above. The 3, 6 and 12 incidence rates were 9.0, 17.3% and 29.7% for the prior TJR group, 6.2, 12.1% and 23.3% for the OA group, and 7.6, 13.6% and 25.1% for the OA +C1M group. The age-dependent prevalence and incidence for the first TJR. The prevalence was insignificant for the age group younger than 60 years old ( Conclusions Within a timeframe of 3, 6 or 12 years TJR incidence for women with an OA diagnosis reached 6, 12% and 23%, which was a doubling compared to the All population. The incidence increased by adding a single diagnostic measure. This reflects that TJRs are frequent amongst elderly women and that if designed minutiously, such as including specific diagnostic criteria (e.g. biomarker, OA diagnose), it may be feasible to conduct clinical studies with TJR as an endpoint. However, special attention much be directed to the objectiveness of the criteria for TJR. This may build a case for design of outcome studies (joint failure) for developing drugs in OA. Disclosure of Interest A. Bay-Jensen Shareholder of: Nordic Bioscience, Grant/research support from: ApproacH (IMI support), Employee of: Nordic Bioscience, C. Bager Employee of: Proscion, A. Bihlet Shareholder of: Nordic Bioscience, Employee of: Nordic Bioscience, C. Thudium Employee of: Nordic Bioscience, I. Byrjalsen Employee of: Nordic Bioscience, H. Nielsen Employee of: Nordic Bioscience, J. Andersen Shareholder of: Nordic Bioscience, Employee of: Nordic Bioscience, B. Riis Shareholder of: Nordic Bioscience, C. Christiansen Shareholder of: Nordic Bioscience, M. Karsdal Shareholder of: Nordic Bioscience, Grant/research support from: ApproacH (IMI support), Employee of: Nordic Bioscience

Background There are two major needs in clinical development of DMOADs: 1) Identifying a suitable population with an active and progressive disease in order to demonstrate significant improvements by an efficacious intervention; and 2) Phenotyping patients and linking them to a corresponding treatment mode-of-action (e.g. anti-inflammatory). The biochemical marker CRPM is a neoepitope of C-reactive protein (CRP) and is released from the local inflamed tissue when CRP is degraded by proteases such as matrix metalloproteinases Objectives The purpose of this study was to translate the CRPM, from rheumatoid arthritis (RA), where it has been extensively tested, to OA, and to test whether it is predictive of radiographic OA. Methods The placebo arms of two phase III OA trial (clinicaltrial.gov: NCT00486434 and NCT00704847), a phase III RA study (the LITHE study, N=490), which included patients with active, moderate-severe RA (NCT00106535), as well as in an early RA cohort (N=92) were used. Subjects with symptomatic and radiographic knee OA: WOMAC pain ≥150mm and/or WOMAC function ≥510mm, and Kellgren-Lawrence grade (KLG) 2 or 3. KLG were scored for both knees at baseline and year 2 (Y2). Serum CRPM and hsCRP were measured at baseline. The association between serum CRPM levels and disease activity score (DAS28) and hsCRP was investigated by Spearman9s correlations. Quartile ranges of CRPM in the early RA cohort were used to define the cut-off between inflammatory OA and non-inflammatory OA. OA knees were divided into cases and controls based on a terminology proposed by the FNIH-OAI consortium (1); knees with KLG≥2 at BL were excluded, and incidence OA at Y2 was defined KLG≥2. Logistic regression was used to compare cases and controls. Results There was a significant correlation between disease activity measures and CRPM in both RA studies. Seventy-five percent of the LITHE patients had high or very high levels of CRPM at BL, which was changed to a pattern similar to early RA after treatment. The mean CRPM levels were significantly lower in OA (8.5 [95% CI 8.3–8.8] ng/mL) compared to the RA patients (15.6 [9.5–21.6] ng/mL); however, a significant subset of OA patients (41% and 31% in SMC2301 and SMC2302) had CRPM levels ≥9ng/mL, as 75% of patients with early RA. Patients with BL or Y2 CRPM levels ≥9ng/mL were more likely to develop knee OA than patients with low level of CRPM. Overall, moderate to very high levels of CRPM at BL and Y2 were predictive of incidence OA with odds ratio of 4.6 [1.2–17] and 2.5 [1.2–4.8]. Conclusions A subset of OA patients, up to 41%, appear to have tissue inflammation comparable to that of RA, reflected by the level of CRPM. Furthermore, high CRPM levels was prognostic of incident knee OA. These data suggest that CRPM is blood-based biochemical marker for finding OA patients with an inflammatory phenotype. References Longitudinal validation of periarticular bone area and 3D shape as biomarkers for knee OA progression? Data from the FNIH OA Biomarkers Consortium.Hunter D et al.Ann Rheum Dis. 2016 Sep;75(9):1607–14. Disclosure of Interest A. Bay-Jensen Shareholder of: Nordic Bioscience, Grant/research support from: DBOARD, Employee of: Nordic Bioscience, A. Bihlet Shareholder of: Nordic Bioscience, Employee of: Nordic Bioscience, I. Byrjalsen Employee of: Nordic Bioscience, J. Andersen Shareholder of: Nordic Bioscience, Employee of: Nordic Bioscience, Y. He Employee of: Nordic Bioscience, A. S. Siebuhr Employee of: Nordic Bioscience, C. Thudium Employee of: Nordic Bioscience, B. Riis Shareholder of: Nordic Bioscience, C. Christiansen Shareholder of: Nordic Bioscience, M. Karsdal Shareholder of: Nordic Bioscience, Employee of: Nordic Bioscience