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Background Pain is the principal clinical symptom of osteoarthritis (OA), and development of safe and effective analgesics for OA pain is needed. Trials of new analgesics for OA pain is impaired by substantial placebo-response (PR), and data describing characteristics and pain sub-types particularly associated with placebo-response is needed. Objectives The purpose of this post-hoc analysis was to investigate clinical characteristics and pain subtypes associated with PR as measured by the five pain questions of the Western Ontario and McMasters Arthritis (WOMAC) Index of the target (T)- and the non-target (NT) knees in the pooled data of two phase III randomized clinical trials of an oral treatment in OA. Methods Pooled data from the placebo-groups of two phase III randomized clinical trials (NCT00486434 and NCT00704847) in patients with knee OA followed for two years were analyzed. Main inclusion criteria for T knees were a Kellgren-Lawrence grade of 2 or 3, Joint-Space Width (JSW) of minimum of 2.0 mm at the medial tibio-femoral joint, and WOMAC pain ≥150 out of 500 mm. All analyses were performed on data from the T knees (N=771) and a sub-group of NT knees matching the pain inclusion criteria of the T knees (N=256). All subjects in the analysis belonged to the Per-Protocol population. Pain of the T and NT knees was measured using the WOMAC pain sub-index, five questions: Q1; during walking on a flat surface, Q2; using stairs, Q3 at night while in bed, Q4; sitting or lying and Q5; while standing. Changes in percent from baseline pain were calculated at months 1, 6, 12 and 24, and differences between individual questions were assessed using a repeated measures ANOVA. Pain by category (“under load”; WOMAC questions 1, 2 and 5 and “idle”; WOMAC questions 3 and 4) were similarly analyzed for change over time, and compared in a repeated measures ANOVA. Selected patient baseline characteristics; pain by WOMAC question, Joint-space width (JSW), age, and BMI were assessed for association with PR defined as change in percent from baseline to year two using Spearman9s correlation. Results Baseline pain was significantly higher in WOMAC Q2, compared to other pain questions (p The level of PR was significantly higher in questions related to pain while under load (Q1, Q2, Q5) compared to pain while idle (Q3, Q4), and this was statistically significant in the T knee (p Baseline BMI, age and JSW was not associated with PR. This indicates while no common clinical characteristics were associated with PR, other, perhaps psychological, factors may affect the susceptibility to PR. Conclusions These results indicate that the level of PR is significantly different between pain subtypes, as pain under load is significantly more susceptible to lead to PR than pain while idle. Disclosure of Interest A. Bihlet Shareholder of: Nordic Bioscience, Employee of: Nordic Bioscience, M. Karsdal Shareholder of: Nordic Bioscience, Employee of: Nordic Bioscience, I. Byrjalsen Employee of: Nordic Bioscience, A.-C. Bay-Jensen Shareholder of: Nordic Bioscience, Employee of: Nordic Bioscience, C. Christiansen Shareholder of: Nordic Bioscience, Employee of: Nordic Bioscience, J. Andersen Shareholder of: Nordic Bioscience, Employee of: Nordic Bioscience, H. Guhring: None declared, C. Ladel: None declared, M. Michaelis: None declared, B. Riis Shareholder of: Nordic Bioscience, Employee of: Nordic Bioscience, I. Valter: None declared

Background Cartilage and synovium are two central tissues remodeled in osteoarthritis (OA). Recent data has shown that type II collagen degradation (CTX-II) is a biomarker of cartilage and subchondral turnover. CRPM and C3M are biomarkers of synovial inflammation and turnover. Objectives To identify different subtypes of OA related to progression by measuring biomarkers of cartilage degradation and synovial inflammation. Methods Fasting serum (n=767) and urine (n=620) samples from knee OA patients, of the placebo arms of two phase III RCTs (NCT00486434 and NCT00704847) were analyzed for Serum C3M, CRPM, (type III collagen and C-reactive protein neo-epitope) and creatinine-corrected urinary CTX-II (type II collagen C-terminal telopeptide). The relationship between the biomarkers and the 5 baseline-reported WOMAC pain subscale questions, using the sum of target and non-target knee, were analyzed: A; during walking on a flat surface, B; using stairs (up or down), C; at night while in bed, D; sitting or lying and E; while standing. Joint space width was analyzed at baseline and at 24 months. Log-transformed data were analyzed by Spearman9s rho and by multiple regression analysis, where WOMAC or radiographic scores were the dependent variable and biomarkers, age, gender and BMI as covariates. Cut-offs was based on reference value and difference between the high/low groups was analyzed by Mann-Whitney. Results CTX-II was significantly correlated with WOMAC with all 5 sub-questions (p Conclusions CTX-II was associated with all types of pain, especially with pain associated with walking on a flat surface, indicating that CTX-II is related to pain from continuous skeletal load, supported by the strong correlation with JSW. C3M, from the synovium, was weakly correlated pain by using stairs and standing still. C3M was correlated to progression indicating that patients with certain levels of C3M had a higher likelihood for progression. We found that the two inflammatory markers could facilitate patient segregation. These biomarkers may assist in identification of the inflammation driven OA phenotype, which needs to be treated different than non-inflammatory OA. Acknowledgements The CSMC021C2301/2 investigators Disclosure of Interest A. Bay-Jensen Shareholder of: Nordic Bioscience, Grant/research support from: EC FP7 programs, Employee of: Nordic Bioscience, I. Byrjalsen Employee of: Nordic Bioscience, K. Musa Employee of: Nordic Bioscience, A. Bihlet Shareholder of: Nordic Bioscience, Employee of: Nordic Bioscience, P. Alexandersen: None declared, J. Andersen: None declared, B. Riis: None declared, C. Christiansen Shareholder of: Nordic Bioscience, M. Karsdal Shareholder of: Nordic Bioscience, Grant/research support from: EC FP7 programs, Employee of: Nordic Bioscience

Background Osteoarthritis (OA) is recognized as a heterogeneous disorder, with several possible drivers of disease progression, including involvement of bone, cartilage and synovium. The degree of joint pain has been shown to be both diagnostic and prognostic for OA, but meaningful clinical characteristics to identify the group of patients at risk of rapid progression are still needed. Objectives The aim of this analysis was to identify key pain characteristics (WOMAC 5 pain questions) associated with risk of structural progression, and notable changes in reported pain over time. Methods A combined post-hoc analysis of two phase III RCTs (NCT00486434 and NCT00704847), evaluating the efficacy and safety of oral salmon calcitonin in patients with painful knee OA (N=2,206) was performed. Analysis of structural progression was made based on data from the placebo group only, stratifying patients into quintiles of baseline (BL)-reported WOMAC pain level and further investigating the 5 WOMAC pain subscale questions: Q1; during walking on a flat surface, Q2; using stairs (up or down), Q3 at night while in bed, Q4; sitting or lying and Q5; while standing. The association between joint space narrowing (JSN) and WOMAC pain was assessed in a mixed model with JSN as dependent variable and other relevant BL variables as fixed effects. Results Spearman correlation coefficients indicates that each WOMAC pain sub-score expresses individually different information, as rho coefficients ranged from a minimum of 0.40 between Q2 and Q3, and maximally 0.67 for Q3 and Q4 (p The relative change in overall WOMAC pain-score at year 2 was not significantly influenced by level of BL pain score. For each of the sub-score questions, a trend towards higher BL pain level being associated with higher relative and absolute pain relief was observed at year two, with some differences among the individual sub-score questions. Separate analysis of target and contralateral knees revealed interesting differences in association of BL pain level and structural progression. JSN of target knees appeared to be independent of BL levels of Q1-Q5, whereas in contra-lateral knees there was a tendency of higher BL levels of Q1, Q2 and Q5 being associated with higher JSN (Figure). These results highlight differences in perceived pain caused by osteoarthritis over time, and may be indicative of individual pain phenotypical characteristics. The results indicate that acute, likely nociceptive, pain associated with walking and standing was more associated with structural progression than what may be interpreted as a possibly different, perhaps centrally augmented pain experienced without direct mechanical loading of the joint. Conclusions These data from a large clinical trial dataset in OA describe significant associations between pain, pain subtypes and progression in OA, which may be related to different biochemical disease drivers. Acknowledgements We wish to sincerely thank all the participants and investigators of the CSMC021C2301/02 studies. Disclosure of Interest A. Bihlet: None declared, A.-C. Bay-Jensen Shareholder of: Nordic Bioscience, Employee of: Nordic Bioscience, M. Karsdal Shareholder of: Nordic Bioscience, Employee of: Nordic Bioscience, I. Byrjalsen Employee of: Nordic Bioscience, B. Riis Shareholder of: Nordic Bioscience, Employee of: Nordic Bioscience, C. Christiansen Shareholder of: Nordic Bioscience, Employee of: Nordic Bioscience, J. Andersen Shareholder of: Nordic Bioscience, Employee of: Nordic Bioscience, H. Guhring Employee of: Merck Serono, M. Michaelis Employee of: Merck Serono, C. Ladel Employee of: Merck Serono

Background Cartilage and bone are the central tissues affected by osteoarthritis (OA). Remodeling of these tissues can be measured by soluble biomarkers. Recent data has shown that urinary type II collagen C-terminal telopeptide (u-CTX-II) is a biomarker of cartilage and subchondral bone turnover. Bone resorption may be quantified by type I collagen cross-linked C-terminal degradation in serum (s-CTX-I). Objectives The purpose of this analysis was to investigate the association between cartilage and bone remodeling, measured by u-CTX-II and s-CTX-I, and clinically recorded knee pain and KL score, as well as the OA risk factor Body Mass Index (BMI). Methods Fasting serum (n=767) and urine (n=620) samples were collected at baseline from patients with painful knee OA participating in the placebo arms of two phase III RCTs (NCT00486434 and NCT00704847). Creatinine-corrected u-CTX-II (IDS PLC, United Kingdom]) and s-CTX-I (Roche, United Kingdom) were measured. The relationship between the biomarkers and baseline-reported WOMAC pain level of the target knee, radiographic OA score (KL) and BMI were analyzed by Spearman9s correlations on log-transformed biomarker data and by multiple regression analysis (OLS), where WOMAC, KL score or BMI were set as the dependent variable and biomarkers, BMI and age as covariates, adjusted for gender. Results Both CTX-I and CTX-II were significantly correlated to BMI (r=-0.26, p Conclusions This cross-sectional analysis of data from a large clinical trial dataset shows strong correlations between the biomarkers CTX-I, CTX-II and pain and obesity. These findings may be a reflection of high mechanical joint loading caused by overweight, contributing to pathological bone and cartilage wear which could lead to increased pain. Longitudinal data to support this hypothesis is needed. These data indicate that CTX-I and CTX-II may assist in identifying disease drivers of a specific, painful OA phenotype to be further investigated. Acknowledgements We wish to thank the participants and investigators of the CSMC021C2301/2 trials. Disclosure of Interest A. Bihlet Shareholder of: Nordic Bioscience, Employee of: Nordic Bioscience, A.-C. Bay-Jensen Shareholder of: Nordic Bioscience, Employee of: Nordic Bioscience, M. Karsdal Shareholder of: Nordic Bioscience, Employee of: Nordic Bioscience, I. Byrjalsen Employee of: Nordic Bioscience, B. Riis Shareholder of: Nordic Bioscience, Employee of: Nordic Bioscience, C. Christiansen Shareholder of: Nordic Bioscience, Employee of: Nordic Bioscience, J. Andersen Shareholder of: Nordic Bioscience, Employee of: Nordic Bioscience, K. Musa Employee of: Nordic Bioscience, P. Alexandersen Grant/research support from: Nordic Bioscience

Background Early gains in total hip BMD are desirable to improve hip strength early in the treatment of osteoporosis. Objectives To determine if women treated with 18-months of abaloparatide (ABL) were more likely to increase BMD than those treated with either TPTD or placebo (PBO), we performed a responder analysis comparing the percentage of subjects experiencing BMD gains of >3% at all three anatomic sites (total hip (TH), femoral neck (FN), lumbar spine (LS)). Methods In an 18 month phase 3 study of postmenopausal women aged 50-85 with a T-score ≤-2.5 at the spine or hip with either a prior vertebral or non-vertebral fracture, subjects were randomized to receive the PTHrP analog, ABL (80-μg SC daily), TPTD (20-μg SC daily), or placebo. All subjects were also treated with calcium and vitamin D supplementation per local practice. Treatment comparisons were performed using a 2-sided Chi-square test. Results 18-months of treatment with ABL (N=824) resulted in significantly greater increases in BMD relative to placebo (N=821) at 6, 12 and 18 months at TH, FN and LS. There were also significantly greater increases in BMD with ABL relative to TPTD (N=818) at TH and FN at 6, 12 and 18 months and at LS at 6 and 12 months. Overall, a significantly higher percentage of patients experienced >3% BMD gain in the ABL group (54%) compared to the PBO group (3.38%, p Conclusions In postmenopausal women with osteoporosis, more subjects treated with ABL experienced BMD increases at all 3 sites compared to those treated with TPTD or PBO. Disclosure of Interest P. Miller Grant/research support from: Radius Health, G. Hattersley Employee of: Radius Health, E. Lau Grant/research support from: Radius Health, P. Alexandersen Grant/research support from: Radius Health, T. Hala Grant/research support from: Radius Health, S. Mustatea Grant/research support from: Radius Health, B. Nedergaard Grant/research support from: Radius Health, A. Krogsaa Grant/research support from: Radius Health, J. Slessinger Grant/research support from: Radius Health, C. Zerbini Grant/research support from: Radius Health, I. Valter Grant/research support from: Radius Health, Z. Visockiene Grant/research support from: Radius Health, B. Jendrych Grant/research support from: Radius Health, C. Kulak Grant/research support from: Radius Health, F. Marquez Grant/research support from: Radius Health, A. Harris Employee of: Radius Health, G. Williams Employee of: Radius Health, M.-Y. Hu Employee of: Radius Health, D. Black Consultant for: Radius Health, B. Riis Consultant for: Radius Health, L. Russo Grant/research support from: Radius Health, C. Christiansen Consultant for: Radius Health

OBJECTIVE--To study the effect of salmon calcitonin (salcatonin) given intranasally on calcium and bone metabolism in early postmenopausal women. DESIGN--Double blind, placebo controlled, randomised group comparison. SETTING--Outpatient clinic for research into osteoporosis. SUBJECTS--52 Healthy women who had had a natural menopause two and a half to five years previously. INTERVENTIONS--The 52 women were allocated randomly to two years of treatment with either salcatonin 100IU given intranasally (n = 26) or placebo (n = 26). Both groups received a calcium supplement of 500 mg daily. Seven of the women receiving salcatonin and six of those receiving placebo left the study before its end. MAIN OUTCOME MEASURES--Bone mineral content in the spine, the total skeleton, and the forearms after two years of treatment. RESULTS--Bone mineral content in the spine was significantly higher in the women who had received salcatonin than in those who had received placebo both after one year and after two years of treatment. After one year the difference was 3.8% (95% confidence interval 0.0 to 7.6%) and after two years it was 8.2% (3.8 to 12.6%). In contrast, the bone mineral content in the distal and proximal forearms and in the total skeleton declined similarly in both groups by about 2% each year, and after two years of treatment the differences between the groups were not significant. Biochemical estimates of bone turnover were not affected by salcatonin. CONCLUSION--The results suggest that salcatonin given intranasally in the dose used prevents bone loss in the spine of early post menopausal women but does not affect the peripheral skeleton.

Regional values of bone mineral content and bone mineral density were calculated from total body dual photon absorptiometry scans of 52 early postmenopausal women treated with oestrogen for one year and of 52 similar women treated with placebo. The six regions were head, arms, chest, spine, pelvis, and legs. In addition, bone mineral density of the lumbar spine was measured by dual photon absorptiometry and bone mineral content of the forearm by single photon absorptiometry, using separate special purpose scanners. All regions were unchanged after one year of treatment with oestrogen, excluding the lumbar spine, for which values rose. Values for all regions except the lumbar spine fell significantly in the placebo group. The rates of loss ranged from 2% to 8%, with no significant differences among the regions. It is concluded that loss of bone in the early menopause is a generalised phenomenon, affecting all parts of the skeleton. Furthermore, oestrogen prophylaxis for loss of bone is effective in all parts of the skeleton. Finally, it is suggested that the measurement of bone mineral content in the forearm should be used for clinical follow up of bone changes, as this method is superior to others in the ratio of change to precision.