Background/Purpose: Osteoarthritis (OA) is a heterogeneous disorder, with several possible drivers of disease progression. Up to 50% of OA patients do not structurally progress, emphasizing the importance for identification of fast progressors, and the phenotypes associated with that. There is therefore a medical need for in-depth, post-hoc analysis of clinical studies in OA. The aim of the analysis was to investigate the associations between JSW, KL-score, pain and JSN (joint space narrowing), as well as BMI, by combining data from two phase III studies (N=2,206) to identify key characteristics for disease progression.

Methods: This is a post-hoc analysis of two randomized, double-blind, multi-center, placebo-controlled trials NCT00486434 and NCT00704847 evaluating the efficacy and safety of 2-years treatment with oral salmon calcitonin in subjects with painful knee OA, enrolling 1,176 and 1,030 subjects. The analysis includes baseline data on KL-score, JSW, pain and function scores from the WOMAC questionnaire, as well as demographics.

Results: Diagnostic measures; At baseline, combined analysis of signal and non-signal knees, the mean JSW was comparable in knees of KL-0 and -1 and significantly decreased with increasing KL-2, -3 and -4 (p<0.01). JSW (KL2/3) was significantly lower in the non-target knees as compared to the target knees (3.32±0.03mm vs. 3.42±0.02mm, p<0.0001, mean±SEM). There was a clear positive and significant correlation between KL-score and WOMAC pain and total WOMAC, albeit the variance in pain measures was from min-to-max for all KL categories, emphasizing the heterogeneity of this patient population and pain perception. Prognostic measures; 32% of target knees did not progress, and only 51% had changes over minimum significant change (MSC). Only minor differences were observed between target and non-target and KL-2 versus KL-3. The mean JSN at 2-years for the non-target knee was 0.25±0.02mm and 0.32±0.02 for the target knee (p<0.01). Patients were stratified in quartiles for WOMAC pain and BMI, as well as WOMAC pain and KL-scores, and investigated for JSN. Q3 WOMAC pain progressed more than Q2 and Q4 in both scenarios.

Conclusion: These data from the largest clinical trial dataset in OA to date clearly describe significant associations between KL-score, JSW, pain and BMI in patients with symptomatic knee OA.  50% of patients did not progress more than MSC, highlighting the importance for identification of structural progressors and the phenotypes associated with these. Patients with symptomatic OA at baseline progressed significantly faster than patients with asymptomatic disease, however with important variations that need accounting for when designing clinical trials, such as relations to pain, BMI and JSN. Different levels of progression were observed in relation to KL score and pain, in which the third WOMAC pain quartile (Q3), but not the fourth quartile (Q4), progressed significantly faster than the first and second pain quartiles. These results suggest that disease phenotypes rather than disease status are responsible for disease progression. Consequently, this dataset is ideally suited for identification of different phenotypes of OA, and biomarkers associated with those.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/oa-phenotypes-rather-than-disease-stage-drive-structural-progression-identification-of-structural-progressors-from-2-phase-iii-randomized-clinical-studies-with-symptomatic-knee-oa/