Different osteoarthritis progression rates within early-stage knee osteoarthritis: a retrospective cohort study using machine learning cluster analysis from the osteoarthritis initiative database

Knee osteoarthritis (OA) is a heterogeneous disease with varying progression rates among patients within the same severity grade. This study aimed to identify clinically interpretable radiographic phenotypes among knees with baseline Kellgren and Lawrence (KL) grade 2 osteoarthritis and to compare their 4-year radiographic progression patterns using baseline radiographic features, lifetime exercise patterns, and demographic characteristics.

Data of patients with baseline KL grade 2 from the Osteoarthritis Initiative database were retrieved. Unsupervised clustering was performed using uniform manifold approximation and projection (UMAP) for dimensionality reduction, followed by hierarchical density-based spatial clustering of applications with noise (HDBSCAN) to identify distinct subgroups. The proportion of knees progressing to KL grade ≥ 3 within 4 years was compared between subgroups, followed by a survival analysis until knee replacement or progression to KL grade 4.

A total of 1997 knees with a mean follow-up of 103.3 months (maximum, 108 months) were included. A total of seven subgroups were identified and classified into accelerated osteoarthritis progression (AOP) group and slow osteoarthritis progression (SOP) group according to whether their 4-year KL grade progression proportions were above or below the training-set average. In a supportive long-term survival analysis, the AOP group also showed significantly earlier progression to knee replacement or KL grade 4 than the SOP group (training set, P < 0.001; test set, P = 0.049), although the absolute difference in mean survival time was modest (8.3 versus 8.5 years in the training set; 8.4 versus 8.6 years in the test set). The AOP group was characterized mainly by lateral joint space narrowing (JSN) and medial JSN with subchondral sclerosis, whereas the SOP group was characterized by medial JSN without subchondral sclerosis, osteophyte-dominant patterns without JSN, or chondrocalcinosis-dominant patterns; these differences were statistically significant across clusters.

Within baseline KL grade 2 knees, clinically interpretable radiographic phenotypes, including lateral JSN, medial JSN with subchondral sclerosis, osteophyte-dominant changes without JSN, and chondrocalcinosis-dominant patterns, were associated with different 4-year KL grade progression rates. These findings support viewing KL grade 2 knee OA as a heterogeneous radiographic stage that may be further stratified into phenotype-based subgroups with different short-term radiographic prognoses.