The authors read with interest the letter from Pegreffi et al.1 that helpfully highlights the interplay between obesity, inflammation, and knee osteoarthritis (OA). This important point illustrates recent advances in the understanding of OA heterogeneity and that the future stratification of OA subtypes will be critical for the accurate interpretation of clinical studies and the identification of potential future therapeutic targets relating to OA. It is now well established that OA has distinct phenotypes (clinical presentations) and endotypes (underlying molecular pathways), including the inflammatory and metabolic disease driven disease processes.2 Early-stage knee OA could present a “window of opportunity” in which to arrest the disease process at the early stages and restore joint homeostasis.3 Similarly, stratification of patients may allow clearer understanding of the individualized response to treatment in clinical studies. We agree that the effect of obesity on OA and OA progression itself should be considered beyond the scope of biomechanical cause and effect. The secretion of pro-inflammatory adipokines, including leptin, resistin, and adiponectin, contributes to a local and systemic environment that may accelerate joint degeneration irrespective of joint biomechanics.4, 5 While this perspective augments our understanding, we must consider the methodological limitations of the original study by Lin et al.6 covered in our original letter to the editor.7 The retrospective design, lack of stratification of both OA and body mass index severity, and absence of biomechanical markers or cross-sectional imaging to quantify inflammation or cartilage status limit applicability of data and formation of conclusions regarding causation or mechanisms. In summary, the letter from Pegreffi et al.1 expands on the dialogue initiated by Tollefson et al.7 where effective OA management both during conservative and postsurgical management must integrate mechanical, metabolic, and immunological insight to provide personalized joint preservation strategies. The authors (I.R.M., R.F.L.) declare the following financial interests/personal relationships which may be considered as potential competing interests: I.R.M. reports a relationship with Arthrex Inc that includes: consulting or advisory; reports a relationship with Smith reports a relationship with Stryker that includes: consulting or advisory; reports a relationship with Bone and Joint Research that includes: editorial or governing board; reports a relationship with Journal of Bone and Joint Surgery—British that includes: editorial or governing board; R.F.L. reports a relationship with Ossur Americas that includes: consulting or advisory; reports a relationship with Smith and Nephew Inc that includes: consulting or advisory; reports a relationship with Linvatec Europe that includes: consulting or advisory; reports a relationship with Responsive Arthroscopy that includes: consulting or advisory; reports a relationship with Ossur Americas Inc that includes: funding grants; reports a relationship with Smith and Nephew Inc that includes: funding grants; reports a relationship with Arthroscopy Association of North America that includes: funding grants; reports a relationship with American Orthopaedic Society for Sports Medicine that includes: funding grants. The other authors (J.T.S., L.V.T.) declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this article.
Super et al. (2026) studied this question.