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The aim of this exploratory and hypothesis-generating study was to develop a clinically actionable tool for predicting molecular endotypes of KOA using blood-based biomarkers, and to explore the potential for differential treatment effects across biomarker-based endotypes in prior phase II-III KOA drug trials.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Fourteen biomarkers from 226 KOA participants from IMI-APPROACH were assessed for a multinomial logistic regression model to predict structural damage, inflammation, and low tissue turnover endotypes. An optimized panel of six serum biomarkers (C2M, C3M, N-MID, PRO-C2, PRO-C4, sCTX-I) was identified quantitatively by testing all biomarker combinations in models adjusting for age, sex, and BMI. These biomarkers were used for endotype predictions in KOA participants from the randomized placebo-controlled trials MIV-711 (\n                      <jats:italic>n<\/jats:italic>\n                      \u2009=\u2009244) (NCT02705625), salmon calcitonin (\n                      <jats:italic>n<\/jats:italic>\n                      \u2009=\u2009947) (NCT00486434), and UBX0101 (\n                      <jats:italic>n<\/jats:italic>\n                      \u2009=\u2009175) (NCT04129944).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>The structural damage endotype showed the greatest numerical 26-week reduction in NRS knee pain when treated with MIV-711 (-6.46%; 95% CI: -16.23%, 3.31%). Notably, only the structural damage endotype had a significant two-year reduction in WOMAC pain when treated with salmon calcitonin (-6.19%; 95% CI: -10.55%, -1.83%). Considering the subset treated with salmon calcitonin with the top 20% highest probability of belonging to the structural damage endotype, a 9\u201315% reduction in standard deviation of the two-year change in WOMAC pain was observed. Enriching the trial for this subset with lower outcome variability could have led to an 18\u201328% reduction in the needed sample size.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>This exploratory study suggests the feasibility of predicting KOA endotypes using a minimal panel of tissue-turnover biomarkers. The observed treatment effects of anti-bone resorptive treatments and reduced outcome variability in the structural damage endotype may subtly indicate that aligning treatments with endotypes and drug modes of action can possibly enhance their therapeutic efficacy. Further investigation is needed to establish the true clinical utility of biomarker-based endotyping. Endotype-informed trial design and recruitment may represent a promising strategy to increase the likelihood of success in future KOA clinical trials.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s13075-026-03825-7","type":"journal-article","created":{"date-parts":[[2026,5,7]],"date-time":"2026-05-07T00:44:27Z","timestamp":1778114667000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Therapeutic subtypes of knee osteoarthritis: differential treatment effects among predicted endotypes in past clinical trials"],"prefix":"10.1186","volume":"28","author":[{"given":"Monica T.","family":"Hannani","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peder","family":"Frederiksen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Morten A.","family":"Karsdal","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cecilie L.","family":"Bager","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Asger R.","family":"Bihlet","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karin","family":"Tunblad","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fredrik","family":"\u00d6berg","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jamie E.","family":"Collins","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Virginia B.","family":"Kraus","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David J.","family":"Hunter","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jaume","family":"Bacardit","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anne-Christine","family":"Bay-Jensen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian S.","family":"Thudium","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,5,7]]},"reference":[{"issue":"8065","key":"3825_CR1","doi-asserted-by":"publisher","first-page":"1217","DOI":"10.1038\/s41586-025-08771-z","volume":"641","author":"K Hatzikotoulas","year":"2025","unstructured":"Hatzikotoulas K, Southam L, Stefansdottir L, Boer CG, McDonald ML, Pett JP, et al. 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