{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2026,11,3]],"date-time":"2026-11-03T21:44:09Z","timestamp":1793742249788,"version":"4.6.1"},"posted":{"date-parts":[[2026,4,17]]},"group-title":"Orthopedics","reference-count":46,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,4,17]],"date-time":"2026-04-17T00:00:00Z","timestamp":1776384000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,10,29]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:sec>\n                  <jats:title>Objective<\/jats:title>\n                  <jats:p>Knee osteoarthritis (KOA) is a leading cause of disability, yet which patients will experience structural decline remains unclear. Body mass index (BMI) and lower limb alignment are established risk factors for KOA, but their independent and interactive effects on compartment-specific cartilage loss and total knee replacement (TKR) have not been characterized at scale.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Design<\/jats:title>\n                  <jats:p>We analyzed 5,930 limbs from 3,191 participants in the Osteoarthritis Initiative followed over 0-60 months. Cartilage thickness in the weight-bearing medial and lateral femur and tibia was quantified, and lower limb alignment was measured using hip-knee-ankle (HKA) angle obtained from full-limb radiographs. Linear mixed-effects models estimated the associations of BMI and lower limb alignment with longitudinal changes in cartilage thickness, modeled as interactions with time and with each other and adjusted for age, sex, and baseline Kellgren-Lawrence grade. Logistic regression with participant-clustered standard errors modeled TKR odds within five and ten years after each limb\u2019s baseline.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>\n                    In the medial compartment, BMI and varus alignment interacted, with their combined effect exceeding the sum of independent effects (femur: \u03b2 = 0.0016 mm\/year per 1-SD BMI x 1-SD HKA, 95% CI [0.0001, 0.0031]; tibia: \u03b2 = 0.0018, 95% CI [0.0008, 0.0028]). In the lateral compartment, alignment, but not BMI, was associated with faster cartilage loss, and its association was nonlinear (time x HKA\n                    <jats:sup>2<\/jats:sup>\n                    : femur \u03b2 = -0.0032 mm\/year, 95% CI [-0.0038, -0.0027]; tibia \u03b2 = -0.0033, 95% CI [-0.0040, -0.0026]). TKR odds increased 1.11-fold at five years (95% CI [1.04, 1.18]) and 1.14-fold at ten years (95% CI [1.08, 1.21]) per 1-degree greater absolute HKA deviation from the radiographically healthy reference angle (\u22121.0\u00b0). BMI did not modify the association between HKA deviation and TKR.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Conclusion<\/jats:title>\n                  <jats:p>BMI and lower limb alignment influence structural KOA progression through compartment-specific pathways. The compounding interaction in the medial compartment identifies high BMI combined with varus malalignment as a high-risk phenotype for medial structural progression.<\/jats:p>\n                <\/jats:sec>","DOI":"10.64898\/2026.04.15.26350819","type":"posted-content","created":{"date-parts":[[2026,4,17]],"date-time":"2026-04-17T17:50:21Z","timestamp":1776448221000},"source":"Crossref","is-referenced-by-count":1,"title":["BMI and Varus Malalignment Compound to Define a High-Risk Phenotype for Compartment-Specific Knee Osteoarthritis Progression"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6864-138X","authenticated-orcid":false,"given":"McKenzie S.","family":"White","sequence":"first","affiliation":[{"name":"Department of Radiology, Stanford University, Stanford, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0580-7308","authenticated-orcid":false,"given":"Feliks","family":"Kogan","sequence":"additional","affiliation":[{"name":"Department of Radiology, Stanford University, Stanford, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9643-7551","authenticated-orcid":false,"given":"Scott L.","family":"Delp","sequence":"additional","affiliation":[{"name":"Department of Bioengineering, Stanford University, Stanford, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4998-5846","authenticated-orcid":false,"given":"Constance R.","family":"Chu","sequence":"additional","affiliation":[{"name":"Department of Orthopedic Surgery, Stanford University, Stanford, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4849-7514","authenticated-orcid":false,"given":"Seth L.","family":"Sherman","sequence":"additional","affiliation":[{"name":"Department of Orthopedic Surgery, Stanford University, Stanford, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3186-9660","authenticated-orcid":false,"given":"Pai S","family":"Anoosha","sequence":"additional","affiliation":[{"name":"Department of Radiology, Stanford University, Stanford, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3207-822X","authenticated-orcid":false,"given":"Garry E.","family":"Gold","sequence":"additional","affiliation":[{"name":"Department of Radiology, Stanford University, Stanford, CA, 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