Antiresorptive medications have been explored for treating knee osteoarthritis (OA); however, little data exist on the effects of today’s more potent nitrogen-containing oral bisphosphonates on radiographic disease-progression in patients with varying disease-severity, especially those who are not overweight. The primary objective of this cohort study was to determine if the use of bisphosphonates is protective against 2-year radiographic-progression of knee OA in Osteoarthritis Initiative (OAI) participants, stratified by baseline radiographic disease-status. Secondary objectives were to examine effects in non-overweight participants (body mass index [BMI] < 25 kg/m ) and cumulative bisphosphonate exposure effects. We identified female OAI participants aged ≥50 years and excluded those missing baseline radiograph readings, bisphosphonate use information, or all clinical questionnaire information at baseline. Participants reporting bisphosphonate use (69% alendronate) were propensity-matched 1:1 to non-bisphosphonate-users and followed until first radiographic knee OA-progression (1-unit increase in Kellgren and Lawrence [KL] grade) or data were censored (first missed visit or end of 2-year follow-up). Discrete-time logistic regression models estimated hazard-ratios between bisphosphonate-users versus non-users, with an interaction term for baseline KL grade (KL < 2 or KL≥2). We identified 1,977 eligible women (N = 346 bisphosphonate-users). Propensity-matched results indicated that bisphosphonate-users with KL grade < 2 were protected against progression (HR 0.53 [95% CI 0.35 to 0.79])), while bisphosphonate use was not associated with radiographic progression in those with KL grade ≥ 2 (HR 1.06 [95% CI 0.83 to 1.35]). When restricting analyses to those with BMI < 25 kg/m , effects were strengthened (HR 0.49 [95% CI 0.26 to 0.92]; HR 0.69 [95% CI 0.33 to 1.26]). Duration of bisphosphonate use had no effect on progression, though sample size was limited. Bisphosphonate therapy may be protective against radiographic knee OA progression in early-stage patients, particularly those who are non-overweight, but less so for those with more advanced disease or more weight-bearing joint stress. This article is protected by copyright. All rights reserved.This article is protected by copyright. All rights reserved.