Perceived chondroprotective benefits of extra-label bisphosphonates, such as clodronate disodium (CD), in juvenile horses led to widespread use despite little scientific understanding of intra-articular impacts. The objective was to determine the effects of CD on articular cartilage hypothesizing that administration of CD would decrease cartilage degradation following an acute inflammatory challenge by lipopolysaccharide (LPS). To test this, 32 yearling Quarter Horses were stratified by age (500 ± 13 d), BW (336 ± 26 kg), sex (n = 16 female; n = 16 male) and initial bone optical density into 4 treatment groups. The 140-d study consisted of 2 phases: phase 1 (d 0–83) emulated sales prep and phase 2 (d 84–140) mimicked early performance training. Horses were housed individually (3.6 m × 7.3 m) and fed to meet exercise requirements. Treatments consisted of control (CON; n = 8), single-dose (1X; n = 8; d 84), 2-doses (2X; n = 8; d 0, 84), and 4-doses (4X; n = 8; d 0, 42, 84, 126). All horses received iso-volumetric intramuscular injections of 1.8mg/kg BW clodronate disodium (OSPHOS®) or saline (placebo) on d 0, 42, 84, and 126. Post treatment administration on d 126, radial carpal joints of each horse were injected with 0.8 mL of either 0.5 ng sterile LPS derived from Escherichia coli O55:B5 or sterile lactated Ringer's solution as a contralateral control. Synovial fluid was collected before LPS injection(h 0) and at 6, 12, 24, and 336 h post induction. Carpal circumference (CC), heart rate (HR), respiration rate (RR), and rectal temperature (RT) were recorded before each collection. Synovial fluid was analyzed for carboxypropeptide of type II collagen (CPII) and collagenase cleavage neopeptide (C2C) by ELISA. Data were analyzed using PROC MIXED of SAS. Treatment had no effect on HR, RR, or RT. As expected, intra-articular LPS increased CC, CPII, C2C, and CPII:C2C (P ≤ 0.01). There was a trend for a treatment effect for CC (P = 0.09) where CC was greater in 2X and 4X compared with 1X with CON being intermediate. There tended to be a treatment by hour interaction in CPII (P = 0.06) where CPII was greater in 4X and 2X compared with 1X and CON at h 24 and 336. Likewise,there was a trend for a treatment effect onCPII:C2C (P = 0.06) with 2X and 4X having greater synthesis:degradation than 1X and CON. In conclusion, LPS administration resulted in an expected increase in carpal circumference. Trends of increasing CPII and CPII:C2C in the 2X and 4X treatment group indicate a net increase in articular cartilage synthesis following 2–4 doses of CD despite larger CC, suggesting a greater inflammatory response.