Evaluation of clinical effects and plasma metabolomic profiles after the administration of grapiprant in dogs affected by osteoarthritis: a prospective, off–on–off, clinical study

Introduction Osteoarthritis (OA) is a prevalent cause of chronic pain and impaired mobility in dogs. Grapiprant, an EP4 prostaglandin receptor antagonist, represents a novel therapeutic option with a favorable safety profile compared to traditional NSAIDs. Aim To evaluate the clinical efficacy of grapiprant in dogs with naturally occurring OA and to investigate systemic metabolomic changes using proton nuclear magnetic resonance ( 1 H-NMR) spectroscopy. Methods Thirty-six dogs with mild to moderate OA were enrolled in a prospective off–on–off study (30 days pre-treatment, 60 days grapiprant treatment at 2 mg/kg, 30 days post-treatment). Outcomes included owner questionnaires (LOAD, CBPI), pressure-sensitive walkway gait analysis (GLS), orthopedic evaluation, and plasma metabolomics. Results Grapiprant significantly reduced LOAD scores at T30 and T60 compared with baseline (* p < 0.05), with partial regression at Tpost. GLS improved significantly at T60 (** p < 0.01). Metabolomic analysis (both unsupervised and supervised methods) highlighted a clear discrimination between pre-and post-treatment plasma samples, revealing a statistically significant decrease in lactate, N-acetyl glycoproteins and formate in pretreatments samples and, on the contrary a significantly increase in citrate ( p < 0.05). Conclusion Grapiprant improved mobility and pain control in dogs with OA and induced metabolomic shifts consistent with reduced inflammation and improved energy metabolism. This is the first study to integrate clinical outcomes with metabolomics in canine OA, supporting the translational value of metabolic biomarkers for monitoring therapeutic response.