Osteoarthritis (OA) is a frequent cause of disability in pet dogs, yet available medical options are mostly symptomatic and often limited by adverse effects. EF-M2, a precisely formulated derivative of the vitamin D-binding protein, has shown the ability in cell culture to steer macrophages toward a restorative, anti-inflammatory state. To evaluate its clinical potential, we performed a randomized, double-masked, placebo-controlled clinical study (IMPAWS-OA-1) involving 60 privately owned dogs naturally suffering from hip or elbow OA. Subjects received subcutaneous EF-M2 at 0.1 µg/kg either three or two times weekly, or placebo saline injections, for a 4-week treatment phase followed by 4 weeks without medication. The principal outcome was the change in the Canine Brief Pain Inventory-Pain Severity Score (CBPI-PSS) at Day 28. EF-M2 produced improvements dependent on administration frequency: LS-mean ΔPSS values were −2.11 for three times per week, −1.42 for twice weekly, and −0.54 in the placebo arm (p < 0.001). Parallel enhancement was seen in objective metrics such as peak vertical force and activity tracking. Serum data showed macrophage repolarization (higher ARG1/iNOS ratio, IL-10 elevation, and TNF-α reduction), aligning with the observed clinical effects. Side effects were scarce and mild, with no increase relative to placebo. In summary, EF-M2 yielded meaningful reductions in pain and mobility gains along with favorable biomarker alterations, demonstrating for the first time in dogs that macrophage-directed therapy could offer a disease-modifying route for osteoarthritis.
