A neurotrophic withdrawal hypothesis for multisystem adverse events associated with anti-NGF therapy for canine osteoarthritis pain.

Post-marketing reports in dogs treated with bedinvetmab (Librela™, Zoetis), the first anti-nerve growth factor (NGF) monoclonal antibody approved for canine osteoarthritis pain, include musculoskeletal, autonomic, and neurological events. Existing interpretations address these domains separately or focus on the limitations of pharmacovigilance systems. Here, we propose a complementary, integrative interpretation: at least some of these events may share an on-target component arising from systemic NGF sequestration97an iatrogenic state of neurotrophic withdrawal. The evidence derives mainly from bedinvetmab, but the recent authorization of a second canine anti-NGF agent, izenivetmab (Lenivia™, Zoetis), raises a testable class-level safety question. Drawing on neurotrophin biology, human anti-NGF development programs, regulatory data, and the most recent evidence linking somatosensory innervation to skeletal repair, we outline how reduced NGF-mediated trophic support might affect joint protection and load adaptation/fracture repair, autonomic regulation, and central neuronal maintenance, particularly in geriatric animals. We set out the predictions that distinguish this account from unrelated background disease, and the studies that would test them.