Michael Hadjiargyrou, Blake E. Hildreth, Frank Ko, Uma Sankar, Tao Yang
The National Institutes of Health (NIH) has launched a major initiative to expand human-based New Approach Methodologies (NAMs) in biomedical research and reduce reliance on animal models. While NAMs offer powerful complementary tools, animal-based research remains indispensable in musculoskeletal science for understanding complex cellular and systemic processes, disease onset and progression, and developing effective therapies. Foundational knowledge of embryonic development, disease mechanisms, tissue regeneration, gene function, and systemic pharmacology has emerged from animal models and will continue to do so. This review underscores the essential role of animal models in five key areas of musculoskeletal biology: osteoporosis, osteoarthritis, bone fracture repair and regeneration, bone cancer, and Inherited Skeletal Disorders (ISDs). We also examine NAMs including organoids, engineered scaffolds, organ-on-chip platforms, and Artificial Intelligence (AI)/computational modeling, highlighting their strengths in mechanistic and high-throughput studies but also their limitations in replicating in vivo structural, physiological, biomechanical, and systemic complexity. Animal models remain the gold standard for exploring disease mechanisms, testing preclinical therapeutic and diagnostic efficacy and safety, and translating discoveries into clinical practice. Rather than replacing animal research, NAMs should be integrated as complementary approaches to advance understanding and innovation. Curtailing animal research would jeopardize medical progress and hinder life-saving interventions for humans and animals alike. This review aims to inform the public and policymakers on the continued necessity of ethically conducted animal research as a cornerstone of musculoskeletal health.