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While NAMs offer powerful complementary tools, animal\u2010based 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\u2010on\u2010chip platforms, and Artificial Intelligence (AI)\/computational modeling, highlighting their strengths in mechanistic and high\u2010throughput studies but also their limitations in replicating in\u00a0vivo 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\u2010saving 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.<\/jats:p>","DOI":"10.1096\/fba.2025-00313","type":"journal-article","created":{"date-parts":[[2026,2,9]],"date-time":"2026-02-09T17:40:14Z","timestamp":1770658814000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["The Scientific Case for Animal Models: A Perspective From Musculoskeletal Researchers"],"prefix":"10.1096","volume":"8","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8927-2333","authenticated-orcid":false,"given":"Michael","family":"Hadjiargyrou","sequence":"first","affiliation":[{"name":"Department of Biological and Chemical Sciences New York Institute of Technology  Old Westbury New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4631-1117","authenticated-orcid":false,"suffix":"III","given":"Blake E.","family":"Hildreth","sequence":"additional","affiliation":[{"name":"Department of Pathology, Heersink School of Medicine University of Alabama at Birmingham  Birmingham Alabama USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7305-7946","authenticated-orcid":false,"given":"Frank","family":"Ko","sequence":"additional","affiliation":[{"name":"Department of Anatomy and Cell Biology Rush University Medical Center  Chicago Illinois USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9406-5686","authenticated-orcid":false,"given":"Uma","family":"Sankar","sequence":"additional","affiliation":[{"name":"Department of Anatomy, Cell Biology and Physiology Indiana University School of Medicine  Indianapolis Indiana USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9856-9929","authenticated-orcid":false,"given":"Tao","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Cell Biology Van Andel Institute  Grand Rapids Michigan USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,2,9]]},"reference":[{"key":"e_1_2_12_2_1","unstructured":"\u201cNIH to Prioritize Human\u2010Based Research Technologies \u201d(2025) https:\/\/www.nih.gov\/news\u2010events\/news\u2010releases\/nih\u2010prioritize\u2010human\u2010based\u2010research\u2010technologies."},{"key":"e_1_2_12_3_1","unstructured":"\u201cHow Medicines are Made\u201d https:\/\/fbresearch.org\/."},{"key":"e_1_2_12_4_1","unstructured":"\u201cStatement of Principles for the Use of Animals in Research and Education\u201d."},{"key":"e_1_2_12_5_1","unstructured":"D.Shoback R.Martinez S.Harris andS.Trikudanathan \u201cOsteoporosis Treatment \u201d(2022) https:\/\/www.endocrine.org\/patient\u2010engagement\/endocrine\u2010library\/osteoporosis\u2010treatment."},{"key":"e_1_2_12_6_1","unstructured":"\u201cRheumatoid Arthritis Treatment\u201d https:\/\/www.hopkinsarthritis.org\/arthritis\u2010info\/rheumatoid\u2010arthritis\/ra\u2010treatment\/."},{"issue":"10","key":"e_1_2_12_7_1","article-title":"Gout Treatment and Clinical Considerations: The Role of Pegloticase, Colchicine, and Febuxostat","volume":"15","author":"Quintana M. 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