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Osteoarthritis (OA) cases have doubled over the last two decades, now exceeding 32 million in the US and over 240 million worldwide. Dextrose prolotherapy is a potential alternative treatment for OA that demonstrates a good safety profile and is less costly than bio-injectables or partial or full joint replacement. This comprehensive review aims to provide background information and summarize findings from dextrose prolotherapy use in clinical trials, from January 2013 to December 2024. Human clinical trials using dextrose prolotherapy show promising clinical outcomes in reducing pain and improving function while maintaining a high degree of safety.