Dual amylin and calcitonin receptor agonists as multifaceted disease-modifying osteoarthritis drugs.

Obesity is a powerful driver in the development and progression of osteoarthritis (OA), contributing to increased mechanical load and metabolic stress, making it a valuable target for treatment. Weight loss is a cornerstone of OA management, improving patients' quality of life and disease outcomes. This review examines the potential of dual amylin and calcitonin receptor agonists (DACRAs) as disease-modifying osteoarthritis drugs. We highlighted the relevant pathophysiological pathways of metabolically driven OA, previously studied pharmacotherapies, and clinical and preclinical evidence demonstrating that DACRAs target multiple OA pathways. Among the investigated pharmacotherapies, there have been no extensive evaluations of weight-loss drugs for OA. More potent weight-loss pharmacotherapies have been tested in clinical trials for the treatment of OA in recent years. However, not all weight-loss pharmacotherapies possess the qualities essential for OA management. DACRAs are notable for their multifaceted effects on OA management. DACRAs induce weight loss by activating the amylin receptor, thereby improving patients' quality of life and reducing OA pain intensity. Additionally, DACRAs activate the calcitonin receptor, known for its skeletal pain-relieving effects and for slowing down bone remodeling, potentially preserving the joint's cartilage and bone. With their dual action on metabolic and skeletal pathways, DACRAs offer a unique combination of weight loss, pain relief, and a positive influence on joint structures, distinguishing them from other weight-loss pharmacotherapies and making them a worthy candidate for further investigation in osteoarthritis, particularly when driven by metabolic dysfunction.