Progress on novel compounds for the treatment of bone metabolism-related disorders: focus on osteoporosis and beyond.

Bone metabolism-related disorders represent a significant global health burden, due to their high prevalence and substantial socioeconomic costs, particularly osteoporosis. Conventional antiresorptive and anabolic agents have well-established clinical utility, such as bisphosphonates, denosumab, teriparatide, and romosozumab. Nevertheless, their long-term clinical use remains limited by safety concerns and inadequate efficacy in a subset of patients. In this review, we highlight recent chemical innovations designed to mechanistically reprogram the skeletal microenvironment and overcome those longstanding barriers. We also analyze how the metabolic coupling signals govern bone bioenergetics, particularly within the Wnt and RANKL axes. We place specific focus on three emerging and transformative strategies: proteolysis-targeting chimeras (PROTACs), bone-targeted senolytics, and direct metabolic modulators. Ultimately, we provide a multidisciplinary roadmap for the development of next-generation therapeutics to achieve durable skeletal restoration in patients with bone metabolic disorders.