Traditional medicine-derived natural products as anti-osteoporotic Agents: A review on structural modifications, mechanisms, and structure-activity relationships.

Osteoporosis is a chronic disease affecting over 200 million people globally. It imposes a heavy burden on healthcare systems, societies, and families. Currently, clinical anti-osteoporotic drugs have various adverse effects limiting long-term use; although natural products from traditional medicines show therapeutic potential, their clinical translation is restricted by poor druggability. This article highlights how targeted chemical modifications, including heterocycle fusion, side-chain optimization, and functional group introduction, can significantly enhance anti-osteoporotic activity, improve pharmacokinetics, and reduce toxicity. Key compound classes discussed include terpenoids, alkaloids, flavonoids, coumarins, and polyphenols, with a focus on their mechanisms involving the RANKL/RANK/OPG, NF-κB, MAPK, and Wnt/β-catenin signaling pathways. The review underscores the potential of structure-activity relationship-guided design to transform traditional medicine-derived leads into promising drug candidates for osteoporosis treatment.