Natural Coumarins: Unveiling Mechanisms for Osteoporosis Treatment.

Osteoporosis (OP) is a common metabolic bone condition characterized by the breakdown of bone microarchitecture and a reduction in bone mass, which notably heightens the likelihood of fracture, especially among older adults. Currently, therapeutic strategies for OP include antiresorptive and anabolic drugs. However, these treatments are often associated with adverse effects such as an increased risk of osteosarcoma, cardiovascular complications, and atypical fractures. This has led to an increased focus on alternative therapies, particularly those derived from traditional Chinese medicine (TCM). Natural coumarins (NC), which are naturally occurring compounds from various plants, have shown promise in modulating bone metabolism by controlling the function of osteoblasts and osteoclasts. Representative compounds such as osthole, psoralen, isopsoralen, and fraxin have demonstrated strong anti-osteoporotic potential through distinct mechanisms: osthole enhances osteoblast differentiation via the Wnt/β-catenin and BMP2 pathways; psoralen activates estrogen receptor α signaling to promote osteogenesis and inhibit osteoclastogenesis; isopsoralen alleviates oxidative stress to support osteogenic gene expression; and fraxin suppresses osteoclast formation by inhibiting ROS/NF-κB while promoting osteoblast-mediated bone formation through the Nrf2/GPX4 pathway. Collectively, these findings highlight that NC exert multifaceted effects on bone metabolism by regulating classic pathways (OPG/RANKL/RANK, Wnt/β-catenin, BMP/Smad, NF-κB, MAPK, and estrogen signaling) as well as cellular processes such as oxidative stress, autophagy, apoptosis, and adipogenesis. By synthesizing the current body of research, this review underscores the therapeutic potential of NC and encourages further innovation in OP treatment strategies.