Esculin and esculetin protect against bone loss in osteoporosis by rebalancing osteoblast and osteoclast functions

Background Osteoporosis is characterized by uncoupled bone remodeling where resorption outpaces formation. This study investigated the roles of two natural coumarins, Esculin (ECL) and Esculetin (ECLT), in bone metabolism. Methods We evaluated the bidirectional effects of ECL and ECLT on primary osteoblasts and RAW264.7-derived osteoclasts in vitro . In vivo , the translational protective efficacy of the compounds was assessed using ovariectomized (OVX) and sciatic nerve transection (DEN) mouse models, representing postmenopausal and disuse osteoporosis, respectively. Evaluations included serum biochemical analysis, histological staining, micro-computed tomography (Micro-CT), and three-point bending biomechanical tests. Results In vitro assays identified optimal pharmacological concentrations of 50 μM for ECL and 10 μM for ECLT, with both compounds dose-dependently promoting osteoblast proliferation and mineralization while simultaneously inducing osteoclast apoptosis and downregulating key resorptive genes. Co-administration of ECL and ECLT demonstrated enhanced efficacy, greater than either monotherapy in several key readouts. In both OVX and DEN in vivo models, the combinatorial regimen markedly ameliorated systemic inflammation and oxidative stress, and successfully rebalanced circulating bone turnover markers. Furthermore, the dual therapy robustly prevented the deterioration of three-dimensional trabecular and cortical bone microarchitecture and substantially improved the functional biomechanical strength of the femurs. Conclusion The concurrent application of ECL and ECLT protects against bone loss by concurrently promoting osteoblast function and suppressing osteoclast formation, representing a promising bidirectional strategy for osteoporosis management.