Salvianolic Acid A Mitigates Osteoporotic Bone Loss by Repressing Reactive Oxygen Species via the Nrf2–HO‐1 Pathway

ABSTRACT Osteoporosis, characterized by osteoclastic bone resorption, has been the focus of research. Studies implicate that reactive oxygen species (ROS) accumulate intracellularly during osteoclastogenesis. Salvianolic acid A (SAA), a compound derived from Salvia miltiorrhiza , has been widely used to treat cardiovascular and cerebrovascular disorders, owing to its antioxidant and anti‐inflammatory properties. In this study, we investigated the therapeutic effects of SAA on osteoporotic bone loss in vitro and in osteoporotic mice induced by ovariectomy (OVX) and explored the underpinning mechanisms. In vitro, SAA significantly restrained osteoclastogenesis and osteoclastic resorption in a dose‐ and time‐dependent manner. SAA markedly blocked the expression of osteoclast‐specific genes and proteins such as NFATc1 and c‐Fos. Specifically, SAA reduced ROS production by enhancing the expression and nuclear translocation of nuclear factor erythroid 2‐related factor 2 (Nrf2) to activate HO‐1 and catalase, with no effect on Bach1. In addition, SAA simultaneously suppressed the NF‐κB and mitogen‐activated protein kinase (MAPK) signaling pathway, ultimately arresting NFATc1 expression to constrain the differentiation and function of osteoclasts. Micro‐CT and histological evidence demonstrated that SAA at a nontoxic dose successfully reduced bone loss induced by OVX, with fewer mature osteoclasts. These findings revealed that SAA provides a potential treatment strategy for reducing osteoclast‐related bone ailments, including osteoporosis.