Postmenopausal osteoporosis (PMOP), as a major type of primary osteoporosis, inflicts harm on more than 50% of postmenopausal European women (Ni et al., 2023). In China, PMOP has a prevalence of 40.1% which makes it as a nonnegligible health problem (Zhang et al., 2023). The detrimental impacts of PMOP are reported as severe phenotypes, such as reduced bone mass, mineralized matrix, and microarchitecture deterioration of bone tissues (Jones et al., 2023). Accordingly, the potential mechanism of PMOP is worthy to be discovered. The causative factors of PMOP are intricate, including aging (Cui et al., 2022), hormone levels (Ma et al., 2019), immune microenvironment (Liu et al., 2023) and genetic susceptibility (Suthon et al., 2022), among which estrogen deficiency seems to be the initial factor.

Estrogen exerts an osteoprotective effect at the macroscopic level. At the microscopic level, estrogen coordinates the functions of osteocytic mechanical- and endocrine-responsive properties, osteoclastic bone resorption and osteoblastic bone formation (Mills et al., 2021). Estrogen deficiency results in osteoporosis with bone resorption outpacing bone formation (He et al., 2023). Notwithstanding the pivotal role of estrogen in PMOP, estrogen replacement therapy (ERT) and selective estrogen receptor modulators (SERM) manifest limited efficacy and significant side effects (Whelan et al., 2022). To address this, the mild effects of phytoestrogens have become the focus of research.

Siwu decoction (SWD) is known as "the first prescription of gynecology" in traditional Chinese medicine, consisting of Rehmannia glutinosa (Gaertn.) DC., Angelica sinensis (Oliv.) Diels, Paeonia lactiflora Pall., Ligusticum striatum DC.. As a classic prescription, it is widely used in gynecological diseases (Zhou et al., 2021). In female mice, SWD stimulated mineralized nodules formation through PI3K/Akt/NF-κB pathway (Wu et al., 2013). Our previous reports have shown that SWD has estrogen-like effects on uterus, aorta, femur, hippocampus and regulates the expressions of key regulators of estrogen-related signaling pathway (Zhang et al., 2022). However, relevant evidences on estrogen-like effect of SWD on PMOP are not sufficient. It will be interesting to see if SWD exerts a phytoestrogenic effect to ameliorate osteoporosis in PMOP.

Here we adopted network pharmacology to investigate the possible mechanism of SWD on PMOP. Subsequently, experiments in vitro and in vivo were performed to verify estrogen-like effects, regulatory effects on PI3K/AKT pathway and osteoprotective effects of SWD. Our study provides powerful evidences and molecular mechanisms of SWD treatment on PMOP.