Bone metabolic homeostasis is essential for maintaining skeletal health. This dynamic balance relies on the finely regulated interplay between osteoblast-mediated bone formation and osteoclast-driven bone resorption (Engelmann et al., 2022). Disruption of this balance leads to reduced bone mass and degenerative changes in the trabecular microstructure, ultimately resulting in bone-related diseases such as osteoporosis, delayed fracture healing, and osteosclerosis (Park et al., 2025; Song et al., 2022; Sun et al., 2024).

Current clinical treatments for bone metabolism imbalance have notable limitations. Most drugs exhibit unidirectional effects, such as bisphosphonates, which primarily inhibit bone resorption, or parathyroid hormone analogs that promote bone formation. However, long-term use of these drugs can lead to increased bone fragility, diminished therapeutic efficacy, and poor patient compliance (Imaz et al., 2009; Kharwadkar et al., 2017; Lloyd et al., 2017; Silverman et al., 2018). Therefore, recent research has focused on developing drugs with dual-regulatory effects that can both stimulate bone formation and suppress bone resorption. Among these, sclerostin (SOST) inhibitors have garnered considerable attention (Ferrari, 2018; Xu et al., 2023; Yu et al., 2022). Romosozumab, the only SOST inhibitor currently approved worldwide, has been shown in clinical studies to rapidly increase bone mineral density and significantly reduce fracture risk (Cosman et al., 2016; Saag et al., 2017). Nevertheless, its application is limited by adverse effects, including allergic reactions and increased cardiovascular risk, as well as patient compliance issues (Lewiecki et al., 2018; Ting-Chien et al., 2025). These challenges highlight the escalating need for safe, and orally bioavailable dual-regulatory agents or functional foods to address bone metabolism disorders.

Traditional Chinese Medicines (TCM) offer unique advantages in restoring physiological balance and ensuring safety, supported by thousands of years of clinical practice (Cao et al., 2024; Yuan et al., 2016). Mulberry (Morus alba L.) is a widely recognized medicinal and edible plant and has been one of the most commonly used TCM in China for strengthening bones and joints (Chinese Pharmacopoeia, 2020; European Medicines, 2021; National Health Commission of the People's Republic of, 2023). However, modern scientific evidence elucidating its functional properties and molecular mechanisms remains limited. This lack of mechanistic insight creates a gap between “traditional use” and contemporary “mechanistic evidence”, hindering its full clinical potential.

In our investigation of various medicinal components of mulberry, we isolated a water-soluble ethanol precipitate—referred to as mulberry polyphenol extract (ABRU)—which exhibited potential to promote osteoblast differentiation. Building on this preliminary finding, the current study aims to investigate whether ABRU exerts a dual-regulatory effect by promoting osteoblast differentiation and inhibiting osteoclast function, thereby affecting bone metabolic balance. In addition, we evaluate its in vivo effects and explore its underlying molecular mechanisms. This research not only introduces innovative intervention strategies for nutritional management of bone health, but also provides systematic experimental evidence supporting the unique value of “balanced regulation” in medicinal and edible homologous substances. It further promotes the shift of these ingredients from traditional experiential consumption toward modern, research-driven nutritional foods.