Formononetin ameliorates simulated microgravity-induced bone loss by suppressing bone turnover in rats

Rapid bone loss exposed to spaceflight is one of the highest risk factors for astronauts which can increase the occurrence of fracture risk and lead to serious health problems, but the therapeutic effects of the current countermeasures still have certain limitations and deficiencies. This study aims to find novel potential drugs for the prevention of the bone loss caused by microgravity. Therefore, the systems pharmacology was utilized to discover the active natural compound formononetin in Radix Astragali as the potential drug for the prevention of bone loss. Further, we investigated the therapeutic effects of formononetin in the prevention of bone loss induced by microgravity. Here, the hind limb unloading (HLU) rats’ model was established to simulate the weightlessness, and the HLU rats were treated with formononetin (30 mg· kg⁻¹·day⁻¹) for 4 weeks. The results showed that formononetin treatment clearly ameliorated the microstructure of the trabecular bone, accelerated bone mineral apposition rate and increased bone mineral density, additionally improving biomechanical properties of the bone. Furthermore, the results of the bone turnover biomarkers in serum indicated that formononetin administration effectively decreased the levels of both the bone formation biomarkers and bone resorption biomarkers. In addition, we observed the levels of bone remodeling cytokines including IFN-γ, IL-6, IL-8, IL-12, IL-4, IL-10 and TNF-α were partially recovered by formononetin administration. All of the above indicated that formononetin administration could prevent bone loss induced by HLU treatment due to its ability to inhibit bone turnover and regulate bone remodeling cytokines. These results may contribute to elucidate the novel effects of formononetin against bone loss and further illustrate its potential application value as a leading compound in drug development.