Fufang Zhenzhu Tiaozhi (FTZ), as an effective traditional Chinese medicine, has been prescribed for more than 20 years. It has proven clinical efficacy as a prescription for patients with dyslipidemia, glucocorticoid- and high-fat-induced osteoporosis, but its effect on osteoporosis induced by aging is still unclear. The aim of this study was to investigate the anti-osteoporosis effect of FTZ in aging mice and revealed its biochemical action mechanism using metabolomics. Model of primary osteoporosis induced by aging was established. The mice in treatment group received a therapeutic dose of oral FTZ extract once daily during the experiment. The model and control groups received the corresponding volume of oral normal saline solution. Plasma samples of all three groups were collected after 12 weeks. Clinical biochemical parameters and biomechanics were determined in the osteoporosis model induced by normal aging to evaluate anti-osteoporosis effect of FTZ. Ultra performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UPLC-QTOF/MS) was used to analyze metabolic changes. The changes of histomorphometric and biomechanic parameters of femurs, as well as osteoblast and osteoclast activity indicated that FTZ administration reduced the risk of osteoporosis. Partial least squares discriminant analysis (PLS-DA) score plot revealed a clear separation trend between model and controls. Moreover, PLS-DA score plot indicated the anti-osteoporosis effect of FTZ with sphingosine 1-phosphate, LPA (16:0) and arachidonic acid (AA) among key biomarkers. The pivotal pathways revealed by pathway analysis including sphingolipid metabolism, glycerophospholipid metabolism, and AA metabolism. The mechanism by which FTZ reduces the risk of primary age-related osteoporosis in mice might be related to disorders of the above-mentioned pathways. FTZ has a protective effect against osteoporosis induced by aging, which may be mediated via interference with sphingolipid, glycerophospholipid, and AA metabolisms in mice.

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