The Mechanism Exploration of Traditional Chinese Medicine's “Different Treatments for Same Disease” Concept in Osteoporosis Therapy: A Serum Metabolomics Study

The "different treatments for same disease" is an important concept of traditional Chinese medicine (TCM) therapy. In TCM, osteoporosis (OP) treatment is aimed at invigorating blood, strengthening spleen, and tonifying kidneys, and their typical herbs are Angelica sinensis (Oliv.) Diels (Danggui, DG), Poria cocos (Schw.) Wolf (Fuling, FL), and Achyranthes bidentata Blume (Niuxi, NX). Nevertheless, molecular mechanisms of these different therapies of OP under the concept of "different treatments for same disease" are still unclear. The objective of this study was to identify the related metabolites and biological processes in these three distinct therapeutic approaches for osteoporosis, by using serum metabolomics analysis. A model of postmenopausal OP (PMOP) was created using bilateral ovariectomized rats and then administered with DG, FL, or NX for 12 weeks. To assess the efficacy of the three treatments, we performed gross pathology evaluation, micro-computed tomography (micro-CT) scan, bone-strength test, and histopathologic examination. The results demonstrated that the treatment groups improved weight, rectal temperature, and 24-h urine output when compared to the model group. Furthermore, the PMOP models exhibited significant increases in bone strength, bone mass, and physical bone parameters after three distinct treatments. Serum metabolomics analysis subsequently showed that DG was predominantly associated with glycerophospholipids, prenol lipids, and steroid lipid metabolism. FL was primarily linked to glycerophospholipid and amino acid metabolism. The primary metabolisms associated with NX include sphingolipid, glycerophospholipid, amino acid, and purine metabolisms. In conclusion, the DG, FL, and NX herbs effectively alleviate PMOP by regulating lipid metabolism, while FL is also involved in amino acid metabolism and NX in amino acid and purine metabolisms. Our results provide biological evidence for the TCM principle of "different treatments for same disease".