Fig. 5

Pathological mechanisms of osteoporosis induced by diabetes, glucocorticoids, and psychological stress. a Glucocorticoid (GC) inhibits the proliferation and increases the apoptosis of osteoblasts by downregulating Wnt signaling, repressing the production of sex steroids, decreasing calcium absorption, and reducing growth factors. GC decreases the differentiation of adipocytes in bone marrow by decreasing the Wnt/β-catenin pathway. GCs also promote the apoptosis of osteocytes by increasing the influx of Ca²⁺. GCs decrease apoptosis and promote the survival of osteoclasts by upregulating RANKL and downregulating M-CSF. b T2DM-associated osteoporosis is characterized by decreased bone turnover and impaired microarchitecture, which has a complex pathological mechanism and involves multiple signaling pathways. T2DM affects bone metabolism, demineralization, bone marrow adiposity, and calcium balance through hyperglycemia. Other coexisting conditions in T2DM, such as obesity, impaired renal function, hypercalciuria, reactive oxygen species (ROS), more advanced glycation end products (AGEs) accumulation, inflammation, and peptides in the gastrointestinal (GI) tract, contribute to the higher prevalence of osteoporosis in T2DM patients. Estrogen and androgen can scavenge ROS directly or indirectly by changing cytokine profiles and exert protective effects by nonskeletal mechanisms such as the regulation of adipose tissues. Estrogen protects pancreatic β cells and increases insulin production to indirectly alleviate diabetic osteoporosis. c Psychological stress contributes to osteoporosis through the hypothalamic‒pituitary‒adrenal (HPA) axis and the brain-immune connection. Psychological stress promotes bone loss by regulating growth hormones, glucocorticoids, sex hormones, and pro-inflammatory cytokines. MSCs mesenchymal stem cells, M-CSF macrophage colony-stimulating factor, OPG osteoprotegerin, RANKL receptor activator of nuclear factor kappa-B ligand, AGEs advanced glycation end products, ROS reactive oxygen species, SOST sclerostin, GLP-1 glucagon-like peptide-1, GI tract gastrointestinal tract, GIP gastric inhibitory polypeptide, IGF insulin-like growth factor, GC glucocorticoid, CRH cortisol-releasing hormone, GnRH gonadotrophin-releasing hormone, GHRH growth hormone-releasing hormone, SNS sympathetic nervous system, NPY neuropeptide Y, NMU neuromedin U, ACTH adrenocorticotrophic hormone, GH growth hormone, FSH follicle-stimulating hormone, LH luteinizing hormone, PICs pro-inflammatory cytokines