Osteoporosis is a skeletal system disease characterized by low bone mass and altered bone microarchitecture, with an increased risk of fractures. Classical theories hold that osteoporosis is essentially a bone remodeling disorder caused by estrogen deficiency/aging (primary osteoporosis) or secondary to diseases/drugs (secondary osteoporosis). However, with the in-depth understanding of the intricate nexus between both bone and the immune system in recent decades, the novel field of “Immunoporosis” was proposed by Srivastava et al. (2018, 2022), which delineated and characterized the growing importance of immune cells in osteoporosis. This review aimed to summarize the response of the immune system (immune cells and inflammatory factors) in different types of osteoporosis. In postmenopausal osteoporosis, estrogen deficiency-mediated alteration of immune cells stimulates the activation of osteoclasts in varying degrees. In senile osteoporosis, aging contributes to continuous activation of the immune system at a low level which breaks immune balance, ultimately resulting in bone loss. Further in diabetic osteoporosis, insulin deficiency or resistance-induced hyperglycemia could lead to abnormal regulation of the immune cells, with excessive production of proinflammatory factors, resulting in osteoporosis. Thus, we reviewed the pathophysiology of osteoporosis from a novel insight-immunoporosis, which is expected to provide a specific therapeutic target for different types of osteoporosis.

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Background: Aging and oxidative stress are considered to be the proximal culprits of postmenopausal osteoporosis. Eldecalcitol (ED-71), a new active vitamin D derivative, has shown a good therapeutic effect on different types of osteoporosis, but the mechanism is unclear. This study focused on exploring whether ED-71 could prevent bone loss in postmenopausal osteoporosis by regulating the cell senescence of bone mesenchymal stem cells (BMSCs), and explaining its specific mechanism of action.Materials and methods: An ovariectomized (OVX) rat model was established and 30 ng/kg ED-71 was administered orally once a day. The weight of rats was recorded regularly. Micro-computed tomography (CT) and histochemical staining were used to evaluate bone mass, histological parameters, and aging-related factors. Rat bone mesenchymal stem cells were extracted and cultivated in vitro. Aging cells were marked with senescence-associated β-gal (SA-β-gal) dyeing. The mRNA and protein levels of aging-related factors and SIRT1-Nrf2 signal were detected by RT-PCR, Western blot, and immunofluorescence staining. The reactive oxygen species (ROS) levels were detected by DCFH-DA staining.Results: Compared with the Sham group, the bone volume of the ovariectomized group rats decreased while their weight increased significantly. ED-71 prevented bone loss and inhibited weight gain in ovariectomized rats. More importantly, although the expression of aging-related factors in the bone tissue increased in the ovariectomized group, the addition of ED-71 reversed changes in these factors. After extracting and in vitro culturing bone mesenchymal stem cells, the proportion of aging bone mesenchymal stem cells was higher in the ovariectomized group than in the Sham group, accompanied by a significant decrease in the osteogenic capacity. ED-71 significantly improved the bone mesenchymal stem cells senescence caused by ovariectomized. In addition, ED-71 increased the expression of SIRT1 and Nrf2 in ovariectomized rat bone mesenchymal stem cells. Inhibition of SIRT1 or Nrf2 decreased the inhibitory effect of ED-71 on bone mesenchymal stem cells senescence. ED-71 also showed a suppression effect on the reactive oxygen species level in bone mesenchymal stem cells.Conclusion: Our results demonstrated that ED-71 could inhibit the cell senescence of bone mesenchymal stem cells in ovariectomized rats by regulating the SIRT1-Nrf2 signal, thereby preventing bone loss caused by osteoporosis.

Background and Objectives: The incidence of diabetic osteoporosis, an important complication of diabetes mellitus, is increasing gradually. This study investigated the combined effect of the Zuogui pill (ZGP) and eldecalcitol (ED-71), a novel vitamin D analog, on type 2 diabetic osteoporosis (T2DOP) and explored their action mechanism. Materials and Methods: Blood glucose levels were routinely monitored in db/db mice while inducing T2DOP. We used hematoxylin and eosin staining, Masson staining, micro-computed tomography, and serum biochemical analysis to evaluate changes in the bone mass and blood calcium and phosphate levels of mice. Immunohistochemical staining was performed to assess the osteoblast and osteoclast statuses. The MC3T3-E1 cell line was cultured in vitro under a high glucose concentration and induced to undergo osteogenic differentiation. Quantitative real-time polymerase chain reaction, Western blot, immunofluorescence, ALP, and alizarin red staining were carried out to detect osteogenic differentiation and PI3K–AKT signaling pathway activity. Results: ZGP and ED-71 led to a dramatic decrease in blood glucose levels and an increase in bone mass in the db/db mice. The effect was strongest when both were used together. ZGP combined with ED-71 promoted osteoblast activity and inhibited osteoclast activity in the trabecular bone region. The in vitro results revealed that ZGP and ED-71 synergistically promoted osteogenic differentiation and activated the PI3K–AKT signaling pathway. The PI3K inhibitor LY294002 or AKT inhibitor ARQ092 altered the synergistic action of both on osteogenic differentiation. Conclusions: The combined use of ZGP and ED-71 reduced blood glucose levels in diabetic mice and promoted osteogenic differentiation through the PI3K–AKT signaling pathway, resulting in improved bone mass. Our study suggests that the abovementioned combination constitutes an effective treatment for T2DOP.