In recent decades, the mechanism underlying bone metabolic disorders based on energy metabolism has been heavily researched. Bone resorption by osteoclasts plays an important role in the occurrence and development of osteoporosis. However, the mechanism underlying the osteoclast energy metabolism disorder that interferes with bone homeostasis has not been determined. Bone resorption by osteoclasts is a process that consumes large amounts of adenosine triphosphate (ATP) produced by glycolysis and oxidative phosphorylation. In addition to glucose, fatty acids and amino acids can also be used as substrates to produce energy through oxidative phosphorylation. In this review, we summarize and analyze the energy-based phenotypic changes, epigenetic regulation, and coupling with systemic energy metabolism of osteoclasts during the development and progression of osteoporosis. At the same time, we propose a hypothesis, the compensatory recovery mechanism (involving the balance between osteoclast survival and functional activation), which may provide a new approach for the treatment of osteoporosis.

Background: Multiple studies have shown that an imbalance in the intestinal microbiota is related to bone metabolism, but the role of the intestinal microbiota in postmenopausal osteoporosis remains to be elucidated. We explored the effect of the intestinal microbiota on osteoporosis. Methods: We constructed a postmenopausal osteoporosis mouse model, and Micro CT was used to observe changes in bone structure. Then, we identified the abundance of intestinal microbiota by 16S RNA sequencing and found that the ratio of Firmicutes and Bacteroidetes increased significantly. UHPLC-MS analysis was further used to analyze changes in metabolites in feces and serum. Results: We identified 53 upregulated and 61 downregulated metabolites in feces and 2 upregulated and 22 downregulated metabolites in serum under OP conditions, and interestedly, one group of bile acids showed significant differences in the OP and control groups. Network analysis also found that these bile acids had a strong relationship with the same family, Eggerthellaceae. Random forest analysis confirmed the effectiveness of the serum and fecal models in distinguishing the OP group from the control group. Conclusions: These results indicated that changes in the gut microbiota and metabolites in feces and serum were responsible for the occurrence and development of postmenopausal osteoporosis. The gut microbiota is a vital inducer of osteoporosis and could regulate the pathogenesis process through the “microbiota-gut-metabolite-bone” axis, and some components of this axis are potential biomarkers, providing a new entry point for the future study on the pathogenesis of postmenopausal osteoporosis.

Postmenopausal osteoporosis is a prevalent metabolic bone disorder characterized by a decrease in bone mineral density and deterioration of bone microstructure. Despite the high prevalence of this disease, no effective treatment for osteoporosis has been developed. Exercise has long been considered a potent anabolic factor that promotes bone mass via upregulation of myokines secreted by skeletal muscle, exerting long‐term osteoprotective effects and few side effects. Irisin was recently identified as a novel myokine that is significantly upregulated by exercise and could increase bone mass. However, the mechanisms underlying exercise‐induced muscle‐bone crosstalk remain unclear. Here, we identified that polyunsaturated fatty acids (arachidonic acid and docosahexaenoic acid) are increased in skeletal muscles following a 10‐week treadmill exercise programme, which then promotes the expression and release of FNDC5/irisin. In osteoblasts, irisin binds directly to Cav1, which recruits and interacts with AMP‐activated protein kinase α (AMPKα) to activate the AMPK pathway. Nrf2 is the downstream target of the AMPK pathway and increases the transcription of HMOX1 and Fpn. HMOX1 is involved in regulating the cell cycle and promotes the proliferation of osteoblasts. Moreover, upregulation of Fpn in osteoblasts enhanced iron removal, thereby suppressing ferroptosis in osteoblasts. Additionally, we confirmed that myotube‐derived exosomes are involved in the transportation of irisin and enter osteoblasts through caveolae‐mediated endocytosis. In conclusion, our findings highlight the crucial role of irisin, present in myotube‐derived exosomes, as a crucial regulator of exercise‐induced protective effects on bone, which provides novel insights into the mechanisms underlying exercise‐dependent treatment of osteoporosis.

Bone fracture healing is a dynamic process that relies on coordinated cellular interactions for effective tissue regeneration. We employ optimized spatial transcriptomics to delineate the locations and interactions of the involved cell types within a mouse femur fracture model on Day 0 before fracture and at Days 5 and 15 postfracture. We improve RNA quality significantly by optimizing our decalcification method using Morse’s solution, coupled with the use of the Visium CytAssist platform and integrated analyses through the Seurat, CARD, and Monocle packages. This approach allows us to accurately localize critical cell populations, such as periosteum progenitor cells, and identify pivotal transcription factors that regulate their activation and differentiation into chondrocytes or osteogenic cells. We particularly focus on the transformation from mesenchymal progenitor cells (MPCs) to regenerative MPCs (rMPCs), revealing how these cells recruit macrophages near the fracture line during early healing stages and their involvement in fracture healing. Furthermore, using CellChat, we explore potential receptor‒ligand pathways that mediate these cellular interactions. The spatial–temporal mapping and molecular characterization performed in this study substantially deepen our understanding of the cellular and molecular processes involved in fracture healing, highlighting spatial transcriptomics as a robust approach for elucidating the mechanisms governing bone regeneration.