Bone-organ axes involve bidirectional communication between bone and other organs, mediated by cytokines (osteokines), hormones, metabolites, and extracellular vesicles (EVs). This review highlights the critical role of osteokines and EVs in maintaining physiological balance and disease progression. Bone not only provides structural support but also secretes osteokines that influence organ function and vice versa. The review emphasizes the importance of understanding these interactions for developing physiologically relevant in vitro models and therapies for bone-related and systemic diseases. The brain-bone axis is a key example of this bidirectional communication, involving neuropeptides, neurotransmitters, EVs, and hormones. Osteokines like osteocalcin (OCN) and hormones such as testosterone and estrogen influence bone remodeling and development. EVs, particularly those from the brain, contain microRNAs that regulate bone homeostasis. The brain also influences bone through various signaling pathways, including those involving neuropeptide Y (NPY), CART, 5-hydroxytryptamine (5-HT), dopamine (DA), and cannabinoids (CBs). Bone also communicates with the brain through osteokines, hormones, and EVs. For instance, OCN, LCN2, SOST, and DKK1 are involved in bone-organ crosstalk. Bone-derived signals, such as OCN, influence brain development and cognition, while brain-derived EVs can affect bone homeostasis. The lung-bone axis involves factors like osteokines, inflammatory markers, and EVs, with implications for conditions like COPD and lung cancer. The liver-bone axis is influenced by factors such as IL-6, TNF-α, vitamin D, and FGF-21, with EVs playing a role in liver disease and bone metabolism. The heart-bone axis involves EPCs, vascular endothelial cells, and EVs, with implications for cardiovascular health and myocardial repair. The review underscores the importance of understanding these complex interactions for developing targeted therapies and improving in vitro models. It highlights the potential of EVs and microRNAs in therapeutic applications, as well as the need for further research to elucidate the mechanisms underlying bone-organ crosstalk. The review provides a comprehensive overview of the bidirectional communication between bone and other organs, emphasizing the role of cytokines, EVs, hormones, and metabolites in maintaining physiological balance and disease progression.Bone-organ axes involve bidirectional communication between bone and other organs, mediated by cytokines (osteokines), hormones, metabolites, and extracellular vesicles (EVs). This review highlights the critical role of osteokines and EVs in maintaining physiological balance and disease progression. Bone not only provides structural support but also secretes osteokines that influence organ function and vice versa. The review emphasizes the importance of understanding these interactions for developing physiologically relevant in vitro models and therapies for bone-related and systemic diseases. The brain-bone axis is a key example of this bidirectional communication, involving neuropeptides, neurotransmitters, EVs, and hormones. Osteokines like osteocalcin (OCN) and hormones such as testosterone and estrogen influence bone remodeling and development. EVs, particularly those from the brain, contain microRNAs that regulate bone homeostasis. The brain also influences bone through various signaling pathways, including those involving neuropeptide Y (NPY), CART, 5-hydroxytryptamine (5-HT), dopamine (DA), and cannabinoids (CBs). Bone also communicates with the brain through osteokines, hormones, and EVs. For instance, OCN, LCN2, SOST, and DKK1 are involved in bone-organ crosstalk. Bone-derived signals, such as OCN, influence brain development and cognition, while brain-derived EVs can affect bone homeostasis. The lung-bone axis involves factors like osteokines, inflammatory markers, and EVs, with implications for conditions like COPD and lung cancer. The liver-bone axis is influenced by factors such as IL-6, TNF-α, vitamin D, and FGF-21, with EVs playing a role in liver disease and bone metabolism. The heart-bone axis involves EPCs, vascular endothelial cells, and EVs, with implications for cardiovascular health and myocardial repair. The review underscores the importance of understanding these complex interactions for developing targeted therapies and improving in vitro models. It highlights the potential of EVs and microRNAs in therapeutic applications, as well as the need for further research to elucidate the mechanisms underlying bone-organ crosstalk. The review provides a comprehensive overview of the bidirectional communication between bone and other organs, emphasizing the role of cytokines, EVs, hormones, and metabolites in maintaining physiological balance and disease progression.