This review explores the bidirectional crosstalk between bone and various organs, highlighting the role of osteokines, hormones, and extracellular vesicles (EVs) in maintaining physiological balance and modulating disease progression. The brain-bone axis, lung-bone axis, liver-bone axis, heart-bone axis, and kidney-bone axis are discussed in detail, emphasizing the intricate network of communication and reciprocal influence. Key findings include the impact of neuropeptides, neurotransmitters, and EVs on bone metabolism, as well as the role of pituitary hormones and osteokines in regulating bone health. The review also underscores the potential therapeutic applications of understanding these interactions, particularly in the context of bone-on-chip and organoid models, for preventing, diagnosing, and treating bone-related diseases and systemic disorders.This review explores the bidirectional crosstalk between bone and various organs, highlighting the role of osteokines, hormones, and extracellular vesicles (EVs) in maintaining physiological balance and modulating disease progression. The brain-bone axis, lung-bone axis, liver-bone axis, heart-bone axis, and kidney-bone axis are discussed in detail, emphasizing the intricate network of communication and reciprocal influence. Key findings include the impact of neuropeptides, neurotransmitters, and EVs on bone metabolism, as well as the role of pituitary hormones and osteokines in regulating bone health. The review also underscores the potential therapeutic applications of understanding these interactions, particularly in the context of bone-on-chip and organoid models, for preventing, diagnosing, and treating bone-related diseases and systemic disorders.