Deciphering inter-organ communication: The multi-organ-bone axis in osteoporosis and emerging therapeutic strategies.

Background: Osteoporosis has long been considered a disorder confined to bone tissue. Growing evidence now highlights its systemic origins, governed by intricate communication between multiple organs. The multi-organ-bone axis (MOBA) reframes osteoporosis pathogenesis as disrupted communication between bone and peripheral organs. Although dysfunction in organs such as the gut, adipose tissue, and nervous system has been linked to bone loss, a comprehensive integration of this axis and its therapeutic implications remain incomplete. Clarifying this multi-organ network is essential for devising innovative systemic treatment strategies. Methods: This review synthesizes current evidence on the MOBA by conducting a comprehensive literature search in PubMed and Web of Science from inception up to March 2025. Search terms included combinations of "osteoporosis," "multi-organ bone axis," "gut-bone axis," "adipose-bone axis," "neuro-bone axis," "kidney-bone axis," "muscle-bone axis," "probiotics," "prebiotics," "natural products," "small molecule inhibitors," and "exercise." Eligible studies included original research articles, clinical trials, and high-quality reviews published in English that addressed inter-organ communication in bone metabolism. Results: The MOBA framework indicates that bone homeostasis is governed by dynamic interactions among the gut, adipose tissue, nervous system, kidney and skeletal muscle. Dysfunction in these organs perturbs hormonal, inflammatory, immune and neural signaling, thereby driving bone loss through convergent mechanisms. On the basis of this framework, emerging therapeutic strategies can be grouped into five categories: microbiota-directed interventions, natural products, small-molecule inhibitors or agonists, synthetic compounds and exercise. Rather than acting exclusively on bone cells, these approaches aim to restore systemic homeostasis by reprogramming organ crosstalk. Conclusions: The MOBA model offers an integrative framework that conceptualizes osteoporosis as a systemic disorder involving disrupted inter-organ communication. While axis-targeted interventions show preclinical promise, their clinical translation is challenged by mechanistic complexity, model limitations, and insufficient clinical validation. Future research should map precise inter-organ circuits in humans and validate these strategies in patient populations to advance the development of effective systemic osteoporosis therapies. The translational potential of this article is as follows: This Review positions osteoporosis as a systemic disease driven by disordered inter-organ communication. By outlining the MOBA framework and classifying emerging multi-organ-targeted interventions, it shifts the therapeutic focus from bone-centred treatment to system-level recalibration, offering a conceptual basis for more effective prevention and treatment strategies.