Vascular-lymphatic dual circulation in bone health and disease: Mechanistic coupling and translational therapeutics

Specialised skeletal blood-vessel subtypes have established the importance of angiogenesis-osteogenesis coupling in bone development, homeostasis and repair. Emerging evidence further indicates that bone-associated lymphatics contribute to interstitial fluid drainage, immune trafficking, inflammatory resolution, damage-associated molecular pattern clearance and regenerative signalling. However, how vascular and lymphatic compartments are coordinated in the skeletal microenvironment remains incompletely defined.In this review, we propose an evidence-graded working model of skeletal vascular-lymphatic dual circulation. We distinguish established observations from logical extensions and author-proposed analytical constructs. Current evidence is organised into shared upstream cues, blood-vessel-biased programmes, lymphatic identity and functional programmes, proposed coupling interfaces, and disease-integration modules. We discuss their context-dependent relevance across osteoporosis, glucocorticoid-associated skeletal injury, osteoarthritis, rheumatoid arthritis, bone metastasis, Gorham-Stout disease and heterotopic ossification.Finally, we evaluate therapeutic directions aimed at restoring pro-osteogenic vascular competence, lymphatic drainage and clearance, and vascular-lymphatic-immune coordination. This framework is intended to organise current evidence, define knowledge gaps and guide future validation rather than to assert a validated disease taxonomy or clinical stratification system.

This review offers an evidence-graded translational framework for skeletal repair and bone disease by integrating vascular niche competence, lymphatic drainage and clearance, osteoimmune regulation, and stromal repair. It highlights functional endpoints, including perfusion quality, lymphatic transport, inflammatory resolution, pathological osteoclastogenesis, and repair quality, that may improve preclinical study design and therapeutic evaluation. Vascular-skewed and lymphatic-skewed features are used as heuristic descriptors rather than diagnostic categories. After validation of skeletal vascular-lymphatic biomarkers, imaging tools, and functional endpoints, this framework may inform future stratification and network-informed combination therapy.