Coordination between osteogenesis and angiogenesis is required for bone homeostasis. Here, we show thatmiR-29cb2 is a bone-specificmiRNA and plays critical roles on angiogenesis-osteogenesis coupling during bone remodeling. Mice with deletion ofmiR-29cb2 exhibit osteopenic phenotypes and osteoblast impairment, accompanied by pronounced decreases in specific H vessels. The decrease in bone miR- 29cb2 was associated with pathological ovariectomy stimuli. Mechanistically, hypoxia-inducible factor (HIF)-3 alpha, as a target for miR-29cb2, inhibits HIF-1 alpha activity by competitively bonding with HIF-1 beta. Notably, miR-29cb2 in peripheral blood (PB) nearly is undetectable in sham and significantly increases in ovariectomy mice. Further evaluation from osteoporosis patients demonstrates similar signatures. ROC analysis shows miR-29cb2 in PB has higher sensitivity and specificity for diagnosing osteoporosis when compared with four clinical biomarkers. Collectively, these findings reveal that miR-29cb2 is essential for bone remodeling by inhibiting HIF-3 alpha and elevated bone-specificmiR-29cb2 in PB, which may be a promising biomarker for bone loss