RNA Binding Proteins (RBPs) interact with RNA and ubiquitously regulate RNA transcripts during their life cycle. Previous works showed that RBPs play fundamental roles in the progression of angiogenesis-related diseases. However, the role of RBPs in skeletal endothelium-dependent bone formation and osteogenesis is unclear. Here, we show that RBP-Ybx1 was strongly reduced in bone vasculature of OVX mice. Endothelial cell-specific deletion of Ybx1 impaired CD31hiEMCNhi endothelium morphology and resulted in low bone mass, while its overexpression promoted angiogenesis-dependent osteogenesis and ameliorated bone loss in OVX mice. Mechanistically, Ybx1 deletion disrupted CD31, EMCN and BMP4 stability in an m5C-dependent manner and blocked endothelial-derived BMP4 release, thereby inhibiting osteogenic differentiation of BMSCs. Administration of recombinant BMP4 protein restored impaired bone formation in Ybx1iΔEC mice. Finally, tail vein injection of CD31-modified PEG-PLGA carrying sciadopitysin, a natural Ybx1 agonist, pharmacologically partially reversed CD31hiEMCNhi vessels decline and improved bone mass both in OVX and aging animals. These findings demonstrated the role of RBP-Ybx1 in angiogenesis-dependent bone formation and provided a novel therapeutic approach for ameliorating osteoporosis.