Osteoporosis, a common disease diagnosed primarily by bone mineral density (BMD), has elusive genetic determinants. In this study, we conducted genome-wide association studies (GWAS) of BMD measured using dual-energy X-ray absorptiometry at 11 skeletal sites in nearly 40,000 individuals. We identified 18 novel genetic association loci, including 5 candidate genes whose causal involvement in bone disease remains unestablished. Among these loci, rs2247355-T was significantly associated with lower head BMD and was 6-13-fold less frequent in African populations (0.029) than elsewhere (0.180-0.388), consistent with their generally higher BMD and lower fracture risk. Located in the AZIN1 promoter, rs2247355 overlaps an H3K27ac-marked super enhancer, and eQTL analysis showed that its T allele was associated with lower AZIN1 gene expression. Gene-based and summary-data-based Mendelian randomization analyses supported a positive causal link between genetically determined AZIN1 gene expression and head BMD. By integrating head BMD GWAS and scRNA-seq data from different tissues, including bone and brain, we discerned MSCs, osteoblasts, monocytes, macrophages, astrocytes, and other cell types through which the risk variants impact head BMD. Bulk RNA-seq data analysis of BMSCs from young individuals and senile osteoporosis patients indicated that AZIN1 mRNA levels and RNA editing (a post-transcriptional modification) were decreased in BMSCs from aged participants, suggesting a potential role of AZIN1 in age-related bone loss. Utilizing pseudotime results of scRNA-seq data generated from bone of WT mice, we observed a temporal pattern of Azin1 expression during osteoblast differentiation, with its levels rising in pre-osteoblasts, peaking in osteoblasts and declining in terminal osteocytes. Importantly, Azin1 knockdown significantly inhibited osteoblast differentiation and mineralization in MC3T3-E1 pre-osteoblast cells while promoting osteoclastogenesis in RAW264.7 cells. μCT analysis showed decreased bone volume in Azin1^f/f;Prx1^cre and Azin1^f/f;OCN^cre mice. Moreover, compared to overexpression of the WT form of Azin1, overexpression of RNA-edited Azin1 enhanced osteogenic differentiation and mineralization of MC3T3-E1 cells while suppressing cell proliferation, whereas non-edited Azin1 had opposite effects in vitro. Mechanistically, CoIP-MS data revealed that RNA-edited Azin1 exhibited an increased affinity to interact with osteoblast differentiation-related proteins, including transcriptional factors such as Ddx5, suggesting that RNA-edited Azin1 entered nucleus to promote osteogenic differentiation. Additionally, AZIN1 knockdown in MC3T3-E1 or knockout in H9 hESCs dramatically reduced PIEZO1 protein levels, which could crosstalk with osteoclasts by regulating YAP/Col-II/IX axis, thereby promoting osteoclast differentiation. Collectively, our findings unveil the candidate determinants of BMD and highlight the role of AZIN1 in regulating bone homeostasis, which may be leveraged to prevent bone loss.