Osteoporosis is a condition characterized by decreased bone mineral density (BMD) and reduced bone strength, leading to an increased risk of fractures. Here, to identify novel risk variants for susceptibility to osteoporosis-related traits, an exome-wide association study is performed with 6,485 exonic single nucleotide polymorphisms (SNPs) in 2,666 women of two Korean study cohorts. The rs2781 SNP inUBAP2gene is suggestively associated with osteoporosis and BMD withp-values of 6.1 × 10−7(odds ratio = 1.72) and 1.1 × 10−7in the case-control and quantitative analyzes, respectively. Knockdown ofUbap2in mouse cells decreases osteoblastogenesis and increases osteoclastogenesis, and knockdown ofubap2in zebrafish reveals abnormal bone formation.Ubap2expression is associated with E-cadherin (Cdh1) and Fra1 (Fosl1) expression in the osteclastogenesis-induced monocytes.UBAP2mRNA levels are significantly reduced in bone marrow, but increased in peripheral blood, from women with osteoporosis compared to controls. UBAP2 protein level is correlated with the blood plasma level of the representative osteoporosis biomarker osteocalcin. These results suggest that UBAP2 has a critical role in bone homeostasis through the regulation of bone remodeling.