High bone mass (HBM) is usually caused by gene mutations, and its mechanism remains unclear. In the present study, we identified a novel mutation in the long noncoding RNA Reg1cp that is associated with HBM. Subsequent analysis in 1,465 Chinese subjects revealed that heterozygous Reg1cp individuals had higher bone density compared with subjects with WT Reg1cp. Mutant Reg1cp increased the formation of the CD31hiEmcnhi endothelium in the bone marrow, which stimulated angiogenesis during osteogenesis. Mechanistically, mutant Reg1cp directly binds to Krüppel-like factor 3 (KLF3) to inhibit its activity. Mice depleted of Klf3 in endothelial cells showed a high abundance of CD31hiEmcnhi vessels and increased bone mass. Notably, we identified a natural compound, Ophiopogonin D, which functions as a KLF3 inhibitor. Administration of Ophiopogonin D increased the abundance of CD31hiEmcnhi vessels and bone formation. Our findings revealed a specific mutation in lncRNA Reg1cp that is involved in the pathogenesis of HBM and provides a new target to treat osteoporosis.