Osteoporosis is a skeletal disorder characterized by low bone mineral density (BMD) and deterioration of bone microarchitecture. To identify novel genetic loci underlying osteoporosis, an effective strategy is to focus on scanning of variants with high potential functional impacts. Enhancers play a crucial role in regulating cell-type-specific transcription. Therefore, single-nucleotide polymorphisms (SNPs) located in enhancers (enhancer-SNPs) may represent strong candidate functional variants. Here, we performed a targeted analysis for potential functional enhancer-SNPs that may affect gene expression and biological processes in bone-related cells, specifically, osteoblasts, and peripheral blood monocytes (PBMs), using five independent cohorts (n = 5905) and the genetics factors for osteoporosis summary statistics, followed by comprehensive integrative genomic analyses of chromatin states, transcription, and metabolites. We identified 15 novel enhancer-SNPs associated with femoral neck and lumbar spine BMD, including 5 SNPs mapped to novel genes (e.g., rs10840343 and rs10770081 in IGF2 gene) and 10 novel SNPs mapped to known BMD-associated genes (e.g., rs2941742 in ESR1 gene, and rs10249092 and rs4342522 in SHFM1 gene). Interestingly, enhancer-SNPs rs10249092 and rs4342522 in SHFM1 were tightly linked, but annotated to different enhancers in PBMs and osteoblasts, respectively, suggesting that even tightly linked SNPs may regulate the same target gene and contribute to the phenotype variation in cell-type-specific manners. Importantly, ten enhancer-SNPs may also regulate BMD variation by affecting the serum metabolite levels. Our findings revealed novel susceptibility loci that may regulate BMD variation and provided intriguing insights into the genetic mechanisms of osteoporosis.