Technical Abstract: Apolipoprotein E (APOE) has been studied for its potential role in osteoporosis risk. It is hypothesized that genetic variation at common APOE loci, known as E2, E3, and E4, may modulate bone mineral density (BMD) through its effects on lipoproteins and vitamin K transport. To determine the association of the APOE-E4 gene polymorphism with bone-related phenotypes, we conducted a meta-analysis that combined newly-analyzed individual data from two community-based cohorts, the Framingham Offspring Study (N=1,495) and the Vitamin K Clinical Trial (N=377), with fifteen eligible published reports. Bone phenotypes included BMD measurements of the hip (total hip and trochanteric and femoral neck sites) and lumbar spine (between the L2 and L4 vertebrae) and prevalence or incidence of vertebral, hip and other fractures. In sex-pooled analyses, APOE4 carriers had a 0.018 g/cm2 lower weighted mean trochanteric BMD than non carriers (p=0.0002) with no evidence for between-study heterogeneity. A significant association was also detected with lumbar spine BMD (p=0.006); however, inter-study heterogeneity was observed. Associations with lumbar spine and trochanteric BMD were observed predominantly in women and became less significant in meta-regression (p=0.055 and 0.01, respectively). There were no consistent associations of APOE4 genotype with BMD at other skeletal sites or with fracture risk. Based on these findings, there is insufficient evidence to support a strong and consistent association of the APOE genotype with BMD and fracture incidence.