Bone mineral density (BMD) is a reflection of both genetic and lifestyle factors. The interplay of genetic (vitamin D receptor [VDR] gene polymorphisms) and lifestyle factors on BMD at the lumbar spine and proximal femur was examined in 470 healthy premenopausal women, aged 44-50 years, using a Hologic QDR 2000 densitometer. The objective of this study was to examine the genetic and lifestyle determinants of premenopausal BMD. Each participant was genotyped for BsmI polymorphism at the VDR gene locus. The presence of a restriction site within VDR, specified as bb (189, 40.2%) (n, %) was associated with reduced spinal BMD, whereas absence of this site in BB (97, 20.6%) conferred greater spinal BMD, as did the genotype Bb (184, 39.1%). Associations between smoking, alcohol use, oral contraceptives, education level, multivitamins, number of children, degree of obesity, body weight, physical activity, dietary calcium intake, and VDR genotype to BMDs were examined. VDR genotype, body weight, degree of obesity, physical activity, and dietary calcium intake were all significant determinants of BMD. The association of VDR genotype with BMD at the femoral neck appeared to be modified by calcium intake (BB and Bb: 0.797 +/- 0.11 g/cm2 vs. 0.844 +/- 0.11 g/cm2, interaction term, p = 0.06) for low (< 1036 mg/day) and high (> or = 1036 mg/day; upper quartile) calcium intakes, respectively. A similar trend was demonstrated for physical activity. These findings suggest that prophylactic interventions aimed at achieving and maintaining optimal BMD, such as greater calcium intake or physical activity, may be important in maximizing one's genetic potential for BMD.