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Gene effects on osteoporosis have been studied separately and may have been masked by gene–gene and gene–environment interactions. We evaluated gene–gene and gene–physical activity interactions of the variants of tumor necrosis factor-α ( TNF-α ) and vitamin D receptor ( VDR ) genes on osteoporosis. A total of 472 elders were included. Seven variants ( TNF-α : rs1799964, rs1800629, rs3093662;  VDR : rs7975232, rs1544410, rs2239185, rs3782905) were genotyped. Bone mineral densities of the lumbar spine, femoral neck, and total hip were measured by dual-energy X-ray absorptiometry. Predictive models’ ability to discriminate osteoporosis status was evaluated by areas under the receiver operating characteristics (AUROC) curve. After multivariable adjustment, significant interactions of  TNF-α  rs1800629 and  VDR  rs3782905 were observed on overall and lumbar spine osteoporosis. In elderly women, we found that those carrying the CG/CC genotype of  VDR  rs3782905 were significantly associated with increased odds of overall osteoporosis compared with those carrying the GG genotype of  VDR  rs3782905 among those carrying  TNF-α  rs1800629 GG genotype. The adjusted odds ratios (ORs) for  VDR  rs3782905 CG/CC genotype in elderly women carrying  TNF-α  rs1800629 AG/AA and GG genotypes were 0.1 (0.01, 0.98) and 3.54 (1.51, 8.30), respectively. We observed significant differences in AUROCs between the model with traditional covariates plus variants and their interaction term and the model with traditional covariates only (AUROCs: 0.77 and 0.81;  p  = 0.028). Although the sample size of this study may have been relatively small, our results suggest that the interaction of the CG/CC genotype of  VDR  rs3782905 with  TNF-α  rs1800629 GG genotype was associated with increased odds of overall and lumbar spine osteoporosis in elderly women.

Important gene–gene interaction of TNF-α and VDR on osteoporosis in community-dwelling elders