Osteoporosis is a major public health problem, mainly quantified by low BMD. Eleven polymorphisms were investigated in this study; TNFalpha-857 (rs1799724), TGFbeta1-509 (rs1800469), osteocalcin (rs1800247), TNFalpha-308 (rs1800629), PTH BstB I (rs6254), PTH Dra II (rs6256), IL-1ra (VNTR), HSP70 hom (rs2227956), HSP 70-2 (rs1061581), CTR (rs1801197), and BMP-4 (rs17563). The relationship between the combined polymorphisms in different genomic regions and BMD variation was investigated. Among the female subjects, the proportion of subjects with low BMD in low BMI group (< or = 18.50) was significantly higher than that of the middle (18.51-22.99) and high (> or = 23.00) BMI groups (P < 0.05). In post-menopausal women, there was a significant association between low BMD and genotypes ranging from 2 to approximately 7 SNPs. For two combined SNPs, the portion of subjects with low BMD was significantly higher in those with CC-AA genotypes in rs1799724-rs1800629, compared to those with non-CC-AA genotypes in post-menopausal women and the combination of all women. Similarly, part of the combined SNPs with rs1799724-rs1800629-rs6254-rs6256-IL-1ra-rs2227956-rs1801197 was significantly associated with reduced BMD. After controlling for age and BMI, post-menopausal women with certain specific SNP combination had a 3.54- to 4.68-fold increased risk for low BMD, comparing to other SNP combinations. In conclusion, our data suggest that several gene polymorphisms may be cooperatively involved in the development of osteoporosis.