Twins and family studies have shown that genetic factors are important determinants of bone mass. Important aspects of bone mineral density (BMD) regulation are endocrine systems, notably hormonal regulation of adrenal corticoids, as indicated by clinical knowledge of glucocorticoid-induced osteoporosis. Glucocorticoid is known to negatively regulate bone mass in vivo, and glucocorticoid increases thrombospondin messenger ribonucleic acid (mRNA) levels. We studied single nucleotide polymorphisms (SNPs) in genes encoding thrombospondin, type 1, domain-containing 4 and 7A (THSD4 and THSD7A) for possible association with lumbar and femoral BMD among 337 Japanese women with osteoporosis who participated in the BioBank Japan project. Genetic variations of THSD4 and THSD7A loci displayed significant association with lumbar and femoral BMD. Most significant correlation was observed for THSD7A SNP rs12673692 with lumbar BMD (P = 0.00017). Homozygous carriers of the major (G) allele had the highest BMD [0.886 +/- 0.011 g/cm2, mean +/- standard deviation (SD)], whereas heterozygous carriers were intermediate (0.872 +/- 0.013 g/cm2) and homozygous A-allele carriers had the lowest (0.753 +/- 0.023 g/cm2). THSD4 SNP rs10851839 also displayed strong association with lumbar BMD (P = 0.0092). In addition, both THSD7A and THSD4 displayed significant association with femoral BMD in a recessive model (P = 0.036 and P = 0.0046, respectively). Results suggest that variations of THSD7A and THSD4 loci may be important determinants of osteoporosis in Japanese women.