Osteoporosis as well as osteopenia are common human conditions considered to result from the interplay of multiple genetic and environmental factors. Twin and family studies have yielded strong correlation between measures of bone mass and a number of genetic factors. Certain genes (e.g., cytokines such as interleukin-1, interleukin-6, or tumor necrosis factor-alpha) are capable of regulating metabolism, formation, and resorption of bone; all processes that determine bone mass. We tested 192 sib-pairs of adult Japanese women from 136 families for genetic linkage between osteoporosis and osteopenia phenotypes and allelic variants at the tumor necrosis factor-alpha (TNFA) locus, using a dinucleotide-repeat polymorphism located near the gene. The TNFA locus showed evidence for linkage to osteoporosis, with mean allele sharing of 0.478 (P = 0.30) in discordant pairs and 0.637 (P = 0.001) in concordant affected pairs. Linkage with osteopenia was also significant in concordant affected pairs (P = 0.017). Analyses limited to the post-menopausal women in our cohort showed similar or even stronger linkage for both phenotypes. The results provide evidence that genetic variations within the TNFA locus or adjacent genes affect regulation of mineral metabolism in bone and some of them confer risk for osteoporosis in adult women.