Osteoporosis is commonly considered a women's health problem, but is also a significant health concern for older men. Less is known about the predictors of osteoporosis and bone mineral density (BMD) in men. The aging of the population and expected increase in osteoporosis prevalence makes understanding the determinants of BMD of great public health importance.Genetics is an important determinant of BMD, but little is known about specific loci associated with BMD in men and even less is known about the genetic influences on volumetric BMD (vBMD). With this in mind, we investigated 4108 single nucleotide polymorphisms (SNPs) in 383 candidate genes for their association within a population of older Caucasian men. In addition, we investigated 148 of these SNPs in 28 WNT pathway genes for gene-gene interactions and gene-environment interactions with physical activity and body weight. We identified several SNPs that were associated with lumbar spine and femoral neck integral vBMD and explained 3.5% and 1.7% of the phenotypic variation in these traits, respectively. SNPs in two genes, adenomatous polyposis coli (APC) and the homeo box A gene cluster (HOXA) were associated with integral vBMD at both the femoral neck and lumbar spine. Analysis of cortical and trabecular vBMD at the femoral neck identified SNPs that explained 1.8% and 4.0% of the phenotypic variance, respectively. None of the SNPs for cortical vBMD were associated with trabecular vBMD. Statistically significant gene-gene and gene-environment interactions were also identified. Of note, statistically significant interaction effects of SNPs in the low density lipoprotein receptor-related protein 5 and physical activity level on integral vBMD at the femoral neck and lumbar spine were identified. Although additional work is needed to confirm and extend these findings we identified a number of novel associations for vBMD in older Caucasian men. Our results suggest the presence of genetic loci that are skeletal-site specific and specific to either cortical or trabecular bone. Additionally, these findings underscore the importance of evaluating genetic variation in the context of other genes and environmental factors
