Phosphorous (P) is essential to bone growth and maintenance; however, little research has focused on the genetic mechanisms controlling P utilization. Thirty-six pigs from 2 sire lines known to differ in bone structure (heavier-boned, HB, and lighter-boned, LB) were assigned to three diets for 2 weeks (P adequate, P repletion, or P deficient). In HB, but not LB pigs, the P deficient diet caused a decrease in weight gain (P<0.01). For both lines, P deficiency caused a reduction in radial bone strength (P<0.01), but HB P deficient animals had greater (P<0.10) bone integrity than LB P deficient pigs. In HB, but not LB pigs, dietary treatment affected the expression of CALCR (P<0.05), VDR (P<0.04), IGF1 (P<0.11), and IGFBP3 (P<0.06). There was also a trend of increased IL6, TFIIB, and S0X9 expression with P deficiency in HB, but not LB, pigs. A trend of increased expression of OXTR was seen in P deficient animals in both genetic backgrounds. Expression of RANKL, BGLAP, OPG, ARAF1, and IGFBP5 was not affected by genetic background or diet. These data suggest that HB pigs were more responsive to dietary P restriction than LB pigs. Differences in growth rate, bone integrity, and gene expression within the bone marrow suggest a difference in the homeorhetic control of P utilization between these genetic lines. The genes that were differentially expressed based on genetic background and dietary treatment interaction were then examined for single nucleotide polymorphisms (SNPs). We identified SNPs in CALCR, VDR, IGFBP3, and OXTR genes, and PCR restriction fragment length polymorphism (PCR-RFLP) tests were developed using restriction enzymes Banll, HpyCH4IV, BsaHl, and Aval, respectively. These polymorphisms were associated with several growth performance measurements. Most interestingly, the CALCR Banll polymorphism showed significant associations with bone strength. Understanding the interaction between nutrition and genotype could lead to novel treatments for osteoporosis and aid in the development of tests for identifying those at risk before peak bone mineral density has been achieved. This new knowledge could also lead to genotype-specific dietary intervention strategies which will likely be more effective in reducing the incidence of osteoporosis.