Genetic factors have been shown to play a major role in the development of peak bone mass, with hereditability accounting for about 50-85% of the variance in bone mass. Numerous candidate genes involved in osteoporosis have been proposed, but the precise genes and their relative contribution remain unknown.To gain insight into the genetic basis of idiopathic low bone mineral density in Israeli patients by analyzing the impact of two candidate genes: polymorphism of the vitamin D receptor gene and polymorphism A986S in the calcium-sensing receptor gene.We analyzed 86 Jewish Israeli patients with LBMD: 38 premenopausal women and 48 men, and compared the allelic pattern distribution with that of the general population (126 men and 112 women). Genotyping of the VDR gene was performed in three polymorphic sites using restriction enzymes, and allelic analysis of A986S polymorphism in the CaSR gene was performed using the denaturing gradient gel electrophoresis technique.In LBMD women the distributions of VDR alleles in Apal polymorphism were AA = 7/28, Aa = 16/28 and aa = 5/28; in Taql polymorphism TT = 10/31, Tt = 16/31 and tt = 5/31; and in Bsml polymorphism BB = 7/32, Bb = 14/32 and 11/32. In LBMD men the distributions were AA = 17/39, Aa = 21/39 and aa = 1/39; in Taql polymorphism TT = 12/42, Tt = 23/42 and tt = 7/42; and in Bsml polymorphism BB = 12/41 Bb = 18/41 and bb = 11/32. The distributions of all these polymorphisms in the control groups were not significantly different. Adjusting for the independent age and gender parameters confirmed that these three polymorphisms of the VDR gene did not have a significant effect on bone mineral density. Thirty percent (24/79) of LBMD patients of either sex displayed heterozygosity of the CaSR A986S polymorphism, compared with 40 of 203 controls (19.7%) (P = 0.059). Adjusting for age and gender in these patients revealed a significant difference in the femoral neck BMD between homozygotes and heterozygotes (p = 0.002). The age at menarche of the LBMD women was found to predict 61% of the variance of femoral neck BMD.In Israeli Jewish men and premenopausal women VDR gene alleles do not seem to be associated with lower lumbar spine or femoral neck BMD. A trend towards heterozygosity for a CaSR polymorphism missense mutation was noted in the LBMD patients. Age at menarche in the LBMD women was found to be an important predictor of BMD. A significant difference was found between LBMD women and healthy control women towards heterozygosity for a CaSR polymorphism, as well as between homozygotes and heterozygotes for a CaSR polymorphism in BMD. The significance of these findings and their applicability to a larger population awaits further studies.