The association of homocysteine and its determinants MTHFR genotype, folate, vitamin B12 and vitamin B6 with bone mineral density in postmenopausal British women.

We studied the association between plasma total homocysteine (tHcy), its determinants folate, vitamin B(12), vitamin B(6) and MTHFR genotype, and bone mineral density (BMD) in 328 postmenopausal British women. When the subjects were assigned to one of 3 groups (control, osteopenic or osteoporotic) according to their BMD at the os calcis, those in the osteoporotic group had, compared with the controls, a significantly lower serum folate concentration, a significantly higher % of current smokers and a significantly higher incidence of recent fracture. In the population as a whole, we found significant associations of BMD with tHcy (r=-0.130, p=0.033, log tHcy) and folate (r=0.132, p=0.025, log folate). The association of folate with BMD was maintained after correction for age, weight and height (r=0.124, p=0.042, log folate), but the association of tHcy with BMD weakened after correction for age, weight, height and creatinine (r=-0.117, p=0.059, log tHcy). Vitamins B(12) and B(6) were not associated with BMD, but were significantly associated with tHcy, vitamin B(12) (r=-0.34, p<0.0001), vitamin B(6) (r=-0.16, p=0.007), as was folate (r=-0.41, p<0.0001). There was an increasing frequency of the MTHFR TT genotype across the 3 BMD groups, but this did not attain significance. Individuals with the TT genotype had significantly higher plasma tHcy but there was no difference between the genotypes (CC, CT, TT) for folate or BMD. Smoking was associated with a highly significant reduction in BMD and lower weight, and a significant reduction in circulating folate and vitamin B(6) concentrations, but no change in tHcy or vitamin B(12) concentrations when compared with non-smokers. We conclude that low serum folate is a significant risk factor for osteoporosis, with plasma tHcy having a lesser effect. Both vitamins B(12) and B(6), by acting through tHcy, may also have an effect on the skeleton, albeit a weaker one than folate. Cigarette smoking is a strong determinant of BMD, and may act through effects on folate and vitamin B(6).