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Background: Several clinical trials have reported B vitamins to be associated with osteoporosis. Objective: Our objective was to investigate whether low serum B vitamins are associated with altered structural and biomechanical properties of human bone. Design: Femoral heads of 94 men and women who underwent hip arthroplasty were analyzed by using dual-energy X-ray absorptiometry (DXA), biomechanical testing (indentation method), and histomorphometry. In addition, blood was collected to measure serum concentrations of homocysteine, folate, vitamin B-6, vitamin B-12, the bone formation marker osteocalcin and the bone resorption marker tartrate-resistant acid phosphatase (TRAP). Measurement outcomes were grouped according to subjects with high and low serum concentrations, respectively, of folate, vitamin B-6, and vitamin B-12 (n = 47 for each group). Results: Histomorphometric analysis showed a significantly lower trabecular thickness and trabecular area in subjects with low serum folate concentrations than in those with high serum folate concentrations and a significantly lower trabecular number in subjects with low serum vitamin B-6 concentrations than in those with high serum vitamin B-6 concentrations. In contrast, we found a comparable trabecular structure in subjects with high and low serum vitamin B-12 concentrations. DXA and biomechanical testing did not show significant differences between subjects with high and low serum B vitamin concentrations. Osteocalcin was significantly lowered in subjects with a low serum B vitamin concentration, whereas there was no association between serum B vitamins and TRAP. Conclusion: The results of the present study indicate that low serum folate and vitamin B-6 concentrations, but not low serum vitamin B-12 concentrations, are associated with an altered morphology of human bone. doi: 10.3945/ajcn.2009.28116.

A major focus in attempts to ameliorate homocystinuria and neural tube defects is supplementation of the diet with B vitamins. The metabolic defect in these cases may be due in part to a deficiency of methyl groups. B vitamin supplementation supports the need for enzyme cofactors but cannot provide substrate in the form of methyl groups. L-Methionine is an essential amino acid and is required for protein synthesis, but it also plays a unique role in metabolism as S-adenosylmethionine, which is the primary methyl donor in metabolism. The observation that L-homocysteine, which is produced in the metabolism of L-methionine, is remethylated 2-4 times before it is destroyed is key to understanding the possibility of a methyl group deficiency. This suggests that the requirement for methyl groups (ie, S-adenosylmethionine) may be 2-4 times that for methionine in support of protein synthesis. L-Homocysteine can be remethylated to form L-methionine by betaine or [N.sup.5]-methyltetrahydrofolate. Betaine and one-carbon sources that lead to the production of [N.sup.5]-methyltetrahydrofolate and the remethylation of L-homocysteine to form L-methionine should be considered along with B vitamin supplementation in the treatment of homocystinuria and neural tube defects. KEY WORDS Betaine, methyltetrahydrofolate, homocystinuria, neural tube defects

Background: High concentrations of homocysteine have been linked to a greater risk of Alzheimer disease, dementia, and cognitive decline. Objective: We evaluated the association between homocysteine and 4.5-y combined incidences of dementia and cognitive impairment without dementia (CIND) in a cohort of 1779 Mexican Americans aged 60-101 y. Design: Homocysteine, red blood cell (RBC) folate, and plasma vitamin B-12 were measured at baseline. New cases of dementia or CIND were ascertained by neuropsychological and clinical examinations and expert adjudication. We used proportional hazards models to estimate the risk of homocysteine-associated dementia or CIND and the influence of RBC folate and plasma vitamin B-12 on that association. Results: High homocysteine concentrations were associated with a greater risk of dementia or CIND: hazard ratio (HR): 2.39; 95% CI: 1.11, 5.16. Plasma vitamin B-12 modified the association between homocysteine and the outcome. The rates of dementia or CIND associated with homocysteine for those in the lowest and highest tertiles of vitamin B-12, respectively, were significantly higher (HR: 1.61, P = 0.04) and lower (HR: 0.94, P = 0.015) than the risk for those in the middle tertile. Conclusions: Homocysteine is an independent risk factor for both dementia and CIND. Higher plasma vitamin B-12 may reduce the risk of homocysteine-associated dementia or CIND. KEY WORDS Homocysteine, B vitamins, dementia, cognitive impairment without dementia, red blood cell folate

Background: In recent prospective studies, higher homocysteine concentrations were shown to be a risk factor for osteoporotic fractures in older persons. Supplements containing folate and vitamins B-12 and B-6 lower homocysteine concentrations. Objective: The objective of the study was to determine in healthy older persons whether lowering homocysteine with B vitamins affects plasma biomarkers of bone turnover. Design: Healthy older persons (n = 276; aged [greater than or equal to] 65 y) were randomly assigned to receive either a daily supplement containing folate (1 mg), vitamin B-12 (500 [micro]g), and vitamin B-6 (10 mg) or a placebo for 2 y. Of these participants, we selected 135 with baseline homocysteine concentrations > 15.0 [micro]mol/L, and we measured serum bone-specific alkaline phosphatase, a marker of bone formation, and bone-derived collagen fragments, a marker of bone resorption, at baseline and 2 y later. Results: At 2 y, plasma homocysteine concentrations were 5.2 [micro]mol/L (95% CI: 3.9, 6.6 [micro]mol/L; P < 0.001) lower in the vitamin than in the placebo group. No significant differences were found in either serum bone-specific alkaline phosphatase (-0.3 [micro]g/L; 95% CI: -2.8, 2.1 [micro]g/L; P = 0.79) or bone-derived collagen fragments (-0.0 [micro]g/L; 95% CI: -0.1,0.1 [micro]g/L; P = 0.76) between the vitamin and placebo groups, respectively, with 2 y of supplementation. Conclusion: Supplementation with folate and vitamins B-6 and B-12 lowered plasma homocysteine but had no beneficial effect on bone turnover at the end of 2 y, as assessed by biomarkers of bone formation and resorption. KEY WORDS Homocysteine, bone biomarkers, folate, vitamin B-12, vitamin B-6, clinical trial, older persons

Background: High concentrations of homocysteine and low concentrations of vitamin B- 12 and folic acid are frequently observed in subjects with dementia. Objective: We assessed whether serum concentrations of homocysteine, vitamin B- 12, or folic acid predict cognitive decline in old age. Design: This was a prospective, population-based, longitudinal study of 599 subjects (Leiden 85-Plus Study, Netherlands). The subjects were administered a battery of cognitive tests (including the Mini Mental State Examination, the Stroop test, a letter digit coding test, and a word recall test) at 85 y of age and yearly thereafter until 89 y of age. Serum concentrations of homocysteine, vitamin B- 12, and folic acid were measured at 85 and 89 y of age. Cross-sectional associations between serum concentrations and cognition were assessed at 85 and 89 y of age. The association between baseline serum concentrations and subsequent longitudinal cognitive decline was assessed with the use of mixed linear models. Results: In the cross-sectional analyses, serum concentrations of homocysteine and folic acid were significantly associated with cognitive performance, but serum concentrations of vitamin B-l 2 were not. In the longitudinal analyses, there were no significant associations of serum concentrations of homocysteine, vitamin B-12, or folic acid with rate of cognitive decline. Conclusions: Elevated serum concentrations of homocysteine and reduced folic acid are associated with cognitive impairment in elderly persons hut do not predict an increased rate of cognitive decline. The association of high serum concentrations of homocysteine and low folic acid with cognitive impairment in old age is likely to be a consequence of disease and not a contributory cause. KEY WORDS Homocysteine, folic acid, vitamin B-12, elderly persons, cognitive decline

Background: Vitamin B-12 deficiency is usually accompanied by elevated concentrations of serum total homocysteine (tHcy) and methylmalonic acid (MMA). Folate deficiency also results in elevated tHcy. Measurement of these metabolites can be used to screen for functional vitamin B-12 or folate deficiency. Objective: We assessed the prevalence of vitamin B-12 and folate deficiency in a population-based study (n = 1562) of older persons living in Oxford City, United Kingdom. Design: We postulated that, as vitamin B-12 or folate concentrations declined from adequate to impaired levels, tHcy (or MMA) concentrations would increase. Individuals were classified as being at high risk of vitamin B-12 deficiency if they had low vitamin B-12 (< 150 pmol/L) or borderline vitamin B-12 (150-200 pmol/L) accompanied by elevated MMA (> 0.35 [micro]mol/L) or tHcy (> 15.0 [micro]mol/L). Individuals were classified as being at high risk of folate deficiency if they had low folate (< 5 nmol/L) or borderline folate (5-7 nmol/L) accompanied by elevated tHcy (> 15 [micro]mol/L). Results: Cutoffs of 15.0 [micro]mol/L for tHcy and 0.35 [micro]mol/L for MMA identified persons with normal or elevated concentrations. Among persons aged 65-74 and [greater than or equal to] 75 y, respectively, [approximately equal to] 10% and 20% were at high risk of vitamin B-12 deficiency. About 10% and 20%, respectively, were also at high risk of folate deficiency. About 10% of persons with vitamin B-12 deficiency also had folate deficiency. Conclusion: Use of tHcy or MMA among older persons with borderline vitamin concentrations may identify those at high risk of vitamin B-12 deficiency who should be considered for treatment. Am J Clin Nutr 2003;77:1241-7. KEY WORDS Screening, folate, vitamin B-12, homocysteine, methylmalonic acid, elderly

Background: An elevated plasma total homocysteine (tHcy) concentration is associated with an increased risk of cardiovascular diseases. Folate, riboflavin, vitamin B-6, and vitamin B-12 are essential in homocysteine metabolism. Objective: The objective was to describe the association between dietary intakes of folate, riboflavin, vitamin B-6, and vitamin B-12 and the nonfasting plasma tHcy concentration. Design: A random sample of 2435 men and women aged 20-65 y from a population-based Dutch cohort examined in 1993-1996 was analyzed cross-sectionally. Results: Univariately, intakes of all B vitamins were inversely related to the plasma tHcy concentration. In multivariate models, only folate intake remained inversely associated with the plasma tHcy concentration. Mean plasma tHcy concentrations (adjusted for intakes of riboflavin, vitamin B-6, vitamin B-12, and methionine and for age, smoking, and alcohol consumption) in men with low (first quintile: 161 [micro]g/d) and high (fifth quintile: 254 [micro]g/d) folate intakes were 15.4 and 13.2 [micro]mol/L, respectively; in women, plasma tHcy concentrations were 13.7 and 12.4 [micro]mol/L at folate intakes of 160 and 262 [micro]g/d, respectively. In men, the difference in the mean plasma tHcy concentration between men with low and high folate intakes was greater in smokers than in nonsmokers (2.8 compared with 1.6 [micro]mol/L) and greater in nondrinkers than in drinkers of [is greater than] 2 alcoholic drinks/d (3.5 compared with 1.4 [micro]mol/L). In women, the association between folate intake and plasma tHcy was not modified by smoking or alcohol consumption. Conclusions: In this Dutch population, folate was the only B vitamin independently inversely associated with the plasma tHcy concentration. Changing dietary habits may substantially influence the plasma tHcy concentration in the general population. KEY WORDS Folate, riboflavin, vitamin B-6, vitamin B-12, plasma homocysteine, population-based study, Netherlands

Evidence of the importance of the B vitamins folic acid, vitamin B-12, and vitamin B-6 for the well-being and normal function of the brain derives from data showing neurologic and psychologic dysfunction in vitamin deficiency states and in cases of congenital defects of one-carbon metabolism. The status of these vitamins is frequently inadequate in the elderly and recent studies have shown associations between loss of cognitive function or Alzheimer disease and inadequate B vitamin status. The question that arises is whether these B vitamin inadequacies contribute to such brain malfunctions or result from aging and disease. From a theoretical standpoint, these inadequacies could give rise to impairment of methylation reactions that are crucial to the health of brain tissue. In addition or perhaps instead, these inadequacies could result in hyperhomocysteinemia, a recently identified risk factor for occlusive vascular disease, stroke, and thrombosis, any of which may result in brain ischemia. Advances in the understanding of this putative relation between inadequate vitamin status and loss of cognitive function in the elderly are likely to be slow and may depend on the outcomes of both prospective studies and longitudinal studies in which nutritional intervention is provided before cognitive decline occurs. Am J Clin Nutr 2000;71 (suppl):614S-20S. KEY WORDS Alzheimer disease, cognitive function, cognitive decline, dementia, folate, folic acid, vitamin B-12, vitamin B-6, homocysteine, hyperhomocysteinemia, brain, B vitamins, elderly, aging