Category Archives: Homocysteine

Low Riboflavin Predicts Fracture Risk in MTHFR T Postmenopausal Women

Abstract

Low dietary riboflavin but not folate predicts increased fracture risk in postmenopausal women homozygous for the MTHFR 677 T allele.

The MTHFR C677T polymorphism is associated with mildly elevated homocysteine levels when folate and/or riboflavin status is low. Furthermore, a mildly elevated homocysteine level is a risk factor for osteoporotic fractures. We studied whether dietary intake of riboflavin and folate modifies the effects of the MTHFR C677T variant on fracture risk in 5,035 men and women from the Rotterdam Study. We found that the MTHFR C677T variant interacts with dietary riboflavin intake to influence fracture risk in women.
The MTHFR C677T polymorphism is associated with mildly elevated homocysteine (Hcy) levels in the presence of low folate and/or riboflavin status. A mildly elevated Hcy level was recently identified as a modifiable risk factor for osteoporotic fracture. We studied whether dietary intake of riboflavin and folate modifies the effects of the MTHFR C677T polymorphism on BMD and fracture risk.
We studied 5,035 individuals from the Rotterdam Study, >or=55 yr of age, who had data available on MTHFR, nutrient intake, and fracture risk. We performed analysis on Hcy levels in a total of 666 individuals, whereas BMD data were present for 4,646 individuals (2,692 women).
In the total population, neither the MTHFR C677T polymorphism nor low riboflavin intake was associated with fracture risk and BMD. However, in the lowest quartile of riboflavin intake, female 677-T homozygotes had a 1.8 (95% CI: 1.1-2.9, p = 0.01) times higher risk for incident osteoporotic fractures and a 2.6 (95% CI: 1.3-5.1, p = 0.01) times higher risk for fragility fractures compared with the 677-CC genotype (interaction, p = 0.0002). This effect was not seen for baseline BMD in both men and women. No significant influence was found for dietary folate intake on the association between the MTHFR C677T genotype and fracture risk or BMD. In the lowest quartile of dietary riboflavin intake, T-homozygous individuals (men and women combined) had higher (22.5%) Hcy levels compared with C-homozygotes (mean difference = 3.44 microM, p = 0. 01; trend, p = 0.02).
In this cohort of elderly whites, the MTHFR C677T variant interacts with dietary riboflavin intake to influence fracture risk in women.

Yazdanpanah N, Uitterlinden AG, Zillikens MC, Jhamai M…
J. Bone Miner. Res. Jan 2008
PMID: 17725378

Homocysteine Associated with Bone Loss in Elderly Women

Abstract

Associations between homocysteine, bone turnover, BMD, mortality, and fracture risk in elderly women.

Homocysteine has been suggested to be a risk factor for fracture, but the causal relationship is not clear. In 996 women from the OPRA study, high homocysteine level was associated with high bone marker levels and low BMD at baseline. During a mean 7-year follow-up, high homocysteine level was associated with mortality, but no clear association to fracture risk existed.
Recently, the association between high serum homocysteine (Hcy) levels and an increased risk of fracture has been described.
Hcy levels were measured at baseline in 996 women, all 75 years old. Vitamin B(12), folate, serum cross-linking telopeptide of type I collagen (CTX), serum TRACP5b, serum osteocalcin, urine deoxypyridinoline, PTH, areal BMD (aBMD), calcaneal quantitative ultrasound (QUS), and physical performance were assessed at baseline. Fractures and mortality were recorded during a mean follow-up of 7.0 years.
Bone marker levels were higher in women with Hcy in the highest quartile compared with all other women (p < 0.05). The most evident correlation between Hcy and a bone marker was seen with CTX (r = 0.19, p < 0.001). aBMD (hip) was 4% lower, QUS was up to 2% lower, and gait speed was 11% slower among women with Hcy in the highest quartile compared with the other women (p < 0.05). During the follow-up, 267 women sustained at least one low-energy fracture (including 69 hip fractures). When women in the highest Hcy quartile were compared with all other women, the hazard ratios (HRs) for sustaining any type of fracture was 1.18 (95% CI, 0.89-1.36) and for hip fracture was 1.50 (95% CI, 0.91-1.94). For the same group of women, the mortality risk was 2.16 (95% CI, 1.58-2.55). Adjustments for confounders did not substantially change these associations. Adjustment for PTH increased the HR for hip fracture to 1.67 (95% CI, 1.01-2.17). Low vitamin B(12) or folate was not associated with increased fracture risk or mortality.
High Hcy levels were associated with higher bone turnover, poor physical performance, and lower BMD. There was no clear association to fracture risk. The increased mortality among women with high Hcy levels indicates that a high Hcy level may be a marker of frailty.

Gerdhem P, Ivaska KK, Isaksson A, Pettersson K…
J. Bone Miner. Res. Jan 2007
PMID: 17032146

Low B12 or High Homocysteine Associated with Increased Fracture Risk

Abstract

Homocysteine and vitamin B12 status relate to bone turnover markers, broadband ultrasound attenuation, and fractures in healthy elderly people.

Hyperhomocysteinemia may contribute to the development of osteoporosis. The relationship of Hcy and vitamin B12 with bone turnover markers, BUA, and fracture incidence was studied in 1267 subjects of the Longitudinal Aging Study Amsterdam. High Hcy and low vitamin B12 concentrations were significantly associated with low BUA, high markers of bone turnover, and increased fracture risk.
Hyperhomocysteinemia may contribute to the development of osteoporosis. Vitamin B12 is closely correlated to homocysteine (Hcy). The main objective of our study was to examine the association of Hcy and vitamin B12 status and the combined effect of these two with broadband ultrasound attenuation (BUA), bone turnover markers, and fracture.Subjects were 615 men and 652 women with a mean age of 76 +/- 6.6 (SD) years of the Longitudinal Aging Study Amsterdam (LASA). At baseline (1995/1996), blood samples were taken after an overnight fast for dairy products. Plasma Hcy was measured with IMx, serum vitamin B12 with competitive immunoassay (IA) luminescence, serum osteocalcin (OC) with immunoradiometric assay (IRMA), and urinary excretion of deoxypyridinoline (DPD) with competitive IA and corrected for creatinine (Cr) concentration. CVs were 4%, 5%, 8%, and 5%, respectively. BUA was assessed in the heel bone twice in both the right and left calcaneus. Mean BUA value was calculated from these four measurements. CV was 3.4%. After baseline measurements in 1995, a 3-year prospective follow-up of fractures was carried out until 1998/1999. Subjects were grouped by using two different approaches on the basis of their vitamin B12 concentration, normal versus low (<200 pM) or lowest quartile (Q1) versus normal quartiles (Q2-Q4), and Hcy concentration, normal versus high (>15 microM) or highest quartile (Q4) versus normal quartiles (Q1-Q3). Analysis of covariance was performed to calculate mean values of BUA, OC, and DPD/Cr(urine) based on the specified categories of Hcy and vitamin B12 and adjusted for several confounders (potential confounders were age, sex, body weight, body height, current smoking [yes/no], mobility, cognition). The relative risk (RR) of any fracture was assessed with Cox regression analysis. Quartiles were used when Hcy and vitamin B12 were separately studied in their relationship with fracture incidence.
Fourteen percent of the men and 9% of the women had high Hcy (>15 microM) and low vitamin B12 (<200 pM) concentrations. Women with vitamin B12 levels <200 pM and Hcy concentrations >15 microM had lower BUA, higher DPD/Cr, and higher OC concentrations than their counterparts. In men, no differences were found between the different Hcy and vitamin B12 categories in adjusted means of BUA, OC, or DPD/Cr(urine). Twenty-eight men and 43 women sustained a fracture during the 3-year follow-up period. The adjusted RR for fractures (95% CI) for men with high Hcy and/or low vitamin B12 concentrations was 3.8 (1.2-11.6) compared with men with normal Hcy and vitamin B12 concentrations. Women with high Hcy and/or low vitamin B12 concentrations had an adjusted RR for fractures of 2.8 (1.3-5.7).
High Hcy and low vitamin B12 concentrations were significantly associated with low BUA, high markers of bone turnover, and increased fracture risk.

Dhonukshe-Rutten RA, Pluijm SM, de Groot LC, Lips P…
J. Bone Miner. Res. Jun 2005
PMID: 15883631

Riboflavin May Help Regulate Bone Density in Those With MTHFR TT Genotype

Abstract

Methylenetetrahydrofolate reductase polymorphism interacts with riboflavin intake to influence bone mineral density.

Bone mineral density is a complex trait regulated by an interaction between genetic and environmental factors. Recent studies have identified a functional polymorphism affecting codon 677 of the methylenetetrahydrofolate reductase (MTHFR) gene that is associated with reduced bone mineral density (BMD) in Japanese and Danish postmenopausal women and increased risk of fracture in elderly Danish women. Since dietary B vitamins can influence circulating homocysteine (tHcy) levels, we examined the relationship among MTHFR genotype, B complex vitamins (folate, vitamin B12, vitamin B6 and riboflavin), BMD, and rate of change in BMD in a longitudinal study of 1241 Scottish women aged 45-54 years, at the time of initial study, who were followed up for a mean (SD) of 6.6 (0.7) years. There was no significant association between BMD and either MTHFR genotype or B complex vitamins when examined separately. However, we detected a significant interaction among quartile of energy-adjusted riboflavin intake, MTHFR ‘TT’ genotype, and BMD (P = 0.01 for baseline FN BMD, P = 0.02 for follow-up FN BMD). Increasing dietary riboflavin intake correlated with LS BMD and FN BMD in homozygotes for the MTHFR ‘T’ allele, which remained significant for FN after adjustment for confounders (r = 0.192, P = 0.036 for baseline; r = 0.186, P = 0.043 at follow-up) but not in the other genotypes. This raises the possibility that riboflavin intake and MTHFR genotype might interact to regulate BMD. Further work is required to determine if this association holds true for other populations and ethnic groups.

Macdonald HM, McGuigan FE, Fraser WD, New SA…
Bone Oct 2004
PMID: 15454103

TMG No Benefit for Bones in Homocystinuria

Abstract

The effect of oral betaine on vertebral body bone density in pyridoxine-non-responsive homocystinuria.

Five pyridoxine-non-responsive homocystinuric patients aged 5 to 32 years were treated with oral betaine, 3 g b.i.d, in a double-blind, placebo-controlled, two-year crossover study of its effect on bone mineralization. Betaine therapy significantly reduced mean plasma homocystine (36 +/- 9 (SEM) mumol L-1 to 9 +/- 4 mumol L-1), with variable increases in plasma methionine and no adverse effects. Bone density, measured by computerized tomographic scanning of vertebral bodies, was below normal in all patients at the start of the study, and was not significantly altered by betaine therapy administered according to this protocol.

Gahl WA, Bernardini I, Chen S, Kurtz D…
J. Inherit. Metab. Dis. 1988
PMID: 3148071


Why is this interesting? It’s interesting because several studies show an association between homocysteine and osteoporosis. TMG is known to lower homocysteine. Yet, in this study, there was no increase in bone density despite homocysteine being cut 75%.