Category Archives: Homocysteine

Bone Density and Arterial Stiffness Again


Low bone mineral density is associated with increased arterial stiffness in participants of a health records based study.

Many epidemiological studies have shown that low bone mineral density (BMD) and atherosclerosis appear to be related. However, their precise correlation is not completely understood after full adjustment the shared confounders of atherosclerosis and bone metabolism. The aim of this cross-sectional study was to investigate the relationship between BMD and subclinical atherosclerosis in a healthy Chinese population and the difference in gender.
The study population consisted of 2,487 subjects (1,467 men, 1,020 women) who participated in health check-up programs and were selected to be free of major diseases which might affect atherosclerosis and bone metabolism. Bone status was assessed by BMD in lumbar spine. The brachial-ankle PWV (baPWV) was assessed as a functional marker of atherosclerosis. The ankle-brachial index (ABI), carotid artery intima-media thickness (CIMT), estimated glomerular filtration rate (eGRF) and microalbuminuria were evaluated as indexes of structural markers of atherosclerosis.
After adjustment for risk factors, significant association was shown between baPWV and BMD in both genders (male: r=-0.084, P=0.035; female: r=-0.088, P=0.014). The correlation was stronger in females than in males, and in females, the correlation was stronger after menopause. Similarly, mean baPWV differed significantly according to the decreased BMD (normal BMD, Osteopenia, Osteoporosis). In contrast, no significant differences were observed for ABI, CIMT, eGFR or microalbuminuria with BMD.
Independent of confounding factors, low BMD is associated with the functional marker of subclinical atherosclerosis (increased baPWV), but not with structural markers (ABI, CIMT, eGFR or microalbuminuria) among healthy females and males.

Wang YQ, Yang PT, Yuan H, Cao X…
J Thorac Dis May 2015
PMID: 26101634 | Free Full Text

From the full text discussion:

There are several potential mechanisms to explain this link. Both osteoporosis and atherosclerosis share similar or common risk factors. Bone-associated matrix proteins, homocysteine, high levels of OPG, inflammatory mediators, estrogen and vitamin D deficiency all play an important role both in bone metabolism and in the development of atherosclerosis (32).

Homocysteine Correlates with Dizziness and Poor Posture


Biological determinants of postural disorders in elderly women.

Postural control impairments and dizziness, which are major health problems with high secondary morbidity and mortality, increase with aging. Elevated homocysteine (Hcy) level is an age-related metabolic disorder, known to be involved in cardiovascular, neurological, and multisensory dysfunctions. Elevated Hcy level might be involved in sensory balance control systems impairment and dizziness occurrence. Dizziness, fitness Instrumental Activity of Daily Living scale (fitness IADL), systolic arterial pressure with ankle-brachial blood pressure index and homocysteinemia were studied in 61 noninstitutionized elderly women. Clinical balance tests (timed “Up and Go”, 10-m walking and one-leg balance) and posturography (including sensory conflicting situations [SCS] and cognitive conflicting situations [CCS]) were performed. Clinical balance control was lower in dizzy women who presented particularly poor stability in SCS. Dizziness was related to low fitness IADL scores (odds ratio [OR] 0.452, 95% CI 0.216-0.946) and to elevated Hcy (OR 8.084, 95% CI 1.992-32.810). Elevated Hcy was correlated with balance disorders both in SCS and CCS. Dizziness is associated with a reduced ability in balance control management. Hcy is related both to dizziness and low postural performance. This relation between elevated Hcy levels and balance impairments, resulting in dizziness, may be explained by its angiotoxicity and neurotoxicity.

Lion A, Spada RS, Bosser G, Gauchard GC…
Int. J. Neurosci. Jan 2013
PMID: 22909193

Vitamins D + B Improve Bone Markers in Elderly


One year B and D vitamins supplementation improves metabolic bone markers.

Vitamin D and vitamin B deficiency are common in elderly subjects and are important risk factors for osteoporosis and age-related diseases. Supplementation with these vitamins is a promising preventative strategy. The objective of this study was to evaluate the effects of vitamins D3 and B supplementation on bone turnover and metabolism in elderly people.
Healthy subjects (n=93; >54 years) were randomly assigned to receive either daily vitamin D3 (1200 IU), folic acid (0.5 mg), vitamin B12 (0.5 mg), vitamin B6 (50 mg), and calcium carbonate (456 mg) (group A) or only vitamin D3 plus calcium carbonate (group B) in a double blind trial. We measured at baseline and after 6 and 12 months of supplementation vitamins, metabolites, and bone turnover markers.
At baseline mean plasma 25-hydroxy vitamin D [25(OH)D] was low (40 or 30 nmol/L) and parathormone was high (63.7 or 77.9 pg/mL). 25(OH)D and parathormone correlated inversely. S-Adenosyl homocysteine and S-adenosyl methionine correlated with bone alkaline phosphatase, sclerostin, and parathormone. One year vitamin D3 or D3 and B supplementation increased plasma 25(OH)D by median 87.6% (group A) and 133.3% (group B). Parathormone was lowered by median 28.3% (A) and 41.2% (B), bone alkaline phosphatase decreased by 2.8% (A) and 16.2% (B), osteocalin by 37.5% (A) and 49.4% (B), and tartrate-resistant-acid-phosphatase 5b by 6.1% (A) and 36.0% (B). Median total homocysteine (tHcy) was high at baseline (group A: 12.6, group B: 12.3 µmol/L) and decreased by B vitamins (group A) to 8.9 µmol/L (29.4%). tHcy lowering had no additional effect on bone turnover.
One year vitamin D3 supplementation with or without B vitamins decreased the bone turnover significantly. Vitamin D3 lowered parathormone. The additional application of B vitamins did not further improve bone turnover. The marked tHcy lowering by B vitamins may modulate the osteoporotic risk.

Herrmann W, Kirsch SH, Kruse V, Eckert R…
Clin. Chem. Lab. Med. Mar 2013
PMID: 23183751

Review: Homocysteine in Bone Remodeling


The role of homocysteine in bone remodeling.

Bone remodeling is a very complex process. Homocysteine (Hcy) is known to modulate this process via several known mechanisms such as increase in osteoclast activity, decrease in osteoblast activity and direct action of Hcy on bone matrix. Evidence from previous studies further support a detrimental effect on bone via decrease in bone blood flow and an increase in matrix metalloproteinases (MMPs) that degrade extracellular bone matrix. Hcy binds directly to extracellular matrix and reduces bone strength. There are several bone markers that can be used as parameters to determine how high levels of plasma Hcy (hyperhomocysteinemia, HHcy) affect bone such as: hydroxyproline, N-terminal collagen 1 telopeptides. Mitochondrion serves an important role in generating reactive oxygen species (ROS). Mitochondrial abnormalities have been identified during HHcy. The mechanism of Hcy-induced bone remodeling via the mitochondrial pathway is largely unknown. Therefore, we propose a mitochondrial mechanism by which Hcy can contribute to alter bone properties. This may occur both through generations of ROS that activate MMPs and could be extruded into matrix to degrade bone matrix. However, there are contrasting reports on whether Hcy affects bone density, with some reports in favour and others not. Earlier studies also found an alteration in bone biomechanical properties with deficiencies of vitamin B12, folate and HHcy conditions. Moreover, existing data opens speculation that folate and vitamin therapy act not only via Hcy-dependent pathways but also via Hcy-independent pathways. However, more studies are needed to clarify the mechanistic role of Hcy during bone diseases.

Vacek TP, Kalani A, Voor MJ, Tyagi SC…
Clin. Chem. Lab. Med. Mar 2013
PMID: 23449525

Homocysteine Decreases Bone Quality and is Antagonized by NAC


Homocysteine alters the osteoprotegerin/RANKL system in the osteoblast to promote bone loss: pivotal role of the redox regulator forkhead O1.

In this study we determined the molecular mechanisms of how homocysteine differentially affects receptor activator of nuclear factor-κB ligand (RANKL) and osteoprotegerin (OPG) synthesis in the bone. The results showed that oxidative stress induced by homocysteine deranges insulin-sensitive FOXO1 and MAP kinase signaling cascades to decrease OPG and increase RANKL synthesis in osteoblast cultures. We observed that downregulation of insulin/FOXO1 and p38 MAP kinase signaling mechanisms due to phosphorylation of protein phosphatase 2A (PP2A) was the key event that inhibited OPG synthesis in homocysteine-treated osteoblast cultures. siRNA knockdown experiments confirmed that FOXO1 is integral to OPG and p38 synthesis. Conversely homocysteine increased RANKL synthesis in osteoblasts through c-Jun/JNK MAP kinase signaling mechanisms independent of FOXO1. In the rat bone milieu, high-methionine diet-induced hyperhomocysteinemia lowered FOXO1 and OPG expression and increased synthesis of proresorptive and inflammatory cytokines such as RANKL, M-CSF, IL-1α, IL-1β, G-CSF, GM-CSF, MIP-1α, IFN-γ, IL-17, and TNF-α. Such pathophysiological conditions were exacerbated by ovariectomy. Lowering the serum homocysteine level by a simultaneous supplementation with N-acetylcysteine improved OPG and FOXO1 expression and partially antagonized RANKL and proresorptive cytokine synthesis in the bone milieu. These results emphasize that hyperhomocysteinemia alters the redox regulatory mechanism in the osteoblast by activating PP2A and deranging FOXO1 and MAPK signaling cascades, eventually shifting the OPG:RANKL ratio toward increased osteoclast activity and decreased bone quality.

Vijayan V, Khandelwal M, Manglani K, Singh RR…
Free Radic. Biol. Med. Mar 2013
PMID: 23500899

Folic Acid and B12 Lowers Homocysteine but not Bone Turnover


Folic acid and vitamin B(12) supplementation lowers plasma homocysteine but has no effect on serum bone turnover markers in elderly women: a randomized, double-blind, placebo-controlled trial.

An elevated homocysteine level is a newly recognized risk factor for osteoporosis. Older individuals may have elevated homocysteine levels due to inadequate folate intake and/or lower absorption of vitamin B(12). The aim of this study was to determine whether there is an impact of folic acid and vitamin B(12) supplementation on homocysteine levels and, subsequently, on bone turnover markers in older women with mildly to moderately elevated homocysteine levels. It is hypothesized that supplementation with folic acid and vitamin B(12) will improve homocysteine levels and, in turn, positively modify bone turnover markers in this population. This randomized, double-blind, placebo-controlled trial included 31 women (65 to 93 years) with homocysteine levels greater than 10 μmol/L. Participants were randomly assigned to receive either a daily folic acid (800 μg) and vitamin B(12) (1000 μg) (n = 17) or a matching placebo (n = 14) for 4 months. The results showed significantly lower homocysteine concentrations in the vitamin group compared to the placebo group (10.6 vs 18.5 μmol/L, P = .007). No significant difference in serum alkaline phosphatase or C-terminal cross-linking telopeptide of type I collagen was found between the vitamin and placebo groups before or after supplementation. The use of folic acid and vitamin B(12) as a dietary supplement to improve homocysteine levels could be beneficial for older women, but additional research must be conducted in a larger population and for a longer period to determine if there is an impact of supplementation on bone turnover markers or other indicators of bone health.

Keser I, Ilich JZ, Vrkić N, Giljević Z…
Nutr Res Mar 2013
PMID: 23507227

B12 Decreases Fracture Risk


Vitamin B12, folate, homocysteine, and bone health in adults and elderly people: a systematic review with meta-analyses.

Elevated homocysteine levels and low vitamin B12 and folate levels have been associated with deteriorated bone health. This systematic literature review with dose-response meta-analyses summarizes the available scientific evidence on associations of vitamin B12, folate, and homocysteine status with fractures and bone mineral density (BMD). Twenty-seven eligible cross-sectional (n = 14) and prospective (n = 13) observational studies and one RCT were identified. Meta-analysis on four prospective studies including 7475 people showed a modest decrease in fracture risk of 4% per 50 pmol/L increase in vitamin B12 levels, which was borderline significant (RR = 0.96, 95% CI = 0.92 to 1.00). Meta-analysis of eight studies including 11511 people showed an increased fracture risk of 4% per μ mol/L increase in homocysteine concentration (RR = 1.04, 95% CI = 1.02 to 1.07). We could not draw a conclusion regarding folate levels and fracture risk, as too few studies investigated this association. Meta-analyses regarding vitamin B12, folate and homocysteine levels, and BMD were possible in female populations only and showed no associations. Results from studies regarding BMD that could not be included in the meta-analyses were not univocal.

van Wijngaarden JP, Doets EL, Szczecińska A, Souverein OW…
J Nutr Metab 2013
PMID: 23509616 | Free Full Text

Folate Prevents Bone Loss in Cyclosporine-Treated Rats


Protective effect of folic acid on cyclosporine-induced bone loss in rats.

Hyperhomocysteinemia is seen in patients with decreased bone mineral density. Cyclosporine can cause alveolar bone loss and osteopenia. It is also associated with elevated serum homocysteine levels. We aimed to investigate the effect of cyclosporine on serum homocysteine level, bone volume, and bone density, and determine whether folic acid had a protective effect against bone loss. In an experimental study, 40 male Sprague-Dawley rats were randomly assigned to five groups and received dietary supplementation for 6 weeks with olive oil (Group A), cyclosporine (Group B), folic acid (Group C), and cyclosporine plus folic acid (Group D), or no supplementation (Group F, control). Serum homocysteine, calcium, alkaline phosphatase, total bone volume, periodontal ligament volume, and volume density of bone were compared between groups. Mean serum homocysteine level (10.84 ± 0.93 μmol/l) was significantly higher in group B (cyclosporine supplementation) compared with the other groups (P = 0.001). Mean total mandibular volume was 46.3 ± 13.6 mm(3) in rats treated with cyclosporine, 80.4 ± 15.70 mm(3) in rats treated with folic acid (P = 0.004), and 73.9 ± 21.3 mm(3) in rats treated with cyclosporine plus folic acid (P = 0.028). In our experimental model, cyclosporine increased serum homocysteine levels and decreased bone volume and density. Folic acid may have a preventive role against bone loss in rats treated with cyclosporine.

Mohammadi A, Omrani L, Omrani LR, Kiani F…
Transpl. Int. Jan 2012
PMID: 22039919

Low B Vitamins May be Risk for Bone Loss


Plasma B vitamins, homocysteine, and their relation with bone loss and hip fracture in elderly men and women.

Elevated homocysteine is a strong risk factor for osteoporotic fractures among elders, yet it may be a marker for low B-vitamin status.
Our objective was to examine the associations of plasma concentrations of folate, vitamin B12, vitamin B6, and homocysteine with bone loss and hip fracture risk in elderly men and women. This was a longitudinal follow-up study of the Framingham Osteoporosis Study.
Community dwelling residents of Framingham, MA, were included in the study.
A total of 1002 men and women (mean age 75 yr) was included in the study.
Baseline (1987-1989) blood samples were used to categorize participants into plasma B-vitamin (normal, low, deficient) and homocysteine (normal, high) groups. Femoral neck bone mineral density (BMD) measured at baseline and 4-yr follow-up was used to calculate annual percent BMD change. Incident hip fracture was assessed from baseline through 2003.
Multivariable-adjusted mean bone loss was inversely associated with vitamin B6 (P for trend 0.01). Vitamins B12 and B6 were inversely associated with hip fracture risk (all P for trend < 0.05), yet associations were somewhat attenuated and not significant after controlling for baseline BMD, serum vitamin D, and homocysteine. Participants with high homocysteine (>14 micromol/liter) had approximately 70% higher hip fracture risk after adjusting for folate and vitamin B6, but this association was attenuated after controlling for vitamin B12 (hazard ratio = 1.49; 95% confidence interval 0.91, 2.46).
Low B-vitamin concentration may be a risk factor for decreased bone health, yet does not fully explain the relation between elevated homocysteine and hip fracture. Thus, homocysteine is not merely a marker for low B-vitamin status.

McLean RR, Jacques PF, Selhub J, Fredman L…
J. Clin. Endocrinol. Metab. Jun 2008
PMID: 18364381 | Free Full Text

B6 and Riboflavin Associated with Increased Bone Density


Effect of dietary B vitamins on BMD and risk of fracture in elderly men and women: the Rotterdam study.

A mildly elevated homocysteine (Hcy) level is a novel and potentially modifiable risk factor for age-related osteoporotic fractures. Elevated Hcy levels can have a nutritional cause, such as inadequate intake of folate, riboflavin, pyridoxine or cobalamin, which serve as cofactors or substrates for the enzymes involved in the Hcy metabolism. We examined the association between intake of Hcy-related B vitamin (riboflavin, pyridoxine, folate and cobalamin) and femoral neck bone mineral density BMD (FN-BMD) and the risk of fracture in a large population-based cohort of elderly Caucasians. We studied 5304 individuals aged 55 years and over from the Rotterdam Study. Dietary intake of nutrients was obtained from food frequency questionnaires. Incident non-vertebral fractures were recorded during a mean follow-up period of 7.4 years, and vertebral fractures were assessed by X-rays during a mean follow-up period of 6.4 years. We observed a small but significant positive association between dietary pyridoxine (beta = 0.09, p = 1 x 10(-8)) and riboflavin intake (beta = 0.06, p = 0.002) and baseline FN-BMD. In addition, after controlling for gender, age and BMI, pyridoxine intake was inversely correlated to fracture risk. As compared to the three lowest quartiles, individuals in the highest quartile of age- and energy-adjusted dietary pyridoxine intake had a decreased risk of non-vertebral fractures (HR = 0.77, 95% CI = 0.65-0.92, p = 0.005) and of fragility fractures (HR = 0.55, 95% CI = 0.40-0.77, p = 0.0004). Further adjustments for other dietary B vitamins (riboflavin, folate and cobalamin), dietary intake of calcium, vitamin D, vitamin A and vitamin K, protein and energy intake, smoking and BMD did not essentially modify these results. We conclude that increased dietary riboflavin and pyridoxine intake was associated with higher FN-BMD. Furthermore, we found a reduction in risk of fracture in relation to dietary pyridoxine intake independent of BMD. These findings highlight the importance of considering nutritional factors in epidemiological studies of osteoporosis and fractures.

Yazdanpanah N, Zillikens MC, Rivadeneira F, de Jong R…
Bone Dec 2007
PMID: 17936100