Monthly Archives: March 2014

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

AKG Prevents Bone Loss in Dexamethasone-Treated Pigs

Abstract

Postnatal administration of 2-oxoglutaric acid improves articular and growth plate cartilages and bone tissue morphology in pigs prenatally treated with dexamethasone.

The potential effects of prenatal administration of dexamethasone (DEX) and postnatal treatment with 2-oxoglutaric acid (2-Ox) on postnatal development of connective tissue of farm animals were not examined experimentally. The aim of this study was to establish changes in morphological parameters of bone and articular and growth plate cartilages damaged by the prenatal action of DEX in piglets supplemented with 2-Ox. The 3 mg of DEX was administered by intramuscular route every second day from day 70 of pregnancy to parturition and then piglets were supplemented with 2-Ox during 35 days of postnatal life (0.4 g/kg body weight). The mechanical properties, BMD and BMC of bones, and histomorphometry of articular and growth plate cartilages were determined. Maternal treatment with DEX decreased the weight by 48%, BMD by 50% and BMC by 61% of the tibia in male piglets while such action of DEX in female piglets was not observed. DEX led to thinning of articular and growth plate cartilages and trabeculae thickness and reduced the serum GH concentration in male piglets. The administration of 2-Ox prevented the reduction of trabeculae thickness, the width of articular and growth plate cartilages in male piglets connected with higher growth hormone concentration compared with non-supplemented male piglets. The result showed that the presence of 2-Ox in the diet had a positive effect on the development of connective tissue in pigs during suckling and induced a complete recovery from bone and cartilage damage caused by prenatal DEX action.

Tomaszewska E, Dobrowolski P, Wydrych J
J. Physiol. Pharmacol. Oct 2012
PMID: 23211309 | Free Full Text

AKG shows Only a Slight Influence on Bone in Rats

Abstract

The effect of dietary administration of 2-oxoglutaric acid on the cartilage and bone of growing rats.

2-Oxoglutaric acid (2-Ox), a precursor to hydroxyproline – the most abundant amino acid in bone collagen, exerts protective effects on bone development during different stages of organism development; however, little is known about the action of 2-Ox on cartilage. The aim of the present study was to elucidate the influence of dietary 2-Ox supplementation on the growth plate, articular cartilage and bone of growing rats. A total of twelve male Sprague-Dawley rats were used in the study. Half of the rats received 2-oxoglutarate at a dose of 0·75 g/kg body weight per d in their drinking-water. Body and organ weights were measured. Histomorphometric analyses of the cartilage and bone tissue of the femora and tibiae were conducted, as well as bone densitometry and peripheral quantitative computed tomography (pQCT). Rats receiving 2-Ox had an increased body mass (P<0·001) and absolute liver weight (P=0·031). Femoral length (P=0·045) and bone mineral density (P=0·014), overall thickness of growth plate (femur P=0·036 and tibia P=0·026) and the thickness of femoral articular cartilage (P<0·001) were also increased. 2-Ox administration had no effect on the mechanical properties or on any of the measured pQCT parameters for both bones analysed. There were also no significant differences in histomorphometric parameters of tibial articular cartilage and autofluorescence of femoral and tibial growth plate cartilage. Dietary supplementation with 2-Ox to growing rats exerts its effects mainly on cartilage tissue, having only a slight influence on bone. The effect of 2-Ox administration was selective, depending on the particular bone and type of cartilage analysed.

Dobrowolski P, Tomaszewska E, Bienko M, Radzki RP…
Br. J. Nutr. Aug 2013
PMID: 23308390

AKG Unimpressive in Omeprazole-Induced Bone Loss in Rats

Abstract

Can 2-oxoglutarate prevent changes in bone evoked by omeprazole?

Proton-pump inhibitors, such as omeprazole, are widely used in the prevention and treatment of gastroesophageal diseases. However, an association between proton-pump inhibitors and the increased risk of bone fractures has been observed, especially in patients treated for extended periods. Conversely, 2-oxoglutarate, a precursor of hydroxyproline, the most abundant amino acid in bone collagen, counteracts the bone loss. The aim of the present study was to elucidate the influence of omeprazole on bone and investigate whether dietary 2-oxoglutarate supplementation could prevent the effects of omeprazole.
Eighteen male Sprague-Dawley rats were used. Rats received omeprazole in the diet and 2-oxoglutarate in the drinking water. Body and organ weights and serum concentrations of cholecystokinin and gastrin were measured. The femurs, tibias, and calvarias were collected. Histomorphometric analysis of bone and cartilage tissues was conducted. Bone densitometric and peripheral quantitative computed tomographic analyses of the femur and tibia were performed.
Omeprazole decreased the femur and tibia weights, the mechanical properties of the femur, the volumetric bone density and content, the trabecular and cortical bone mineral content, the total, trabecular, and cortical bone areas, the mean cortical thickness, and the periosteal circumference of the femur. Omeprazole had a minor effect on the examined bone morphology and exerted negligible effects on the cartilage. 2-Oxoglutarate lowered the gastrin concentration.
Omeprazole treatment exerts its effects mostly on bone mineralization and cancellous bone, adversely affecting bone properties. This adverse effect of omeprazole was not markedly abolished by 2-oxoglutaric acid, which acted as an anti-hypergastrinemic agent.

Dobrowolski P, Tomaszewska E, Radzki RP, Bienko M…
Nutrition Mar 2013
PMID: 23218481

AKG Helps Prevent Induced Osteopenia in Pigs

Abstract

2-Oxoglutaric acid administration diminishes fundectomy-induced osteopenia in pigs.

Partial surgical removal of the stomach (fundectomy, FX) leads to osteopenia in animals and humans. FX adversely affects the bone. 2-oxoglutaric acid is a precursor of glutamine and hydroxyproline–the most abundant amino acid of collagen. The aim of the study was to investigate the effects of 2-oxoglutaric acid on FX-evoked osteopenia in pigs.

Eighteen castrated male pigs of the Puławska breed were used. Twelve pigs were subjected to FX and divided into two groups: FX + AKG (the AKG group; AKG at the daily dosage of 0.4 g/kg of body weight) and FX + Placebo (the FXC group; received CaCO(3) as placebo). Remaining six pigs were sham-operated (the SHO group). The pigs were euthanized at the age of 8 months and long bones were collected. Area bone mineral density (aBMD) and bone mineral content (BMC) were measured; morphology, geometry and biomechanical properties were determined. Moreover, the serum concentrations of selected hormones and one marker of bone metabolism were determined. FX caused osteopenia in the pigs and treatment with AKG greatly reduced these effects of FX in pigs. Negative effect of fundectomy on the skeletal system leading to decreased bone mass in pigs is associated with lowered body gain and activity of the gastric-hypothalamic-pituitary axis. Better definitions of each of the local and systemic hormonal and structural components associated with fundectomy-induced decreased bone mass that separately and together determine the whole bone properties may lead to identify opportunities for prevention.

Śliwa E
J Anim Physiol Anim Nutr (Berl) Oct 2010
PMID: 20487101

PGE2 Increases Bone Strength in Rats

Abstract

Prostaglandin E2 increases bone strength in intact rats and in ovariectomized rats with established osteopenia.

It is well documented that prostaglandin E2 (PGE2) has the ability to stimulate bone formation, improve bone structure, and increase bone mass in intact or osteopenic rat models. However, the effects of PGE2 on the mechanical properties of bone have not been investigated previously.The purpose of our study was to determine the effects of PGE2 on the mechanical strength of bones in rapidly growing, adult, and ovariectomized rat models. In study I, PGE2 at 3 mg/kg per day, or vehicle, was given by daily subcutaneous injections for 30 days to rapidly growing (3-month-old) intact male rats. Compared with controls, PGE2 significantly increased initial maximal load and stiffness of cancellous bone at the distal femoral metaphysis (DFM) as determined by an indentation test. As determined by a compression test, rats treated with PGE2 showed a significant increase in maximal load, and a nonsignificant increase in stiffness in the fifth lumbar vertebral body (L5) when compared with controls. In study II, PGE2 at 3 mg/kg per day, or vehicle, was given by daily subcutaneous injection for 30 days to mature (10-month-old) intact male rats. PGE2 treatment significantly increased initial maximal load and stiffness of the DFM and L5. PGE2 induced a significant increase in maximal load, but not stiffness, in the femoral neck (FN), as determined by a cantilever compression test. There was an increase in maximal load in a three-point bending test at the femoral shaft (FS) although the increase did not achieve statistical significance. No change in stiffness in the FS was found after PGE2 treatment. In study III, 3-month-old female rats were sham-operated or ovariectomized (ovx) for 30 days. Thereafter, PGE, at 1 or 3 mg/kg, or vehicle, were given by daily subcutaneous injection to these rats for 30 days. After 30 and 60 days, ovx induced a significant decrease in initial maximal load and stiffness of cancellous bone at the DFM as compared with sham controls. In ovx rats with established osteopenia, PGE2 at 1 mg/kg per day nonsignificantly increased the initial maximal load and stiffness, whereas, at 3 mg/kg per day, PGE2 completely restored the initial maximal load and stiffness of DFM to sham control levels. Similarly, maximal load and stiffness of L5 decreased significantly in ovx rats compared with sham controls at 30 days postsurgery. PGE2 at 1 mg/kg per day partially restored the maximal load, whereas, at 3 mg/kg per day, it completely restored the maximal load and stiffness of L5 in the established osteopenia, ovx rats. At the FS, PGE2 at 3 mg/kg per day nonsignificantly increased maximal load (+11%) and significantly increased stiffness (+25%) compared with ovx controls. Neither ovx nor PGE2 treatment caused a significant change in the maximal load and stiffness of the FN in this study. These results reveal that PGE2 significantly increased the mechanical strength at various skeletal sites in rapidly growing and mature male rats, although the increase in femoral shafts was not statistically different. Furthermore, PGE2 completely restored mechanical strength to the cancellous bone in ovx rats with established osteopenia.

Ke HZ, Shen VW, Qi H, Crawford DT…
Bone Sep 1998
PMID: 9737347

Low LDL Associated with Osteoporosis in Type 2 Diabetics

Abstract

Association of lower serum cholesterol levels with higher risk of osteoporosis in type 2 diabetes.

To determine whether a correlation exists between bone mineral density and circulating lipoprotein levels and whether these variables are independently associated with osteoporosis in patients with type 2 diabetes.
In a cross-sectional analysis, 159 patients with type 2 diabetes were compared with 70 patients without diabetes selected from an outpatient endocrinology clinic in a tertiary care institute during a 1-year period. Variables were gathered through history, physical examination, and laboratory findings, including blood chemistry studies and dual-energy x-ray absorptiometry.
Of the 229 study patients, 86 (37.6%) had osteoporosis. In the patients with diabetes, the mean +/- SD of age, weight, total cholesterol, and low-density lipoprotein (LDL) cholesterol in those with and without osteoporosis was 72.3 +/- 10.4 years versus 63.6 +/- 11.0 years, 74.2 +/- 14.4 kg versus 83.7 +/- 15.5 kg, 178.4 +/- 33.7 mg/dL versus 194.1 +/- 33.9 mg/dL, and 100.0 +/- 27.1 mg/dL versus 114.2 +/- 30.2 mg/dL, respectively (P<0.01 for all variables). After adjustment for other variables, multiple logistic regression analysis showed that the presence of diabetes was associated with a lower risk of osteoporosis. Similarly, older age and lower body weight, LDL levels, and serum calcium levels were independently associated with lumbar spine osteoporosis in patients with diabetes, in comparison with older age and lower weight in patients without diabetes. Lower weight and older age were associated with femoral neck and total hip osteoporosis in patients with diabetes, in comparison with only older age in patients without diabetes.
The presence of type 2 diabetes is associated with a lower risk of osteoporosis. In patients with type 2 diabetes, a lower LDL level is more likely to be associated with osteoporosis at the lumbar spine.

Afshinnia F, Chacko S, Zahedi T
Endocr Pract Oct 2007
PMID: 17954418