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      Hyperhomocysteinemia decreases bone blood flow

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          Abstract

          Elevated plasma levels of homocysteine (Hcy), known as hyperhomocysteinemia (HHcy), are associated with osteoporosis. A decrease in bone blood flow is a potential cause of compromised bone mechanical properties. Therefore, we hypothesized that HHcy decreases bone blood flow and biomechanical properties. To test this hypothesis, male Sprague–Dawley rats were treated with Hcy (0.67 g/L) in drinking water for 8 weeks. Age-matched rats served as controls. At the end of the treatment period, the rats were anesthetized. Blood samples were collected from experimental or control rats. Biochemical turnover markers (body weight, Hcy, vitamin B12, and folate) were measured. Systolic blood pressure was measured from the right carotid artery. Tibia blood flow was measured by laser Doppler flow probe. The results indicated that Hcy levels were significantly higher in the Hcy-treated group than in control rats, whereas vitamin B12 levels were lower in the Hcy-treated group compared with control rats. There was no significant difference in folate concentration and blood pressure in Hcy-treated versus control rats. The tibial blood flow index of the control group was significantly higher (0.78 ± 0.09 flow unit) compared with the Hcy-treated group (0.51 ± 0.09). The tibial mass was 1.1 ± 0.1 g in the control group and 0.9 ± 0.1 in the Hcy-treated group. The tibia bone density was unchanged in Hcy-treated rats. These results suggest that Hcy causes a reduction in bone blood flow, which contributes to compromised bone biomechanical properties.

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          Most cited references18

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          Vitamin D3 and calcium to prevent hip fractures in the elderly women.

          Hypovitaminosis D and a low calcium intake contribute to increased parathyroid function in elderly persons. Calcium and vitamin D supplements reduce this secondary hyperparathyroidism, but whether such supplements reduce the risk of hip fractures among elderly people is not known. We studied the effects of supplementation with vitamin D3 (cholecalciferol) and calcium on the frequency of hip fractures and other nonvertebral fractures, identified radiologically, in 3270 healthy ambulatory women (mean [+/- SD] age, 84 +/- 6 years). Each day for 18 months, 1634 women received tricalcium phosphate (containing 1.2 g of elemental calcium) and 20 micrograms (800 IU) of vitamin D3, and 1636 women received a double placebo. We measured serial serum parathyroid hormone and 25-hydroxyvitamin D (25(OH)D) concentrations in 142 women and determined the femoral bone mineral density at base line and after 18 months in 56 women. Among the women who completed the 18-month study, the number of hip fractures was 43 percent lower (P = 0.043) and the total number of nonvertebral fractures was 32 percent lower (P = 0.015) among the women treated with vitamin D3 and calcium than among those who received placebo. The results of analyses according to active treatment and according to intention to treat were similar. In the vitamin D3-calcium group, the mean serum parathyroid hormone concentration had decreased by 44 percent from the base-line value at 18 months (P < 0.001) and the serum 25(OH)D concentration had increased by 162 percent over the base-line value (P < 0.001). The bone density of the proximal femur increased 2.7 percent in the vitamin D3-calcium group and decreased 4.6 percent in the placebo group (P < 0.001). Supplementation with vitamin D3 and calcium reduces the risk of hip fractures and other nonvertebral fractures among elderly women.
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            Homocysteine metabolism.

            J Selhub (1999)
            Homocysteine is a sulfur amino acid whose metabolism stands at the intersection of two pathways: remethylation to methionine, which requires folate and vitamin B12 (or betaine in an alternative reaction); and transsulfuration to cystathionine, which requires pyridoxal-5'-phosphate. The two pathways are coordinated by S-adenosylmethionine, which acts as an allosteric inhibitor of the methylenetetrahydrofolate reductase reaction and as an activator of cystathionine beta-synthase. Hyperhomocysteinemia, a condition that recent epidemiological studies have shown to be associated with increased risk of vascular disease, arises from disrupted homocysteine metabolism. Severe hyperhomocysteinemia is due to rare genetic defects resulting in deficiencies in cystathionine beta synthase, methylenetetrahydrofolate reductase, or in enzymes involved in methyl-B12 synthesis and homocysteine methylation. Mild hyperhomocysteinemia seen in fasting conditions is due to mild impairment in the methylation pathway (i.e. folate or B12 deficiencies or methylenetetrahydrofolate reductase thermolability). Post-methionine-load hyperhomocysteinemia may be due to heterozygous cystathionine beta-synthase defect or B6 deficiency. Early studies with nonphysiological high homocysteine levels showed a variety of deleterious effects on endothelial or smooth muscle cells in culture. More recent studies with human beings and animals with mild hyperhomocysteinemia provided encouraging results in the attempt to understand the mechanism that underlies this relationship between mild elevations of plasma homocysteine and vascular disease. The studies with animal models indicated the possibility that the effect of elevated homocysteine is multifactorial, affecting both the vascular wall structure and the blood coagulation system.
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              Homocysteine as a predictive factor for hip fracture in older persons.

              The increased prevalence of osteoporosis among people with homocystinuria suggests that a high serum homocysteine concentration may weaken bone by interfering with collagen cross-linking, thereby increasing the risk of osteoporotic fracture. We examined the association between the total homocysteine concentration and the risk of hip fracture in men and women enrolled in the Framingham Study. We studied 825 men and 1174 women, ranging in age from 59 to 91 years, from whom blood samples had been obtained between 1979 and 1982 to measure plasma total homocysteine. The participants in our study were followed from the time that the sample was obtained through June 1998 for incident hip fracture. Sex-specific, age-adjusted incidence rates of hip fracture were calculated for quartiles of total homocysteine concentrations. Cox proportional-hazards regression was used to calculate hazard ratios for quartiles of homocysteine values. The mean (+/-SD) plasma total homocysteine concentration was 13.4+/-9.1 micromol per liter in men and 12.1+/-5.3 micromol per liter in women. The median duration of follow-up was 12.3 years for men and 15.0 years for women. There were 41 hip fractures among men and 146 among women. The age-adjusted incidence rates per 1000 person-years for hip fracture, from the lowest to the highest quartile for total homocysteine, were 1.96 (95 percent confidence interval, 0.52 to 3.41), 3.24 (0.97 to 5.52), 4.43 (1.80 to 7.07), and 8.14 (4.20 to 12.08) for men and 9.42 (5.72 to 13.12), 7.01 (4.29 to 9.72), 9.58 (6.42 to 12.74), and 16.57 (11.84 to 21.30) for women. Men and women in the highest quartile had a greater risk of hip fracture than those in the lowest quartile--the risk was almost four times as high for men and 1.9 times as high for women. These findings suggest that the homocysteine concentration, which is easily modifiable by means of dietary intervention, is an important risk factor for hip fracture in older persons. Copyright 2004 Massachusetts Medical Society
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                Author and article information

                Journal
                Vasc Health Risk Manag
                Vascular Health and Risk Management
                Vascular Health and Risk Management
                Dove Medical Press
                1176-6344
                1178-2048
                2011
                2011
                25 January 2011
                : 7
                : 31-35
                Affiliations
                Department of Physiology and Biophysics, School of Medicine, University of Louisville, Louisville, KY, USA
                Author notes
                Correspondence: Neetu Tyagi, Department of Physiology and Biophysics, School of Medicine, University of Louisville, Louisville, KY 40202, USA, Tel +1 502 852 4425, Fax +1 502 852 6239, Email n0tyag01@ 123456louisville.edu
                [*]

                These authors have equal authorship

                Article
                vhrm-7-031
                10.2147/VHRM.S15844
                3037087
                21339911
                9d0d8bef-a175-4428-a2c9-824a1f809e21
                © 2011 Tyagi et al, publisher and licensee Dove Medical Press Ltd.

                This is an Open Access article which permits unrestricted noncommercial use, provided the original work is properly cited.

                History
                Categories
                Original Research

                Cardiovascular Medicine
                bone density,homocysteine,tibia
                Cardiovascular Medicine
                bone density, homocysteine, tibia

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