Archive for the 'Osteoporosis' Category

Jun 16 2008

Homocysteine and Osteoporosis

Published by under Osteoporosis

Homocysteine
Its Destructive Role in Cardiovascular, Cognitive and Bone Health
By Jason E. Barker, ND

Homocysteine is one of the most destructive compounds found in the human body. Although oxidized LDL cholesterol (the “bad” cholesterol) is commonly considered the arteries’ worst enemy, homocysteine has emerged as an equally powerful threat to heart health. In fact, research now shows that damage from homocysteine paves the way for LDL to have an even more destructive effect on the vascular system, indicating these two agents can work together to cause heart disease. Furthermore, as time goes on, more and more research is uncovering homocysteine’s role in other health conditions such as infertility, depression, cognitive decline and bone fractures.

Homocysteine is considered a primary risk factor for cardiovascular disease including stroke and deep vein thrombosis.1 Elevated blood levels of homocysteine also are considered an independent risk factor for atherosclerosis and thromboembolism (the obstruction of a blood vessel by a clot), and are correlated with a significant risk for coronary, cerebral and peripheral vascular disease, myocardial infarction (heart attacks), peripheral vascular occlusive disease, cerebral vascular occlusive disease, and retinal vascular disease.2 In fact, high homocysteine, even in the absence of other risks, such as smoking and obesity, is a serious but controllable risk factor for heart disease.

Homocysteine is an amino acid commonly found in the blood as a result of protein metabolism. It is mainly derived from another amino acid known as methionine, which is found in a number of food sources primary among them being meat. Blood levels of homocysteine can also be affected by genetic and physiologic factors.

Homocysteine is thought to cause vascular disease because of its effect on blood vessel walls. Homocysteine binds to certain proteins in the body affecting their structure and function. The binding of homocysteine to proteins will degrade and inhibit repair and maintenance of three main vascular connective tissue structures—cartilage, elastin and proteolgycans—making them more susceptible to disease processes, including vascular disease. Homocysteine can damage the cells lining the artery walls (known as the endothelium) in the vascular system. Homocysteine causes a reduction in nitric oxide activity, impairing blood vessels’ ability to dilate and leaving the endothelium more susceptible to oxidative damage.3 Damaged vascular walls will then allow more low density lipoprotein (LDL) to be absorbed, further harming the vessel. This damage then promotes the growth of new smooth muscle cells within the vessel, which then narrows it. Endothelial damage also allows for increased platelet adhesiveness and activation of the clotting cascade, increasing the risk of cardiac arrest (heart attack) or cerebrovascular accident (stroke).

homocysteine Homocysteine and OsteoporosisIn the Western world, homocysteine serum levels are most commonly found at 10-12 μmol/L. A level above 12 is generally considered elevated while levels below 6 are considered minimal. An increase of homocysteine levels by 5 μmol/L has been shown to increase the risk of cerebrovascular disease in the general population by 50 percent, and will increase the risk of coronary artery disease by 80 percent in women and 60 percent in men. In general, women have 10-15 percent less homocysteine than men during their reproductive years, which is thought in part to be the reason why women have fewer heart attacks than men, and why they tend to have them 10-15 years later than the time men commonly do.4

Genetic Causes of High Homocysteine

Dietary factors, while often cited as the chief cause for elevated homocysteine, are not the only factor. A rare hereditary disease known as homocystinuria results in several systemic disorders and is charachterized by the accumulation of homocysteine in the blood and an increased rate of excretion in the urine. Nearly 25 percent of people with this disorder die from cardiovascular complications before the age of thirty.

Ten percent of the population in general have another more common yet related condition where they are unable to effectively metabolize homocysteine and will be predisposed to the negative effects of elevated homocysteine levels, including blood clots and cardiovascular disease. This disorder is known as a methylenetetrahydrofolate-reductase (MTHFR) polymorphism genetic trait. People that have this condition are unable to effectively metabolize homocysteine and will be predisposed to the negative effects of elevated homocysteine levels, including blood clots and cardiovascular disease.

Homocysteine’s Widespread Role

Elevated homocysteine, also known as hyperhomocysteinemia, may contribute to many other conditions.

Infertility

Women who have high levels of homocysteine have been shown to have a more difficult time getting pregnant and are two times as likely to have complications during pregnancy. Furthermore, women with high homocysteine levels are at risk of having miscarriages early in pregnancy.5-6 Researchers are not sure what role homocysteine has in infertility, but it has been theorized that high homocysteine contributes to subfertility, or difficulty achieving a pregnancy.

Mental Health

Elevated levels of homocysteine are also a risk factor for diseases affecting the brain. Epidemiologic studies show a dose-dependent relationship between homocysteine levels and risk for neurodegenerative diseases such as stroke, Parkinson’s disease, multiple sclerosis, and depression.7 Researchers continue to collect evidence that correlates several cardiovascular disease risk factors, homocysteine being one, with the incidence of cognitive decline and Alzheimer’s disease.8 High homocysteine by itself is considered a strong independent risk factor for dementia and Alzheimer’s disease. A study looking at data collected from the Framingham Study showed that a homocysteine level over 14 μmol/L increased the risk of developing Alzheimer’s disease by 150 percent.9

Bone Fractures

Homocysteine is considered an independent risk factor for osteoporosis fractures in the elderly.10 It is thought that homocysteine leads to fractures in the same way in which it contributes to heart disease in that homocysteine affects certain connective tissue proteins and prevents them from functioning correctly. In the case of fractures, homocysteine interferes with the cross-linking ability of collagen (a major connective tissue protein) with the tissues it supports such as the skeletal system. Because homocysteine affects the structural proteins of which bone is comprised, it does not actually affect bone density. Therefore, traditional measures used to build bones (weight bearing exercise, adequate calcium and vitamin D, etc.) will not necessarily correct the damage from homocysteine on the bones.

Controlling Elevated Homocysteine

homocysteine Homocysteine and OsteoporosisCurrently, there is no standard recommendation that all people have their homocysteine levels checked. Despite this, the American Heart Association does encourage testing for homocysteine in people with a personal or family history of heart disease. In order to address all possible aspects of heart disease (and other conditions), testing homocysteine levels is a good idea.

Controlling homocysteine can be achieved by supplementing with 4 common nutrients: vitamins B6, B12, folic acid and betaine. Vitamins B6, B12, and folic acid blood levels are found to be inversely related to plasma homocysteine concentration. Combination therapy with the aforementioned vitamins provides an effective way to reduce homocysteine levels,11 and side effects of this therapy are relatively unknown.12 Another supplement that has demonstrated usefulness in lowering homocysteine levels is betaine, also known as trimethylglycine.

High dietary consumption of methionine, which can be found in meats and dairy products, can result in the overproduction of homocysteine. Once homocysteine is produced it is metabolized in the body through one of two possible pathways—remethylation or transsulfuration. Remethylation is a process that utilizes folate, vitamin B12 or betaine (trimethylglycine) to convert homocysteine back to methionine. Alternately, transsulfuration utilizes vitamin B6 (pyridoxal-5-phosphate) to break down excess homocysteine into a number of metabolites for eventual excretion from the body.13,3 B6 has been shown to be effective in reducing homocysteine levels following the ingestion of significant amounts of methionine.14

Vitamin B12 in the form of methylcobalamin is needed for the conversion (remethylation) of homocysteine back to methionine.15 This remethylation reaction also requires folic acid. B12 is thought to provide an additive effect to the lowering of homocysteine when supplied in conjunction with folic acid.16

Folic acid is needed for the metabolism of homocysteine; low levels of folate in the blood are associated with higher levels of homocysteine. Folic acid is involved in one of the two pathways (remethylation) by which homocysteine is metabolized; this pathway also requires vitamin B12. Enzymes involved in remethylation of homocysteine are dependent upon folate and vitamin B12.17-18 Supplementation with folic acid will increase the activity of the remethylation pathway and thereby reduce homocysteine levels.19

Betaine is derived from choline and occurs naturally in the body. It can also be found in foods like cereal, seafood, spinach and beets, to name a few. Betaine acts as a methyl donor and contributes in the remethylation pathway when converting homocysteine back to methionine,20 thereby reducing homocysteine levels. Betaine has been shown to lower homocysteine levels in the majority of patients unresponsive to vitamin B6 therapy. In one study, daily doses of 250 mg of vitamin B6, 5 mg of folic acid, and 6 gm of betaine by themselves or in combination normalized the majority of high homocysteine levels in patients administered high doses of methionine.21

Homocysteine-lowering strategies also include a diet low in methionine since homocysteine is an intermediate product of methionine metabolism in the body. Foods rich in methionine include cheddar cheese, eggs, chicken, and beef.

Conclusion

Homocysteine is considered a primary, independent risk factor for cardiovascular disease and is thought to contribute to a host of other conditions such as miscarriages and difficult pregnancy, bone fractures, strokes, blood clots, depression, dementia, Alzheimer’s and Parkinson’s diseases. Due to this amino acid’s role in a host of diseases, individuals at risk for high homocysteine levels should consider a supplement regimen that includes vitamins B12 and B6, folic acid, and betaine.

References

1. Blum A, Hijazi I, Eizenberg MM, Blum N. Homocysteine (Hcy) follow-up study. Clin Invest Med. 2007;30(1):21-5.

2. Lentz SR. Mechanisms of homocysteine-induced atherothrombosis. J Thromb Haemost. 2005 Aug;3(8):1646-54.

3. Keebler ME, De Souza C, Fonesca V. Diagnosis and treatment of hyperhomocysteinemia. Curr Atheroscler Rep. 2001;3:54-63.

4. Boushey CJ, Beresford SA, Omenn GS, Motulsky AG. A quantitative assessment of plasma homocysteine as a risk factor for vascular disease. Probable benefits of increasing folic acid intakes. JAMA. 1995;274:1049-57.

5. D’Uva M, Di Micco P, Strina I, et al. Hyperhomocysteinemia in women with unexplained sterility or recurrent early pregnancy loss from Southern Italy: a preliminary report. Thromb J. 2007 Jul 11;5:10.

6. Forges T, Monnier-Barbarino P, Alberto JM, et al. Impact of folate and homocysteine metabolism on human reproductive health. Hum Reprod Update. 2007 May-Jun;13(3):225-38. Epub 2007 Feb 16.

7. Herrmann W, Lorenzl S, Obeid R. Review of the role of hyperhomocysteinemia and B-vitamin deficiency in neurological and psychiatric disorders–current evidence and preliminary recommendations] Fortschr Neurol Psychiatr. 2007 Sep;75(9):515-27.

8. Rosendorff C, Beeri MS, Silverman JM. Cardiovascular risk factors for Alzheimer’s disease. Am J Geriatr Cardiol. 2007 May-Jun;16(3):143-9.

9. Seshadri S, Beiser A, Selhub J, et al. Plasma homocysteine as a risk factor for dementia and Alzheimer’s disease. N Engl J Med. 2002 Feb 14;346(7):476-83.

10. Perier MA, Gineyts E, Munoz F, Sornay-Rendu E, Delmas PD. Homocysteine and fracture risk in postmenopausal women: the OFELY study. Osteoporos Int. 2007 Oct;18(10):1329-36.

11. Krishnaswamy K, Lakshmi AV. Role of nutritional supplementation in reducing the levels of homocysteine. J Assoc Physicians India 2002 May;50 Suppl:36-42.

12. O’Connor JJ, Meurer LN. Should patients with coronary disease and high homocysteine take folic acid? J Fam Pract. 2003 Jan;52(1):16-8.

13. Sunder-Plassmann G, Winkelmayer WC, Fodinger M. Therapeutic potential of total homocysteine-lowering drugs on cardiovascular disease. Exp Opin Invest Drugs. 2000;9:2637-51.

14. Mayer EL, Jacobsen DW, Robinson K. Homocysteine and coronary atherosclerosis. J Am Coll Cardiol. 1996;27:517-27.

15. Selhub J, Jacques PF, Bostom AG, et al. Relationship between plasma homocysteine and vitamin status in the Framingham study population. Impact of folic acid fortification. Publ Health Rev. 2000;28:117-45.

16. Landgren F, Israelsson B, Lindgren A, et al. Plasma homocysteine in acute myocardial infarction: homocysteine-lowering effect of folic acid. J Intern Med. 1995;237:381-8.

17. Woodside JV, Yarnell JW, McMaster D, et al. Effect of B-group vitamins and antioxidant vitamins on hyperhomocysteinemia: a double-blind, randomized, factorial-design, controlled trial. Am J Clin Nutr. 1998;67:858-66.

18. Fohr IP, Prinz-Langenohl R, Bronstrup A, et al. 5,10-Methylenetetrahydrofolate reductase genotype determines the plasma homocysteine-lowering effect of supplementation with 5-methyltetrahydrofolate or folic acid in healthy young women. Am J Clin Nutr. 2002;75:275-82.

19. Vermeulen EG, Stehouwer CD, Twisk JW, et al. Effect of homocysteine-lowering treatment with folic acid plus vitamin B6 on progression of subclinical atherosclerosis: a randomised, placebo-controlled trial. Lancet. 2000;355:517-22.

20. Brouwer IA, Verhoef P, Urgert R. Betaine supplementation and plasma homocysteine in healthy volunteers (letter). Arch Intern Med. 2000;160:2546-7.

21. Boers GHJ. Hyperhomocystinemia: A Newly Recognized Risk Factor For Vascular Disease. Netherlands Journal of Medicine. 1994; 45:34-41.

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Jun 16 2008

Vitamin D3 – Osteoporosis

Published by under Osteoporosis,Vitamin D3

Vitamin D3:
Higher Doses Reduce Risk of Common Health Concerns
By Chris D. Meletis, ND

Vitamin D3 is one of the most useful nutritional tools we have at our disposal for improving overall health. This vitamin is unique because cholecalciferol (Vitamin D3) is a vitamin derived from 7-dehyrocholesterol; however, Vitamin D3 acquires hormone-like actions when cholecalciferol (Vitamin D3) is converted to 1,25-dihydroxy Vitamin D3 (Calcitriol) by the liver and kidneys. As a hormone, Calcitriol controls phosphorus, calcium, and bone metabolism and neuromuscular function. Vitamin D3 is the only vitamin the body can manufacture from sunlight (UVB). Yet, with today’s indoor living and the extensive use of sunscreens due to concern about skin cancer, we are now a society with millions of individuals deficient in life-sustaining bone building and immune modulating 1,25-dihydroxy Vitamin D3.

For more than a century, scientists have recognized that Vitamin D3 is involved in bone health. Research has continued to accumulate, documenting Calcitriol’s role in the reduction of the risk of fractures to a significant degree. The latest research, however, shows that 1,25-dihyroxy Vitamin D3 deficiency is linked to a surprising number of other health conditions such as depression, back pain, cancer, both insulin resistance and pre-eclampsia during pregnancy, impaired immunity and macular degeneration.

As it becomes clear that Vitamin D3 plays a wide role in overall health, it’s becoming equally clear that a large percentage of individuals are deficient in this important nutrient, which has hormone-like activity. The fear of skin cancer has stopped many individuals from obtaining beneficial amounts of sunlight. The skin uses the energy of UVB to convert 7-dehydrocholesterol into Vitamin D3. Even individuals, who venture out into the sun often and use suntan lotion, may be deficient in Vitamin D3. Furthermore, as we age, we are less equipped to produce sufficient quantities of this vital nutrient. One study found that age-related declines in kidney function may require older people to ingest more Vitamin D3 to maintain the same blood levels as younger people.1

The Recommended Daily Intake (RDI) of Vitamin D3 is set so low those mature individuals who consume this small amount (400 to 600 International Unites (I.U.’s)) are still likely to be deficient if they live north of the Tropic of Cancer or south of the Tropic of Capricorn. In fact, researchers have discovered that the RDI, which was considered adequate to prevent osteomalacia (a painful bone disease) or rickets, is not high enough to protect against the majority of diseases linked to 1,25-dihyroxy Vitamin D3 deficiency. For example, an analysis of the medical literature found that at least 1,000 to 2,000 IU of Vitamin D3 per day is necessary to reduce the risk of colorectal cancer and that lower doses of Vitamin D3 did not have the same protective effect.2

Researchers Call for Higher Doses

In an editorial in the March 2007 edition of the American Journal of Clinical Nutrition, a prominent group of researchers from leading institutions such as the University of Toronto, Brigham and Women’s Hospital, Tufts University and University Hospital in Zurich, Switzerland, lashed out at the conventional media for its inaccurate reporting of Vitamin D supplementation.3

The researchers wrote, “Almost every time the public media report that Vitamin D nutrition status is too low, or that higher Vitamin D intakes may improve measures of health, the advice that accompanies the report is outdated and thus misleading. Media reports to the public are typically accompanied by a paragraph that approximates the following: ‘Current recommendations from the Institute of Medicine call for 200 IU/day from birth through age 50 years, 400 IU for those aged 51–70 years, and 600 IU for those aged >70 years. Some experts say that optimal amounts are closer to 1,000 IU daily. Until more is known, it is wise not to overdo it.’ The only conclusion that the public can draw from this is to do nothing different from what they have done in the past.”

The researchers point out that supplemental intake of 400 IU per day barely raises blood concentrations of 25(OH)D, which is the circulating Vitamin D metabolite that serves as the most frequently measured indicator of Vitamin D status. To raise 25(OH)D from 50 to 80 nmol/L requires an additional intake of 1,700 IU Vitamin D per day.

The researchers went on to write that, “The balance of the evidence leads to the conclusion that the public health is best served by a recommendation of higher daily intakes of Vitamin D. Relatively simple and low-cost changes, such as increased food fortification or increasing the amount of Vitamin D in Vitamin supplement products, may very well bring about rapid and important reductions in the morbidity associated with low Vitamin D status.”

One of the challenges is the outdated acceptable upper limit for Vitamin D3 consumption, which was set at 2,000 IU. However, researchers point out that more recent studies have shown that 10,000 IU is the safe upper limit.4

Dr. R. Vieth, one of the foremost authorities on Vitamin D3 supplementation, has extensively studied Vitamin D, and lamented the low requirements for Vitamin D3 in a recent issue of the Journal of Nutrition: “Inappropriately low UL [upper limit] values, or guidance values, for Vitamin D have hindered objective clinical research on Vitamin D nutrition; they have hindered our understanding of its role in disease prevention, and restricted the amount of Vitamin D in multivitamins and foods to doses (that are) too low to benefit public health.”5

When examining the medical literature, it becomes clear that Vitamin D3 affects human health in an astonishing number of ways and that not obtaining enough of this important nutrient can leave the door open to developing a number of health conditions.

Depression

Vitamin D3 deficiency is common in older adults and has been implicated in psychiatric and neurologic disorders. For example, in one study of 80 older adults (40 with mild Alzheimer’s disease and 40 nondemented persons), Vitamin D3 deficiency was associated with low mood and with impairment on two of four measures of cognitive performance.6

Back Pain

Musculoskeletal disorders have been linked to Vitamin D3 deficiency in a number of studies. One of the newest studies explored the role that low Vitamin D3 levels play in the development of chronic low back pain in women. Sixty female patients in Egypt complaining of low back pain lasting more than three months were studied. Researchers measured levels of Vitamin D3 in the women with low back pain and compared those levels to those of 20 matched healthy controls.

The study revealed that patients with low back pain had significantly lower Vitamin D3 levels than controls. Low Vitamin D3 levels (25 OHD < 40 ng/ml) were found in 49/60 patients (81 percent) and 12/20 (60 percent) of controls.7

Bone Health

One of the best known and long-established benefits of Vitamin D3 is its ability to improve bone health and the health of the musculoskeletal system. It is well documented that Vitamin D3 deficiency causes osteopenia, precipitates and exacerbates osteoporosis, causes a painful bone disease known as osteomalacia, and exacerbates muscle weakness, which increases the risk of falls and fractures. Vitamin D3 insufficiency may alter the regulatory mechanisms of parathyroid hormone (PTH) and cause a secondary hyperparathyroidism that increases the risk of osteoporosis and fractures.8

Cognitive Enhancement

Scientists are developing a greater appreciation for Vitamin D3’s ability to improve cognition. In a recent study, Vitamin D3 deficient subjects scored worse on mental function tests compared to individuals who had higher levels of the Vitamin.9 The researchers wrote, “In conclusion, the positive, significant correlation between serum 25(OH)D concentration and MMSE [mental state examination scores] in these patients suggests a potential role for Vitamin D in cognitive function of older adults.”

Cancer

One researcher first noted the connection between Vitamin D3 and protection from cancer in the 1940s, when he discovered that individuals at sunny latitudes had a reduced rate of deaths from cancer. He suggested that sunlight provided “a relative cancer immunity.”
Since then, a number of studies have strongly suggested that Vitamin D3 deficiency is associated with an increased risk of developing many forms of cancer including breast, ovarian, prostate and colon cancer.10 In one recent clinical trial, researchers studied 1,179 healthy, postmenopausal women (all 55 years or older and free of known cancers for at least 10 years prior to entering the study) who were taking large amounts of Vitamin D3 with calcium. The subjects were randomly assigned to take daily dosages of: (1) 1,400-1,500 mg supplemental calcium, (2) 1,400-1,500 mg supplemental calcium plus 1,100 IU of Vitamin D3, or (3) placebos. Over the four-year trial, women in the calcium/Vitamin D3 group experienced a 60 percent or greater reduced risk of cancer than their peers in the placebo group, who were not consuming these supplements.

Because there was the chance that some women may have had undiagnosed cancers at the study’s start, the researchers threw out the first-year results and then analyzed the results from the last three years of the trial. These later years resulted in even more dramatic decrease, with the calcium/Vitamin D3 group experiencing a 77 percent reduction in cancer risk.

There was no statistically significant difference in cancer incidence between the participants taking placebos and subjects consuming only calcium supplements.11

Another interesting study demonstrated that in vitro Vitamin D3 may cause tumor cells to be more sensitive to chemotherapy drugs, increasing the efficacy of the cancer treatment.12

Immunity

Scientists have linked various aspects of immune health to a Vitamin D3 deficiency. Vitamin D3 regulates T cells, which are important to the functioning of a strong immune system. Vitamin D3 acts as an immune system modulator, preventing excessive expression of inflammatory cytokines and increasing the killing efficiency of macrophages. In addition, it dramatically stimulates the expression of potent anti-microbial peptides, which exist in immune system cells such as neutrophils, monocytes, natural killer cells, and in cells lining the respiratory tract. These Vitamin-D3-stimulated peptides play a major role in protecting the lung from infection.13

In addition, Vitamin D3 deficiency may influence development and progression of various autoimmune diseases.14

Multi-Talented Nutrient

Vitamin D3 deficiency has been linked to a host of other conditions such as high blood pressure, fibromyalgia, diabetes, multiple sclerosis, rheumatoid arthritis, and an increased risk of pre-eclampsia and insulin resistance during pregnancy.11,15-16 Most recently, low Vitamin D3 levels have been linked to an increased prevalence of early age-related macular degeneration.17

Proper Dosage

In many of my patients, even after consuming 2,000 to 4,000 IU of Vitamin D3 per day, their test results indicate that their Vitamin D3 levels have not increased. These patients needed to consume 8,000 IU of Vitamin D3 per day to achieve proper blood levels of the Vitamin. Patients should, therefore, have their physicians test their serum 1,25-dihyroxy D3 levels to determine the proper level of supplementation required. Testing is very important due to the fact that, in a small number of patients, Vitamin D3 supplementation can raise calcium levels to an excessively high level. I have found this to be especially true in African American patients. Testing for 1,25-dihyroxy Vitamin D3, PTH and calcium blood levels should therefore become a part of every woman’s regular blood work.

Conclusion

A growing number of researchers who have widely studied Vitamin D3 are almost begging the general public to consume more of this important nutrient. Due to Vitamin D3’s high safety profile in doses up to 10,000 IU per day and because of the wide role it plays in our health, consuming 2,000 to 4,000 IU per day of this nutrient at times of the year when sunlight is scarce is a prudent way to improve overall health.

References

1. Vieth R, Ladak Y, Walfish PG. Age-related changes in the 25-hydroxyVitamin D versus parathyroid hormone relationship suggest a different reason why older adults require more Vitamin D. J Clin Endocrinol Metab. 2003 Jan;88(1):185-91.
2. Gorham ED, Garland CF, Garland FC, Grant WB, Mohr SB, Lipkin M, Newmark HL, Giovannucci E, Wei M, Holick MF. Optimal Vitamin D status for colorectal cancer prevention: a quantitative meta analysis. Am J Prev Med. 2007 Mar;32(3):210-6.
3. Vieth R, Bischoff-Ferrari H, Boucher BJ, Dawson-Hughes B, Garland CF, Heaney RP, Holick MF, Hollis BW, Lamberg-Allardt C, McGrath JJ, Norman AW, Scragg R, Whiting SJ, Willett WC, Zittermann A. The urgent need to recommend an intake of Vitamin D that is effective. American Journal of Clinical Nutrition. March 2007;85(3):649-650.
4. Hathcock JN, Shao A, Vieth R, Heaney R. Risk assessment for Vitamin D. Am J Clin Nutr. 2007 Jan;85(1):6-18.
5. Vieth R. Critique of the considerations for establishing the tolerable upper intake level for Vitamin D: critical need for revision upwards. J Nutr. 2006 Apr;136(4):1117-22.
6. Wilkins CH, Sheline YI, Roe CM, Birge SJ, Morris JC. Vitamin D deficiency is associated with low mood and worse cognitive performance in older adults. Am J Geriatr Psychiatry. 2006 Dec;14(12):1032-40.
7. Lotfi A, Abdel-Nasser AM, Hamdy A, Omran AA, El-Rehany MA. HypoVitaminosis D in female patients with chronic low back pain. Clin Rheumatol. 2007 Mar 22; [Epub ahead of print].
8. Pérez-López FR. Vitamin D and its implications for musculoskeletal health in women: An update. Maturitas. 2007 Jun 28; [Epub ahead of print].
9. Przybelski RJ, Binkley NC. Is Vitamin D important for preserving cognition? A positive correlation of serum 25-hydroxyVitamin D concentration with cognitive function. Arch Biochem Biophys. 2007 Apr 15;460(2):202-5.
10. Grant WB. An estimate of premature cancer mortality in the U.S. due to inadequate doses of solar ultraviolet-B radiation. Cancer. 2002 Mar 15;94(6):1867-75.
11. Lappe J, Travers-Gustafson D, Davies K, Recker R, Heaney R. Vitamin D and calcium supplementation reduces cancer risk: results of a randomized trial. American Journal of Clinical Nutrition. June 8;85(6):1586-1591.
12. Ma Y, et al. Study presented at the 2007 centennial meeting of the American Association for Cancer Research (AACR), April 14 to 18, 2007, Los Angeles.
13. Cannell JJ, Vieth R, Umhau JC, Holick MF, Grant WB, Madronich S, Garland CF, Giovannucci E. Epidemic influenza and Vitamin D. Epidemiol Infect. 2006 Dec;134(6):1129-40.
14. Kuryłowicz A, Bednarczuk T, Nauman J. [The influence of Vitamin D deficiency on cancers and autoimmune diseases development.] [Article in Polish] Endokrynol Pol. 2007;58(2):140-152.
15. Bodnar LM, Catov JM, Simhan HN, Holick MF, Powers RW, Roberts JM. Maternal Vitamin D deficiency increases the risk of preeclampsia. J Clin Endocrinol Metab. 2007 May 29; [Epub ahead of print].
16. Maghbooli Z, Hossein-Nezhad A, Karimi F, Shafaei AR, Larijani B. Correlation between Vitamin D(3) deficiency and insulin resistance in pregnancy. Diabetes Metab Res Rev. 2007 Jul 2; [Epub ahead of print].
17. Parekh N, Chappell RJ, Millen AE, Albert DM, Mares JA. Association Between Vitamin D and Age-Related Macular Degeneration in the Third National Health and Nutrition Examination Survey, 1988 Through 1994. Arch Ophthalmol. May 2007;125: 661-669.

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Supply of hospital pharmacies operating externally due to cost savings will continue to grow all over the next years. Even today, 90% of all pharmacies pribolnichnyh organized in cooperation provisioning This shows that the Canadian pharmacy online has become not take seriously the business partner compared with the pharmaceutical industry. However, the development of recent years shows that the industry sees its price registration stronger with the number of sales, thus strengthening the competitiveness of supplying hospital pharmacies in the long term due to more efficient logistics and a lot of sales.