Family Practice Advance Access originally published online on September 30, 2008
Family Practice 2008 25(Supplement 1):i44-i49; doi:10.1093/fampra/cmn058
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This article appears in the following Family Practice issue: Creating Supportive Environments for Nutrition Guidance: Towards a Synergy Between Primary Care and Public Health. Proceedings of the Fifth Heelsum International Workshop 10-12 December 2007. [View the issue table of contents]
Perspectives on obesity and sweeteners, folic acid fortification and vitamin D requirements
Department of Internal Medicine, Genome and Biomedical Science Facility, University of California Davis, Davis, CA 65616, USA; Email: chhalsted{at}ucdavis.edu
Received 15 May 2008; Revised 29 July 2008; Accepted 26 August 2008.
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Abstract |
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 Top Abstract IntroductionControversy 1: obesity and...Controversy 2: folic acid...Controversy 3: recommended...DeclarationReferences |
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This review summarizes three controversial areas of clinical practice that were discussed in many articles that appeared in the American Journal of Clinical Nutrition during the author's tenure as editor in chief.
Controversy 1—obesity and high-fructose corn syrup. The increased frequency of obesity in the US is paralleled by increasing annual consumption of high-fructose corn syrup, an extracted sweetener that is routinely added to soft drinks and to many processed foods in the US diet. Metabolic studies implicate increased fructose consumption in increased body fat and obesity and with increased circulating triglyceride levels and hypercholesterolaemia in children.
Controversy 2—folic acid fortification and supplements. Together with widespread use of supplemental multivitamins, fortification of the US diet with folic acid has resulted in high serum folate levels in much of the population, which may be associated with increased risk of cognitive decline in ageing people with low vitamin B12 status, decreased natural killer T-cell immune function and increased risk of recurrent advanced precancerous colorectal adenomas and breast cancer.
Controversy 3—recommended intakes of vitamin D. Levels of serum 25(OH)D sufficient for fracture prevention are at least 75 nmol/l (30 ng/ml) but cannot be achieved by the current recommended dietary intakes in the US. A recent fracture risk prevention trial showed that the 4-year incidence of all cancers was reduced in US women who received high supplemental doses of both calcium and vitamin D.
Keywords. Obesity, folic acid, vitamin D.
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Introduction |
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TopAbstractIntroductionControversy 1: obesity and...Controversy 2: folic acid...Controversy 3: recommended...DeclarationReferences |
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On June 30, 2007, I completed an 11- year term as editor in chief of the American Journal of Clinical Nutrition (AJCN). During my tenure, I was able to bring about a number of changes that are summarized in my swan-song editorial that appeared in the June 2007 issue.1 Between July 1996 and June 2007, the AJCN grew from 950 to 1270 original annual submissions, representing a spectrum of interest areas that included obesity, lipids, carbohydrate metabolism and diabetes, cardiovascular risk, nutritional status, vitamins, minerals, phytochemicals, pregnancy and lactation, growth and development, cancer, nutritional epidemiology and public health and bone metabolism. As the acceptance rate for new original manuscripts fell from 40% to 25% of submissions, the impact factor of the AJCN rose from an average of 3.4 to 6.5 citations for each published article, review and editorial. The most recent impact factor places the AJCN at the top of the list of all peer-reviewed journals related to nutrition and in the middle third of all published scientific journals. The truly international flavour of the AJCN is reflected in the origins of the authors. In 2006, 53% of published original articles came from the US and Canada, while there were 34% from Europe and the remainder from Australia, New Zealand and Asian countries. During my tenure, the AJCN focused on many areas of topical and controversial interest, that include the role of the changed composition of the American diet in the epidemic of obesity in the US, the benefits and potential risks of folic acid fortification of the diet and changing concepts on the realistic human requirement for vitamin D as a vitamin essential for bone health. I have chosen these three controversies for greater discussion in view of their ongoing topical importance and relevance to both clinical nutrition and public health.
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Controversy 1: obesity and high-fructose corn syrup |
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TopAbstractIntroductionControversy 1: obesity and...Controversy 2: folic acid...Controversy 3: recommended...DeclarationReferences |
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The incidences of overweight [body mass index (BMI) >25 kg/m2 or >95th percentile for same age and sex weight in childhood] and adult obesity (BMI > 30 kg/m2) have increased at alarming rates over the past 15 years in the US and in many European and other developed countries. Statistics from the US Center for Disease Control and Prevention showed that 66.3% of US adults were overweight, including 32.2% who met the criteria for obesity in 2006, each representing a >10% rise in prevalence since 1994, whereas the prevalence of childhood overweight including obesity is nearing 20%.2 The conventional recognized causes of obesity include predisposing genetic abnormalities and a combination of habitual overeating with inadequate exercise. In a review article published in 2004, Bray and Popkin summarized evidence for a novel concept that the obesity epidemic is caused to a great extent by a shift in the American diet towards increasing emphasis on the use of high-fructose corn syrup (HFCS) as a sweetener. This concept was emphasized by the parallel relationship since 1975 between the increasing prevalence of overweight and obesity and the yearly consumption of HFCS, which represents half of all food sweeteners and is the sole source of sweeteners in soft drinks3 (Fig. 1). Subsequently, the same authors published a review that indicated that sweetened beverages constitute about half the daily fluid intake and 10% of the calories of the average adult American.4 As described by Michael Pollan, Professor of Journalism at the University of California Berkeley, increased consumption of HCFS can be traced to the US government's long-standing food policy which mandates large financial subsidies to American farmers to produce grains including corn, which is used in the manufacture of HFCS that is added to many beverages and processed foods. Because of the US governmental subsidy, processed foods that contain HCFS can be marketed at lower prices than non-processed fresh foods. Coupling relative lower expense with their high caloric density and lower satiety properties, processed foods are in greater use by the poor, who are consequently at greater risk for obesity.5 Furthermore, a recent study by the US Department of Agriculture found that one in four US adults consumes high calorie fast foods and beverages at least once per day and are at greatest risk of obesity.6 Nutrition composition data from McDonald's corporation, a leading purveyor of fast foods, show that a typical meal may include a ‘Big Mac’ hamburger with 540 kCal (with 9 g sugar) a small portion of French fries with 250 kcal and a 32 oz cup of Coca Cola with 310 kCal (all from 86 g sugar as HCFS).7
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Metabolic evidence for the weight gain and body fat-promoting effects of HFCS and understanding of their metabolic basis has been developed from animal and human experiments. For example, feeding a fructose solution in water increased both body and liver fat in mice compared to feeding a sucrose solution.8 Unlike glucose which is metabolized by the rate-limiting regulatory enzyme phosphofructokinase, dietary fructose is rapidly converted to glycerol which is the backbone of triglyceride, the circulating and storage form of body fat.9 In contrast to findings from feeding eucaloric glucose, studies of healthy human volunteers showed that the ingestion of a high-fructose meal at 30% of kCal resulted in lower post-prandial responses of leptin, a satiety hormone, and a higher response of ghrelin, a hormonal inhibitor of satiety, along with a greater increase in serum triglyceride levels.10 A recent review in AJCN describes the association of elevated uric acid, a principal product of fructose metabolism, with hypertension and renal dysfunction.11 A study of 74 Swiss children found an association of excessive intakes of fructose-rich sweets with elevated levels of small particle size low-density lipoprotein, which is a predictor of subsequent cardiovascular disease.12 Current trends in fructose consumption and its metabolic effects are summarized in a recent AJCN editorial.13 However, an opposing view holds that there is no convincing epidemiological or metabolic relationship between consumption of HCFS and weight gain and is summarized in the findings of a recent consensus conference.14 Clearly, more definitive prospective studies on the metabolic consequences of HCFS in human subjects will be required to settle this controversy.
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Controversy 2: folic acid fortification and supplements |
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TopAbstractIntroductionControversy 1: obesity and...Controversy 2: folic acid...Controversy 3: recommended...DeclarationReferences |
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Folate, a water soluble vitamin, plays a central role in cellular metabolism by regulating nucleic acid incorporation into DNA and, in a vitamin B12-dependent reaction, is a methyl donor for methionine metabolism and the epigenetic regulation of the expressions of many genes. Clinically, folate deficiency is associated with abnormal embryonic development and increased risks of neural tube defects (NTDs), anaemia due to delayed generation of red blood cells, elevated homocysteine levels with increased risk for cardiovascular diseases and, owing to its interaction with vitamin B12, with increased risk of cognitive decline in ageing. On the basis of abundant evidence that newborn NTD that occurred at a rate of 6 per 10 000 live births in the US are related to maternal folate deficiency, in 1998 the US government adopted a public health policy to fortify all grain products with folic acid at a dose of 150 µg/100 g, which was considered sufficient to increase daily folate intake to its requirement of 400 µg/day. Subsequently, the incidence of US newborn NTDs was reduced by about 20%, and the incidence of low serum folate levels (<3 ng/ml) in childbearing age women was reduced from 21% to less than 1% (Fig. 2). However, at the same time, the frequency of high serum folate level (>20 ng/ml) in children and older adults increased from 5 and 7% to 42 and 38%.15
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Several studies have addressed concerns that elevated levels of circulating folate may have deleterious health effects. A study of immune function in post-menopausal women found that natural killer (NK) T-cell activity was influenced by the consumption of supplemental folic acid at levels of at least 400 µg/day. NK activity is important in defense against infection as well as surveillance and elimination of nascent cancer cells and was decreased by 25% of normal levels among women who consumed diets adequate in folate that were supplemented with folic acid, 78% of whom were found to have un-metabolized folic acid in the blood.16 Because of their metabolic interactions, both folate and vitamin B12 interact in protection against anaemia and cognitive decline. A study that evaluated relationships between vitamin B12 and folate status according to their serum levels in over 1500 elderly subjects found that low B12 with normal folate status (20% of the group) doubled the risk of anaemia from 3.5% to 7% and increased the risk of dementia from 18% to 25%. However, the incidences of anaemia and dementia in those with low B12 but high folate status due to supplement use (3.3% of the group) were significantly increased to 15% and 45% of subjects, respectively.17 Several recent large clinical trials have shown relationships between the use of supplemental folic acid and increased cancer risk. For example, a 10-year prospective study of more than 25 000 post-menopausal women found an overall 19% increased incidence of breast cancer among those taking supplemental folic acid, while there was a 32% increased risk of breast cancer among women in the highest quintile of folate intake from both diet and supplements.18 These data contrast with those from a 9-year prospective study of more than 11 000 subjects in Sweden, a country with no folic acid fortification, that showed a 40% decrease in breast cancer incidence in those receiving the highest dietary folate intake.19 A prospective study of more than 1000 men and women followed by colonoscopic surveillance for 10 years after surgical resection of colorectal cancer found a 52% greater risk of recurrent high-grade dysplastic adenomas in those taking folic acid supplements (10.9%), compared to those taking placebo (4.3%).20
There are several postulated mechanisms for increased disease risk among individuals taking folic acid supplements with resultant high serum folate levels and the frequent occurrence of un-metabolized folic acid in the circulation. First, since folic acid shares cellular transport mechanisms with physiological methyltetrahydrofolate (MTHF) in most tissues, high circulating folic acid could compete for the cellular transport of MTHF that is necessary for normal metabolic reactions. In this regard, a recent study demonstrated that the gene expression levels of cellular folate transporters were reduced after incubation of human intestinal and renal cells with high concentrations of folic acid.21 Second, the presence of high intracellular levels of folic acid could promote the synthesis and utilization of higher levels of MTHF which, through its B12-dependent pathway for DNA synthesis, could deplete B12 that is ultimately required for brain uptake and maintenance of cognitive function. Third, while low levels of folate enhance DNA instability and may increase the initiation of cancer, excessively high folate levels may promote the proliferation of dormant cancer cells, especially in the context of reduced NK cell anticancer cell surveillance,16 resulting in a U-shaped cancer risk paradigm for both ends of the folate status spectrum.22 Fourth, high intracellular folate levels could promote enhanced gene methylation and silencing, which, in the case of tumour suppressor genes, would have the net effect of enhancing carcinogenesis.23 Much more needs to be learned about potential mechanisms for folic acid toxicity and cellular dysfunction.
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Controversy 3: recommended intakes of vitamin D |
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TopAbstractIntroductionControversy 1: obesity and...Controversy 2: folic acid...Controversy 3: recommended...DeclarationReferences |
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The main physiologic function of vitamin D is to maintain calcium absorption and homeostasis in the body, and the principal signs of its deficiency are osteoporosis and bone fracture in adults, skeletal developmental deformity in newborns and maintenance of lower extremity muscle function in the elderly. The forms of vitamin D include vitamin D3 (cholecalciferol), which circulates in the blood and is derived from photosynthesis, fish oils, egg yolks, fortified milk and dietary supplements. Vitamin D2 (ergocalciferol) is derived from dietary plant sources and is converted to vitamin D3. Vitamin D2 is less well absorbed and plays a much lesser metabolic role than vitamin D3.
Vitamin D deficiency can occur through insufficient exposure to sunlight by persons living at elevated latitudes, elderly and other stay-at-homes, darker skinned persons and in persons living in cultures that practice extensive skin covering. A recent AJCN study of ethnic effects on vitamin D status in pregnant women residing in The Hague, Netherlands, found deficient blood levels in 8% of white Caucasian Dutch women, compared to low levels in more than 60% of women of Moroccan or Turkish origin.24 Since these authors used an unconventional low cut-off point for the normal 25-hydroxy vitamin D (25[OH]D) level (25 nmol/l or 10 ng/ml), the incidence of vitamin D deficiency is probably much higher in pregnant Dutch women of all ethnicities than in women living at lower latitudes who are exposed to more sunlight. Another study found that 51% of elderly Dutch men and women had serum 25(OH)D levels less than 50 nmol/l (20 ng/ml), which is a marginal cut-off point (see below) and that time spent outdoors, lower body weight and ingestion of fatty fish and fortified margarine were the main determinants for adequate vitamin D status in The Netherlands. The authors point to the need for adequate vitamin D supplementation in countries such as The Netherlands where vitamin D deficiency is a risk due to limited food fortification and direct sun exposure due to its far northern latitude.25
In recent years, it has become apparent that the recommended daily allowances for vitamin D intakes adopted by the US (200 i.u./day for all up to age 50, 400 i.u./day for age 50–70 and 600 i.u./for those over age 70) are set at unrealistically low levels for the prevention of osteoporosis and bone fractures. This controversy has been extensively aired in several AJCN review articles that focus on optimal daily doses to assure serum levels of 25(OH)D that are consistent with prevention of bone fractures, and the urgent need to revise current recommended daily intakes is summarized in a recent AJCN review.26 For example, Heaney27 pointed out that while most laboratory ranges for normal levels of serum 25(OH)D extend from about 37.5 to 100 nmol/l (15 ng/ml to 40 ng/ml), a composite of studies indicate that the maximal physiological absorption of calcium is not reached below serum 25(OH)D levels of at least 80 nmol/l (32 ng/ml). An extensive meta-analysis of 12 randomized control trials established relationships between bone mineral density and serum 25(OH)D levels in more than 13 000 US adults enrolled in the US National Health and Nutrition Examination Survey, who were grouped by age younger and older than 50 years. As shown in Fig. 2, while there was some discrepancy according to race, optimal bone mineral density values were obtained at serum 25(OH)D levels near 100 nmol/l (40 ng/ml). The same study showed that the daily intake of at least 1000 i.u. vitamin D was associated with blood levels of 25(OH)D at 75 nmol/l in just half the subjects with optimal bone mineral density, suggesting need for higher intakes to sustain adequate bone health.28 Whereas the US Food and Nutrition Board established 2000 i.u. as the upper limit of tolerable daily vitamin D intake, an extensive review of multiple studies found that toxicity manifest by hypercalcaemia and hypercalciurea was not evident at daily doses as high as 10 000 i.u.29
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50 years; B) adults according to ethnicity and after adjustment for sex, age, BMI, smoking, calcium intake, oestrogen use, month of vitamin D measurement and poverty income ratio. Whites are represented by open circles, Mexican Americans by open squares and African Americans by open triangles. Reproduced from Heaney RPVitamin D has important properties that extend beyond optimization of calcium absorption and bone health. For example, vitamin D enhances lower extremity strength essential for minimizing falls among the elderly. In
4100 US adults over aged 60, a cut-off for optimal speed of walking 8 feet occurred in those with serum 25(OH)D levels above 80 nmol/l (32 ng/ml).30 Decreased incidences at inverse proportion to serum 25(OH)D levels have been noted for a wide variety of cancers, including prostate31 and colorectal cancer.32 A recent AJCN study found a 4-year decreased incidence of a variety of cancers including breast, colon, lung and uterus among 1179 women enrolled in a fracture prevention study who received 1100 i.u. vitamin D with supplemental calcium.33 Summarizing, these three controversies were extensively aired during my tenure as the editor in chief of the AJCN. Considerable evidence was published to support emerging concepts that (i) the increasing addition of HFCS to the US diet may contribute substantially to the epidemic of obesity and its associated co-morbidities; (ii) that folic acid fortification of the US diet together with widespread use of multivitamin supplements that routinely contain folic acid may have multiple deleterious effects including reduced immune surveillance for cancer, a greater incidence of cognitive defects in the elderly and the proliferation of nascent cancer cells; and (iii) that the current US dietary reference intakes for vitamin D are set too low to influence the incidence of osteoporosis and bone fractures.
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Declaration |
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TopAbstractIntroductionControversy 1: obesity and...Controversy 2: folic acid...Controversy 3: recommended...DeclarationReferences |
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Funding: None.
Ethical approval: Not applicable.
Conflicts of interest: None.
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Acknowledgments |
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During his tenure as editor in chief of the AJCN, the author received an annual honorarium from the American Society of Nutrition.
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Notes |
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Halsted CH. Perspectives on obesity and sweeteners, folic acid fortification and vitamin D requirements. Family Practice 2008; 25: i44–i49.
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References |
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TopAbstractIntroductionControversy 1: obesity and...Controversy 2: folic acid...Controversy 3: recommended...DeclarationReferences |
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4 Popkin BM, Armstrong LE, Bray GM, et al. A new proposed guidance system for beverage consumption in the United States. Am J Clin Nutr (2006) 83:529–542.
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10 Teff KL, Elliott SS, Tschop M, et al. Dietary fructose reduces circulating insulin and leptin, attenuates postprandial suppression of ghrelin, and increases triglycerides in women. J Clin Endocrinol Metab (2004) 89:2963–2972.
11 Johnson RJ, Segal MS, Sautin Y, et al. Potential role of sugar (fructose) in the epidemic of hypertension, obesity and the metabolic syndrome, diabetes, kidney disease, and cardiovascular disease. Am J Clin Nutr (2007) 86:899–906.
12 Aeberli I, Zimmermann MB, Molinari L, et al. Fructose intake is a predictor of LDL particle size in overweight schoolchildren. Am J Clin Nutr (2007) 86:1174–1178.
13 Bray GA. How bad is fructose? Am J Clin Nutr (2007) 86:895–896.
14 Forshee RA, Storey ML, Allison DB, et al. A critical examination of the evidence relating high fructose corn syrup and weight gain. Crit Rev Food Sci Nutr (2007) 47:561–582.[CrossRef][Web of Science][Medline]
15 Pfeiffer CM, Johnson CL, Jain RB, et al. Trends in blood folate and vitamin B-12 concentrations in the United States, 1988–2004. Am J Clin Nutr (2007) 86:718–727.
16 Troen AM, Mitchell B, Sorensen B, et al. Unmetabolized folic acid in serum is associated with reduced natural killer cell cytotoxicity among postmenopausal women. J Nutr (2006) 136:189–194.
17 Morris MS, Jacques PF, Rosenberg IH, et al. Folate and vitamin B-12 status in relation to anemia, macrocytosis, and cognitive impairment in older Americans in the age of folic acid fortification. Am J Clin Nutr (2007) 85:193–200.
18 Stolzenberg-Solomon RZ, Chang SC, Leitzmann MF, et al. Folate intake, alcohol use, and postmenopausal breast cancer risk in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. Am J Clin Nutr (2006) 83:895–904.
19 Ericson U, Sonestedt E, Gullberg B, et al. High folate intake is associated with lower breast cancer incidence in postmenopausal women in the Malmo Diet and Cancer cohort. Am J Clin Nutr (2007) 86:434–443.
20 Cole BF, Baron JA, Sandler RS, et al. Folic acid for the prevention of colorectal adenomas: a randomized clinical trial. JAMA (2007) 297:2351–2359.
21 Ashokkumar B, Mohammed ZM, Vaziri ND, et al. Effect of folate oversupplementation on folate uptake by human intestinal and renal epithelial cells. Am J Clin Nutr (2007) 86:159–166.
22 Ulrich CM. Folate and cancer prevention: a closer look at a complex picture. Am J Clin Nutr (2007) 86:271–273.
23 Jones PA, Baylin SB. The fundamental role of epigenetic events in cancer. Nat Rev Genet (2002) 3:415–428.[Web of Science][Medline]
24 van der Meer IM, Karamali NS, Boeke AJ, et al. High prevalence of vitamin D deficiency in pregnant non-Western women in The Hague, Netherlands. Am J Clin Nutr (2006) 84:350–353. quiz 468–469.
25 van Dam RM, Snijder MB, Dekker JM, et al. Potentially modifiable determinants of vitamin D status in an older population in the Netherlands: the Hoorn Study. Am J Clin Nutr (2007) 85:755–761.
26 Vieth R, Bischoff-Ferrari H, Boucher BJ, et al. The urgent need to recommend an intake of vitamin D that is effective. Am J Clin Nutr (2007) 85:649–650.
27 Heaney RP. Functional indices of vitamin D status and ramifications of vitamin D deficiency. Am J Clin Nutr (2004) 80(6 suppl):1706S–1709S.
28 Bischoff-Ferrari HA, Giovannucci E, Willett WC, et al. Estimation of optimal serum concentrations of 25-hydroxyvitamin D for multiple health outcomes. Am J Clin Nutr (2006) 84:18–28.
29 Hathcock JN, Shao A, Vieth R, et al. Risk assessment for vitamin D. Am J Clin Nutr (2007) 85:6–18.
30 Bischoff-Ferrari HA, Dietrich T, Orav EJ, et al. Higher 25-hydroxyvitamin D concentrations are associated with better lower-extremity function in both active and inactive persons aged > or = 60 y. Am J Clin Nutr (2004) 80:752–758.
31 Ahonen MH, Tenkanen L, Teppo L, et al. Prostate cancer risk and prediagnostic serum 25-hydroxyvitamin D levels (Finland). Cancer Causes Control (2000) 11:847–852.[CrossRef][Web of Science][Medline]
32 Giovannucci E. The epidemiology of vitamin D and colorectal cancer: recent findings. Curr Opin Gastroenterol (2006) 22(1):24–29.[Web of Science][Medline]
33 Lappe JM, Travers-Gustafson D, Davies KM, et al. Vitamin D and calcium supplementation reduces cancer risk: results of a randomized trial. Am J Clin Nutr (2007) 85:1586–1591.
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