Vitamin D’s New Imortance

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New findings about vitamin D’s role in a healthy diet bring questions from patients, especially older ones. Mounting evidence suggests that increasing vitamin D offers health benefits and that today’s recommended levels are too low.

Over the past few years, many articles in the literature have addressed whether vitamin D provides health benefits beyond bone strength. Some of these studies are less reliable than others; correspondingly, numerous reports based on these studies have appeared in the mass media, many of which have been incomplete or inaccurate. This has led to confusion about vitamin D and to patients asking health care providers for clarification. While the media often have incorrectly extrapolated some of the research findings to all ages, most recent vitamin D research subjects have been postmenopausal women and age-equivalent men, and so the findings are particularly important to the geriatric population.

What Is Vitamin D?

The term “vitamin D” is applied to many substances, from precursors that can be obtained through exposure to ultraviolet B (UVB) radiation, diet or supplementation to biologically inactive and active metabolites (Table). Nevertheless, the Institute of Medicine’s Food and Nutrition Board posits that the best clinical indicator of vitamin D status is serum concentration of calcifediol, which corresponds to the sum of cutaneous vitamin D synthesis and vitamin D ingestion.1 The active form of vitamin D, calcitriol, has only a four- to six-hour serum half-life and is tightly regulated by parathyroid hormone and the kidneys, while its precursor, calcifediol, has a serum half-life of about 14 days. For this reason, calcitriol is not considered a valuable marker for serum vitamin D status. The current optimal concentration of calcifediol is 25 ng/mL, with insufficiency below 20 ng/mL and deficiency below 15 ng/mL.2

Vitamin D & the Sun

By far, the most efficient way to obtain vitamin D is via the sun. UVB radiation reacts with 7-dehydrocholesterol in the epidermis to form cholecalciferol, the precursor to calcifediol. The conversion occurs quickly: In general, a fair-skinned, prone-to-burning person needs only five minutes of whole-body unprotected summer sun to make 10,000 to 50,000 IU of cholecalciferol.3 The maximum net circulating cholecalciferol is about 10,000 IU/day, regardless of sun exposure, since UVB also converts cholecalciferol into inert sterols-a natural guard against vitamin D toxicity.

A National Institutes of Health vitamin D fact sheet states that most people meet their vitamin D needs through exposure to sunlight.2 However, as the fact sheet itself mentions, above 42 degrees north latitude (an area that includes half of the United States, all of Canada, almost all of Europe and all of Russia and Scandinavia), UVB energy from November through February is insufficient for cutaneous vitamin D synthesis. And, melanin content, time of day, cloud cover and smog, as well as shade and time spent outdoors, affect UVB exposure. Moreover, sunscreen with an SPF of 8 reduces cutaneous production of cholecalciferol by about 95%, and an SPF of 15 reduces the capacity by more than 99%.3

Diet & Supplements

Few foods naturally contain vitamin D, with the exception of fatty fishes such as sardines, mackerel, salmon, cod and herring, a serving of which can provide 100% (sardines) to 800% (herring) of the dietary reference intake (DRI).1 A tablespoon of cod liver oil can provide 5,000% of the DRI of vitamin D, provided the refining process has not removed it (see sidebar).

Milk, breakfast cereals and certain orange juice brands are vitamin D-fortified, but analyses of milk’s vitamin D content found that as many as 62% of samples throughout the United States and Canada contained less than the minimum per quart allowance and found that as many as 14% of skim milk samples had no detectable vitamin D.1 Elderly populations have special problems obtaining vitamin D. Sun exposure may be limited because of less time spent outdoors and less skin exposed. Diet also may become less varied, further lowering vitamin D content. Most importantly, the skin’s ability to synthesize cholecalciferol decreases with age as a result of decreasing 7-dehydrocholesterol levels in the skin. By age 50, the levels are generally half that of children; by age 70, the levels decrease by 75%.4 And, renal calcitriol production decreases with diminishing renal function.5 These changes in vitamin D metabolism place the aging population at exceptional risk for vitamin D deficiency.

Vitamin D supplements are readily available in multivitamins and as singular preparations, but no consensus exists about optimal daily amounts. The DRI until age 50 is 200 IU/day, increasing to 400 IU/day after age 50 and to 600 IU/day after age 70, but these values are unchanged from when they first appeared as part of the recommended dietary allowances published in 1941 by the National Academy of Sciences.6In 2003, the American Academy of Pediatrics issued new recommended intakes that doubled existing recommendations,7 and some studies have concluded that even 400 IU/day is insufficient to raise calcifediol levels in deficient persons.4 In 2007, a controversial and provocative editorial contended that the optimal serum concentration of calcifediol is at least 30 ng/mL, and that intakes of approximately 1,700 IU/day are needed to raise concentrations from 20 ng/mL to optimal.8 The Institute of Medicine’s Food and Nutrition Board’s tolerable upper intake level for vitamin D supplementation in adults is 2,000 IU/day,1 although the body’s photoproduction of vitamin D adjusts downward based on circulating amounts up to 10,000 IU/day, and daily oral doses much higher than 2,000 IU/day have been implemented in some situations.1 Nevertheless, vitamin D toxicity produces hypercalcemia; thus, moderation and individualized dosing are key.

Calcifediol is a fat-soluble vitamin, but calcitriol, the active form, is a steroid hormone that can affect calcium and phosphorus level maintenance in the blood and bones. Calcitriol binds to the vitamin D receptor (VDR) in the nuclei of target cells, allowing the VDR to act as a modulating transcriptor for the gene expression of transport proteins.9 VDRs are found in the cells of most organs and in some leukocytes;10 for example, VDRs in the intestinal wall produce substances that assist with calcium absorption.11

The Immune System

Calcitriol regulates the immune system response by modulating expression of interleukins and tumor necrosis factor by macrophages, and by decreasing expression of interleukin by lymphocytes, thereby promoting phagocytosis and anti-tumor activity and preventing excessive or prolonged inflammatory responses.12 Calcitriol has a potent in vitro antimycobacterial effect in infected monocytes13 and macrophages,14 and in a recent trial, vitamin D supplementation reduced mycobacterium activity in the infected blood of patients by 20% compared with those who were not supplemented.15 Autoimmune diseases, including rheumatoid arthritis;16 inflammatory bowel diseases such as Crohn’s;17 multiple sclerosis (MS) and diabetes have a lymphocytic component to their inflammation and have been associated with vitamin D deficiency. Munger and colleagues18 found that women who took vitamin D supplements were 40% less likely to develop MS than were women who did not take it. VDRs have been identified in pancreatic beta cells, and vitamin D deficiency is known to impair insulin synthesis and secretion.19 A meta-analysis published in 2007 found that, in patients with baseline impaired fasting glucose, calcium plus vitamin D (Ca/D) supplementation significantly slowed the increases in glycemia and insulin resistance that normally occur over time,20 and another study showed a 34.3% increase in first-phase insulin secretion in diabetic patients receiving cholecalciferol.21

Falls & Agility

Increased serum calcifediol is associated with a reduced risk of physical decline and falls in the elderly. Most studies in this area have measured falls as an outcome, and most have found a significant reduction, from 10″ to 46%,23 in fall risk among patients receiving vitamin D supplements. However, while these studies generally suggest that older patients receive vitamin D supplements, one study’s authors did not believe that a 17.6% risk reduction for falls was significant enough to suggest it.24 Another group that found only a 5.8% reduction in fractures22 concluded that vitamin D should be included in osteoporosis treatment but did not suggest that the older population in general receive supplementation.

Another study, based on the hypothesis that the fall reduction in other studies was a result of prolonged neuromuscular agility, directly measured the physical performance of older persons. It found a 58% reduction in physical decline over three years in the group receiving vitamin D.25

Hypertension

More than a decade ago, Krause and colleagues reported that hypertensive patients exposed to UVB radiation for three months had a more than 180% increase in circulating concentrations of calcifediol and a 6 mm Hg decrease in diastolic and systolic blood pressures.26 More recently, Li and colleagues were able to prove that calcitriol is a primary negative regulator of both renin expression and renin promoter activity, thereby reducing blood pressure,27 and VDRs in the myocardium have been shown to directly affect that tissue’s proliferation and contractility, maintaining heart cell structure and function and aiding in blood pressure regulation.28,29 Vitamin D appears to enhance the beneficial effects of weight loss. One study30 measured the effects of Ca/D supplementation on lipid and lipoprotein profiles in otherwise healthy, overweight menopausal women during a structured weight-loss program. The authors found statistically significant changes in LDL, total cholesterol-to-LDL ratio and LDL-to-HDL ratio in the Ca/D group compared with placebo. The authors recommended calcium supplementation in this patient population but did not mention vitamin D.

Cancer

The role of calcitriol in regulation of gene expression also affects cellular differentiation and proliferation. Observational studies long have suggested an association between vitamin D deficiency and increased cancer risk,31 but clinical trials exploring the link only recently have begun.

The results of a study on large-bowel adenoma recurrence in a geriatric population32 noted no significant change in recurrence for the calcium-only supplement group compared with the placebo group, but the secondary study results proved more interesting: Among subjects in the supplement arm, a baseline serum calcifediol level above the overall median of 29.1 ng/mL was associated with a 28.7% reduced risk or recurrence compared with those in the same arm whose serum calcifediol was at or below the overall median. Even more interesting, the effect also was seen within the placebo group, where calcifediol levels above the median imparted a 14% reduced risk.

Another study31 showed a 58% relative risk (RR) reduction in cancer of any type for Ca/D supplementation over placebo and a 23.6% reduction over calcium alone. And a retrospective analysis of initial and one-year serum calcifediol levels, as a predictor for development of cancer, found that for every 10 ng/mL increase in serum calcifediol, the RR of cancer decreased 35%.31 A Difference of Opinion

A dissenting voice in the discussion comes from the large series of studies attached to the Women’s Health Initiative Hormone Therapy and Dietary Modification Trials. Several sets of researchers tested the 36,282 postmenopausal women for Ca/D’s effects on physical decline,33 to diabetes,34 cardiovascular events35 and various cancers.36 No effect was seen for any of these studied outcomes, and many editorialists have held up these results as a proof that vitamin D is not as beneficial as others suggest,37,38 despite that WHI subjects were, on average, severely vitamin D deficient at baseline, that the supplement doses were minimal to subminimal for the age range of the subjects based on DRI, and that medication compliance was poor. Many of the studies’ authors noted these confounders in their conclusions and suggested that the hypotheses be tested again with larger doses of supplement or better compliance, or both.

A Beneficial Vitamin

All these new findings about vitamin D are not really so new. In 1997, Hayes and colleagues39 noted that at the equator, where a person would receive the most UV radiation over time, MS occurrence is near zero, while the prevalence increases to 50 cases per million people at 45 degrees north or south latitude. As early as 1986, Inomata and colleagues40 showed that calcitriol enhanced insulin secretion in type 2 diabetics, and in the preantibiotic era, vitamin D was used as a tuberculosis treatment.41 What is new is a wider recognition of vitamin D’s abilities, along with this observation: The serum calcifediol level at or above which the most benefit was seen in most recent studies is 30 ng/mL. This adds to the growing body of evidence suggesting that increased amounts of circulating vitamin D impart increased benefits, and that currently recommended levels likely are too low.

While vitamin D is no panacea, it does seem to convey some protections, and it seems reasonable to suggest that patients 50 years old or older maintain serum calcifediol at or above 30 ng/mL.

SIDEBAR: Cod Liver Oil and Vitamin D

Remember cod liver oil? Unless you grew up in the 1950s or earlier, probably not. Your patients who do remember, though, likely would describe it as fishy, salty and slimy. They may even recall standing in the kitchen each day, siblings in a row, as their mother spooned the slick stuff into their mouths.

Cod liver oil was suggested as a defense against rickets as early as 1824 in the medical literature,1 although at that time, and for nearly a century afterwards, the scientific community didn’t understand why it worked any more than they knew why children contracted rickets in the first place. (Research of the day implicated a lack of fresh air, exercise and sunshine.2) What they did know, however, was that rickets was epidemic in the northern United States and much of Europe. One article reported that 96% of autopsied children younger than 18 months old in New York City at the turn of the 20th century had the disease.3 So doctors told parents to give cod liver oil, parents dutifully complied, and children held their noses and whined.

In 1922, Dr. Frederick Gowland Hopkins isolated the “vital amine” in cod liver oil that defended against rickets and, since vitamins A, B and C already had been identified, labeled it vitamin D.4 After vitamin D’s discovery, much of the research centered on its bone-building capacity and new ways of providing it to the masses, with little thought to other possible uses. The advent of vitamin D-fortified milk caused children everywhere to rejoice at no longer needing their fishy “medicine,” and vitamin D quietly fell from public awareness until recently.

-Andrea L. Boyd, PA-C

Sidebar References

  1. Rajakumar K. Vitamin D, cod-liver oil, sunlight, and rickets: a historical perspective. Pediatrics. 2003;112(2):e132-e135.
  2. Hess AF, Unger LJ, Pappenheimer AM. Experimental rickets in rats: VII. The prevention of rickets by sunlight, by the rays of the mercury vapor lamp, and by the carbon arc lamp. J Exp Med. 1922(36):427-446.
  3. Hess AF, Unger LJ. Infantile rickets: the significance of clinical, radiographic and chemical examinations in its diagnosis and incidence. Am J Dis Child. 1922;24(4):327-338.
  4. Wolf G. The discovery of vitamin D: the contribution of Adolf Windaus. J Nutr. 2004;134(6):1299-1302.

References

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  2. U.S. Department of Health and Human Services, National Institutes of Health, Office of Dietary Supplements. Dietary Supplement Fact Sheet: Vitamin D. http://dietary-supplements.info.nih.gov/factsheets/vitamind.asp. Published April 18, 2008. Updated December 11, 2008. Accessed July 22, 2009.
  3. Matsuoka LY, Ide L, Wortsman J, MacLaughlin J, Holick MF. Sunscreens suppress cutaneous vitamin D3 synthesis. J Clin Endocrinol Metab. 1987;64(6):1165-1168.
  4. Holick MF. Vitamin D deficiency. N Engl J Med. 2007;357(3):266-281.
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  7. Gartner LM, Greer FR. Prevention of rickets and vitamin D deficiency: new guidelines for vitamin D intake. Pediatrics. 2003;111(4):908-910.
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  13. Rook GA, Steele J, Fraher L, et al. Vitamin D3, gamma interferon, and control of proliferation of Mycobacterium tuberculosis by human monocytes. Immunology. 1986;57(1):159-163.
  14. Crowle AJ, Ross EJ, May MH. Inhibition by 1,25(OH)2-vitamin D3 of the multiplication of virulent tubercle bacilli in cultured human macrophages. Infect Immun. 1987;55(12):2945-2950.
  15. Martineau AR, Wilkinson RJ, Wilkinson KA, et al. A single dose of vitamin D enhances immunity to mycobacteria. Am J Respir Crit Care Med. 2007;176(2):208-213.
  16. Merlino LA, Curtis J, Mikuls TR, Cerhan JR, Criswell LA, Saag KG. Vitamin D intake is inversely associated with rheumatoid arthritis: results from the Iowa Women’s Health Study. Arthritis Rheum. 2004;50(1):72-77.
  17. Rodriguez-Bores L, Fonseca GC, Villeda MA, Yamamoto-Furusho JK. Novel genetic markers in inflammatory bowel disease. World J Gastroenterol. 2007;13(42):5560-5570.
  18. Munger KL, Zhang SM, O’Reilly E, et al. Vitamin D intake and incidence of multiple sclerosis. Neurology. 2004;62(1):60-65.
  19. Maestro B, Dávila N, Carranza MC, Calle C. Identification of a vitamin D response element in the human insulin receptor gene promoter. J Steroid Biochem Mol Biol. 2003;84(2-3):223-230.
  20. Pittas AG, Lau J, Hu FB, Dawson-Hughes B. The role of vitamin D and calcium in type 2 diabetes: a systematic review and meta-analysis. J Clin Endocrinol Metab. 2007;92(6):2017-2029.
  21. Borissova AM, Tankova T, Kirilov G, Dakovska L, Kovacheva R. The effect of vitamin D3 on insulin secretion and peripheral insulin sensitivity in type 2 diabetic patients. Int J Clin Pract. 2003;57(4):258-261.
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  24. Burleigh E, McColl J, Potter J. Does vitamin D stop inpatients falling? A randomised controlled trial. Age Ageing. 2007;36(5):507-513.
  25. Wicherts IS, van Schoor NM, Boeke AJ, et al. Vitamin D status predicts physical performance and its decline in older persons. J Clin Endocrinol Metab. 2007;92(6):2058-2065.
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  27. Li YC, Kong J, Wei M, Chen ZF, Liu SQ, Cao LP. 1,25-dihydroxyvitamin D(3) is a negative endocrine regulator of the renin-angiotensin system. J Clin Invest. 2002;110(2):229-238.
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  37. Lee C, Majka DS. Is calcium and vitamin D supplementation overrated? J Am Diet Assoc. 2006;106(7):1032-1034.
  38. Liu JH. The WHI and the postmenopausal woman: no magic bullet. Journal Watch Women’s Health. http://womens-health.jwatch.org/cgi/content/full/2006/502/1. Published May 2, 2006. Accessed July 22, 2009.
  39. Hayes CE, Cantorna MT, DeLuca HF. Vitamin D and multiple sclerosis. Proc Soc Exp Biol Med. 1997;216(1):21-27.
  40. Inomata S, Kadowaki S, Yamatani T, Fukase M, Fujita T. Effect of 1 alpha (OH)-vitamin D3 on insulin secretion in diabetes mellitus. Bone Miner. 1986;1(3):187-192.
  41. Martineau AR, Griffiths CJ, Wilkinson RJ. Vitamin D in the treatment and prevention of tuberculosis. Expert Rev Endocrinol Metab. 2008;3(2):105-107.
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About Author

Andrea L. Boyd, PA-C

Andrea L. Boyd is a PA at Southwest Neurosurgery in Middleburg Heights, Ohio. She indicates no relationships to disclose related to the contents of this article.

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