For unless they see the sky
But they can’t and that is why
They know not if it’s dark outside or light
Bernie Taupin, Elton John, 1972
If we define a vitamin as a required substance that is not endogenously produced, vitamin D does not meet the criteria. It is produced in skin upon UVB exposure, acting on 7-dehydrocholesterol and undergoing hydroxylation in the liver and kidneys. It behaves, in fact, more like a steroid hormone, binding to vitamin D receptors throughout the body.1 As humankind becomes increasingly urban and specialized, life choices have consequences, including reduced exposure of skin to sunlight and so, reduced ability of skin to synthesize vitamin D.2 Predicted future environmental changes could have unpredictable consequences. If weather becomes excessively wet or hot, people might be driven indoors. Should the behavioural response to warmer temperatures be increased time in the sun, use of sunscreens or sunblocks might be mandated to protect skin from the strengthened UVB rays from atmospheric ozone depletion, minimizing exposure necessary to vitamin D production. With the passage of time, it could be that vitamin D will become a true vitamin after all. Optimal health might, therefore, require an exogenous source, as there are few natural food sources apart from fatty fish.
Life choices and risk factors
The genesis of mankind was almost certainly in sub-Saharan Africa, and these people were probably deeply pigmented. As some of them migrated northward some 60 000 years ago, they experienced less direct UVB radiation from the sun, and there were periods of time when no radiation was available during winter months.2,3 As they moved north and adapted to these conditions, their skin became increasingly depigmented, providing a survival advantage over more deeply pigmented subgroups whose vitamin D deficiency produced problems with mobility and reproduction.4 The possible exceptions were the Inuit in the far north, who consumed a diet of fat and oily fish, one of the few food sources high in vitamin D.
Adaptation occurred gradually over generations and is reflected in such features as skin colour, clothing, rituals, and diet. These days there can be rapid changes in location and environment that cause new stresses, advantages, and deprivations without time for adaptation. A variety of these changes and life choices strongly affect vitamin D levels, and some, such as advancing age, reduced exercise, obesity, and lack of sun exposure, act in synergy. Table 1 identifies risk factors, which can act individually or in concert to produce low levels of vitamin D.4–19
Risk factors for vitamin D deficiency
Prevalence of vitamin D deficiency
Hepatic hydroxylation of vitamin D3 produced in skin or taken orally produces 25-hydroxyvitamin D (25[OH]D), a major metabolite, which has a long half-life, allowing measurement of serum vitamin D levels. There is no complete consensus on optimum serum levels of 25(OH) D needed for prevention of disease. There is some support, however, for using the following benchmarks20:
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Deficiency: less than 25 nmol/L; leads to short-latency disease seen in rickets in children and osteomalacia in adults.
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Insufficiency: 25 to 75 nmol/L; leads to long-latency disease such as osteoporosis, fractures, and falls.
Even in the sunniest places, such as Saudi Arabia and Australia, 30% to 50% of adults and children have deficient or insufficient levels of vitamin D.5 At the latitude of Edmonton, Alta, 90% of children have deficient or insufficient levels.6 There were 104 confirmed cases of rickets in Canada between 2002 and 2004.22 The frail elderly have particularly low levels, with one study showing an average decrease of 6 nmol/L over a 2-year period.23
Average 25(OH)D levels are also tending to fall over time. A US nutrition survey done in an interval between 1988 and 2004 showed prevalence increases in levels of marked deficiency from 2% to 6%, while prevalence of adequate levels fell from 45% to 23%.24
The evidence conundrum
The development of evidence demonstrating the health effects of vitamin D deficiency has been delayed and confused owing to a combination of multiple factors:
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The marketplace drives much research. There are low profit margins in vitamin D manufacturing. Some statins, for example, are thought to increase levels of vitamin D.25 Both statin administration26 and vitamin D levels27 correlate inversely with the prevalence of multiple sclerosis. Several prospective dosing studies treating multiple sclerosis with statins have now been done, with both negative28 and positive29 results; however, to date, no dosing studies have been done with vitamin D.
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Dosage is clearly important. Early, larger randomized trials used dosages that were probably too low to show statistically significant benefits.30–32 Subsequent smaller trials using higher dosages have had positive results, but have had less influence on outcomes when meta-analyses were done. Subgroup analysis to control dose heterogeneity has demonstrated the benefits of higher dosing.33
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Control subjects in larger studies were not prevented from taking vitamin D on their own, potentially masking differences between groups.34
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Food supplementation led to the assumption that deficiency was prevented and that no further studies were needed.35 It took some time to recognize the effects of insufficiency leading to long-latency disease.
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Calcium was often administered concurrently, which could have independently influenced end points.36,37
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Despite a multitude of epidemiologic studies showing the association between low vitamin D levels and common diseases (Table 2),27,38–45 few follow-up, randomized, prospective dosing studies have been done, despite suggestions such studies are needed.27,46,47 Evidence frequently has never gone beyond hypothesis generation.
Epidemiologic association or conflicting studies suggesting potential benefits of vitamin D supplementation
Proven and potential benefits
Consequences of vitamin D deficiency were comprehensively outlined in this journal in 2007,48 and have been further addressed in recent reviews and meta-analyses. The more established benefits are summarized in Table 3.49–57
Currently established benefits of vitamin D
Potential benefits from epidemiologic studies or those for which level I and II studies provide conflicting evidence appear in Table 2.27,38–45 While these conditions can only be said to be associated with low levels of 25(OH)D, there are compelling data to prompt larger-scale randomized trials.
Supplementation to achieve adequate levels
Available higher-level evidence provides some guidance on vitamin D intakes for health maintenance:
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400 IU daily is sufficient to prevent rickets in children and osteomalacia in adults, but is insufficient to achieve adequate serum levels of 25(OH)D.1
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700 to 1000 IU daily is the minimum required to reduce risk of falling in the elderly.53
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400 to 800 IU daily is the minimum required to reduce risk of fracture in the elderly.51
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500 to 1500 IU daily reduced cancer mortality and all-cause mortality in various studies.49,50,58
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2000 IU daily reduced the incidence of type 1 diabetes in young children.56
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1000 IU daily is required to bring 50% of adults to 25(OH)D levels above 75 nmol/L (considered adequate).59
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2000 IU daily is required to bring 85% to 90% of the adult population to 25(OH)D levels above 75 nmol/L.59
The Canadian Paediatric Society22 has expressed concerns about insufficient vitamin D intake in children, particularly at northern latitudes, where rickets continues to be reported. They also suggest higher doses than currently recommended might be required in adolescents and adults to achieve and maintain adequate bone mass, particularly during pregnancy. Recent recommendations by the Food and Nutrition Board of the US Institute of Medicine appear in Table 4.60 These doses do not seem adequate in view of current evidence.61
Adequate intakes of vitamin D
Clearly, any decision made that increases dosing must take potential toxicity into consideration. Fortunately there seems to be a wide margin of safety, with trials of supplementation from 4000 to 10 000 IU daily causing no rise in serum or urinary calcium and no adverse events.3,62,63 An increase in urinary tract stones was reported as 5.7 per 10 000 participants in the Women’s Health Initiative study, despite the low-dose supplementation. This might reflect the relatively high calcium intakes of the study population.34,64 We might, however, expect a slightly increased incidence of stones in a vitamin D–replete population. Maintaining vitamin D deficiency seems a poor strategy for preventing renal colic.
Given the favourable risk-to-benefit ratio, it seems reasonable, and quite conservative, to recommend a supplemental intake of 1000 to 2000 IU daily to patients older than 1 year of age (Table 5). Higher-risk patients, such as the obese, those with chronic disease, or the elderly could take 2000 IU daily.65,66
Suggested update to adequate intakes for vitamin D based on best evidence
Patients with deficiency or insufficiency will require larger doses to raise 25(OH)D levels to normal. Increased doses are necessary for repletion, although it does not matter whether these doses are given daily, weekly, or monthly.67,68 The best-studied regimen is to give 600 000 IU of vitamin D2 (which is 60% less available than vitamin D3 at high doses)5,67,69 over a period of 8 weeks. Vitamin D2 is available in 50 000-IU capsules. Administration could then be 3 capsules of 50 000 IU every 2 weeks 4 times before reducing intake to maintenance levels. As D3 is now available in 50 000-IU capsules as well, a similar strategy could be employed using a lower dose. Serum levels can then be tracked. Other strategies are obviously possible, including intramuscular administration.
Options for health care providers
There are 2 approaches to prevention of disease: individual- or population-based strategies.70 Population-based programs, such as adding vitamin D to foodstuffs or increasing daily dosage recommendations, are of minimal benefit to individuals, and are very sensitive to slim risk-benefit ratios.70 With this scenario, as with vaccination, success is often a nonevent. Population-based programs do, however, speak to the etiology of the illness in the population, and are of great public health importance.
Recent guidelines reflect a gradually increasing acceptance of enhanced supplementation. The US Institute of Medicine’s recently released recommendations for vitamin D intake60 suggested that most Americans and Canadians up to age 70 needed no more than 600 IU of vitamin D daily to maintain health, and those 71 years of age and older might need 800 IU. These doses are still very conservative. In their review of more than 1000 studies, they found that considerable evidence confirmed the role of vitamin D in bone health, and that while numerous studies point to other possibilities that warrant further investigation, those studies have yielded conflicting and mixed results and do not offer the evidence needed to confirm that vitamin D has other health effects. New 2010 Canadian guidelines for management of osteoporosis71 recommend higher intakes, with routine supplementation at 400 to 1000 IU daily for those at low risk and up to 2000 IU daily for high-risk individuals.
Until further research is done and more appropriate population strategies are made available, the office practitioner can make use of the individual or case-finding approach, identifying patients most likely to be vitamin D deficient by history. These individuals might need repletion therapy, while the remainder should probably consider maintenance supplementation. Screening serum levels would seldom be necessary unless used for treatment follow-up or patient motivation. The intervention of supplementation at 1000 to 2000 IU daily has a wide margin of safety, and the potential for individual health improvement is likely to be substantial.21,59,66 This measure would be an interim expedient to protect our patients until a more adequate population-level strategy is crafted.
Footnotes
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This article has been peer reviewed.
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La traduction en français de cet article se trouve à www.cfp.ca dans la table des matières du numéro de janvier 2011 à la page e1.
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Competing interests
None declared
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The opinions expressed in commentaries are those of the authors. Publication does not imply endorsement by the College of Family Physicians of Canada.
- Copyright© the College of Family Physicians of Canada
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