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Can Fam Physician
Vol. 53, No. 5, May 2007, pp.841 - 854
Copyright © 2007 by The College of Family Physicians of Canada
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Clinical Review

Not enough vitamin D

Health consequences for Canadians

Gerry Schwalfenberg, MD CCFP
Clinical lecturer in the Department of Family Medicine at the University of Alberta in Edmonton

Correspondence to: Dr Gerry Schwalfenberg, #301, 9509-156 St, Edmonton, AB T5P 4J5; telephone 780 484-1433; fax 780 489-1211; e-mail schwalfe{at}ualberta.ca

This article reviews the guidelines for adequate intake of vitamin D (VTD), some of the basic physiology of VTD, and the relevance of the VTD receptor in some disease states. The definition of VTD status, and the prevalence, etiology, and treatment of inadequate status for various diseases will be discussed.

Quality of evidence

MEDLINE was searched using the words "vitamin D" and "vitamin D receptor" combined with "insufficiency," "deficiency," "osteoporosis," "neuromuscular function," "falls," "cardiovascular disease," "autoimmune disease," "diabetes," "cancer," and "treatment." Articles containing levels I, II, and III evidence were found. Original studies reviewed in this paper are listed in Table 1.1–53


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  		Table 1 Articles reviewed, number of subjects, design, outcomes, and comments

 
Past and current (1997) guidelines for adequate intake of vitamin D (VTD) are shown in Table 2.54–57 Some have recommended that new guidelines for breastfed infants and people with osteoporosis are needed. New guidelines might be forthcoming after review of new data relating to our understanding of VTD and its role in chronic diseases with long latency periods.58


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  		Table 2 Canadian recommendations for adequate intake of vitamin D: 1975 to 2007.

 
Background

Vitamin D, a steroid hormone produced in the skin, has specific regulatory or functional effects on other parts of the body. Vitamin D is hydroxylated in the liver to 25-hydroxyvitamin D (25[OH]D) and further hydroxylated in the kidney to 1,25-dihydroxyvitamin D. Hydroxylation in the kidney is regulated closely by parathyroid hormone (PTH), hypocalcemia, and hypophosphatemia and is inhibited by 1,25-dihydroxyvitamin D.59 As well, 1,25-dihydroxyvitamin D (produced locally within cells) regulates gene transcription through nuclear high-affinity VTD receptors.60 These receptors are found in the classic target organs: gut, bone, kidney, and parathyroid61 and many other tissues as well, such as brain, breast, colon, heart, pancreas, prostate, skin, and immune system. Vitamin D regulates cell growth and maturation, inhibits renin production, stimulates insulin secretion, and modulates the function of activated T- and B-lymphocytes and macrophages62,63 (Table 3,1,2,4,33,59,62,64–82 Figure 1).


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  		Table 3 Studies of functions of vitamin D

 

Figure 10530841
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  		Figure 1 Physiologic actions and potential benefits of vitamin D: References are listed in Tables 1,3, and 7.

 
Assessing VTD status

The major circulating metabolite of VTD is serum 25(OH)D, which has a half-life of between 10 and 19 days.5 It is the best indicator of VTD status and reflects levels from dietary intake and synthesis in the skin.83 Levels <25 nmol/L are generally considered deficient; levels <80 nmol/L are considered insufficient.84 There is some concern about the reliability and consistency of serum 25(OH)D laboratory results,85 although there has been some improvement in the quality of tests in the past few years. The 2 main assays commercially available are listed in Table 4.86,87 Liquid chromatography, which is the criterion standard, is not readily available.


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  		Table 4 Assessment of vitamin D levels

 
Prevalence of VTD insufficiency or deficiency

Globally, VTD insufficiency or deficiency has been noted in many countries, from high school students in Iran7 to healthy western Canadians.8 Substantial seasonal variability has been noted in both Canada and Australia above and below the 37th parallel, respectively, with up to 97% of Canadians having inadequate levels of VTD at some time during the winter or spring.8,9

Mothers and infants among native Canadian Cree in Manitoba have been found to be severely deficient in VTD, even in midsummer.10 In Inuvik, 48% of Inuit mothers were found to be deficient in VTD despite supplementation.11 Seasonal variations were found in a Canadian study of healthy women in Toronto, Ont, and supplementation with 400 IU of VTD did not prevent insufficiency in the winter.12 A study in Edmonton, Alta, showed that children and adolescents had low levels of VTD.13,88

Three studies in the United States, Finland, and Israel found that inpatients had insufficient or deficient levels of VTD.14–16 Only 30% of patients in 3 Canadian long-term care facilities got adequate amounts of VTD through diet alone.17 Long-term care residents in Toronto had VTD deficiency that increased from 9% in the fall to 18% in the spring.18 Not only are inpatients at risk, but internal medical residents who work long hours indoors are also.19 A global study of VTD in postmenopausal women with osteoporosis showed that levels were deficient in 28.4% of them. There was no significant difference in levels among community-dwelling people and nursing-home patients. Deficiency increases with age; about 50% of those aged 70 and 80% of those aged 90 are deficient.89 In a study of North American postmenopausal women, all taking an agent to treat or prevent osteoporosis and 59% taking =400 IU of VTD daily, 18% had levels below 50 nmol/L, and 52% had levels below 75 nmol/L. Despite supplementation, about 50% of women have suboptimal VTD levels.20 A systematic review of 30 articles written in the past 10 years on VTD inadequacy in menopausal women supports these findings.21

Etiology of VTD deficiency and insufficiency

The risk factors that contribute to low levels of VTD are numerous and are summarized in Table 5.10,22–24,90–110


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  		Table 5 Risk factors for low serum vitamin D levels

 
Classic effects of VTD insufficiency or deficiency on disease

Vitamin D deficiency causes rickets in children and osteomalacia in adults. Rickets cases are still being reported in Canada.25,111 Osteomalacia also still occurs, but its symptoms are much less specific and are easily missed.112 Vitamin D is used to treat osteoporosis, but studies using calcium and 400 IU of VTD showed little effect on fractures. Most but not all studies using calcium and 700 to 800 IU of VTD did show a reduction in fractures.26–28,113 No benefit was seen from 1000 mg of calcium and 800 IU of VTD in a primary prevention trial29 and a secondary prevention trial.30,114 Compliance was poor in both studies, and only 63% of patients were still taking treatment after 12 months in the former study, and only 1.1% of patients had baseline VTD levels taken in the latter study.

Supplementing with 400 IU of VTD for 8 weeks raised the measured 25(OH)D level by a mere 11 nmol/L in healthy men.5 To date, no studies have ensured that all subjects in treatment groups consistently had VTD levels >78 nmol/L. There is still great controversy over the benefit of VTD in fracture control.

Effects of insufficiency or deficiency on other disease states

Neuromuscular effects
Vitamin D acts on the VTD receptor in skeletal muscle cells by binding to the nuclear receptor and also to a cell membrane receptor, which results in numerous physiologic actions.71 Severe VTD deficiency is associated with muscle weakness, limb pain, and impaired physical function.3,31,115 A meta-analysis looking at ambulatory and institutionalized older patients found a reduction in falls of more than 20% with use of VTD. This effect was independent of calcium supplementation.32 In the most current multidose study of institutionalized older patients, supplementation with 800 IU of VTD resulted in a 72% reduction in falls.116 Another review found no such association.3 There is also evidence that idiopathic low back pain in patients with VTD deficiency markedly improves when VTD levels are restored.35 Low levels of VTD are also common in patients with fibromyalgia and chronic refractory nonspecific musculoskeletal pain.36,37,117

Type 1 and 2 diabetes
A prospective study (begun in 1966) using 2000 IU of VTD in children resulted in an 80% reduction in development of type 1 diabetes during the next 30 years.38 Studies using 400 IU of VTD early in life did not show a protective effect, and higher doses are being suggested.39,118 Increasing VTD levels from 25 to 75 nmol/L results in a 60% improvement in insulin sensitivity.4,119 Low VTD levels were also shown to have a negative effect on beta cell function.120 The improvement in insulin sensitivity was greater with VTD than improvement seen with either troglitzone (54%) or metformin (13%).4,121

Multiple sclerosis and rheumatoid arthritis
Living at higher than 37° latitude increases the risk of developing multiple sclerosis by >100%. Taking a multivitamin with 400 IU of VTD reduces the risk by 40%.44,122 Women taking a multivitamin with 400 IU of VTD reduced their risk of developing rheumatoid arthritis by 40%.45,122

Cardiovascular disease
Increased VTD levels suppress renin expression and renin levels and thus result in down-regulation of the renin-angiotensin system in animals.123 Several mechanisms have been suggested for VTD’s protective role in cardiovascular disease.68

Supplementation with calcium and VTD results in a substantial 9.3% decrease in systolic blood pressure and a 5.4% decrease in heart rate.40 Supplementing with VTD substantially reduces C-reactive protein levels in critically ill patients.41 Low VTD levels might contribute to congestive heart failure.2 In 3 large prospective cohort studies, however, higher intake of VTD was not associated with lower risk of hypertension.42 Clinical trials are needed to evaluate whether the morbidity and mortality associated with cardiovascular disease are reduced by optimal intake of oral VTD.

Cancer
Evidence from 63 observational studies indicates that inadequate VTD levels are a risk factor for certain types of cancer, such as breast, colon, ovarian, and prostate cancer.43,124,125 Vitamin D and VTD analogues can induce cell death in some cancer cell lines.74,75 Exposure to the sun might increase risk of skin cancer, but VTD has been shown to suppress growth and increase apop-tosis in melanoma cells.126 The risks and benefits of sun exposure are a topic of hot debate at this time.46,127,128

Psoriasis
Vitamin D analogues are used for psoriasis along with ultraviolet-B light. Treatment is successful because of the antiproliferative, immunosuppressive, and prodifferentiating effects of VTD.73,129

Sources of VTD

The best way to increase VTD levels is to expose the skin to the sun. This has never been known to cause toxicity because of self-regulatory factors in the skin. Other sources of VTD are listed in Table 6.47,91,130,131


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  		Table 6 Sources of vitamin D

 
Treatment of VTD insufficiency and deficiency

The beneficial effects of VTD on various diseases are listed in Table 7.4,35,38,44,45,48–50,73,77,78,98,111,112,117,132–145 The question is, how can one vitamin influence so many disorders in a positive way? Just as abnormal levels of thyroid hormone can affect many cell systems, abnormal levels of VTD, a hormone, appear to affect many cell systems. Our understanding of the non-bone effects has greatly increased in the last 10 years.


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  		Table 7 Benefits of vitamin D for various diseases, dosages, and comments

 
To maintain a healthy blood level of 25(OH)D (80 to 100 nmol/L), most healthy patients require at least 1000 IU of VTD each day if they do not get exposure to the sun.63,146 Topping up to adequate levels quickly is the goal. Recommended repletion therapy consists of 50 000 IU of vitamin D2 weekly for 8 weeks or 2000 IU of vitamin D3 daily for 8 weeks.147 Doses of 4000 IU of vitamin D3 have been used safely for several months, and there is evidence that doses up to 2000 IU/d can be considered safely (Table 851–53,148–153).52


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  		Table 8 Reported side effects of vitamin D include nausea, vomiting, headache, metallic taste, vascular or nephrocalcinosis, and pancreatitis. Reported contraindications to vitamin D include hypercalcemia in sarcoidosis; metastatic bone disease148; other granulomatous diseases, such as tuberculosis and Crohn disease (active phase) that have disordered vitamin D metabolism in activated macrophages149; and Williams syndrome150 (infantile hypercalcemia).

 
Conclusion

Low levels of VTD are considered a major public health problem in Canada, especially during the winter. Those with risk factors should be screened for low 25(OH)D levels and repletion therapy instituted if needed. Researchers have estimated that the oral dose of vitamin D3 to attain and maintain 25(OH)D levels >80 nmol/L is 2200 IU/d if baseline levels are 20 to 40 nmol/L, 1800 IU/d if levels are 40 to 60 nmol/L, and 1160 IU/d if levels are between 60 and 80 nmol/L.64

We need to ensure that patients have healthy blood levels of 25(OH)D to prevent levels of parathyroid hormone from rising and to maximize absorption of calcium, magnesium, and phosphate. Positive effects on bone are marginal at best unless patients consume at least 800 IU/d of VTD. The emerging and exciting role of the VTD receptor and the actions of VTD in maintaining health in other cell types have become more apparent during the last decade.


EDITOR’S KEY POINTS

  • Inadequate levels of vitamin D (VTD) have classically been associated with bone disorders, such as rickets, osteomalacia, and osteoporosis.
  • New research has demonstrated that VTD receptors are present throughout the body and that VTD has much broader effects than previously believed.
  • Current recommendations for VTD supplementation might be inadequate to ensure appropriate blood levels of VTD.

 

Footnotes

This article has been peer reviewed.

Competing interests

None declared

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