VITAMIN D:
The Current State in Canada
Prepared for
Canadian Council of Food and Nutrition
August 2008
Prepared by
Hope Weiler, PhD, RD
School of Dietetics and Human Nutrition
McGill University
Contents
Abbreviations ................................................................................................................................ ii
I. Introduction—How the Landscape has Changed .............................................................. 1
II. Background on Vitamin D Nutrition .................................................................................. 2
1. Dietary Recommendations ..................................................................................................... 2
2. Vitamin D in Canadian Foods and Supplements ................................................................... 4
3. Vitamin D Metabolism and Status ......................................................................................... 6
4. Functions of Vitamin D ......................................................................................................... 1
5. Consequences of Vitamin D Deficiency ............................................................................... 2
A. Skeletal Consequences .................................................................................................................. 2
B. Non-Skeletal Chronic Diseases ..................................................................................................... 5
III. Life Stage Groups ................................................................................................................. 8
1. Infancy ................................................................................................................................... 8
A.
B.
C.
D.
Dietary Vitamin D Intake of Canadian Infants ............................................................................. 8
Vitamin D Status of Canadian Infants........................................................................................... 8
Evidence of Vitamin D Related Health Issues in Canadian Infants .............................................. 8
Solutions for Improving Vitamin D Nutrition in Canadian Infants .............................................. 9
2. Childhood ............................................................................................................................. 10
A.
B.
C.
D.
Dietary Vitamin D Intake of Canadian Children ........................................................................ 10
Vitamin D Status of Canadian Children ...................................................................................... 10
Evidence of Vitamin D Related Health Issues in Canadian Children ......................................... 11
Solutions for Improving Vitamin D Nutrition in Canadian Children ......................................... 11
3. Young Adulthood................................................................................................................. 12
A. Dietary Vitamin D Intake of Canadian Men and Women 18–50 Years of Age ......................... 12
B. Vitamin D Status of Canadian Men and Women 18–50 Years of Age ....................................... 13
C. Evidence of Vitamin D Related Health Issues in Canadian Men and Women 18–50
Years of Age .............................................................................................................................. 13
D. Solutions for Improving Vitamin D Nutrition in Canadian Men and Women 18–50
Years of Age .............................................................................................................................. 13
4. Reproduction: Maternal–Fetal, Maternal–Infant ................................................................. 13
A. Dietary Vitamin D Intake of Canadian Women during Reproduction ....................................... 13
B. Vitamin D Status of Canadian Women during Reproduction ..................................................... 14
C. Evidence of Vitamin D Related Health Issues in Canadian Women during
Reproduction ............................................................................................................................. 15
D. Solutions for Improving Vitamin D Nutrition in Canadian Women during
Reproduction ............................................................................................................................. 16
5. Aging and Advanced Aging (50 Years of Age and Older) .................................................. 20
A.
B.
C.
D.
Dietary Vitamin D Intake of Aging Canadian Adults................................................................. 20
Vitamin D Status of Aging Canadian Adults .............................................................................. 20
Evidence of Vitamin D Related Health Issues in Aging Canadian Adults ................................. 20
Solutions for Improving Vitamin D Nutrition in Aging Canadian Adults .................................. 20
IV. Implications ........................................................................................................................... 21
1. General Implications ............................................................................................................ 21
2. Implications for Doctors and Other Health Care Professionals ........................................... 21
3. Implications for Industry...................................................................................................... 22
4. Implications for Consumers ................................................................................................. 22
5. Implications for Research—Knowledge Gaps for Canada .................................................. 23
V. References ............................................................................................................................ 24
Vitamin D: The Current State in Canada • CCFN Report • August 2008
i
Abbreviations
Abbreviation Meaning
1,25(OH)2D
25(OH)D
AI
BMD
BMI
CCHS
CI
CNF
CSFII
DBP
DIN
DRI
GDM
HOMA-IR
HPLC
IOM
IU
LC-MS
NHANES
NIH
NOAEL
OR
PE
PTH
RCT
RR
RT
SPF
UL
UVB
Vitamin D2
Vitamin D3
1,25-dihydroxyvitamin D, or calcitriol (active state)
25-hydroxyvitamin D, 25-hydroxycalciferol, or calcidiol
Adequate Intake
Bone mineral density
Body mass index (kg/m2)
Canadian Community Health Survey
Confidence Interval
Canadian Nutrient File
Continuing Survey of Food Intake by Individuals (U.S.)
Vitamin D binding protein
Drug Identification Number
Dietary Reference Intakes
Gestational diabetes mellitus
Homeostasis model assessment-insulin resistance
High performance liquid chromatography
Institute of Medicine (U.S.)
International Unit
Liquid chromatography–mass spectrometry
National Health and Nutrition Examination Survey (U.S.)
National Institutes of Health (U.S.)
No Observed Adverse Effect Level
Odds ratio
Preeclampsia
Parathyroid hormone
Randomized Controlled Trials
Relative risk
Randomized Trials
Sun Protection Factor
Tolerable Upper Intake Limit
Ultraviolet beta solar radiation
Ergocalciferol
Cholecalciferol
Vitamin D: The Current State in Canada • CCFN Report • August 2008
ii
I. Introduction—How the Landscape has Changed
Vitamin D is considered an essential nutrient, with the main function widely accepted as being
vital to maintain calcium homeostasis and bone health. Emerging roles for vitamin D point to
prevention of not only osteoporosis, but also other chronic diseases including cancer, multiple
sclerosis, diabetes and schizophrenia (1). Since the inaugural introduction of the USA–Canada
Dietary Reference Intakes (DRI) that began in 1997 with the report on calcium and related
nutrients including vitamin D (2), the volume of research related to vitamin D has increased
vastly. Unfortunately, reports of vitamin D status in Canadians of all ages are not yet
forthcoming, although it is clear that many Canadians are deficient in vitamin D. Deficiency has
been observed across the Canadian multicultural population from south to north and is likely a
function of both limited endogenous synthesis and limited dietary sources. In addition to the
widespread assessment of vitamin D status, a number of societies have put forth new targets for
vitamin D intake and status with the goal to optimize health outcomes. These are much different
from the values presented in 1997 for the DRI recommendations. The amount of dietary
vitamin D required to prevent a deficiency is much less than that thought to be required for
optimal status. While vitamin D can be obtained endogenously through exposure to solar
radiation, health care professionals agree upon diet as the safest source. This document provides
a comprehensive summary of vitamin D nutrition across the lifespan in Canada and identifies
gaps in knowledge that need to be addressed to improve vitamin D nutrition and food supply in
Canada.
Vitamin D: The Current State in Canada • CCFN Report • August 2008
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II. Background on Vitamin D Nutrition
1. Dietary Recommendations
The underpinning philosophy of dietary recommendations is to safely meet the needs of the
majority of people. In 1997, the Institute of Medicine (IOM) published DRI values for
vitamin D (2) to be used by both USA and Canada (Table 1). The Adequate Intake (AI) for
vitamin D was set at 200 IU/d for all individuals from birth to 50 years of age, 400 IU/d for those
50 to 70 years of age and 600 IU/d for those over 70 years of age (2). The IOM acknowledged
that exposure to sunlight may not be the best approach to ensuring adequate vitamin D status of
populations as this can be dependent on culture, skin pigmentation, and/or behaviour related to
use of sun block (2, 3). Thus the AI is designed to cover the needs of most individuals for
vitamin D in the absence of exposure to ultraviolet beta solar radiation (UVB). The Tolerable
Upper Intake Level (UL) for vitamin D was set at 1000 IU/d for infants under 12 months of age
and 2000 IU/d for all others. These values are set to have the highest likelihood of safety for the
public. The No Observed Adverse Effect Level is somewhat higher and was based on the
available science at that time (2). This value is not used in public policy per se, but was used to
set the UL to ensure public safety.
For infants, it is assumed that physiological requirements for vitamin D are the same whether the
infant is fed breast milk or formula, and that consuming one litre of formula or cows milk daily
upon weaning provides 400 IU vitamin D (2). The IOM stated that 400 IU would not be
excessive. For children 1 to 8 years of age, there were no data upon which to base the AI;
therefore the AI value for this age group was extrapolated from data on older children. However,
for ages 9 through 18 years, the IOM stated: “children who live in the far northern and southern
latitudes may be unable to synthesize enough vitamin D in their skin to store for use in the
winter. These children may need a vitamin D supplement.” The IOM also acknowledged that
there was “little scientific information that related vitamin D intake, bone health and vitamin D
status … in young adults and adult age groups”. There was no reason to believe that pregnant or
lactating women had increased needs for vitamin D. For adults 51 to 70 years of age, the ability
to synthesize vitamin D endogenously was acknowledged to decrease with age. For those over
70 years of age, the IOM reported that “the evidence is strong that the elderly are at high risk for
vitamin D deficiency, which causes secondary hyperparathyroidism and osteomalacia and
exacerbates osteoporosis, resulting in increased risk of skeletal fractures” (2).
Vitamin D: The Current State in Canada • CCFN Report • August 2008
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Table 1. Dietary Reference Intakes for Vitamin D (2)
Life Stage
Adequate Intake
Tolerable Upper
Group (y)
(IU/d)
Intake Level (IU/d)
Males and Females
0 to 0.5
200
1000
0.5 to 1
200
1000
1 to 3
200
2000
4 to 8
200
2000
9 to 18
200
2000
19 to 50
200
2000
51 to 70
400
2000
>70
600
2000
Pregnancy and Lactation
200
2000
≤18
19 to 50
200
2000
No Observed Adverse
Effect Level (IU/d)
2000
2000
2400
2400
2400
2400
2400
2400
2400
2400
Other Canadian recommendations exist:
‰ Health Canada recommends that exclusive breastfeeding be accompanied with a 400 IU
supplement of vitamin D daily until 400 IU can be achieved through foods (3). This
higher value compared to the AI is used within Canada based on evidence of widespread
deficiency as indicated by the prevalence of rickets.
‰ A working group of the Canadian Paediatric Society recommends 800 IU/d for infants
residing in northern Native communities during the winter months and that pregnant and
lactating women take a supplement of 2000 IU/d (4).
‰ The Canadian Osteoporosis Society recommends 400 IU/d for women of childbearing
years and both men and women under 50 years of age (5), and 800 IU/d for those over
50 years of age.1
‰ The Canadian Cancer Society recommends that adults living in Canada should consider
taking a daily vitamin D supplement of 1000 IU during the fall and winter.2 The Society
also recommends that adults at higher risk of having lower vitamin D levels should
consider taking a vitamin D supplement of 1000 IU/d all year round. This includes
people who are older, who have dark skin, who do not go outside often, and who wear
clothing that covers most of their skin.
‰ The Canadian Dermatology Association recommends that people who are concerned
about vitamin D levels take 1000 IU/d of vitamin D supplements.3
‰ Health Canada’s Eating Well with Canada’s Food Guide recommends that adults over
50 years of age take a supplement of 400 IU/d (6).
‰ An international panel that includes Canadian experts recommends 1000 IU/d for adults (7).
1
The Canadian Osteoporosis Society’s recommendation is soon to be updated. Refer to www.osteoporosis.ca.
See www.cancer.ca/ccs/internet/mediareleaselist/0,,3172_1613121606_1997621989_langId-en.html
3
www.dermatology.ca/media/position_statement/vitamin_d.html
2
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The recommendations for vitamin D in all age groups are increasingly being scrutinized as more
and more scientists, societies and institutions debate their adequacy based on a high prevalence
of vitamin D deficiency in North America and throughout the world. In September 2007, the
IOM held a 2-day conference on vitamin D4 to review the evidence-based science of vitamin D
nutrition and bone health (8) and to begin looking forward to resolution of the discrepancy in
recommendations and optimization of vitamin D status. At that meeting, the systematic review
on vitamin D funded by the U.S. National Institutes of Health (NIH) was summarized (8). In
addition, Health Canada is updating guidelines for nutrition in pregnancy.5
2. Vitamin D in Canadian Foods and Supplements
In assessing vitamin D intake, the Canadian Nutrient File (CNF) is incomplete for vitamin D.
Many values are assumed to be zero as no information is available. Additionally, many foods
consumed by indigenous peoples are not in the file. Health Canada acknowledges this limitation
and is presently working to reduce this barrier to assessment of vitamin D intake from foods.6
There are two types of dietary sources of vitamin D: one from plants (ergocalciferol; vitamin D2)
and one from animals (cholecalciferol; vitamin D3). Most food sources and supplements in
Canada have the latter mammalian form. Vitamin D3 is estimated to be approximately 1.7 to 3
times more potent than vitamin D2 based on the rise in serum 25(OH)D in adults (9, 10). One
recent study suggests that if the supplement is taken daily, both isoforms equally maintain
25(OH)D.7 Such relative potency studies have not been conducted in infants, children or
pregnancy/lactation and thus the optimal intake of either isoform to support the theoretical
concentration of 25(OH)D is uncertain. Nonetheless, vitamin D2 likely has a shorter half-life
since it does not bind as readily to the plasma carrier protein, vitamin D binding protein (DBP)
(11). Thus if vitamin D2 is not consumed on a daily basis, it might not be effective in sustaining
adequate status in the longer term. This is important if dosing regimens in the form of highdosage bolus administration (oral or intramuscular) are used as suggested by numerous research
groups studying children (12), pregnant women (13, 14) and adults (8).
Since there are too few natural dietary sources of vitamin D available to realistically compensate
for low endogenous synthesis, fortification of milk and margarine is mandated in Canada (15).
Main food sources of vitamin D include fortified cows milk, infant formula and margarine, as
well as natural sources from salmon, eggs and beef. Additional products are fortified soy
beverages, rice beverages and orange juice, and yogurt made from fortified cows milk (Table 2).
Sources of vitamin D typical to the exclusively breastfed infant’s diet include small amounts in
the mother’s milk, vitamin D drops/syrup, and perhaps cod liver oil, although the vitamin A
content of liver oils should be considered due to the risk of toxicity at sufficiently high levels.
Upon weaning or through introduction of complementary foods, other sources of vitamin D
include fortified cows milk or formula and possibly margarine. Consuming ~1 L of formula or
cows milk upon weaning would provide ~400 IU vitamin D daily which would not be excessive
(2). However, most infants do not consume this much milk and should receive a supplement
4
http://vitamindandhealth.od.nih.gov:80/default.aspx
The revised guidelines are expected in Summer 2008. See www.hc-sc.gc.ca/fn-an/nutrition/prenatal/index-eng.php
for updates.
6
Personal communication, February 2008.
7
e-pub ahead of print http://jcem.endojournals.org/cgi/rapidpdf/jc.2007-2308v1.
5
Vitamin D: The Current State in Canada • CCFN Report • August 2008
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until such volume is achieved. Other vitamin D containing foods such as egg yolks or salmon
are not usually consumed by infants less than 9 months of age. Other products that include
vitamin D, such as fortified soy and rice beverages and yogurt made from fortified cows milk,
also are not typical to the infant diet. An older child or adult who drinks 2 cups of fortified milk
or fortified soy beverage plus eats a 3-oz serving of salmon a week would meet the AI
recommendation of 200 IU/d. Inclusion of 2 cups of fortified orange juice and regular
consumption of eggs and beef would approximately double this to 400 IU/d. However, many
adults do not consume fortified orange juice and do not regularly eat fish. While beef and eggs
are consumed more often and represent a source of vitamin D intake, the daily intake is typically
<40 IU/d.8 Furthermore, the AI is thought to be too low. In attempts to elevate vitamin D
intakes through less commonly consumed foods, the energy and nutrient balance accompanying
such high intake of juice would have to be countered against high nutrient density foods. This
suggests that if the USA–Canada recommendation for vitamin D is increased to >200 IU/d, the
food supply will require modification to meet the needs of vitamin D status without jeopardizing
other aspects of a healthy diet. Otherwise reliance on supplements to achieve higher intakes of
vitamin D must be reinforced through careful education of health care professionals and the
public. It is for these reasons that the Canada’s Food Guide launched in 2007 includes a
recommendation for adults over the age of 50 years to take a daily supplement containing 400 IU
of vitamin D (6).
Table 2. Common Dietary Sources of Vitamin D1
Food (volume)
Vitamin D
(IU)
Cod liver oil (1 tbsp)
1360
Salmon (100 g cooked)
2722
Pasteurized fortified cows milk (250 ml)
~88
Fortified plant beverages
~80
including soy, rice or orange juice (250 ml)
Yogurt made with fortified cows milk (100 g) ~25
Egg yolk (1)
~25
Beef (100 g cooked)
~25
Margarine (1 tsp)
~25
Infant vitamin D syrup/drops (1 ml)
400
Infant formula (250 ml)
100
1
Source: Canadian Nutrient File (CNF). According to the CNF Web Site, “the CNF is the standard reference food
composition database reporting the amount of nutrients in foods commonly consumed in Canada. This nutrition
research tool is integral to many activities within Health Canada such as setting policies, standards and regulations,
risk assessment studies and food consumption surveys.” Information available at: www.hc-sc.gc.ca/fnan/nutrition/fiche-nutri-data/cnf_aboutus-aproposdenous_fcen-eng.php.
2
Nutrient content for salmon will vary according to source (farmed vs wild) and by variety (e.g. CNF #3183
Salmon, Atlantic, farmed, baked or broiled: 272 IU/100 g; #3156 Salmon, Atlantic, wild, baked or broiled 328
IU/100 g; #3053 Salmon, sockeye (red), baked or broiled, a Pacific salmon: 904 IU/100 g).
8
Source: Gray-Donald K, Johnson-Down L. Analysis of Canadian Community Health Survey Data on Food and
Nutrients. Report to the Beef Information Centre, 2007.
Vitamin D: The Current State in Canada • CCFN Report • August 2008
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For any individual not able to meet vitamin D requirements through food, reliance on
supplementation is routine. Regarding vitamin D supplements in Canada, pediatric and adult
formulations contain variable amounts of vitamin D, suggesting that the brand names of vitamins
should be solicited when conducting dietary assessments and when advising individuals or health
care professionals about supplementation. In addition to multivitamin sources of vitamin D,
supplements containing only vitamin D at various dosages exist and can range from 200 IU to
1000 IU per tablet. For example, most multivitamins contain 400 IU/tablet while vitamin D
supplements are typically 200, 400 or 1000 IU/tablet. For a quick reference of vitamin
supplement contents, refer to the Health Canada Drug Product Database.9
3. Vitamin D Metabolism and Status
Vitamin D can be obtained through endogenous synthesis upon exposure to UVB (290–310 nm)
or through foods. The endogenous isoform is cholecalciferol, also known as vitamin D3, which
can be obtained from animal-based food sources like fish or eggs. Another dietary isoform is
ergocalciferol, also known as vitamin D2, which can be obtained from mushrooms in natural form
or in rice beverages through fortification. Very few other sources of vitamin D2 exist with amounts
that significantly contribute to intakes.
Endogenous synthesis occurs in skin exposed to UVB. During the winter months in Canada,
endogenous synthesis is suppressed because all of Canada is north of the 42nd parallel and
therefore UVB radiation is not strong enough to elicit endogenous synthesis (16). Typically it is
assumed that endogenous synthesis can only occur from April to October (16), but this does not
take into account the wide range in latitude across the Canadian north–south gradient. Regions in
the far north likely do not accommodate endogenous synthesis in spring or fall, since UVB is
reduced as a result of the zenith angle and the atmosphere, in addition to cold temperatures that
necessitate warm clothing and thereby preclude exposure. This scenario is not unique to Canada;
residents in all parts of the world above the 42nd parallel north or below the 42nd parallel south are
vulnerable in the winter, and individuals who are not able to be outdoors are vulnerable yearround. Both groups will not meet the body’s requirements for vitamin D unless regularly
consuming a dietary source.
Upon exposure of skin to UVB, 7-dehydrocholesterol is converted to precholecalciferol, which
in turn is isomerized to vitamin D3. The skin pigment melanin can reduce photosynthesis of
vitamin D by 50-fold, placing individuals with darker skin at higher risk for vitamin D deficiency
(17). Since the Canadian population is multicultural, this is a limiting factor for many people in
this country. Age is also of relevance to vitamin D status of Canadians since age limits
endogenous synthesis of vitamin D (18) and Canada has a rapidly aging population. It is
estimated that by 2041, nearly 25% of the Canadian population will be over the age of 65 years,
which represents 9.4 million individuals (19). Global trends forecast that by year 2030, 20.3% of
the population in North America will be over 65 years of age (20). Sunscreen containing a sun
protection factor (SPF) of 8 or greater also suppresses endogenous synthesis of vitamin D (17);
this includes products designed for regular outdoor activity and for children as well as cosmetic
products such as facial foundations.
9
Health Canada Drug Product Database: www.hc-sc.gc.ca/dhp-mps/prodpharma/databasdon/index-eng.php
Vitamin D: The Current State in Canada • CCFN Report • August 2008
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After entry into the circulation whether through endogenous synthesis or through foods,
vitamin D3 can be transported free or bound to the vitamin D binding protein (DBP). This
protein is synthesized by the liver (21) and not only carries vitamin D3 within the blood and
extends its half-life, but also binds to other forms including vitamin D2 obtained from food.
Approximately 75% of vitamin D is removed from circulation by the liver upon each pass for
further metabolism to 25(OH)D (22). Vitamin D from all sources is hydroxylated to 25(OH)D
by the liver and released into circulation where it again binds to DBP, but with stronger affinity
(21). From dose–response studies, the level of vitamin D required to elevate 25(OH)D by 0.7 to
1.2 nmol/L appears to be 40 IU (7). Because of its lipid solubility, vitamin D can also be
sequestered in adipose tissue. Individuals who are obese have 20% lower vitamin D status after
accounting for exposure to UVB and diet (23). It appears that obesity is a risk factor for having
low vitamin D status. Since 34% of Canadian children are overweight (26% overweight and 8%
obese) (25) and 15% of adult Canadians are obese (26), this reality is an important consideration
in the study of vitamin D.
Vitamin D status is assessed using serum 25(OH)D (2). This is because 25(OH)D is relatively
stable and has a half-life of 10–21 days (2). Serum 25(OH)D (also known as calcidiol) is a
reflection of vitamin D derived from foods or endogenous synthesis and thereby reflects the
cumulative vitamin D status. To assess vitamin D status, a variety of assays are available (27).
Although HPLC and LC-MS methods are the most accurate (27), most institutions use
radioimmunoassays and some are now using automated systems (28). Regardless of the assay, it
is widely accepted that vitamin D deficiency in adults (Table 3) is diagnosed when serum
25(OH)D is <15 ng/ml or <37.5 nmol/L (2) and that insufficient concentrations are between 37.5
and 50 nmol/L. These levels are consistent with the signs and symptoms of osteomalacia, tetany
and myopathy (2). For infants and children, a vitamin D deficiency is defined by a serum
25(OH)D is <11 ng/ml or <27.5 nmol/L (2). These levels are consistent with the signs and
symptoms of rickets (2). While the DRI chapter does not suggest an optimal serum 25(OH)D,
hypervitaminosis D is defined by the range of 400 to 1250 nmol/L.
The suggested target for optimal 25(OH)D in adults is widely accepted as at least 75 nmol/L, as
recommended by an international panel of experts (7). This value is based on dose–response
studies of vitamin D supplementation in men and women where a plateau in parathyroid hormone
(PTH) was observed (24, 29).10 Whether these concentrations are appropriate for other life stage
groups has not been proven. There is however a growing body of information indicating that other
life stage groups can achieve a serum 25(OH)D concentration of 75 nmol/L. Similar cut-off
values have been recently proposed for infants and pregnant women (Table 3) by the working
group of the Canadian Paediatric Society (4).
10
For a description of the inter-relationship between of vitamin D and PTH, see Section 4: Functions of Vitamin D.
Vitamin D: The Current State in Canada • CCFN Report • August 2008
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Table 3. Definition of Vitamin D Status Based upon Serum 25(OH)D (nmol/L)
Category of
Institute of Medicine and
Canadian Paediatric Society
Health Canada (2)
(4)
Vitamin D
Status
Infants and Children
Adults
Infants and
Pregnant/Lactating Women
Deficient
<27.5
<37.5
<25
Insufficient
NA
NA
25–75
Optimal
NA
NA
75–225
Pharmacological
NA
NA
>225
Potentially toxic
NA
400 to 1250
>500
NA: Not applicable
There are many examples of studies in adults supporting the optimal range of 75 nmol/L. For
older adults >70 years of age, PTH seems to plateau at 100 nmol/L (7). Six studies are well
summarized by Dawson-Hughes et al. (7) who suggest that after correction for different assays,
75 nmol/L is the consensus concentration at which PTH plateaus in adults <70 years of age.
Such consensus does not exist for children.
Caution is warranted in using these values for infants and children since dose–response studies
have not been forthcoming. Particularly in infants and young children under 7 years of age there
are scant data upon which to establish such criteria. In randomized controlled trials (RCT) (30)
or case–control studies (31, 32) of infants where 25(OH)D was different among groups, PTH
was not significantly different. However, in the only high-dosage study of vitamin D
supplementation, an inverse relationship was observed between 25(OH)D and PTH (33).
Unfortunately, the simple linear approach was not suitable to identify a threshold at which PTH
plateaus. It is thus speculative as to whether a 25(OH)D of 75 nmol/L is optimal for infants.
Data for children under 7 years of age are lacking, but some data exist for older children. In the
United States, 25(OH)D levels ≥90 nmol/L in postmenarcheal females 12 to 18 years of age were
associated with plateaus in PTH (34). Similarly, in other countries such as France, a 25(OH)D
level of 83 nmol/L in healthy males 13 to 17 years of age was associated with a plateau in PTH
(35). For females 14 to 16 years of age in Finland, a 25(OH)D level >40 nmol/L was reported as
necessary to reduce PTH, although only 3 females had a 25(OH)D level >80 nmol/L and the
authors indicated that actual plateaus in PTH had not been observed (36). Even in warmer
climates such as Lebanon, 25(OH)D levels >75 nmol/L in male and female children
10 to 16 years of age were associated with no abnormal PTH values (37). Thus it is unclear if a
25(OH)D of 75 nmol/L is optimal for children.
4. Functions of Vitamin D
The most widely understood function of vitamin D is in calcium homeostasis, but knowledge of
emerging roles in other tissues is rapidly evolving. While the best serum indicator of vitamin D
status is 25(OH)D, the active form required in physiology is 1,25(OH)2D. Synthesis of
1,25(OH)2D from 25(OH)D is catalyzed by the enzyme 1-alpha-25-hydroyvitamin D in the
kidney for the purpose of calcium homeostasis and in other tissues for non-calcemic functions
(38).
Vitamin D: The Current State in Canada • CCFN Report • August 2008
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Physiologically, when the blood calcium level falls, PTH is released to promote hydroxylation of
25(OH)D to 1,25(OH)2D. Both PTH and 1,25(OH)2D mobilize calcium from bone and enhance
absorption of calcium from the diet and glomerular filtrate. Vitamin D and PTH follow similar
circannual rhythms, with PTH fluctuating 20% above and below the annual mean in winter and
summer, respectively (39). It is now accepted that PTH plateaus within the normal range when
25(OH)D concentration is over 50–80 nmol/L regardless of seasonality (7). This plateau of PTH
likely is positively associated with bone accretion since a 25(OH)D concentration >75 nmol/L is
associated with higher bone mass (40). Changes in 25(OH)D are followed 1 month later by
changes in PTH, and changes in bone resorption follow changes in PTH by 1 to 2 months (41).
Elevated PTH levels characteristically seen in individuals with inadequate vitamin D status can
result in the long latency disease of osteoporosis (42), but might more readily associate with acute
complications such as tetany and myopathy. In infants and children, vitamin D deficiency causes
rickets and in adults it causes osteomalacia. A high PTH can also result from low dietary calcium,
making the study of vitamin D status, PTH and calcium homeostasis complex.
In addition to calcium homeostasis, vitamin D in its active state (1,25(OH)2D) has the capacity to
modify cellular activity, cell differentiation and proliferation (43, 44), and is thus said to have a
pleiotropic role in physiology and health. Vitamin D receptors have been reported in all organs
(e.g. immune cells, brain, heart, pancreas, intestine), suggesting functionality in these tissues (45).
When vitamin D receptors bind 1,25(OH)2D, the complex heterodimerizes with the retinoid X
receptor, which in turn binds to the vitamin D response element of genes. Depending on the cell
type, protein transcription is regulated in response to 1,25(OH)2D.
5. Consequences of Vitamin D Deficiency
A. Skeletal Consequences
Rickets
Collagen type 1 makes up greater than 90% of the organic matrix of bone (46). At about 8 weeks
gestation, the appearance of primary ossification centres marks the beginning of bone
mineralization (47) followed by an expected transfer of 30 g of calcium from mother to infant
(48). Because of the pleiotropic actions of vitamin D (43, 44), a deficiency is associated with not
only reduced fetal mineralization (31, 49), but also reduced bone growth (50) and in some cases
defective bone modeling resulting in congenital rickets (51). Even if congenital rickets is not
evident at birth, such deficiency is associated with a higher incidence of infant morbidity. These
include symptomatic hypocalcemia that may present as seizures (52, 53), hypoplastic lungs
presenting as respiratory distress syndrome (51, 54), and hypotonic musculature (54).
Vitamin D status positively relates to APGAR scores (an acronym relating to the infant’s
Activity, Pulse, Grimace, Appearance, and Respiration) (55), suggesting a role in critical vital
signs. Thus, correction of maternal vitamin D deficiency has vast implications for fetal and
neonatal health outcome.
Vitamin D deficiency in mothers (56-61) and infants (57-63) is evident throughout the world,
covering a wide range of geographic regions and cultures. Vitamin D deficiency has caused
congenital rickets (51, 54) and re-emergence of vitamin D dependent rickets in infants (64-68).
These studies imply that maternal–fetal transfer of vitamin D is not adequate to achieve optimal
health outcomes in the offspring. Lack of maternal–fetal transfer of vitamin D also manifests as
Vitamin D: The Current State in Canada • CCFN Report • August 2008
2
neonatal vitamin D deficiency thought to be reversible by vitamin D supplementation (3) or
feeding infant formula or milks that are fortified with vitamin D upon weaning. However, the
high incidence of rickets in Canada suggests that these strategies are not adequate to prevent
deficiency and far from that postulated to represent optimal vitamin D status. According to the
recent pediatric surveillance assessment of rickets in Canada, an estimated 2.9 cases per 100,000
occur in infants ranging from 2 weeks to 6 years of age (69). The majority of cases were
characterized by darker skin pigmentation and lack of vitamin D supplementation. In the United
States, 9 cases per million children were estimated to have rickets between 1990 and 1998 (70).
African American children had the highest risk (75% of cases), but Caucasian (20%) and Asian
(5%) children also developed rickets. The common factor among all cases was that they were
breastfed term infants and supplementation practices were questionable. Even some infants fed
formula will develop rickets (53) presumably since maternal–fetal transfer of vitamin D is
inadequate and consumption of only 200 IU/d (0.5 L of formula) is not enough to compensate for
deficiency acquired in utero.
B. Early Life Programming of Bone Mass
The fetal origins of adult disease hypothesis (71-73) is grounded in the intrauterine and early life
environment. In this hypothesis, programming is defined as the “process whereby a stimulus or
insult at a critical period during development, most often during gestation and infancy, has lasting
or lifelong effect(s)” (71). The most common diseases associated with programming include
cardiovascular diseases, diabetes, obesity and more recently osteoporosis (72). Being born small
for gestational age of unknown causes is associated with lower bone mass in children (74) and
elderly men (75) plus a higher incidence of hip fracture in men and women (76). In contrast,
better nourishment as indicated by higher yet normal birth weights is associated with higher adult
whole body, lumbar and hip bone mass even after accounting for age, sex and height plus adult
behavioural factors including smoking, alcohol intake, dietary calcium and exercise (77). With
respect to vitamin D and programming, maternal vitamin D status in the third trimester of
pregnancy positively associated with bone mass in the offspring at 9 years of age (78). Optimal
nutrition during infancy, including breastfeeding (79, 80) and vitamin D supplementation (81), is
also linked to higher bone mass in children. These studies collectively suggest that bone mass is
programmed through nutrition both in utero and postnatally. Providing a vitamin D supplement in
infancy (median duration, 12 months) associates with higher bone mineral density (BMD) at
7 to 9 years of age (81). The BMD of the distal radius was 6% higher and the BMD of the femoral
neck was 9% higher in those who received a vitamin D supplement in infancy (81). The distal
radius and the femoral neck are common sites for osteoporotic fractures later in life (82, 83),
further implying that optimization of vitamin D early in life may formulate an important aspect in
the primary prevention of osteoporosis. Additionally, infants who are breastfed have higher
osteocalcin (84), and osteocalcin also positively associates with vitamin D status (85). Higher
values for osteocalcin early in life continue into childhood (86). Overall, early life nutrition,
including the intrauterine environment, breast milk and vitamin D, is documented to have longlasting affects on bone. The growing evidence that early life nutrition programs later bone health
(72, 76, 87), combined with growing evidence that vitamin D status is compromised through
pregnancy and childhood, places many Canadians at risk for poor bone health.
C. Children
Other age groups are also vulnerable to the effects of vitamin D deficiency on skeletal health.
Strategies to optimize bone mass in children should begin early and continue throughout their
Vitamin D: The Current State in Canada • CCFN Report • August 2008
3
lives. In addition to the possible early life programming of bone mass in fetal and infant stages,
bone mineral accretion throughout the growing years is important. Canadian data demonstrate
that maximal calcium accretion is achieved at the age of 12.5 years for girls and 14.0 years for
boys (88). This is important since bone mass attained early in life is considered the most
important determinant of bone health later in life (89). Peak bone mass is defined as the highest
bone mass achieved and in Canada this is reached by 25 years of age (90). Thus, childhood (birth
to 18 years of age) accounts for most of the biological window whereby bone mass is developed.
A recent study in peri-pubertal females (ages 9 to 15 y; n=171) (91) underscores the importance of
vitamin D status to support bone mineral accretion. In particular, this study points to the effects of
deficient vitamin D status, versus adequate or optimal status, on bone mineral accretion. Over the
3 years of study, girls with highest vitamin D status at baseline (no intervention) had the largest
positive change in lumbar spine BMD, even if adjusted for body size. Girls with 25(OH)D
concentrations of 19.2 nmol/L (~7.7 ng/ml) had smaller changes in spine BMD—0.111 vs
0.140 g/cm2, a difference of 0.029 g/cm2 or relative elevation of 26.1% if 25(OH)D approaches
adequacy. Whether higher concentrations 25(OH)D (73–83 nmol/L [29–33 ng/ml]) would elevate
mineral accretion further is not known. Another study whereby adolescent girls were randomized
to placebo, 200 or 400 IU/d of vitamin D for 1 year showed significant improvements in bone
mass of the lumbar spine and hip with the 400 IU dosage (92). The lower dosage of 200 IU/d also
improved lumbar spine bone mass, but not hip.
D. Young Adults and Aging
Clinical practice guidelines for the management of osteoporosis, a disorder occurring later in life,
include weight-bearing activity, calcium, and vitamin D (5) with primary prevention being key (5).
In Canada, the prevalence of low bone mass is higher than in other countries located
predominantly south of 40°N (90). In theory, this observation could be linked to vitamin D status.
The most well-studied age group with respect to vitamin D nutrition is adults, with emphasis on
those over 65 years of age. Vitamin D supplementation trials have shown that higher intakes of
vitamin D associate with higher vitamin D status, which is associated with better bone mass, tooth
retention, fewer falls and some improvements in physical ability (8). This research area is well
reviewed in the NIH systematic review (8) and thus not detailed herein. From that review,
however, the majority of studies have used 800 IU as the upper end of the dose–response (8).
The areas requiring further study, however, are the amounts of vitamin D required to optimize
peak bone mass during the consolidation years; that is, in young adults 18 through 40 years of age.
It is thought that peak bone mass is achieved somewhere between 25 and 40 years of age based on
stable BMD in cross-sectional studies (90) .
E. Reproductive Women
Bone loss in women with vitamin D deficiency during pregnancy and lactation may also be a risk
factor for osteoporosis. It is estimated that a woman can lose up to 10% of her bone mass during
lactation (93-98), with greater losses evident in women who breastfeed longer (93). Notably,
trabecular bone mass is lost in the femoral head and lumbar spine with lactation (99). Yet, it
seems in some studies that lactation does not have long-term negative effects on the skeleton (100102), and might in fact present an opportunity to increase bone mass or protect against
osteoporotic fracture at trabecular sites (103). While vitamin D status of a woman is not expected
to be compromised by pregnancy or lactation to a great extent (i.e. small amounts are transferred
Vitamin D: The Current State in Canada • CCFN Report • August 2008
4
to the infant), women with low vitamin D status may not recover as well from the demands of
pregnancy/lactation with respect to bone mass. This is evidenced in a study of healthy Saudi
women in which total duration of lactation had a negative relationship with bone mass (104).
These women had very low vitamin D status, leading the authors to conclude that women with
vitamin D deficiency do not fully recover bone mass after lactation (104). In many ways the
hormonal milieu of pregnancy is similar to that of postmenopausal women; that is, lack of
estrogen and losses of bone mass up to 7% over a short period of time (94). It is reasonable to
expect that bone health of mothers will benefit from improvements in vitamin D status. This
speculation is highly supported by recent work in lactating women in which high dosage
vitamin D supplementation (2000 to 4000 IU/d for 3 months) had a positive affect on 25(OH)D
concentrations (105) into the range associated with optimal bone mass (7). In another study,
women receiving 400 IU/d vitamin D plus 1 g of calcium readily recovered mineral losses during
pregnancy and lactation after an equal period of weaning (94). Thus, the benefits of lactation on
bone mass might best be realized in association with optimal vitamin D status. This is an
important question to address since women consolidate bone between 25 and 40 years of age (90).
If bone mass lost during pregnancy and lactation is not replenished due to the high incidence of
vitamin D deficiency observed in Canada (106, 107), this poses another challenge to acquisition
and maintenance of peak bone mass in our population.
B. Non-Skeletal Chronic Diseases
Non-skeletal chronic diseases that might originate from vitamin D deficiency and the genomic
response include cancer, multiple sclerosis, schizophrenia and diabetes (1), but the associations
between vitamin D exposure and development of these chronic diseases is not yet as convincing as
it is for bone. Epidemiological studies reveal that the prevalence of these diseases is greater as
latitude increases, suggesting that lower exposure to UVB radiation and associated decreases in
vitamin D synthesis may play a role in their pathology. Cancers associated with vitamin D
deficiency include non-Hodgkin lymphoma (108), leukaemia (109), and breast cancer (110).
Additionally, glioblastoma is most frequently diagnosed in a winter month (111) and incidence of
brain tumours in adults is higher in those born in the winter (112). None of these studies were
conducted in a Canadian population. Canada, however, is leading the path in describing the role
of vitamin D in multiple sclerosis (113), while Australian research shows that during the winter
months with less UVB, there is a 7–10% increase in the number of people born with schizophrenia
(114). Vitamin D is also proposed as a critical neuroactive substance as it has wide-ranging
effects in brain including induction of nerve growth factor (115). In recent studies, rat pups born
to vitamin D deficient mothers had profound alterations in the brain at birth (116). The possible
etiology of different cancers might be rooted in development and function of the immune system
(1, 43, 117). These findings suggest that low maternal vitamin D has important ramifications for
the developing immune system and brain. However, these studies were done at extreme vitamin D
deficiencies, and the long-term effects and a clear link to learning have yet to be determined.
Epidemiological studies examining early vitamin D supplementation and the risk of type 1
diabetes (118-121) suggest vitamin D protects against development of this autoimmune disease
(117). One study (120) linked subsequent type 1 diabetes status to vitamin D supplementation in
infancy. The relative risk of for developing type 1 diabetes was reduced (RR=0.12, CI 0.03–
0.47) with 2000 IU vitamin D supplementation. More recent intervention studies are lacking and
studies showing that optimal maternal vitamin D status in pregnancy reduces the incidence of
Vitamin D: The Current State in Canada • CCFN Report • August 2008
5
type 1 diabetes in the child are also lacking. Vitamin D status is also associated with glucose
metabolism and insulin sensitivity index in adults even after correcting for age, gender and BMI
(122). This was confirmed in a secondary analysis of vitamin D supplementation originally
designed to test for bone health (123). In non-pregnant adults with impaired fasting glucose,
vitamin D supplementation (700 IU/d plus 500 mg/d calcium) over 3 years limited further
elevation in fasting plasma glucose (123). In a short one-month RCT using 1332 IU/d vitamin D
in adults with type 2 diabetes, the initial secretion of insulin following an intravenous glucose
challenge was significantly elevated by 34% accompanied by non-significant reductions (24%)
in insulin resistance (124). Even though 25(OH)D concentrations increased over the month
(124), longer durations are required in adults to arrive at optimal concentrations of >75 nmol/L
(24) that are thought to be required for glucose homeostasis (125).
Women are vulnerable to complications associated with vitamin D deficiency in pregnancy.
Preeclampsia (PE) is a pregnancy disorder characterized by maternal hypertension, proteinuria,
edema, and fetal growth restriction. Epidemiological studies and clinical studies demonstrate
alterations in maternal calcium metabolism in PE and relationships to dietary calcium intake
(126, 127). In this context, PE is characterized by lower serum calcium concentration (128),
hypocalciuria (129, 130), raised PTH concentration (131) and decreased plasma 1,25(OH)2D
concentration (130) in the mother and low birth weight in the offspring. All of these clinical
symptoms also are associated with vitamin D deficiency, implicating vitamin D in the
development of PE. This speculation is supported by a case–control study that reported an early
pregnancy vitamin D <37.5 nmol/L (deficient) was associated with a five-fold elevation in the
odds of developing PE (adjusted OR 5.0; 95% CI 1.7–14.1) (132). Such low values prior to
22 weeks of pregnancy were particularly associated with PE (132). Further, reduction in
25(OH)D to values lower than 50 nmol/L resulted in a two-fold risk of developing PE (OR 2.4,
CI 1.1–5.4). On average this decline was between 10 and 39 weeks of pregnancy. This
association was independent of race, season, BMI and education. Interestingly, 93% of the
women took a prenatal supplement. However, based on the Health Canada Drug Product
Database,11 this is most certainly less than 400 IU/d on average and not enough to provide for
optimization of vitamin D status. Transfer of vitamin D to the fetus is also compromised in that
infants of women with PE had a two-fold elevation in the prevalance of a cord 25(OH)D
<37.5 nmol/L. In another small case–control study of women with normal pregnancies (n=24)
and women with PE (n=24), serum 1,25(OH)2D was also lower in the women with PE (133), as
is typically seen in states of vitamin D deficiency. RCT are few in the area of vitamin D and PE.
In women given calcium and vitamin D supplements, the incidence of PE was reduced from
16.9% to 10.9% (134). This complements an older study from 1987 whereby women were
randomly given 375 mg/d calcium and 1200 IU/d vitamin D at 20 to 24 weeks of pregnancy. At
32 and 36 weeks of pregnancy, blood pressure was lower in the intervention group, but incidence
of eclampsia was not different (6 and 9%) (135). Large-scale RCT are required to establish if
optimization of vitamin D throughout pregnancy is effective in reducing the incidence of
pregnancy-induced hypertension and PE. The value of such a study might translate into
generations of health since vitamin D status in pregnancy is now reported to be a predictor of PE
later in reproductive years (136). Improvements in vitamin D function through 1,25(OH)2D
treatment is also proposed to reduce spontaneous abortions (137).
11
www.hc-sc.gc.ca/dhp-mps/prodpharma/databasdon/index-eng.php
Vitamin D: The Current State in Canada • CCFN Report • August 2008
6
As noted earlier in this report, obese women are at higher risk of vitamin D deficiency (138).
Coincidently they are also at heightened risk for developing gestational diabetes mellitus (GDM)
if they do not already have type 2 diabetes. A very recent report shows that severe vitamin D
deficiency (<12.5 nmol/L) is more commonly observed in women with GDM compared to the
controls (22 nmol/L) and that vitamin D status strongly associates with the HOMA-IR
(homeostasis model assessment-insulin resistance) index (139). Even glucose intolerance was
associated with intermediate deficiency (18 nmol/L). These low values within the realm of
deficiency demonstrate a dose-effect for different health outcomes, again implying that
deficiency should be eradicated to promote both maternal and fetal health. The limitation with
readily drawing conclusions from this study, however, is that the women with GDM also had a
higher BMI than the control women. However, in a non-pregnant state, vitamin D status was
strongly related to the insulin sensitivity index even after correcting for age, gender and BMI
(122). Thus, the relationship between vitamin D and GDM might not necessarily be confounded
by BMI and requires clarification. Pursuing such a potential intervention is important not only
for prevention of GDM and the associated pregnancy complications, but also because of the
possibility of reducing susceptibility to development of type 2 diabetes postpartum (140).
Primary prevention of other cancers is also linked to vitamin D. There are now many
epidemiological studies suggesting that vitamin D is important in cancer prevention.
Intervention studies show that for men, higher vitamin D status is associated with slower
progression of prostate cancer (141). Vitamin D in a case–control study shows that higher
intakes and status are associated with lower risk of breast cancer in women (142). These two
studies were conducted in a Canadian population.
Vitamin D: The Current State in Canada • CCFN Report • August 2008
7
III. Life Stage Groups
1. Infancy
A. Dietary Vitamin D Intake of Canadian Infants
Assessment of vitamin D intake by infants in Canada is limited as a primary outcome. In
primiparous mothers (n=1937) in Quebec, 58.1% of those exclusively breastfeeding gave their
infant vitamin D supplements in the first six months and 62.1% of those feeding formula did not
(143). However, the volume of the supplement was not reported although use of supplements
was associated with having post-secondary education (143). There are no data on older infants
in Canada, but in a report by Nolan et al. (144) from New York, vitamin D intake was inadequate
in infants 12 to 18 months of age among low-income urban families, suggesting that transition to
weaning foods might be an issue in Canada as well. The Canadian Community Health Survey
(CCHS) has also examined infant diets, but data are not readily available.
B. Vitamin D Status of Canadian Infants
From the 1990s it was apparent that in Northern Canada, most infants were born with a serum
25(OH)D concentration less than 30 nmol/L (145). It was estimated that up to 80% of the nonwhite infants were at risk for vitamin D deficiency (145). More recently in Manitoba, 36% of
infants from white or non-white parents were found to be deficient in vitamin D at birth, defined
as a serum 25(OH)D <27.5 nmol/L (49). In a Northern Manitoba community, 43% of older
infants 3 to 24 months of age had serum vitamin D levels below the normal range (146). While
not Canadian data, but included here to reflect the Arctic, in Alaska infants between
6 and 22 months of age enrolled in the Women, Infants and Children program were studied for
vitamin D status and feeding practices (147). While the study spanned 13 months that would
have included summer months, 11% of infants had a vitamin D deficiency defined as a 25(OH)D
<37.5 nmol/L. Infants who were breastfed had a 12-fold higher likelihood of having a deficiency
and among infants who were still breastfeeding, only 34% received a supplement of vitamin D at
least occasionally.
C. Evidence of Vitamin D Related Health Issues in Canadian Infants
According to the recent pediatric surveillance assessment of rickets in Canada, there are 2.9
cases per 100,000 in those ranging in age from 2 weeks to 6 years (69). The majority of cases
were characterized by darker skin pigmentation and lack of vitamin D supplementation. Even
some infants fed formula will develop rickets (53), presumably since maternal–fetal transfer of
vitamin D is inadequate and consumption of only 200 IU/d (0.5 L of formula) is not enough to
compensate for any deficiency acquired in utero. Similarly, from 1990 to 1998 in the United
States, 9 cases per million of children were estimated to have rickets (70). African American
children have the greatest risk (75% of cases), but Caucasian (20%) and Asian (5%) children also
developed rickets. The common factor among all cases was that they were breastfed term infants
for whom perinatal supplementation practices were questionable. Thus the reemergence of
rickets is not unique to Canada.
Vitamin D: The Current State in Canada • CCFN Report • August 2008
8
D. Solutions for Improving Vitamin D Nutrition in Canadian Infants
Very few dose–response studies exist for vitamin D supplementation in infancy. The challenge
is that the current recommendations have not been rigorously tested through hypothesis-driven
research designs that include dosages above the suggested intake values of 400 to 800 IU/d.
There are three randomized trials (RT) that were all conducted at latitudes similar to Canada, but
only in infants ≤6 months of age.
One RT in breastfed infants in China (148) tested 100, 200 and 400 IU/d of vitamin D2 but not
higher amounts such as 800 IU/d. To highlight key data of the available randomized studies, an
intake of 100 to 400 IU/d of vitamin D2 in Chinese infants increased 25(OH)D on average, but
some infants in the northern regions of China (40–47ºN) still had undetectable values after
6 months of supplementation even with the higher dosage (148). Compliance was not clear in
this study and PTH and bone mass were not measured. Alkaline phosphatase (isoform not
specified) was measured, but did not change with increasing vitamin D dosages. Likewise, no
other markers of bone metabolism have been assessed in any randomized study of vitamin D
intake in infants that reflect bone formation or resorption as required for modeling of bone.
In the USA, an RCT tested 400 IU/d vitamin D2 vs placebo in breastfed infants (149). An
average 25(OH)D of 92 (range 67–117) nmol/L was observed by 6 months of age, but PTH was
not affected (149). In this study, bone mineral content (mg/cm) of the distal radius was
measured, but no differences were observed in absolute or delta values by 6 months of age. No
other measurements of bone mass were conducted, such as whole body bone mineral content
which is recommended for assessing infant bone mass today (82).
The only other RT was in France (33) and tested 500 and 1000 IU/d in infants fed formula
(containing vitamin D3), but again the supplemental form was vitamin D2. At these dosages,
serum 25(OH)D concentrations approximated 70 nmol/L. Mean values were 69 nmol/L, with no
value >93 nmol/L. Keeping in mind that the infants received both the supplement and
supplemented formula, these data suggest that intakes >1000 IU/d might be required to optimize
vitamin D status. The problem with this assumption is that the value of 25(OH)D indicative of
optimal status is not clear in infants based on response of bone metabolism, including PTH, and
bone mass. Additionally, those infants with low baseline 25(OH)D did not demonstrate
normalization of PTH. Further, it is becoming well accepted that vitamin D2 (plant form) is not
as suitable as vitamin D3 (mammalian form) due to differences in metabolism.
There are no RCT for vitamin D3, as is used in Canada, at dosages beginning at 400 IU and
extending to 800 IU and above as recommended by Health Canada (3) and the Canadian
Paediatric Society (4). It is important to provide evidence to support an oral dosage of vitamin D
for optimal bone health outcomes, including safety. Two RCT are currently underway, one in
Canada with dosages ranging from 400 to 1600 IU beginning at 1 month of age12 and the other in
the USA using 200 to 600 IU also beginning at 1 month of age.13
12
13
www.clinicaltrials.gov; Identifier NCT00381914
www.clinicaltrials.gov; Identifier NCT00494104
Vitamin D: The Current State in Canada • CCFN Report • August 2008
9
2. Childhood
A. Dietary Vitamin D Intake of Canadian Children
Assessment of the vitamin D intake of Canadian children is limited as a primary outcome, but
there are several studies (published and unpublished) that have included dietary assessment with
either direct (IU vitamin D/d) or indirect (servings of milk) evidence of vitamin D intake. In
Canada, the majority of data emanates from Quebec. For preschoolers in Quebec (n=98),
vitamin D consumption was ~280 IU/d, based on 24-hour recall data, or 425 IU/d based on food
frequency questionnaires (150). Another study in preschool children showed that vitamin D
intake was lower if dietary fat was low (151). Likewise, a report on Montreal children
approximately 10 years of age indicated that only 78% consumed milk each day (the volume
consumed was not quantified) (152). In Alberta, a school intervention program revealed that
girls aged 10 to 12 years are at high risk of not meeting the recommended intake of
vitamin D (153). In First Nations children 10 to 12 years of age, intake of vitamin D from both
traditional foods and non-traditional foods ranged from 100 to 128 IU/d (154). This
complements older reports of inadequate consumption of vitamin D in First Nations children
from the early 1980s (155). In addition many obese and non-obese children do not meet the AI
(156). Lastly, in a school milk promotion program, many females 10 to 12 years of age and
inner-city students were at greatest risk of not meeting the AI (153). Similarly in the Food
Habits of Canadians survey, teens 13 to 17 years of age consumed, on average, 3 servings of
milk per day or approximately 264 IU of vitamin D (157).
These Canadian data are very similar to those in the USA. The 24-hour vitamin D intake for a
sample of 27,045 children 1 to 18 years of age in the 1988-1994 U.S. National Health and
Nutrition Examination Survey (NHANES III),14 and data from two separate 24-hour recall
assessments (Continuing Survey of Food Intakes by Individuals [CSFII] 1994-1996, 1998),
suggested that vitamin D intake for all ages, except for females 14 to 18 years of age, was
>200 IU/d (from a low of 208 IU/d for females 9 to 13 years to a high of 280 IU/d for males
14 to 18 years) (158). Values for females 14 to 18 years of age were 156 IU/d (3.9 µg/d from
CSFII) and 172 IU/d (4.3 µg/d from NHANES III) (158).
Overall, most children in Canada and the USA seem to meet the current recommendation of
200 IU/d. Groups at higher risk for not achieving adequate intake include teenage girls (158)
and First Nations children (154). If the recommendation is increased, however, many if not most
children will be unable to achieve higher intakes unless food fortification policy and
supplementation practices change.
B. Vitamin D Status of Canadian Children
Children in Canada do not appear to have serum 25(OH)D levels consistent with the
hypothesized optimal concentration (i.e. 75–80 nmol/L).15 In fact, in all existing reports a
14
NHANES III was conducted on a nationwide probability sample of approximately 33,994 persons 2 months and
older by the Centers for Disease Control and Prevention in the United States. The survey was designed to obtain
nationally representative information on the health and nutritional status of the population of the United States
through interviews and direct physical examinations.
15
Further research is required to prove that 75–80 nmol/L is the optimal target for 25(OH)D levels in children.
Vitamin D: The Current State in Canada • CCFN Report • August 2008
10
significant proportion have 25(OH)D consistent with vitamin D deficiency. In a 1993 study in a
northern Manitoba community, 43% of infants aged 3 to 24 months had vitamin D levels below
the normal range (146). In the Quebec preschooler study, data on a subset (n=61) of the cohort
have been published as an abstract and include data on vitamin D status in winter and summer.
The overall range of 25(OH)D levels was 41.4 to 158.7 nmol/L, and therefore above the
deficiency level. The intake in this sub-sample was ~380 to 444 IU/d of vitamin D which,
combined with endogenous synthesis, supported vitamin D status above the deficiency cut-off
and in some cases into the optimal range (159). An Edmonton study suggests that children
2 to 16 years of age in Canada are at high risk for low 25(OH)D concentrations. In this study the
definition of deficiency was <25 nmol/L and insufficiency <40 nmol/L (160). Overall, if the
results are combined 40% had values <40 nmol/L. If examined by age and sex, 69% of males
9 to 16 years of age had insufficient status while only 8% of girls aged 2 to 8 years had
insufficient status. Thus, male children might have higher risk for inadequate vitamin D status.
The children in the study were recruited through a hospital emergency department and thus may
not represent children in the general population or unique groups. First Nations children in 1978
were reported to be deficient in vitamin D (161), but more recent reports are not available.
No other Canadian data for vitamin D status in children exist at present. However, in Alaska,
infants between 6 and 22 months of age enrolled in the Women, Infants and Children program
were studied for vitamin D status and feeding practices. While the study spanned 13 months that
included the summer, 11% of infants had a vitamin D deficiency defined as a 25(OH)D
<37.5 nmol/L. Infants who were breastfed had a 12-fold higher likelihood of having a deficiency
and only 34% received vitamin D supplementation at least occasionally (147). In another USA
report, children aged 11 to 18 years in Boston (n=307) were assessed for vitamin D status during
their regular annual physical examinations; 43% were deemed to be vitamin D deficient, with
25(OH)D levels <50 nmol/L(162).16 Thus the problem of vitamin D deficiency is not unique to
Canada.
C. Evidence of Vitamin D Related Health Issues in Canadian Children
Reports of rickets that include children over 1 year of age have been published for many years
(67, 68, 163). The recent pediatric surveillance assessment of rickets in Canada reported a
prevalence rate of 2.9 cases per 100,000 in those ranging in age from 2 weeks to 6 years (69).
The risk factors for children are the same as for infants aside from breastfeeding without
supplementation. Reports of rickets in older children (i.e. >6 years old) are lacking in Canada,
suggesting that either intakes or endogenous synthesis are sufficient to prevent severe deficiency.
D. Solutions for Improving Vitamin D Nutrition in Canadian Children
During the winter months in Canada, in the absence of sunlight or safe exposure to UVB, it is
unclear how much oral vitamin D is required to achieve and maintain optimal 25(OH)D levels in
children. A school milk program did improve intakes (153), but status was not assessed. Some
research has been conducted in other countries as summarized below.
16
Note that the definition of deficiency used in this study differed from the level recommended by the IOM (see
Table 3).
Vitamin D: The Current State in Canada • CCFN Report • August 2008
11
Daily dosages of vitamin D2 and D3 isoforms greater than 400 IU require testing.
•
In Finland, researchers analyzed the amount of vitamin D2 required to normalize vitamin D
status in girls 9 to 15 years of age (n=171). A dosage of 400 IU was adequate in many
individuals in terms of elevating serum 25(OH)D >37.5 nmol/L; supplemented versus
unsupplemented girls had 25(OH)D levels of 45.5 versus 31.8 nmol/L (164). Clearly, 400 IU
was not enough to support the suggested optimal 75 nmol/L.
•
Daily intake of 624 to 1000 IU (15.6–25 µg) of vitamin D2 (ergocalciferol) in children
5.2 years of age with maple syrup urine disease resulted in serum 25(OH)D values
>90 nmol/L (165).
•
A study in France suggested that optimal vitamin D status can only be achieved through
supplementation: 100,000 IU of oral vitamin D3 given every 3 months during the winter
achieved 25(OH)D levels >50 nmol/L (not deficient) in all participants (10–15 years of age).
Without the supplement, the prevalence of deficiency was maintained at 62%. This study
suggests that 1000 IU of vitamin D is required daily in the winter to correct deficiency and
maintain 25(OH)D concentrations (12).17
•
In Spain, elevation of 25(OH)D levels from 32 to 114 nmol/L and significant reductions in
PTH occurred when children 7 to 10 years of age were given 1600 IU of daily vitamin D
supplements for one week in March (166).
Overall, if 75 nmol/L is adopted as the optimal target for all ages, the current AI of 200 IU/d
seems inadequate. It is more likely that RCT designed to test for the dietary intake required to
optimize 25(OH)D will be successful in using dosages over 600 IU/d.
3. Young Adulthood
A. Dietary Vitamin D Intake of Canadian Men and Women 18–50 Years of Age
There are a few reports regarding vitamin D status of men and women 18 to 50 years of age in
Canada. Assessing vitamin D intake is difficult as not many foods contain vitamin D. In
Toronto, Vieth’s work shows that women frequently do not achieve the 200 IU/d AI (106).
Other reports echo this low intake in Punjabi men and women where the intake was 140 and
132 IU/d, respectively (167). In Dene Métis and Inuit adults, Kuhnlein et al. (168) showed that
vitamin D intake ranges from 1405 to 1000 IU/d. Data were not separated based on sex or age.
In the First Nations Bone Health Study (169), which included a group of women 25 to
50 years of age, vitamin D intake was on average 440 IU/d in First Nations and 344 IU/d in
white women. From a study of mammary density in Quebec, vitamin D intake of premenopausal
women was ~188 IU/d from food and 394 IU/d from supplements (170). Based on milk intakes
from the CCHS dataset (171) and the Food Habits of Canadians studies (172), most men and
women do not consume even 2 servings of milk and thus vitamin D intake is most likely
<200 IU/d.
17
The maximum level of vitamin D intake likely to pose no risk of adverse effects is 2000 IU/d for children. (2)
Vitamin D: The Current State in Canada • CCFN Report • August 2008
12
B. Vitamin D Status of Canadian Men and Women 18–50 Years of Age
There are more reports on the vitamin D status of healthy men 19 to 50 years of age than on their
dietary intake. In Calgary, for men and women aged 27 years and older, vitamin D deficiency
was common and it was found that 34% have low vitamin D status in at least one season (107).
For Punjabi immigrants to Canada, men had serum 25(OH)D of 36±13 nmol/L (167) and women
had values of 31±8 nmol/L (167). In Toronto, deficiency is prevalent in 14.8% of white women
and 25.6% of non-white non-black women, even if they consume 200 to 400 IU of vitamin D
daily (106). During the winter months, the prevalence was not significantly affected by dietary
or supplemental vitamin D intakes at values similar to the AI of 200 IU/d (5 µg/d) (106). Recent
results of the 1988-1994 NHANES III indicate that the prevalence of hypovitaminosis D
(defined as 25(OH)D <37.5 nmol/L) was 42.4% among African Americans and only 4.2%
among white American women of reproductive age (173). However, vitamin D status at the
most northern latitudes was not assessed in the winter months, and this likely led to
underestimation of the problem in the white women. Recent research out of the University of
Toronto shows that 25(OH)D <50 nmol/L, consistent with insufficiency, is observed in
university students based on ethnic background: 100% of Black, 85% of Asian, 93% of South
Asian and 34% of European students were insufficient in vitamin D.18
C. Evidence of Vitamin D Related Health Issues in Canadian Men and
Women 18–50 Years of Age
Most health outcomes related to vitamin D are chronic in nature. Within Canada research related
to multiple sclerosis (113), prostate cancer (174) and breast density (142, 170, 175) show that
individuals with higher 25(OH)D have better odds of achieving improved health.
D. Solutions for Improving Vitamin D Nutrition in Canadian Men and
Women 18–50 Years of Age
From studies examining the risk of cancer, the food that most commonly is associated with better
vitamin D status is milk (142, 175). Even in the First Nations Bone Health Study, the foods
contributing the most vitamin D were milk, whether as pasteurized or condensed milk, and
margarine (169). Thus, the mandated food fortification of milk and margarine in Canada (15)
makes significant contributions to vitamin D status. Many of the reports show that vitamin D
supplements are consumed by many Canadians. To achieve higher 25(OH)D, selection of foods
containing vitamin D is important and supplementation required during the winter to achieve
25(OH)D >75 nmol/L (175). In order to achieve 25(OH)D concentrations of 75 nmol/L,
Canadian data suggest that 200 IU/d is inadequate and that intakes of 1000 to 4000 IU/d might
be required in some individuals during the winter months (29).
4. Reproduction: Maternal–Fetal, Maternal–Infant
A. Dietary Vitamin D Intake of Canadian Women during Reproduction
National surveys regarding vitamin D intakes from diet and supplements are lacking in Canada.
In a small-scale study of 50 women from mixed ethnic backgrounds in Winnipeg, only 78% of
the women reported taking multi-nutrient supplements during pregnancy and 46% had 25(OH)D
18
The research findings were released in the Globe and Mail on December 17, 2007, prior to publication.
Vitamin D: The Current State in Canada • CCFN Report • August 2008
13
in the deficient range (49). Only 61% of the mothers with deficiency had taken a supplement,
while almost all of the women without a deficiency had taken a supplement (93%). Dietary
intake from food sources was somewhat lower as well in the deficient women (149 vs 242 IU/d)
(49). No other recent Canadian studies with combined assessment of dietary and supplemental
intake and status of vitamin D exist. In an earlier report, a predicted prevalence of deficiency
was estimated at 48.4% in Native mothers taking a vitamin D supplement and 88.6% in mothers
not consuming a supplement (145). For non-Native mothers taking a supplement, the prediction
was 15.1% and without a supplement 63.5% (145). Similarly, Lebrun et al. (146) reported that
76% of Northern Manitoban women and 43% of the children (3–24 months) had 25(OH)D below
the normal range. Access to food and supplemental sources of vitamin D was limited, forcing
reliance on endogenous synthesis that itself is limited due to latitude and UVB exposure.
Clearly, the cause of vitamin D deficiency in many Canadians is rooted in inadequate
endogenous synthesis combined with exogenous intakes that are not sufficient alone to support
vitamin D status.
Inadequate sources of vitamin D are not unique to Canada. In the Northern USA, 90% of one
cohort (n=400) of pregnant black and white women took a prenatal vitamin supplement at least
once per week in the third trimester, presumably with some vitamin D (176). Despite the
supplementation, approximately 20% of the women had vitamin D deficiency (176). A
relatively recent review paper summarizes the literature on vitamin D status in pregnancy
throughout the world (177). That review covered the periods 1966 up to 2002 and revealed that
35 of 76 (46%) reports included women with 25(OH)D concentrations <35 nmol/L; the majority
of reports emanated from Europe and the UK. Thus, vitamin D deficiency during pregnancy is
common in industrialized nations. The ongoing deficiency in pregnant women through the 21st
century needs to be resolved in view of the early life programming hypothesis and recent
evidence linking vitamin D status to pregnancy outcome for the mother as well. It is clear that
dietary sources of vitamin D and de novo synthesis in today’s environment are not enough to
support optimal vitamin D status (potentially 75 nmol/L (178)) in maternal–infant populations in
Canada.
B. Vitamin D Status of Canadian Women during Reproduction
The total amount of vitamin D transferred from mother to fetus is thought to be small relative to
maternal stores (2). Fetal vitamin D concentrations are frequently lower than maternal
concentrations, with correlations ranging from 0.6 to 0.8 (2, 49), although they can be almost
identical. For example in one study, maternal 25(OH)D pre-delivery correlated with cord blood
25(OH)D with a correlation coefficient of 0.97, meaning the relationship was just under 1 to 1
with values in the infant slightly lower (132). These relationships imply that maternal–fetal
transfer must exist through a passive route (i.e. transfer down a concentration gradient). To date,
the exact mechanism(s) of placental transfer is not known, but likely can be accommodated
through transfer of existing maternal 25(OH)D or placental hydroxylation of maternal dietary
vitamin D (179) that has not been metabolized already by the liver.
Some clinicians suggest that 25(OH)D concentration might decline over pregnancy as a result of
hemodilution and expansion of the plasma volume. One study, however, conducted in Tehran
(35.7ºN) demonstrated that 25(OH)D concentrations actually improved on average from the first
(60% deficient defined as 25(OH)D <50 nmol/L) to third (47% deficient) trimester spanning
Vitamin D: The Current State in Canada • CCFN Report • August 2008
14
summer to winter (180). This suggests that vitamin D status is not necessarily worsened during
pregnancy as a result of the maternal–fetal relationship. For studies in which 25(OH)D declined,
it is possible that utilization by the placenta and fetus might contribute at least to some of the
reduced concentration. However, changes in vitamin D status over pregnancy are more likely
attributed to reductions in both endogenous and exogenous sources rather than a high demand for
fetal vitamin D requirements.
While little data exist in Canada, it appears that individuals who are at high risk for suboptimal
and deficient vitamin D status attributed to low endogenous synthesis include individuals who
reside: (a) predominantly indoors (181, 182), (b) in the far northern or southern hemispheres
(183-185), and/or (c) in moderate latitudes, but who remain fully clothed while outdoors (186189) or use sunscreens with SPF >8 and fail to achieve daily exposure >15 minutes (17). Some
evidence is building that pollution may be emerging as a contributing factor to poor dermal
synthesis of vitamin D (190) and there is another more recent study in New Zealand suggesting
that veiled women are at high risk of vitamin D deficiency (191). However, these researchers
also noted that while only 22% of the women wore veils, 87% of the pregnant women had
25(OH)D concentrations <50 nmol/L and 61.2% had values <25 nmol/L (191), suggesting that
other factors contribute to the deficiency.
Dark skin pigmentation or concealing clothing also yields higher prevalence of deficiency in
infants (63 vs 16%) and higher alkaline phosphatase (192). In Winnipeg, Canada, about 75% of
non-white and 30% of white pregnant women were vitamin D deficient, defined as serum
25(OH)D <37.5 nmol/L (49). In these women, sampled 1 to 2 days postpartum, only five (10%)
had a 25(OH)D concentration >75 nmol/L, with two (4%) having values >100 nmol/L (49). In
another report, up to 80% of women and their infants were at risk of vitamin D deficiency if they
were non-white (145). Not taking supplements can exacerbate this problem. Infants of mothers
with these characteristics are often vitamin D deficient by 3 months of age (193). Even in
warmer countries closer to the equator, infants of darker skin are frequently diagnosed with
rickets (65, 194).
Additionally, low 25(OH)D might be related to maternal weight. There is now evidence that the
relationship between vitamin D intake and vitamin D status may be modified by obesity. Prepregnant BMI <25 is associated with higher adjusted 25(OH)D concentration at 4 to 22 weeks
compared to women with BMI >30 (57 vs 63 nmol/L) (138); the prevalence of deficiency was
61% for the obese and 36% for those with a healthy BMI (138). Interestingly in this same study,
supplementation was more frequent in those with normal pre-pregnancy BMI and not in the
deficient women (176). Thus, it is most likely that supplementation is more important than
screening on the basis of BMI.
C. Evidence of Vitamin D Related Health Issues in Canadian Women during
Reproduction
Within Canada, the consequences of low 25(OH)D are not clear. It is assumed that the
consequences would be the same as those observed in other countries as previously reviewed and
for Canadian women in general. These include bone loss, tetany, gestational diabetes, and
preeclampsia.
Vitamin D: The Current State in Canada • CCFN Report • August 2008
15
D. Solutions for Improving Vitamin D Nutrition in Canadian Women during
Reproduction
It is clear that adequate dietary intake is absolutely required if UVB exposure is limited. In
Canada, the main fortified sources of vitamin D are cows milk, margarine, and more recently
fortified soy and rice beverages, orange juice, and yogurt made from fortified cows milk.
Natural sources include fatty fish, eggs and some mushrooms. A pregnant woman who drinks
2 cups of fortified milk would meet the recommendation of 200 IU/d. Inclusion of 2 cups of
fortified orange juice and regular consumption of eggs would approximately double this to
400 IU/d. In an RT with either no intervention (control), or increased dietary calcium using
orange juice or milk products, adolescent mothers who consumed the milk had significantly
higher 25(OH)D than control (58 vs 108 nmol/L) and those consuming orange juice (195).
Intakes in the milk group approximated 10 µg/d (400 IU/d). The infants in the milk group were
also heavier at birth (240 g) and had higher total body calcium. However, as is discussed earlier
in this chapter, there is great debate regarding the adequacy of an intake of 200 to 400 IU/d.
Many women who achieve this intake have serum 25(OH)D concentrations consistent with
vitamin D deficiency (<37.5 nmol/L 25(OH)D). In the study by Chan et al., the control group
had 25(OH)D well above 37.5 nmol/L (195), suggesting that 400 IU/d in those with relatively
good vitamin D status is still beneficial. Whether higher intakes in the order of 1000 IU/d would
be beneficial to deficient populations is not clear without further research. Nonetheless, 400 IU
in addition to a normal diet appears safe and able to elevate 25(OH)D well into the proposed
target range of >75 nmol/L.
With addition of a pregnancy supplement, an additional 400 IU of vitamin D would be possible
with most supplements. Since formulations contain variable amounts of vitamin D, the brand
names of vitamins should be solicited when advising parents or health care professionals about
supplementation strategies.
The challenge to obstetric care is to find approaches that ensure pregnant women regularly select
vitamin D containing foods and rigorously practice vitamin D supplementation. The magnitude
of this problem is demonstrated by Thomson et al. who followed women postpartum (196). All
of the women studied had a vitamin D deficiency (<50 nmol/L) at delivery despite the
recommendations to take supplements containing vitamin D during pregnancy. Either the
supplement was not adequate to improve vitamin D status or the supplement was not taken as
prescribed. Both are likely underlying problems since 19 of 35 women reported taking the
supplement as prescribed (196). Even in RT, compliance is difficult (197) suggesting that other
strategies might be required to achieve vitamin D status within the optimal range during
pregnancy.
A number of other maternal characteristics associate with low vitamin D status; these are age,
education and smoking. In Finland, where the recommendation is for pregnant women to
consume 10 µg/d (400 IU/d), a survey of 804 women (198) showed that only 40% of pregnant
women took a supplement containing vitamin D, but 85% had intakes below the
recommendation. Results showed that increased intake of a nutrient supplement was associated
with older age, higher education level, leaner pre-pregnancy weight and non-smoking (198).
Low income mothers tend to limit their own intake of food in order to feed their children (199,
Vitamin D: The Current State in Canada • CCFN Report • August 2008
16
200) and thus their vitamin D intake is likely limited as well. Low educational attainment seems
a stronger predictor of low vitamin D status than socioeconomic status (60).
There are no clinical trials or RT of vitamin D intake in pregnant or lactating women in Canada.
However, trials exist from other countries from which we can gain appreciation of the
relationship between vitamin D intake and status. The few RCT of vitamin D supplementation in
pregnancy that exist were conducted in the 1980s; debate continues regarding optimal intakes as
disagreement exists among studies.
For pregnancy, in a 2001 Cochrane Database systematic review (201), only two (202, 203) trials
reviewed at that time met inclusion criteria. Both trials were based on the administration of
1000 IU/d supplementation of vitamin D2 in the third trimester. These studies reported elevated
maternal 25(OH)D, but one trial (202) showed improved birth weights while the other (203)
showed reduced birth weights in the intervention groups relative to the control groups. Seven
other trials (13, 14, 135, 197, 204-206), some conducted since the systematic review, are
summarized in Table 4. It is clear that no two studies agree in regard to elevations in 25(OH)D
at a specific dosage of vitamin D during pregnancy. For example, one trial using 1000 IU/d in
the third trimester documented very high concentrations of 25(OH)D in the order of 168 nmol/L
(202), while others (203, 206) using the same dosage failed to yield 25(OH)D above the deficient
cut-off of 37.5 nmol/L. This discrepancy would suggest that other factors such as geographic
location and exogenous synthesis, endogenous stores of vitamin D and supplement compliance
contributed to the outcome. Moreover, not every trial measured vitamin D status since assays for
measurement of 25(OH)D were not as routinely available in the 1980s. Given the limited
number of studies on vitamin D supplementation in pregnancy, the ideal level of
supplementation in pregnancy is not known. It is for this reason that newer trials are underway
to establish if 1000 IU/d is sufficient to achieve and maintain vitamin D status throughout
pregnancy.19 Thus, while clinicians await the results of new RCT in pregnancy, they should be
aware that the theoretical optimal concentration of 25(OH)D of 75 nmol/L can be achieved in
pregnancy. In one study where vitamin D status was measured before and after the supplement
was taken, serum 25(OH)D in some women reached 80 nmol/L after the supplement (14).
Regarding lactating women, there are now four RT of vitamin D supplementation, with dosages
ranging from 1000 IU to 6000 IU/d (Table 5). Two studies are from the USA (207, 208), one
from Finland (209) and one from the United Arab Emirates (210). From these studies, it seems
that 4000 IU/d is required to elevate maternal 25(OH)D into the 75 nmol/L range (207, 209) and
that women with darker skin pigmentation consuming 2000 IU for 3 months do not fully
optimize vitamin D following a deficiency (210). Information regarding 25(OH)D in the infant
also shows values of ~75 nmol/L when the mother consumes 2000 IU/d (207, 209). It is likely
for this reason that the recent recommendation by the Canadian Paediatric Society is set at
2000 IU for lactating women (4).
19
www.clinicaltrials.gov; Identifier: NCT00292591
Vitamin D: The Current State in Canada • CCFN Report • August 2008
17
Table 4. Summary of Vitamin D Supplementation Studies in Pregnant Women
Study
Location
Vitamin D Intervention
Key 25(OH)D Outcomes
Other Outcomes
Brooke et al. (202)
1980
Asian
women in
UK
1981
Asian
women in
London
1981
Double blind in last trimester:
ƒ Control (n=67)
ƒ 1000 IU D2/d (n=59)
Higher 25(OH)D in mothers of
intervention group at delivery (16
vs 168 nmol/L).
Control group associated with
symptomatic hypocalcaemia,
growth restriction and larger
fontanelles in infants.
Improved maternal weight
gain and infant birth weights.
Higher intakes associated with
higher vitamin D status as
indicated by alkaline phosphatase.
25(OH)D not reported.
Delivery
Control: 9.4 nmol/L
Daily: 25.3 nmol/L
Single dose: 26.0 nmol/L
Birth weights higher with
supplementation.
Maxwell et al. (204)
(companion paper to
Brooke et al. (202))
Marya et al. (205)
Mallet et al. (203)
Delvin et al. (206)
1986
Winter
pregnancy
Northwest
France
1986
France
Marya et al. (135)
1987
Marya et al. (13)
1988
Rohtak
Madelenat et al. (14)
2001
France
Datta et al. (197)
2002
Ethnic
women in
UK
Double blind in last trimester:
ƒ Control (n=67)
ƒ 1000 IU/d (n=59)
Third trimester:
ƒ Control (n=75)
ƒ 1200 IU/d (n=25)
Last trimester:
ƒ Control (n=29)
ƒ 1000 IU D2/d for 3 mo (n=21)
ƒ 200,000 IU single oral dose (n=27)
From 6 mo pregnancy onward:
ƒ Control (n=20)
ƒ 1000 IU vitamin D3/d (n=20)
20 to 24 wk:
ƒ Non-supplemented (n=200)
ƒ Supplemented (n=200) to 375 mg
calcium and 1200 IU vitamin D/d
Third trimester:
ƒ Comparison (n=100)
ƒ 600,000 IU vitamin D at each of
7 and 8 mo (n=100)
27 to 32 wk pregnancy in winter:
ƒ 80,000 IU vitamin D single oral dose
n=80 women 25(OH)D <20 nmol/L:
ƒ 800 to 1600 IU/d during pregnancy
based on serum 25(OH)D response
Both supplements improved
25(OH)D over control.
Reduced birth weights in
supplemented groups.
Term: Elevated 25(OH)D from
~10 to 25 nmol/L (estimated from
graphed data).
25(OH)D not reported.
Maternal and newborn infant
25(OH)D improved by
supplement.
32 to 36 wk lower blood
pressure in supplemented
group.
Vitamin D status not reported.
Supplemented group had
larger infants: weight, length,
head circumference and skin
fold thicknesses.
No comparison group.
All women but one had serum
25(OH)D >25 nmol/L. Range
from to 12 to 80 nmol/L.
Mean elevation of 12 nmol/L
25(OH)D.
Vitamin D: The Current State in Canada • CCFN Report • August 2008
Compliance not assessed. No
comparison group.
18
Table 5. Summary of Vitamin D Supplementation Studies in Lactating Women
Study
Location
Vitamin D Intervention
Key 25(OH)D Outcomes
Other Outcomes
Ala-Houhala et al.
(209)
1986
Finland
ƒ
Extracted from graphed data:
Maternal 25(OH)D increased in
both supplement groups while it
remained relatively stable in the
placebo group. The 2000 IU group
had mean 25(OH)D >75 nmol/L by
15 wk.
Infants receiving 400 IU
directly had 25(OH)D
~75 nmol/L by 15 wk. Infants
in the 2000 IU maternal group
had similar values as the
infants in the 400 IU infant
group, while those in the
maternal 1000 IU group had
values consistent with
deficiency.
Infant 25(OH)D from graphed
data:
ƒ 2000 IU ~27.5 ng/ml
(~69 nmol/L)
ƒ 4000 IU ~30 ng/ml
(~75 nmol/L)
ƒ
ƒ
ƒ
Mothers supplemented from delivery
to 8 wk postpartum. Only infants in
placebo group received vitamin D2
400 IU/d.
0 IU vitamin D3 (n=16)
1000 IU vitamin D3 (n=16)
2000 IU vitamin D3 (n=17)
Hollis and Wagner
(207)
2004
USA
Randomized at 1 mo postpartum to 4 mo:
ƒ 2000 IU total (n=9)
ƒ 4000 IU total (n=9)
Wagner et al. (208)
2006
USA
Saadi et al. (210)
2007
United Arab
Emirates
From 1 to 7 mo postpartum (n=19):
ƒ 0 or 6000 IU/d plus prenatal
supplement with 400 IU vitamin D.
ƒ Infants in placebo group received
300 IU/d.
Randomized at first postnatal visit for
3 mo:
ƒ 2000 IU/d
ƒ 60 000 IU/mo oral
In both groups total 25(OH)D
increased between 1 and 4 mo of
study. From graphed data:
ƒ 2000 IU ~36 ng/ml
(~90 nmol/L)
ƒ 4000 IU ~44.5 ng/ml
(~111 nmol/L)
Significant elevation in 25(OH)D.
Infant 25(OH)D similar
among groups.
Baseline 25(OH)D ~25 nmol/L.
Significant elevations in 25(OH)D
but not >50 nmol/L on average.
Only 21% >50 nmol/L.
Vitamin D: The Current State in Canada • CCFN Report • August 2008
19
5. Aging and Advanced Aging (50 Years of Age and Older)
A. Dietary Vitamin D Intake of Aging Canadian Adults
For aging, information pertaining to vitamin D is more easily combined for men and women
from many countries. However, in Canada there are very few reports on vitamin D intakes in
free living individuals. First Nations women over 50 years of age and white women from
Winnipeg have intakes in the order of 450 and 544 IU/d, respectively (169). These intakes are
consistent with the AI of 400 to 600 IU/d for adults over 50 years of age. Additionally, for Dene
and Inuit, intakes approximate 316 to 1000 IU/d from traditional and market foods (154).
Institutionalized elderly have low dietary intakes of vitamin D of ~450 IU/d (211). One study
shows that novel foods for dysphagia management in long-term care improve vitamin D intakes
to approximately 600 IU/d (212).
B. Vitamin D Status of Aging Canadian Adults
Excellent reports exist regarding vitamin D status, but the relationship with diet remains unclear.
For example, in Canada, deficient vitamin D status is observed in at least one season in 34% of
Calgary residents ~64 years of age (107), but determining the relationship between supplement
use and vitamin D status was not possible since use of supplements was an exclusion criterion.
Some data exist for institutionalized elderly and suggest low vitamin D status (213) despite a
controlled feeding environment. However, the state of community dwelling seniors is far less
clear. In a Montreal study, using a conservative cut-off value for normal 25(OH)D concentration
(25 nmol/L), 36.4% of the ~70-year-old population was deficient (214). A clear seasonal
variation was observed in both 25(OH)D and PTH. However, this study did not address dietary
intake of vitamin D or other biomarkers of bone health. Another study, of thyroid patients in
Toronto, also shows deficiency in adults >70 years of age, but details of nutrition were not
clearly available and complete demographics of the study population not presented (215).
C. Evidence of Vitamin D Related Health Issues in Aging Canadian Adults
The consequences of the vitamin D deficiency observed in Canada are not clear. Much of the
research regarding vitamin D deficiency has focused on bone health and osteoporosis. More
recently, vitamin D deficiency has been associated with other chronic diseases. However, even
for osteoporosis and fractures, a direct linkage to vitamin D status in Canadians is not available.
D. Solutions for Improving Vitamin D Nutrition in Aging Canadian Adults
Unless food fortification policy changes, aging adults will not be able to achieve intakes of
600 IU/d and higher in support of year-round optimal vitamin D status. The new Canada’s Food
Guide recommends a supplement of 400 IU/d for adults over the age of 50 years (6).
Supplementation trials in Canadians over 50 years of age show that both 600 and 4000 IU/d
dosages given over 6 months elevate 25(OH)D to >75 nmol/L (216). For those who are over
70 years of age, however, the suggested target for 25(OH)D might be higher and thus higher
intakes would be required. From the meta-analysis component of the NIH systematic review of
vitamin D (8), it appears that for every 100 IU elevation in vitamin D intake, serum 25(OH)D
will increase by 1 to 2 nmol/L. If this is the case and if 75 nmol/L is the minimum optimal target,
Canadians deficient in vitamin D (i.e. serum level <37.5 nmol/L) would require anywhere from
3750 IU/d to 7000 IU/d. Whether such dosages are warranted in Canada requires further study.
Once deficiency is corrected, lower intakes might possibly provide coverage in the longer-term.
Vitamin D: The Current State in Canada • CCFN Report • August 2008
20
IV. Implications
1. General Implications
The underpinning philosophy of dietary recommendations is to meet the needs of the majority of
people. In 1997, the IOM published DRI values for vitamin D (2) to be used by both the USA
and Canada. For most age groups, the AI for vitamin D was set at 200 IU/d (2). The IOM
acknowledged that exposure to sunlight may not be the best approach to ensuring adequate
vitamin D status of populations as this can be dependent on culture, skin pigmentation, and/or
behaviour related to use of sun block (2, 3). Thus, the AI is designed to cover the needs for
vitamin D in the absence of exposure to UVB. Other institutions and associations have put forth
recommended intakes for vitamin D ranging from 400 IU/d for infants to 2000 IU/d for pregnant
and lactating women.
The state of vitamin D nutrition in Canada suggests that vitamin D intakes are close to the AI
across all ages, but that vitamin D deficiency is very common among all groups studied. The
implication of these observations is that Canada’s current health policy, food fortification policy
and food supply require updating if optimization of vitamin D status is to be achieved.
Additionally, the AI is most likely too low to prevent vitamin D deficiency in most individuals,
regardless of ethnicity, although many ethnic groups have high prevalence of deficiency (as high
as 100% in some studies). While newer recommendations exist for Canadians, these are not yet
all part of Health Canada’s policy update. Only the 400 IU/d for infants has been accepted by
Health Canada (3). Furthermore, if a serum 25(OH)D of 75 nmol/L is accepted as the target
indicative of optimal vitamin D status, further research is required to establish how much daily
dietary vitamin D is required to support healthy outcomes.
Establishment of public policy recommendations is critical to ensuring safety for the public at
large. With the expanse of vitamin D deficiency, the risks of updating the recommendations for
pregnant women without multiple sound intervention trials might be smaller than the risk of not
correcting vitamin D deficiency. Not only are there acute and chronic implications for maternal
health, but also the consequences of missing critical windows for programming of fetal health
and prevention of chronic disease may manifest as an increased burden of chronic disease.
Lastly, the implication of not clarifying the best dietary intake is that the public will receive a
multitude of recommendations and possibly not have confidence in dietary advice. Many will
self-medicate with respect to vitamin D without sound knowledge or medical supervision, and
will thus be less likely to achieve healthy outcomes.
2. Implications for Doctors and Other Health Care Professionals
Since health policy is not readily altered due to the responsibility to ensure public safety and
since many knowledge gaps exist, the responsibility of medical and other health care
professionals to know the facts about vitamin D is most important. To date, there are few reports
of the practices of Canadian health professionals with regard to vitamin D nutrition, and these
only deal with adult clients. From other countries, it seems that vitamin D intakes in children
can be improved with counseling. For example, according to Christie et al. in Arkansas,
vitamin D intake in children with allergies is higher with counseling than without (217). This
research group recommends that children with diagnosed food allergy be counseled yearly and
Vitamin D: The Current State in Canada • CCFN Report • August 2008
21
that their annual nutritional assessments include the status of vitamin D nutrition. Two other
American references report that physicians and nurse practitioners recommend vitamin D
supplements for breastfed infants less than 50% of the time. Physicians and nurse practitioners
are more likely to recommend supplements if they were either trained at a time when rickets was
prevalent or have worked in geographic regions where the risk of rickets is high (218, 219).
From Finland, it seems that while health care professionals feel they educate women on giving
vitamin D to their infants, most women state they have not received this information (220).
From within Canada, 75% of medical professionals are interested in vitamin D and are open to
receiving more education on this topic (221). However, current practice related to use of
vitamin D in treatment of osteoporosis does not match guidelines (222, 223).
From the above reports, it is clear that health care professionals know that vitamin D nutrition is
important, but need to seek further education about current recommendations and follow these
recommendations carefully.
3. Implications for Industry
In Canada, fortification has been questioned for quality control (224). Thus, it is in industry’s
best interest to prove that fortification is under high-level quality control to ensure the food
supply delivers reliable sources of vitamin D. In some studies, milk products are not linked to
vitamin D status in young adults in Canada (106), while in others milk and margarine are clearly
the foods with greatest impact on vitamin D status (142, 169, 175). Newer foods on the market
including orange juice have not yet been assessed for contribution to vitamin D intake and status
in Canada.
For the pharmaceutical industry, there also are implications of this research in that the optimal
intakes of vitamin D associated with optimal outcomes are not clear. It is in industry’s best
interest to clarify the best dosage of vitamin D from all sources that elicits the optimal response
including safety assessments.
Lastly, for all industry clear food labeling is critical for public acceptance of vitamin D. Whether
the product contains vitamin D3 or D2 is important to some segments of the population,
regardless of the dosage.
4. Implications for Consumers
Ultimately, consumers are responsible for their dietary intakes and well-being. Individuals must
seek education as to which foods are the best sources of vitamin D and what are appropriate
serving sizes and frequencies. Compliance in taking supplements and consistency in selecting
foods containing vitamin D are likely critical to achieving better vitamin D status. Consumers
must seek nutritional or medical counseling to learn of the benefits of foods and supplements
while ensuring safe intakes for themselves and any people for whom they are the primary
caregiver. The consumer must be educated upon valid sources of nutrition information and
become skilled in reading food labels.
Vitamin D: The Current State in Canada • CCFN Report • August 2008
22
5. Implications for Research—Knowledge Gaps for Canada
There are a number of knowledge gaps in the area of vitamin D nutrition for healthy outcomes in
Canada. These include:
ƒ
The cause of vitamin D deficiency. Is it low food sources and lack of adherence to
supplementation guidelines, or is the target too low given lifestyle and health risks related to
exposure to UVB?
ƒ
The consequences of a high rate of vitamin D deficiency for all age groups.
ƒ
Definition of optimal vitamin D status in all age groups and among different ethnic
groups. This is critical to harmonization of the various recommended intake
values and to harmonization of policy with public education.
ƒ
Determination of optimal vitamin D intake in all age groups. How much dietary vitamin D
from diet or supplements is required to achieve optimal vitamin D status?
ƒ
The nature and safety of supplementation. Is a bolus dosage safe and effective? What is the
maximum amount of vitamin D supplementation that is safe?
ƒ
Efficacy of food fortification programs.
successfully enhance vitamin D status?
Can food fortification programs safely and
Vitamin D: The Current State in Canada • CCFN Report • August 2008
23
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