Comparing Different Amounts of Vitamin D Supplementation to Preschool Children Living in Northern and Southern Sweden
Condition: Vitamin D Deficiency
MeSH terms: Vitamin D Deficiency
Study type: Interventional

Summary: 
      Vitamin D has a range of biological effects of public health relevance. Vitamin D status is
      assessed on levels of its metabolite 25-hydroxyvitamin D [25(OH)D], where levels < 50 nmol/L
      indicate insufficiency. Despite studies indicating that the vitamin D intake among Swedish
      children are significantly below recommendations, little is known of their vitamin D status.
      The investigators have recently found inadequate vitamin D status in pre-school children
      living in northern Sweden, especially in dark-skinned children and during the winter months
      despite vitamin D intakes meeting the recommendations. Overall, 25% of the light skinned and
      40% of the dark skinned children had S-25(OH) D <50 nmol/L (Öhlund I, unpublished data). The
      aim is to examine which amount of vitamin D is needed to maintain or increase S-25(OH)D to
      ≥50 nmol/L among 97.5% of the participants regardless of skin color or geographic location
      (northern or southern Sweden). Furthermore the investigators will examine if vitamin D status
      affects on health markers as bone density, blood pressure, serum lipids, fatty acids,
      inflammatory and immunological markers and mental wellbeing.

      Children aged 5-8 years living either northern (Umeå) or southern Sweden (Malmö) will be
      recruited to this trial during November-December 2012. They will be randomized to a vitamin D
      supplement of either 10 or 25 g per day, or in Malmö also placebo to be used for three
      months. The randomization will be stratified according to skin color (light or dark)
      according to a method using visual inspection and interviews of parents/guardians. The
      investigators will use a 2×2×2 factorial design to investigate the effects of two different
      doses of vitamin D (10 µg and 25 µg) in children with dark and light skin color, living in
      northern (Umeå) and southern (Malmö), Sweden. In order to achieve a moderate difference
      between groups (effect size 0.25) 20 children per group are required (power> 87%, alpha =
      0.05). With an estimated dropout of 10%, a total of 220 children will be included.

      At baseline, the participants will undergo blood sampling for S-25(OH)D and other biomarkers,
      blood pressure and anthropometrical measurements, including bone densitometry and body
      composition using air displacement pletysmography, and the parents will answer a
      questionnaire on behavioral and emotional problems in the participating child using the Child
      Behavior Checklist. These measurements will be repeated at follow-up in February-March 2013.
    

Detailed description: 
      Vitamin D has a range of biological effects of public health relevance (Prentice et al,
      2008). Besides its well known role in mineralization of bone and teeth, vitamin D also play
      important roles in metabolic functions, the pathogenesis of certain diseases, e.g. type 1
      diabetes, celiac disease, asthma and allergies, as well as in the prevention of cancer
      (Holick, 2008).

      Vitamin D status is assessed on plasma or serum levels of its metabolite 25-hydroxyvitamin D
      [25(OH)D, calcidiol] as it reflects the sum of vitamin D converted in the skin through
      sunlight exposure and from dietary sources. Several reports advocate that levels <37 nmol/L
      denote severe vitamin D deficiency; levels <50 nmol/L insufficient; 50-75 nmol/L suboptimal
      levels and ≥75nmol/L optimal levels (Dawson-Hughes et al, 2005, Huh et al, 2008, Yetley,
      2008). In children, most suggested cut-off values for adequate levels of 25(OH)D are based on
      the absence of rickets, increased measures of bone mineralization and maximal suppression of
      parathyroid hormone (PTH) levels (Greer, 2009).

      The major source of vitamin D is dermal biosynthesis catalyzed by ultraviolet B sunlight
      (Cashman et al, 2011). However, during winter, northern Sweden has limited hours of daylight
      leading to reduced sun exposure. Consequently, the dietary source of vitamin D is of specific
      importance in this region (Brustad et al, 2007, Edvardsen et al, 2007). Fatty fish, eggs,
      vitamin D fortified milk and margarines are the main sources, mainly supplying the most
      active form D3. These are important basic foods which also contain common food allergens.
      Thus, children with food allergies to milk, fish, and egg can be at increased risk of vitamin
      D deficiency. Several dairy products are fortified with vitamin D, but in some products in
      the form of D2 which is not as bioactive as D3.

      Skin color affects the capacity to form vitamin D3 as children with dark complexion need 5-10
      times more sun exposure to generate the same amount of vitamin D3 compared to fair-skinned
      children, and therefore are at increased risk of vitamin D deficiency when exposure to sun is
      limited (Holick, 2005). Recently the recommendations on protecting the skin from sunshine to
      reduce the risk of skin cancer later in life has been debated as it may increase the risk of
      vitamin D deficiency (Stechschulte et al, 2011). Obesity in children might be another risk
      factor for vitamin D deficiency, since an increased proportion of available vitamin D may be
      stored in adipose tissue thus lowering the S-25(OH)D (Prentice, 2008).

      Despite studies indicating that the vitamin D intake among Swedish children and adolescents
      are significantly below recommendations, little is known of their vitamin D status (Garemo et
      al, 2007, Enghardt et al, 2006, Öhlund et al, 2010). Furthermore there is a paucity of
      studies investigating vitamin D intake and status in food-allergic adolescents who may be at
      increased risk of vitamin D insufficiency due to strict avoidance of vitamin D containing
      foods.

      Recently the investigators of Dvisum assessed Vitamin D status in pre-school children (n=90;
      mean age 54+/-7.1 mo), all living in northern Sweden (latitude 63°) and half of them with
      fair skin, half with darker complexion. The study group was examined first in
      August-September (late summer) and then the following January-February (winter). Skin type,
      vitamin D intake, anthropometrics, S-25(OH) D and parathyroid hormone (S-PTH) were assessed.
      The investigators found inadequate vitamin D status in these children living in northern
      Sweden, especially in dark-skinned children and during the winter despite vitamin D intakes
      meeting the recommendations, prompting strategies to improve intake of vitamin D in this
      population. Overall, 25% and 40% of the light and dark skinned had S-25(OH) D <50 nmol/L.

      The aim is to examine which amount of vitamin D is needed to maintain or increase S-25(OH)D
      to ≥50 nmol/L among 97.5% of the participants regardless of skin color or geographic location
      (northern or southern Sweden). Furthermore the investigators will examine if vitamin D status
      affects health markers such as bone density, blood pressure, serum lipids, fatty acids and
      inflammatory and immunological markers and mental wellbeing.

      In order to identify whether there are differences depending on the latitude within Sweden,
      children will be recruited both from northern Sweden (Umeå) and from southern Sweden (Malmo).
      As it is unclear what levels of the serological marker 25 (OH) D that affect the health of
      children, different markers of health will be examined before and after the intervention.
      Children aged 5-8 years, 50% fair-skin 50 % darker skin, in northern Sweden (Umeå) and
      southern Sweden (Malmö) will be included in a longitudinal, randomized trial. The children
      are first examined in November-December and randomized to a vitamin D supplement of either 10
      or 25 g per day, to be used for three months. At the follow up in February-March all
      examinations will be repeated.

      The investigators will use a 2 × 2 × 2 factorial design to investigate the effects of two
      different doses of vitamin D (10 µg and 25 µg) in children with dark and light skin color,
      living in northern (Umeå) and southern (Malmö), Sweden. In order to achieve a moderate
      difference between groups (effect size 0.25) requires 20 children per group (power>87%, alpha
      = 0.05). With this group size, we can see a group difference in the S-25 (OH) D of 3.75
      nmol/L, S-PTH of 0.35 mmol/L and bone mineral density in the lumbar region of 0.075 g/cm2. In
      Skåne, but not Umeå also a placebo group will participate. With an estimated dropout of 10%,
      a total of 220 children will be included.

      The study include sampling for analysis of S-25 (OH) D, calcium, phosphate, alkaline
      phosphatase (ALP), magnesium, PTH and osteocalcin, serum lipids (total cholesterol, HDL
      cholesterol, LDL cholesterol. ApoA1 and ApoB lipoprotein) and fatty acids as well as
      inflammatory and immunological markers (CRP, interleukin (IL) -1 and 2, IL-4, IL-6, I-10,
      Il-17, CD40 ligand, TNF and IFNγ, fibrinogen and antisecretory factor). Before sampling, the
      children receive a topical anesthetic (EMLA).

      Measurements of blood pressure and anthropometric measurements of length, weight, waist
      circumference and bone densitometry (DEXA) and body composition (fat mass% and fat free mass)
      using a Air Displacement Plethysmography ( BOD POD) Questions about diet, vitamin
      supplements, foreign travel, how much time the children spend time outdoors and the use of
      sunscreen as well as questions about the child's health and family situation will be answered
      by the parents through a questionnaire. To investigate the possible association between
      vitamin D status and mental well-being, the investigators will use the Child Behaviour
      Checklist (CBCL).

      This study is national with a multicultural perspective, it is expected to provide knowledge
      about the needs of vitamin D to prevent vitamin D deficiency. The study is also expected to
      provide a better understanding of association between vitamin D status and various markers of
      health among children.

      By preventing vitamin D deficiency, poor bone development, susceptibility to infections, and
      perhaps prone to autoimmune diseases and cardiovascular risk factors could be reduced, and
      hopefully the mental well-being improved, which reduces costs to both society and the
      individual, and reduces unnecessary suffering of individuals.
    

Intervention name(s): Vitamin D 25 microg/d; Vitamin D 10 microg/d; No extra vitamin D
Intervention type(s): Dietary Supplement; Dietary Supplement; Dietary Supplement
Intervention description(s): The vitamin D supplement will be provided as a milk drink taken daily.; The vitamin D supplement will be provided as a milk drink taken daily.; Milk drink with no extra vitamin D (placebo)
Other intervention name(s): Placebo
Intervention MeSH terms: Vitamin D; Ergocalciferols; Cholecalciferol; Vitamins
Allocation: Randomized
Intervention model: Factorial Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Prevention