Vitamin D in children and adolescents

Abstract

Vitamin D is essential for bone growth and development in children and adolescents. Vitamin D deficiency leads to rickets, characterized by defective bone formation, in infants and children. Vitamin D prophylaxis during the first years of life has empirically shown to be effective in combating rickets in infants in some countries. Vitamin D insufficiency can have negative effects on bone health in older children and in adolescents. Vitamin D supplementation has been shown to have an effect on bone mineral density at least in vitamin D deprived older children and adolescents but not in those with a normal vitamin D status. A good vitamin D status during pregnancy seems to be important for bone health in the off-spring later in life, but randomized controlled studies are needed to establish an effect of vitamin D during pregnancy on bone and other health outcomes in the offspring. Vitamin D supplementation during childhood may offer protection against diabetes type 1, but randomized controlled trials are needed to ascertain causality.

Key Words::

• Type 1 diabetes
• bone health
• infants,
• bone density
• bone development

Introduction

Vitamin D is essential for bone growth and development in children and adolescents. Vitamin D deficiency leads to rickets, characterized by defective bone formation, in infants and children. Vitamin D insufficiency can also have negative effects on bone health in older children and in adolescents. Furthermore, vitamin D insufficiency could also be a risk factor for type 1 diabetes and other health outcomes.

Rickets

In rickets the mineralization of growth plate cartilage slows down, the bone formation rate increases, and new osteoid is formed but does not mature because of low mineralization. If diagnosed early, rickets can be cured with extensive vitamin D therapy, but if the deformities are severe and the growth plates have started to mature in puberty, no treatment for rickets is available [1].

Rickets has earlier been a problem in many European countries, and prophylaxis with vitamin D has been successful. Vitamin D, now 10 μg/d, is given to children from the age of 2 weeks to 2 years in Finland. Likewise, vitamin D supplementation is recommended and followed in i.e. Sweden and Norway. Empirically we can state that this dose has been enough for combating rickets. The recommendation is followed well in children during the first year of life, which is reflected in acceptable serum 25-hydroxy-vitamin D (25(OH)D) concentrations [e.g. 2]. Recently, the effect of vitamin D on rickets has been evaluated in two systematic reviews [3,4]. The first one [3], including 13 trials, concluded that “There is fair evidence for an association between low serum 25-(OH)D concentration and established rickets, regardless of assay type. There is inconsistent evidence to determine if there is a threshold concentration of serum 25(OH)D concentrations above which rickets does not occur”. Lerch and Meissner [4], who included only 4 trials, concluded that the there is fair evidence for an association between serum 25(OH)D concentrations and established rickets and that many other studies suggest that the risk for rickets increases at concentrations lower than 27.5 nmol/L.

Vitamin D status during pregnancy and the relationship to bone health outcomes

Birth weight and growth during the first year of life may contribute to skeletal fragility later in life [5]. Maternal vitamin D status during pregnancy affects intrauterine skeletal mineralization [6] and skeletal growth in children [7]. Children of mothers with low vitamin D status during late pregnancy had reduced whole-body bone mineral content (BMC), bone area, and areal bone mineral density (BMD) at the age of 9 yr [7]. Low maternal 25-(OH)D concentrations in late pregnancy may be associated with reduced intrauterine long bone growth and slightly shorter gestation. The positive relationship between maternal PTH concentrations and measures of infant size may relate to increased mineral demands by larger babies, but warrants further investigation. [8].

We have recently studied the associations among maternal vitamin D status during pregnancy and skeletal variables in the newborn [9]. About 69 % of the women and 37 % of the newborns were vitamin D deficient at birth (25(OH)D concentration in women < 50 nmol/L, [10], in infants: < 37.5 nmol/L, [11]). The newborns’ bone variables were measured with peripheral quantitative computed tomography (pQCT) in the tibia. The results showed that maternal vitamin D status affected bone mineral accrual and influenced bone size during the intrauterine period but BMD was not affected by maternal vitamin D status. We thereafter invited the infants and mothers after 14 months for assessment of vitamin D and bone status [2]. The children had voluntarily taken the officially recommended daily vitamin D supplementation (10 μg, vitamin D2 or D3). All children with a low initial 25(OH)D concentration had reached the same concentration as children with a high initial level during this period. The children whose mothers had had a low vitamin D status during pregnancy had smaller bone size than the group whose mothers had a high status after 14 months but the bone accrual and BMD was the same. In conclusion, vitamin D supplementation improved vitamin D status but only partly eliminated the differences in bone variables induced by maternal vitamin D status during the fetal period.

Vitamin D supplementation and type 1 diabetes

There has long been physiological evidence for a role of vitamin D, namely 1,25-dihydroxyvitamin D (1,25(OH)₂D), in experimental autoimmune conditions such as type 1 diabetes. Casual evidence between vitamin D supplementation and decreased risk of type 1 diabetes has been found in experiments in the non-obese diabetic mouse [12].

The incidence of type 1 diabetes is increasing in children in many Western countries. An association between low vitamin D status and the incidence of type 1 diabetes has been shown in a number of studies. Much research interest has been focused on the relationship between vitamin D supplementation and the incidence of type 1 diabetes and there is one systematic review that has studied this [13]. The review included 5 studies, one cohort and 4 case control studies. The overall conclusion of their review was that supplementation with vitamin D in early childhood may offer protection against diabetes type 1, but randomized controlled trials are needed to establish causality.

The only cohort study in the review is from Finland [14]. The incidence of type 1 diabetes in Finland has increased from around 20 in 1965 to over 60 per 100,000 in 2006 in under 15 year olds, which is the highest in the world. Vitamin D prophylaxis to fight rickets has been recommended and given to children between the age of 2 weeks to 2 years since the 1950's. The daily dosage has changed over the years being 100 μg until 1964, 50 μg 1964–1974, 25 μg between 1974 and 1993 and thereafter 10 μg. During the period of highest dose (100 μg/d) hypercalcaemia was found in some infants, but not with the lower recommended doses [15]. Due to prophylaxis rickets has not been a problem in Finland, with the exception of a few cases per year after the beginning of the 1980's, which has been due not complying with the recommended supplementation [16]. Hyppönen et al. [14,17] studied a birth-cohort study in children born in 1966. The primary outcome measure was diagnosis of type 1 diabetes by end of December, 1997. They made use of the different dosages of vitamin D supplementation over the years in their analyses. They showed evidence that those who used the recommended dose of 50 μg regularly had an RR of 0.22 (95 % CI 0.05 to 0.89) compared with those who regularly used less than that dose. Furthermore, the authors showed that with an increase in regularity of supplementation as well as dose used, the incidence of type 1 diabetes tended to decrease. They also reported that those with suspected rickets had an increased risk of developing type 1 diabetes, although the result was not statistically significant (RR 3.0, 95 % CI 1.0 to 9.0).

Bone accrual in childhood and adolescence

Adolescence is a crucial phase for bone development when the most rapid bone accrual occurs. Mølgaard and colleagues [18] found that the increase in bone area and BMC peaked at earlier ages in girls (12.3 years for bone area and 12.5 years for BMC) than boys (13.4 years for bone area and 14.2 years for BMC). They also found that bone size increases before BMC. They calculated that the median annual bone calcium accretion rate in pubertal stage III was 220 mg per day in girls and 317 mg per day in boys. These results show that the adolescence stage is important when studying the effect of, for example, vitamin D on bone as the observed effect could be different depending on whether the investigator is studying bone size or BMC. Furthermore, to achieve an average bone calcium accretion rate, adolescents need a high calcium absorption rate during puberty. They require vitamin D as part of this process.

Effect of vitamin D supplementation on serum 25(OH)D concentration and BMD in children and adolescents

A few vitamin D supplementation studies on the effect on serum 25(OH)D concentration and on BMD have focused on healthy children and adolescents e.g. [19–21]. A French study gave three oral doses (end of September, end of November, end of January) of 2.5 mg of vitamin D3 (40 μg per day) to 54 old boys aged 13–17–year [19]. The investigators measured serum 25(OH)D concentration at several intervals during an 18-month period. They found that the vitamin D₃ supplementation maintained serum 25(OH)D concentration at 55 nmol/L throughout the winter; in contrast, serum 25(OH)D concentration decreased to 21 nmol/L in the placebo group [19]. In a 1-year randomized controlled study in 179 10–17–year-old girls in Lebanon [16], serum 25(OH)D concentration reached 95 nmol/L with weekly vitamin D supplementation equivalent to 50 μg of vitamin D3 a day, but only 40 nmol/L l with weekly vitamin D2 supplementation equivalent to 5 μg of vitamin D3, which did not differ from that of the placebo group. In a 1-year randomized controlled study in Finland in 228 girls, 2-year old at Tanner's stage 1 and 2, the investigators found that both 5 μg and 10 μg per day of vitamin D3 had a significant effect on serum 25(OH)D concentration [21]. At the end of the study, the mean 25(OH)D concentration was 45 nmol/L in the placebo group, 52 nmol/L in the group receiving 5 μg per day, and 60 nmol/L in the group receiving 10 μg per day. The reason for the difference in results between the Lebanese and Finnish studies is not clear, but may be due to the use of different assays for measuring serum 25(OH)D concentration. The difference may also be due to the fact that the Lebanese study administered vitamin D3 orally once a week and the Finnish study administered the supplement orally daily. Daily supplementation could have enhanced vitamin D adsorption or decreased the rate of catabolism.

Several studies have found a positive association between serum 25(OH)D concentration and BMD in children and adolescents [19–24]. Recently a Cochrane review [25] was published, based on 6 randomized controlled trials in children and adolescents (343 participants receiving placebo and 541 receiving vitamin D), aged 1 to < 20 years, focusing on the effect of vitamin D supplementation on BMD. The vitamin D dosage varied from 3.3 μg daily to 350 μg per week and the intervention period in these studies varied between 12 and 24 months. Vitamin D supplementation had no statistically significant effects on total body BMC, hip BMD or forearm BMD. There was a trend to a small effect on lumbar spine BMD). There were no differences in effects between high and low serum vitamin D studies at any site though there was a trend towards a larger effect with low vitamin D for total body BMC. In low serum vitamin D studies, significant effects on total body BMC and lumbar spine BMD were approximately equivalent to a 2.6 % and 1.7 % percentage point greater change from baseline in the supplemented group. The authors concluded that the results do not support vitamin D supplementation to improve bone density in healthy children with normal 25(OH)D concentrations, but suggest that supplementation of deficient children may be clinically useful. Further randomized controlled trials in deficient children are needed to confirm this. One of the studies in the review was done in Lebanon [20] and one in Finland [21].

In the one-year controlled randomized trial in Lebanon, adolescent girls responded to weekly vitamin D supplementation equivalent to 50 μg vitamin D3 per day by increasing total hip BMC when compared to the placebo, but weekly supplementation equivalent to 5 μg of vitamin D3 per day did not have any effect on BMD or BMC [20]. However, in the 1-year randomized controlled study in 225 girls, 11–12 year old, in Finland it was found that both 5 μg and 10 μg of vitamin D3 per day increased BMC augmentation in a dose-dependent manner in both the femur and lumbar spine in participants who had consumed at least 80 % of the vitamin D supplements [21]. Compared to the placebo group, the retention in the femur region was 14.3 % higher in the group that received 5 μg vitamin D3 and 17.2 % higher in the group that received 10 μg. The study found similar results in the lumbar vertebra, although only the highest dose increased BMC augmentation significantly in the entire group. One of the differences between the two studies was that the Finnish study [21] included a very narrow age interval of girls and took their Tanner stage into account, while the girls in the Lebanese study [20] had a much wider age interval and the investigators took Tanner stage into account in a different manner. After dividing the subjects by Tanner stage into early or late puberty, Viljakainen et al. [21] also showed that the effect of vitamin D on BMC in the lumbar vertebra occurred in mid-puberty but not in early puberty. Since spine growth accelerates at puberty [26], this could explain why girls in mid-puberty responded more efficiently to vitamin D supplementation than girls in early puberty. In parallel with the study in Finland [21] a similar study was performed in Denmark [27], which has not been included in the systematic review because it was published after the material was collected for the review [25]. In the double-blinded randomized controlled trial 221 Danish girls aged 11–12 years were randomized to take vitamin D3 (5 μg or 10μg) or placebo during one year. Overall the intervention had no effect on total body or lumbar spine BMC or BMD,which differed from the results from the almost similar study by Viljakainen et al [20]. One of the differences was that Viljakainen et al. [21] which only included girls from September to March whereas Mølgaard et al. [27] recruited subjects throughout the year. Moreover, the distribution of the Tanner stages seems to be different in the two studies, the Finnish girls being more mature (40 % in Tanner 4 and 5) at the end of the study than the Danish (16 % in Tanner 4).

Conclusions

Vitamin D supplementation is effective in combating rickets in infants and it has an effect on bone mineral density at least in vitamin D deprived older children and adolescents. A good vitamin D status during pregnancy seems to be important for bone health in the off-spring later in life, but randomized controlled studies are needed to establish an effect of vitamin D during pregnancy on health outcomes in the offspring. Likewise vitamin D supplementation during childhood may offer protection against diabetes type 1, but randomized controlled trials are needed to ascertain causality.

Questions and Answers

H Morris, Australia

In relation to vitamin D supplementation of children do you think there is a complexity introduced into the randomised control trial data you presented with regard to vitamin D and calcium supplementation having a different effect to supplementation with vitamin D alone?

C Lamberg-Allardt

It is true there could be different effects, but we did consider the calcium issue and it was about the same in both groups.

R Lorenc, Poland

In your presentation, you recommend lowering the supplementation from 10 to 7.5 μg/d above the age of 3 years. What is the reason for this?

C Lamberg-Allardt

We followed the Nordic dietary recommendations for vitamin D; 0–2 yrs 10 μg/d and 3–60 yrs 7.5 μg/d.

R Lorenc

But this is unusual, because the children are growing rapidly between 3 and 18 years and need a bigger supply at this time. Another point is that we have found that normalisation for the child's weight at the beginning is very important in terms of dose requirement. Have you also looked at this?

C Lamberg-Allardt

No, we have not looked at this.

R Vieth, Canada

With regard to pregnancy and 25(OH)D3, I think a very important component that has been recently replicated in multiple case controlled studies is the risk of gestational diabetes (GDM), in relation to the serum 25(OH)D level. You didn't mention that but there is basically an odds ratio between the highest and lowest quartile of first trimester serum 25(OH)D3 concentrations and the relative risk of GDM of approximately 2.5 and in order to benefit or protect the mother, one requires a concentration above 70 nmol/L.

C Lamberg-Allardt

Yes that is a good point.

Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.