Vitamin D supplementation for improving bone density in vitamin D-deficient children and adolescents: systematic review and individual participant data meta-analysis of randomized controlled trials.

BACKGROUND: Vitamin D supplements are widely used for improving bone health in children and adolescents, but their effects in vitamin D-deficient children are unclear. OBJECTIVES: This study aimed to examine whether the effect of vitamin D supplementation on bone mineral density (BMD) in children and adolescents differs by baseline vitamin D status and estimate the effect in vitamin D-deficient individuals. METHODS: This is a systematic review and individual participant data (IPD) meta-analysis. We searched the Cochrane Central Register of Controlled Trials, MEDLINE, MBASE, CINAHL, AMED, and ISI Web of Science (until May 27, 2020) for randomized controlled trials (RCTs) of vitamin D supplementation reporting bone density outcomes after ≥6 mo in healthy individuals aged 1-19 y. We used two-stage IPD meta-analysis to determine treatment effects on total body bone mineral content and BMD at the hip, femoral neck, lumbar spine, and proximal and distal forearm after 1 y; examine whether effects varied by baseline serum 25-hydroxyvitamin D [25(OH)D] concentration, and estimate treatment effects for each 25(OH)D subgroup. RESULTS: Eleven RCTs were included. Nine comprising 1439 participants provided IPD (86% females, mean baseline 25(OH)D = 36.3 nmol/L). Vitamin D supplementation had a small overall effect on total hip areal BMD (weighted mean difference = 6.8; 95% confidence interval: 0.7, 12.9 mg/cm2; I2 = 7.2%), but no effects on other outcomes. There was no clear evidence of linear or nonlinear interactions between baseline 25(OH)D and treatment; effects were similar in baseline 25(OH)D subgroups (cutoff of 35 or 50 nmol/L). The evidence was of high certainty. CONCLUSIONS: Clinically important benefits for bone density from 1-y vitamin D supplementation in healthy children and adolescents, regardless of baseline vitamin D status, are unlikely. However, our findings are mostly generalizable to White postpubertal girls and do not apply to those with baseline 25(OH)D outside the studied range or with symptomatic vitamin D deficiency (e.g., rickets). This study was preregistered at PROSPERO as CRD42017068772. https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42017068772.

Season, dietary factors, and physical activity modify 25-hydroxyvitamin D concentration during pregnancy.

PURPOSE: The objectives of this cross-sectional study were to define maternal and umbilical cord blood (UCB) 25-hydroxyvitamin D (25(OH)D) to characterize maternal factors modifying 25(OH)D during pregnancy and predict UCB 25(OH)D in two subgroups with Declined [Δ25(OH)D <0 nmol/l] and Increased [Δ25(OH)D >0 nmol/l] 25(OH)D concentration. METHODS: A complete dataset was available from 584 women. 25(OH)D was determined at gestational weeks 6-13 and in UCB. Baseline characteristics were collected retrospectively using questionnaires. Δ25(OH)D was calculated as UCB 25(OH)D-early pregnancy 25(OH)D. Dietary patterns were generated with principal component analysis. Multivariate regression models were applied. RESULTS: Vitamin D deficiency was scarce, since only 1% had 25(OH)D concentration <50 nmol/l both in early pregnancy and in UCB. Shared positive predictors of UCB 25(OH)D in the subgroups of Declined and Increased, were early pregnancy 25(OH)D (P < 0.001) and supplemental vitamin D intake (P < 0.04). For the Increased subgroup summer season at delivery (P = 0.001) and "sandwich and dairy" dietary pattern characterized with frequent consumption of vitamin D fortified margarine and milk products (P = 0.009) were positive predictors of UCB 25(OH)D. Physical activity (P = 0.041) and maternal education (P = 0.004) were additional positive predictors in the Declined group CONCLUSIONS: Maternal and newborn vitamin D status was sufficient, thus public health policies in Finland have been successful. The key modifiable maternal determinants for 25(OH)D during pregnancy, and of the newborn, were supplemental vitamin D intake, frequent consumption of vitamin D fortified foods, and physical activity.

Food and Nutrient Intake and Nutrient Sources in 1-Year-Old Infants in Finland: A Cross-Sectional Analysis.

The infant diet has short- and long-term health consequences. Updated data regarding the dietary intake of Finnish infants are lacking. The objectives of this study were to describe infant food and nutrient intake and to identify food sources of the nutrients. Altogether, 739 healthy infants were studied. Dietary intake and breastfeeding frequency were assessed with a three-day food record at 1 year of age. Dietary intake was calculated separately for non-breastfed and breastfed infants. One-third (36%) of the infants were partially breastfed and 95% consumed mass-produced baby foods. The infants' diet consisted mainly of infant formula, dairy milk, porridges, fruit and berry foods, and meat dishes. The mean vegetable, fruit and berry consumption was 199 g/day. Most nutrient intakes were adequate except for fat, linoleic acid, vitamin D and iron from food. Mean sucrose intake, as a percentage of total energy intake (E%), was 5-6 E%. High protein intake (>20 E%) was observed in 19% of non-breastfed infants. Overall, the infants' diet was favorable since vegetable and fruit consumption was reasonably high and nutrient intake was mostly adequate. However, the fat intake was lower, and protein intake higher than recommended. Increasing the consumption of vegetable oils and reducing the intake of red meat and dairy milk may further improve the diet of 1-year-olds.

Development and validation of an interview-administered FFQ for assessment of vitamin D and calcium intakes in Finnish women.

Increased vitamin D fortification of dairy products has increased the supply of vitamin D-containing products with different vitamin D contents on the market in Finland. The authors developed a ninety-eight-item FFQ with eight food groups and with a question on supplementation to assess dietary and supplemental vitamin D and Ca intakes in Finnish women (60ºN). The FFQ was validated in subgroups with different habitual vitamin D supplement use (0-57·5 µg/d) against the biomarker serum 25-hydroxyvitamin D (S-25(OH)D) and against 3-d food records (FR) (n 29-67). Median total vitamin D intake among participants was 9·4 (range 1·6-30·5) µg/d. Spearman's correlations for vitamin D and Ca ranged from 0·28 (P 0·146, FFQ v. S-25(OH)D, persons not using supplements) to 0·75 (P<0·001, FFQ v. FR, supplement use included). The correlations between the FFQ and S-25(OH)D concentrations improved within increasing supplement intake. The Bland-Altman analysis showed wide limits of agreement between FFQ and FR: for vitamin D between -7·8 and 8·8 µg/d and for Ca between -938 and 934 mg/d, with mean differences being 0·5 µg/d and 2 mg/d, respectively. The triads method was used to calculate the validity coefficients of the FFQ for vitamin D, resulting in a mean of 1·00 (95 % CI 0·59, 1·00) and a range from 0·33 to 1·00. The perceived variation in the estimates could have been avoided with a longer FR period and larger number of participants. The results are comparable with earlier studies, and the FFQ provides a reasonable estimation of vitamin D and Ca intakes.

Vitamin D deficiency in children with a chronic illness-seasonal and age-related variations in serum 25-hydroxy Vitamin D concentrations.

INTRODUCTION: Children and adolescents with a chronic illness have potential risk factors for vitamin D deficiency. An optimal vitamin D status might have multiple health effects. This study evaluated vitamin D status and its association with age, gender, and season in a large cohort of chronically ill Finnish patients at a tertiary pediatric outpatient clinic. A cross-sectional register-based study was carried out, involving altogether 1351 children (51% boys, age range 0.2-18 years), who visited the outpatient clinic during 2007-2010 and had their vitamin D status (S-25-OHD) determined. A post-doc analysis was conducted to identify predisposing and preventing factors for vitamin D deficiency. RESULTS: Almost half (47%) of the S-25-OHD values were consistent with subnormal vitamin D status (S-25-OHD <50 nmol/L) while only 12% were >80 nmol/L. Age and season were the most important determinants for S-25-OHD concentration. Mean S-25-OHD concentration differed between age groups (Kruskal-Wallis; p<0.001), adolescents being at highest risk for vitamin D insufficiency. Young age and vitamin D supplementation were preventive factors for deficiency, while non-Finnish ethnic background was a predisposing factor. S-25-OHD showed significant seasonal variation in children older than 6 years. In the whole cohort, S-25-OHD was on average 13 nmol/L higher in summer than in winter, and the prevalence of vitamin D deficiency ( =  S-25-OHD <37.5 nmol/l) varied from 11% in summer to 29% in winter. CONCLUSIONS: The finding that almost half of the studied Finnish children with a chronic illness had suboptimal vitamin D status is alarming. Inferior vitamin D status was noted in adolescents compared with younger children, suggesting that imbalance between intake and requirement evolves with age. Although less common during summer, subnormal vitamin D status was still observed in 28% of those evaluated in summer. Clinicians should identify individuals at risk and actively recommend vitamin D supplementation.

Estimation of the dietary requirement for vitamin D in healthy adolescent white girls.

BACKGROUND: Knowledge gaps have contributed to considerable variation (between 0 and 15 µg/d) in international dietary recommendations for vitamin D in adolescents. OBJECTIVE: We aimed to establish the distribution of dietary vitamin D required to maintain serum 25-hydroxyvitamin D [25(OH)D] concentrations above several proposed cutoffs (25, 37.5, 40, and 50 nmol/L) during wintertime in adolescent white girls. DESIGN: Data (baseline and 6 mo) from 2 randomized, placebo-controlled, double-blind, 12-mo intervention studies in Danish (55°N) and Finnish (60°N) girls (n = 144; mean age: 11.3 y; mean vitamin D intake: 3.7 µg/d) at vitamin D(3) supplementation amounts of 0, 5, and 10 µg/d were used. Serum 25(OH)D was measured with an HPLC assay in a centralized laboratory. RESULTS: Clear dose-related increments (P < 0.0001) in serum 25(OH)D with increasing supplemental vitamin D(3) were observed. The slope of the relation between vitamin D intake and serum 25(OH)D at the end of winter was 2.43 nmol ⋅ L(-1) ⋅ µg intake(-1), and no difference in the slopes between Finnish and Danish girls was observed. The vitamin D intakes that maintained serum 25(OH)D concentrations at >25, >37.5, and >50 nmol/L in 97.5% of the sample were 8.3, 13.5, and 18.6 µg/d, respectively, whereas an intake of 6.3 µg/d maintained a serum 25(OH)D concentration >40 nmol/L in 50% of the sample. CONCLUSION: The vitamin D intakes required to ensure that adequate vitamin D status [defined variably as serum 25(OH)D >25 and >50 nmol/L] is maintained during winter in the vast majority (>97.5%) of adolescent girls (mean age: 11.3 y) at northern latitudes (>55°N) are 8.3 and 18.6 µg/d, respectively. This trial was registered at clinicaltrials.gov as NCT00267540.

Effect of vitamin D, calcium and multiple micronutrient supplementation on vitamin D and bone status in Bangladeshi premenopausal garment factory workers with hypovitaminosis D: a double-blinded, randomised, placebo-controlled 1-year intervention.

Due to little outdoor activity and low dietary intake of vitamin D (VD), Bangladeshi low-income women are at risk for osteoporosis at an early age. The present study assessed the effect of VD, Ca and multiple micronutrient supplementation on VD and bone status in Bangladeshi young female garment factory workers. This placebo-controlled 1-year intervention randomly assigned 200 apparently healthy subjects (aged 16-36 years) to four groups: VD group, daily 10 microg VD; VD and Ca (VD-Ca) group, daily 10 microg VD+600 mg Ca; multiple micronutrient and Ca (MMN-Ca) group, 10 microg VD and other micronutrients+600 mg Ca; a placebo group. Serum 25-hydroxyvitamin D (S-25OHD), intact parathyroid hormone (S-iPTH), Ca, phosphate and alkaline phosphatase were measured. Bone mineral density and bone mineral content were measured by dual-energy X-ray absorptiometry. All measurements were made at baseline and at 12 months. Significantly (P < 0.001) higher S-25OHD concentrations were observed in the supplemented groups than in the placebo group after the intervention. Supplementation had an effect (P < 0.001) on S-iPTH in the VD-Ca and MMN-Ca groups compared with the placebo group. Bone mineral augmentation increased at the femur in the supplemented groups. Supplementation with VD-Ca should be recommended as a strategic option to reduce the risk of osteomalacia and osteoporosis in these subjects. MMN-Ca may have analogous positive health implications with additional non-skeletal benefits.

Habitual high phosphorus intakes and foods with phosphate additives negatively affect serum parathyroid hormone concentration: a cross-sectional study on healthy premenopausal women.

OBJECTIVE: Foods can contain natural phosphorus (NP) and phosphate-containing food additives (AP). The main objective of the present study was to investigate whether NP and AP of habitual diets differ in their effects on markers of Ca metabolism. We also investigated the impact of total habitual dietary P intake on markers of Ca metabolism. DESIGN: Cross-sectional study. Fasting blood samples were collected and participants kept a 4 d food record, from which dietary intake of total P and the consumption of NP (milk and cheese, excluding processed cheese) and AP (processed cheese) sources were calculated. Participants were divided into groups according to their NP- and AP-containing food consumption and into quartiles according to their total P intake. SETTING: Southern Finland. SUBJECTS: One hundred and forty-seven healthy premenopausal women aged 31-43 years. RESULTS: Relative to the lowest total dietary P quartile, mean serum parathyroid hormone (S-PTH) concentration was higher (P = 0.048, analysis of covariance (ANCOVA)) and the mean serum ionized Ca concentration lower (P = 0.016, ANCOVA) in the highest P intake quartile. Mean S-PTH concentrations were higher among participants who consumed processed cheese (P = 0.027, ANCOVA) and less milk and other cheese than processed cheese (P = 0.030, ANCOVA). CONCLUSIONS: High total habitual dietary P intake affected S-PTH unfavourably. Furthermore, phosphate additives may have more harmful effects on bone than other P sources, as indicated by higher mean S-PTH concentration among participants who consumed AP-containing foods. Because of the high dietary P intake and current upward trend in consumption of processed foods in Western countries, these findings may have important public health implications.

Wintertime vitamin D supplementation inhibits seasonal variation of calcitropic hormones and maintains bone turnover in healthy men.

Vitamin D is suggested to have a role in the coupling of bone resorption and formation. Compared with women, men are believed to have more stable bone remodeling, and thus, are considered less susceptible to the seasonal variation of calcitropic hormones. We examined whether seasonal variation exists in calcitropic hormones, bone remodeling markers, and BMD in healthy men. Furthermore, we determined which vitamin D intake is required to prevent this variation. Subjects (N = 48) were healthy white men 21-49 yr of age from the Helsinki area with a mean habitual dietary intake of vitamin D of 6.6 +/- 5.1 (SD) microg/d. This was a 6-mo double-blinded vitamin D intervention study, in which subjects were allocated to three groups of 20 microg (800 IU), 10 microg (400 IU), or placebo. Fasting blood samplings were collected six times for analyses of serum (S-)25(OH)D, iPTH, bone-specific alkaline phosphatase (BALP), and TRACP. Radial volumetric BMD (vBMD) was measured at the beginning and end of the study with pQCT. Wintertime variation was noted in S-25(OH)D, S-PTH, and S-TRACP (p < 0.001, p = 0.012, and p < 0.05, respectively) but not in S-BALP or vBMD in the placebo group. Supplementation inhibited the winter elevation of PTH (p = 0.035), decreased the S-BALP concentration (p < 0.05), but benefited cortical BMD (p = 0.09) only slightly. Healthy men are exposed to wintertime decrease in vitamin D status that impacts PTH concentration. Vitamin D supplementation improved vitamin D status and inhibited the winter elevation of PTH and also decreased BALP concentration. The ratio of TRACP to BALP shows the coupling of bone remodeling in a robust way. A stable ratio was observed among those retaining a stable PTH throughout the study. A daily intake of vitamin D in the range of 17.5-20 microg (700-800 IU) seems to be required to prevent winter seasonal increases in PTH and maintain stable bone turnover in young, healthy white men.

25-Hydroxyvitamin D and functional outcomes in adolescents.

Vitamin D is essential for bone growth and development in children and adolescents. Adolescence is a crucial phase in bone development. Cross-sectional studies have shown a relation between vitamin D status and bone mineral density in adolescents. Long-term supplementation studies have supported the importance of vitamin D for bone health in adolescence. However, we need more studies on the optimal serum 25-hydroxyvitamin D concentration and the optimal vitamin D dosage for bone health in this age group. In addition, we need to evaluate the best way to increase vitamin D status in the general public from a public health point of view.

How much vitamin D3 do the elderly need?

BACKGROUND: Vitamin D insufficiency poses a problem in many parts of the world, the elderly being an especially vulnerable group. This insufficiency results from an inadequate amount of sunshine and a low dietary intake of vitamin D. Typically, insufficiency is accompanied with high intact parathyroid hormone, (S-iPTH) concentrations. AIMS OF THE STUDY: We studied how serum 25-hydroxy vitamin D (S-25-OHD) concentrations respond to different doses of vitamin D3 supplementation. Secondly to determine the smallest efficient dose to maintain serum 25-OHD concentration above the insufficiency level. We also studied which dose would be efficient in decreasing S-iPTH concentration in these subjects. SUBJECTS AND METHODS: Forty-nine 65- to 85-year-old women participated. The women were randomly assigned into one of four groups receiving 0 (placebo), 5, 10 or 20 microg of vitamin D3 daily for 12 weeks. Fasting morning blood was drawn at the beginning of the study, and thereafter every second week. Calciotropic variables were assessed from serum and urine samples. RESULTS: The S-25-OHD concentration increased significantly (p < 0.001) in all supplemented groups [5 microg: by 10.9 (8.5) nmol/L, 10 microg: by 14.4 (6.9) nmol/L, 20 microg: by 23.7 (11.9) nmol/L], whereas it decreased in the placebo group by 8.3 (13.2) nmol/L. Equilibrium in S-25-OHD concentration was reached in all groups after 6 weeks of supplementation at 57.7 (8.9) nmol/L, 59.9 (8.9) nmol/L and 70.9 (8.9) nmol/L in the groups with increasing vitamin D supplementation. The dose-response to supplementation decreased with increasing vitamin D status at baseline, r = -0.513, p = 0.002. S-iPTH tended to decrease in those with highest dose response to supplementation. CONCLUSIONS: A clear dose response was noted in S-25-OHD to different doses of vitamin D3. The recommended dietary intake of 15 microg is adequate to maintain the S-25-OHD concentration around 40-55 nmol/L during winter, but if the optimal S-25-OHD is higher than that even higher vitamin D intakes are needed. Interestingly, subjects with lower vitamin D status at baseline responded more efficiently to supplementation than those with more adequate status.

A positive dose-response effect of vitamin D supplementation on site-specific bone mineral augmentation in adolescent girls: a double-blinded randomized placebo-controlled 1-year intervention.

UNLABELLED: The effect of vitamin D supplementation on bone mineral augmentation in 212 adolescent girls with adequate calcium intake was studied in a randomized placebo-controlled setting. Bone mineral augmentation determined by DXA increased with supplementation both in the femur and the lumbar vertebrae in a dose-responsive manner. Supplementation decreased the urinary excretion of resorption markers, but had no impact on formation markers. INTRODUCTION: Adequate vitamin D intake protects the elderly against osteoporosis, but there exists no indisputable evidence that vitamin D supplementation would benefit bone mineral augmentation. The aim of this 1-year study was to determine in a randomized double-blinded trial the effect of 5 and 10 microg vitamin D3 supplementation on bone mineral augmentation in adolescent girls with adequate dietary calcium intake. MATERIALS AND METHODS: Altogether, 228 girls (mean age, 11.4 +/- 0.4 years) participated. Their BMC was measured by DXA from the femur and lumbar spine. Serum 25-hydroxyvitamin D [S-25(OH)D], intact PTH (S-iPTH), osteocalcin (S-OC), and urinary pyridinoline (U-Pyr) and deoxypyridinoline (U-Dpyr) were measured. Statistical analysis was performed both with the intention-to-treat (IT) and compliance-based (CB) method. RESULTS: In the CB analysis, vitamin D supplementation increased femoral BMC augmentation by 14.3% with 5 microg and by 17.2% with 10 microg compared with the placebo group (ANCOVA, p = 0.012). A dose-response effect was observed in the vertebrae (ANCOVA, p = 0.039), although only with the highest dose. The mean concentration of S-25(OH)D increased (p < 0.001) in the 5-microg group by 5.7 +/- 15.7 nM and in the 10-microg group by 12.4 +/- 13.7 nM, whereas it decreased by 6.7 +/- 11.3 nM in the placebo group. Supplementation had no effect on S-iPTH or S-OC, but it decreased U-DPyr (p = 0.042). CONCLUSIONS: Bone mineral augmentation in the femur was 14.3% and 17.2% higher in the groups receiving 5 and 10 microg of vitamin D, respectively, compared with the placebo group, but only 10 mug increased lumbar spine BMC augmentation significantly. Vitamin D supplementation decreased the concentration of bone resorption markers, but had no impact on bone formation markers, thus explaining increased bone mineral augmentation. However, the positive effects were noted with the CB method but not with IT.