Vitamin D is a fat-soluble micronutrient that can promote calcium absorption in the gut and maintain serum calcium and phosphorus homeostasis (1), and is thus needed for bone growth and bone remodeling by osteoblasts and osteoclasts (2). The deficiency of vitamin D is linked to pediatric rickets and adult osteomalacia (3). However, poor vitamin D status is reported worldwide and estimated to affect nearly 1 billion people with the largest prevalence in children (4).

Generally, vitamin D is considered to enhance childhood growth, although evidence is limited and conflicting. Several epidemiological studies have investigated the effects of maternal or infant vitamin D on height and bone growth (5–12). However, most of the studies were based on the populations below 6 years of age (5–7, 9–12), and some discrepancies existed in their findings due to a limited sample size (< 10,000) (7, 8, 10, 12). For instance, a randomized controlled trial of 2,079 low birthweight infants found that a weekly dose of vitamin D (35 μg/week) resulted in better vitamin D status and benefited weight and length growth at 6 months (12). In contrast, findings from a recent cohort study of 791 children aged 6–30 months were failed to support the viewpoint that poor vitamin D status in early childhood was an important limiting factor for linear growth (8). Additionally, the differences in the associations of vitamin D with height and bone development across gender, weight, and sexually mature status are not well-understood. Adipose tissue can decrease the bioavailability of vitamin D by excess storage of it, and consequently may be an effect modifier of vitamin D function (13). Likewise, the biochemical interaction between vitamin D and growth hormone has been explored by an increasing number of biological studies, which indicates the growth promotion effect of vitamin D may vary according to the stage of development (14).

Therefore, prospective high-quality evidence focusing on the relationships between vitamin D and height and bone growth in school-aged children are still needed to fill the knowledge gaps. In this large population-based cohort study from the School-based Cardiovascular and Bone Health Promotion Program (SCVBH), we aimed to investigate the associations of vitamin D with height growth velocity and low bone mineral density (BMD) in children aged 6~16 years, and further explore the effect modification of gender, age, obesity, and sexual maturity on these associations.

Using this large population-based prospective cohort, we found that higher serum 25(OH)D concentrations in children were associated with increased height growth velocity and reduced risk of incident low BMD outcome. Furthermore, the dose-response analyses found the optimum vitamin D levels for height growth were ~50 and 40 nmol/L in boys and girls, respectively. In addition, for overweight and obese children, the height growth velocity and risk of low BMD did not differ significantly across vitamin D status groups.

Height growth is a complex physiological process that depends on the combined action of genetic, environmental, and nutritional factors (14). Vitamin D is an essential nutrient for calcium and bone homeostasis and, consequently, potentially has a promoted effect on height growth. However, the association between vitamin D and height growth has been evaluated in a limited number of studies, and few of them focused on the school-aged (>6 years) children (6, 7, 9, 11, 12, 22). To our knowledge, this is the first large population-based prospective analysis to investigate the associations between vitamin D and height growth velocity in children aged 6~17 years. A Cochrane review has found that, compared to the placebo or no intervention group, vitamin D supplementation (daily dose 200–2,000 IU) in children aged under 5 years old made little to no difference in height growth (mean difference: 0.66, 95%CI: −0.37~1.68 cm) (7). Similarly, a cohort study of 791 North Indian children aged 6~9 years did not support the notion that poor vitamin D status was a limiting factor for height growth (measured by height for age z-score) in early childhood [β(95%CI): −0.06(−0.24~0.11)] (8). In contrast, our current study found that per 10 nmol/L higher serum 25(OH)D concentration was associated with a 0.15 cm/year higher height growth velocity and 7% decreased risk of low BMD in children aged 6~17 years after adjusting for vitamin D / calcium supplements. And children with sufficient vitamin D levels had significantly higher height growth velocity than those with deficient vitamin D levels. The divergence of results across studies may attribute to the small sample size, different assessments of height growth, different classification methods of vitamin D levels, and inadequate adjustment of residual confounding. A post-hoc analysis of randomized controlled trial from Uday et al. highlighted the importance of overall calorie intake for the skeletal maturation in malnourished children (5). In their findings, quarterly oral vitamin D supplementation did not influence bone age delay, but total calorie intake did. Unlike other studies with one measurement of 25(OH)D concentrations, we used the mean of baseline and follow-up 25(OH)D concentrations for analyses, which might provide a more accurate estimation of vitamin D status during the period of follow-up. In addition, we further adjusted baseline height, birth weight and feeding, parents' height, and the usage of vitamin D / calcium supplements which were potential confounding factors. Moreover, our dose-response relationship analysis showed that an inverse L-shaped association between vitamin D and height growth velocity was observed, and thus this non-linear characteristic may lead to negative results when using linear statistical methods to analyze their relationships. Partially in line with our findings, a randomized clinical trial-based cohort in Northern Europe revealed that vitamin D had an inverse U-shaped association with early growth during the first 2 years of life (6). Therefore, a very high level of 25(OH)D concentration may have no or unfavorable effects on normal growth. Even though vitamin D has many important health benefits, there is controversy regarding how vitamin D deficiency should be defined and what requirements should be met (23). In the current study, the optimum vitamin D levels for height growth promotion in boys and girls were ~50 and 40 nmol/L, respectively. Thus, the highest growth rate came from vitamin D insufficiency group in girls, while that came from sufficiency group in boys. The difference in the optimum vitamin D levels between sexes may be partly explained by the sex dimorphism in body fat mass. Generally, girls have a significantly higher amount of adipose tissue deposition than boys (24), and the bioavailability of vitamin D may be decreased due to excess storage in body fat compartments (25). Thus, girls with sufficiency vitamin D levels did not achieve better height growth velocity as that in boys. This hypothesis was also supported by our results of non-significant associations between the vitamin D status and height growth velocity in obese children. Beyond the aforementioned mechanism, sexual hormones may also play an important role in the discrepancy of optimum levels of vitamin D between sexes. For example, testosterone synthesis in men is appeared to be affected by 25(OH)D (26), we assume that it is possible that higher 25(OH)D concentrations may improve testosterone levels and then increase the height growth velocity in boys. Our multiple linear analyses didn't find significant interactions between weight status and vitamin D on height growth in both sexes (Table 3). This may be due to some reasons such as non-linear association, sample size, residual confounding, etc. However, in contrast with higher height growth velocity observed in normal weight boys with higher vitamin D levels, the height growth velocity didn't significantly differ from vitamin D status in overweight and obese boys. We deduced this result may be partly explained by that the bioavailability of vitamin D decreased due to excess storage in body fat compartments (25). In other words, vitamin D facilitated height growth in normal weight boys. Still, the facilitation effect of vitamin D was no longer statistically significant in overweight and obese boys because the excess storage in body fat compartments decreased the bioavailability of vitamin D.

Beyond the effect of vitamin D on the maintenance of calcium and bone homeostasis, which is potentially the major mechanism underlying that vitamin D and height growth are intertwined, the relationship between vitamin D and growth hormone may also play an important role (14). Their linkage derives partly from the similarity of seasonal variability in the levels: vitamin D levels and stature growth are greater in the summer period, while they are lower during winter (27, 28). Our results revealed a significant interaction effect between vitamin D and sexual maturity status on height growth velocity. The biological mechanisms underpinning the interaction are not clear, but clues may be gained from other studies. Insulin-like growth factor 1 (IGF-1), the mediator of growth hormone (GH), has been found to stimulate the activity of the 1α-hydroxylase enzyme that, in turn, regulates the renal production of vitamin D (29). In addition, both GH and IGF-1 appear to increase CYP27A1 activity and, thus affect catalyzing the 25-hydroxylation of vitamin D (30). On the other hand, vitamin D appears to influence the hepatic secretion of IGF-1 and the expression of IGF-1 receptors (31).

Our current study also supported that higher serum 25(OH)D concentrations were associated with the decreased risk of low BMD in school-aged children. Consistent with our findings, the D-pro randomized trial, which evaluated the effects of vitamin D and high dairy protein intake on bone mineralization and linear growth, found that vitamin D could increase bone mass and spinal BMD in 6–8-year-old children (32). However, it is noteworthy that differing from the normal-weight children, the risk of low BMD does not vary with the changes in serum 25(OH)D concentrations among overweight and obese children in our study. We speculate that the explanation for this is the decreased bioavailability of vitamin D due to excess storage in body fat compartments (25). There is also evidence that the metabolic clearance of vitamin D may increase in obesity due to increased uptake by adipose tissue (33). We found that the vitamin D insufficiency girls achieved the best height growth velocity while those with sufficient vitamin D had best bone density. This results indicate that natural optimum vitamin D levels may vary according to age, sex, race, and health outcome et al., thus using a universal guideline for diagnosing deficiency may be inaccurate. It is now generally accepted that vitamin D deficiency is a worldwide health problem that affects not only musculoskeletal health but also a wide range of acute and chronic diseases. However, there remains cynicism about the lack of randomized controlled trials to support the association studies regarding the no skeletal health benefits of vitamin D. The role of vitamin D in no skeletal health has been under intense debate, with inconsistent results regarding its potential prognostic value and therapeutic role.

This study has several strengths. First, the SCVBH program is a well-established population-based prospective cohort with a large sample of school-aged children, which can avoid reverse causality in causal inference. Second, the dose-response analysis and adjustment of a multitude of potential confounding factors may enhance the validity of the conclusions. Finally, a Vitamin D Standardization-Certification Program certified assay was used to measure serum 25(OH)D concentrations at baseline and follow-up, and the 2-time points measurements of vitamin D were used for analysis. Some potential limitations should be also noted in the current study. First, the generalizability of the conclusion may be limited due to a lack of other ethnic groups in our study population. Second, residual confounding resulting from errors in the measurement of covariates and other unmeasured factors such as vitamin D fortified foods, sun exposure, cannot be eliminated. Finally, considering the large study sample size, we used an ultrasound bone densitometer to assess BMD and, thus may have a disparity in the accuracy.

In conclusion, our results indicate that higher serum 25(OH)D levels were significantly associated with increased height growth velocity and decreased risk of low BMD in children aged 6~17 years. Furthermore, these associations were attenuated or eliminated in overweight and obese children. These findings highlight the importance of maintenance of sufficient 25(OH)D concentrations and healthy body weight during childhood in height growth and bone health promotion.

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

The studies involving human participants were reviewed and approved by Institutional Review Boards of Capital Institute of Pediatrics. Written informed consent to participate in this study was provided by the participants' legal guardian/next of kin.

JM: conceptualization, methodology, supervision, and writing—original draft. PX and HC: data curation, formal analysis, and writing—original draft preparation. PX and HL: visualization and software. LW, DH, and XZ: investigation, reviewing, and editing. XX: methodology, supervision, and investigation. All authors contributed to the article and approved the submitted version.