The Association of Vitamin D Insufficiency with the Prevalence of Obesity in Children: Implications for Serum Calcium Levels, Alkaline Phosphatase Activity, and Bone Maturation

doi:10.21203/rs.3.rs-5022406/v1

Background: Vitamin D deficiency emerges as a potential risk factor implicated in a spectrum of detrimental health outcomes. However, its role in school-aged children’s metabolic regulation remains to be fully elucidated. This study aimed to explore the correlation between vitamin D deficiency and childhood obesity rates, and its impact on serum calcium, alkaline phosphatase, and bone age in children.

Methods: The study analyzed clinical data from 159 school-aged children who underwent medical examinations. The children were divided into the 25-hydroxyvitamin D3 (25(OH)D3) deficiency group and the 25(OH)D3 normalgroup based on their serum levels. The two groups were compared in terms of body mass index (BMI), total cholesterol (TC), triglycerides (TG), fasting blood G=glucose (FBG), hemoglobin A1c (HbA1c), calcium (Ca), alkaline phosphatase (ALP), and bone age differences.

Results: This study showed that the 25(OH)D3 deficiency cohort exhibited notably higher BMI, TC, TG, and ALP levels compared to the 25(OH)D3 normal cohort, whereas Ca and bone age were vigorously lowered in the 25(OH)D3 deficiency group. Moreover, BMI, TC, TG, Ca, ALP, and bone age have a significant diagnostic value in forecasting 25(OH)D3 deficiency in school-aged children. Correlation analysis revealed an inverse relationship between 25(OH)D3 levels and BMI, TC, TG, and ALP, as well as a positive association with serum Ca levels and bone age.

Conclusion: Our findings demonstrated that the deficiency of 25(OH)D3 is positively correlated with the incidence of obesity among school-aged children, which may adversely affect normal skeletal development. Therefore, regularly monitoring the levels of 25(OH)D3 is crucial for clinicians and healthcare providers in accurately assessing and ensuring the proper growth and development of school-aged children.

Vitamin D

School-Aged Children

Obesity

Bone Age

BMI

Vitamin D, a lipid-soluble vitamin, is integral to a myriad of physiological processes, notably enhancing cellular proliferation, facilitating differentiation, and modulating immune responses(1). As an essential nutrient not endogenously produced by the human body, vitamin D must be acquired through dietary intake or sunlight exposure, such as fish liver, egg yolks, and certain dairy products. Once absorbed in the small intestine, dietary sources of vitamin D are transported via chylomicrons into the bloodstream and converted in the liver into 25(OH)D3. This intricate physiological process is the principal form of vitamin D circulating in the bloodstream, serving a vital function in the facilitation of calcium absorption and bone mineralization.

Previous studies showed that infants, children, adolescents, and pregnant women require 400 IU/d of vitamin D, and inadequate dietary intake can lead to insufficiency in vitamin D, increasing the risk of conditions such as adult osteoma Acia and childhood rickets (2-4).

Vitamin D insufficiency is a globally recognized public health challenge, affecting billions of individuals worldwide (5-7). In China, vitamin D deficiency poses an equally pressing concern, notably affecting school-aged children. Ongoing developmental processes in preschool-aged children may render them susceptible to a range of gastrointestinal disorders, potentially hindering efficient vitamin D absorption. Furthermore, selective eating behaviors in this age group increase their risk of vitamin D deficiency(8, 9). Research indicates that 34% of obese children are affected by this deficiency(10). Vitamin D deficiency has been alarmingly associated with a spectrum of severe health conditions, encompassing cardiovascular diseases, metabolic disorders, endocrine imbalances, and even childhood cancers(11). Overall, the issue of vitamin D insufficiency in school-aged children is increasingly gaining attention from various sectors of society.

TC, TG, FBG, and HbA1c are widely acknowledged in glucose and lipid metabolism for their diagnostic value. In clinical practice, the assessment of vitamin D status is conventionally conducted by detecting 25(OH)D3 levels. Therefore, we aim to assess how variations in 25(OH)D3 levels affect Ca levels, ALP activity, and bone age in this pediatric population. This study aims to investigate the risk of childhood obesity and foster optimal skeletal growth and development by addressing vitamin D deficiency in school-aged children. This study aims to examine childhood obesity and promote skeletal growth and development in school-aged children by addressing the deficiency of 25(OH)D3.

2.1. Study setting and participation

We retrospectively analyzed clinical data collected from 159 school-aged children during health examinations and outpatient visits at the Hainan Hospital of PLA General Hospital and Ling Shui Li Autonomous County People's Hospital between April 2019 and April 2022. We adopted the American Academy of Pediatrics' criteria: <15 ng/mL, deficiency; 15–20 ng/mL, insufficiency; 20> ng/mL, sufficiency(12). where 25-(OH)D3≥20 ng/ml was considered sufficient vitamin D, 15 ng/ml≤25-(OH)D3<20 ng/ml was categorized as not having enough vitamin D, and 25-(OH)D3<15 ng/ml was classified as not having vitamin D. In this study, both situations of not having enough and not having vitamin D were combined into the 25(OH)D3 deficiency group (n=56), whereas sufficient levels were placed in the non-25(OH)D3 deficiency group (n=103).

Inclusion criteria: (1) All participants were children undergoing routine health examinations. (2) Age range of 6 to 12 years. (3) Availability of complete clinical data for each participant.

Exclusion criteria: (1) Physical growth abnormalities or deformities. (2) A history of gastrointestinal, respiratory, or other system-related illnesses and recent medication use within the past three months. (3) Immunological disorders or uncontrolled infections. (4) Impaired heart, liver, or kidney functions.

This study adheres to the ethical standards of medical research and has received approval from the institutional ethics committee. Informed consent was obtained from the legal guardians of all children subjected to the assessments.

2.2 Biochemical assessment

A total of 5 mL of venous blood was harvested from all children. TC and TG were assayed using a Siemens ADVIA2400 automated biochemical analyzer manufactured by Beijing Strong Biotechnologies, Inc., and the reagent kits were supplied by Roche (Shanghai, China). FBG was gauged through the assistance of a Hitachi 7060 automated biochemical analyzer via the glucose oxidase method, and the reagent kits were offered by Roche (Shanghai, China). HbA1c was analyzed on a Rayto RT6000 microplate reader via the high-pressure liquid chromatography method, with the reagent kits provided by Roche (Shanghai, China). Ca and ALP were quantified on a Hitachi 7060 automated biochemical analyzer employing the arsenazo III method and the NPP substrate-AMP buffer method, respectively, with the reagent kits supplied by Roche (Shanghai, China). 25(OH)D3 levels were assessed through the use of a Model 680 microplate reader from Bio-Rad (United States) and enzyme-linked immunosorbent assay kits provided by Roche (Shanghai, China).

2.3 Bone age assessment and calculation of body mass index

All children underwent a radiographic examination of the left wrist in the hospital after admission using a Shimadzu X-ray machine. During the radiographic examination, the palm and fingers were placed facing downwards on the detector. The children were instructed by the physician to extend their forearms and hands until the forearm axis aligned with the middle finger axis, with their fingers naturally spread apart. The central axis of the X-ray beam was aligned with the third metacarpophalangeal joint gap, and a perpendicular projection was taken, with the focal-film distance set at 90 cm. Furthermore, the BMI was calculated following the collection of admission statistics for the children, using the formula BMI = body weight (kg) / height² (m²).

2.4 Statistical analysis

Data processing was conducted with the assistance of SPSS22.0 statistical software. Measurement data were evaluated for normality through the Kolmogorov-Smirnov test. Normally distributed data were represented as mean ± standard deviation, and the comparison between the two groups was performed employing independent sample t-tests. Enumeration data were expressed as percentages (%), and intergroup comparisons were made through the χ² test. The value of BMI, TC, TG, Ca, ALP, and bone age in forecasting 25(OH)D3 deficiency in school-aged children was evaluated via the ROC curve analysis. Spearman correlation analysis was harnessed to ascertain the association between 25(OH)D3 levels in children of school age and BMI, TC, TG, Ca, ALP, and bone age. Divergences were confirmed to be statistically significant when P<0.05.

3.1. Basic information of the two groups and comparison of laboratory indices and bone age between the two groups

To explore the correlation between vitamin D deficiency and the prevalence of obesity in children, we conducted a retrospective analysis of the clinical data from 159 school-age children who underwent physical examinations. Among the participants, 109 were male and 50 were female, with ages ranging from 6 to 12 years and an average age of 9.27 ± 2.10 years. No significant differences were observed in gender, age, FBG, and HbA1c between the two cohorts (P>0.05). However, the group with 25(OH)D3 deficiency showed significantly higher levels of BMI, TC, TG, and ALP compared to the non-deficient group. In contrast, Ca levels and bone age were significantly lower in the 25(OH)D3 deficiency group. The general characteristics of these patients are detailed in Table 1.

3.2. Comparison of left wrist normal-position X-rays in the two groups of children

In the present investigation, we collected anteroposterior radiographs of the left hand from a cohort of school-age children for bone age evaluation. Furthermore, we have featured a subset of exemplary radiographic findings. Figure 1A presents a standard anteroposterior X-ray image of the left wrist from a 9-year-old female participant in the non-25(OH)D3 group. The radiographic R-series indicates a bone age advancement of 9 months relative to chronological age, while the C-series demonstrates a normal bone age alignment. Figure 1B likewise represents an anteroposterior radiograph of the left wrist from a 9-year-old male, the R-series suggests a bone age 5 months older than the actual age, and the C-series indicates a 1-year and 2-month difference. Figure 1C shows a radiograph from a 9-year-old male exhibiting 25(OH)D3 insufficiency. The R series indicates a bone age 2 years younger than his actual age, while the C series suggests a bone age 1 year and 10 months older. Similarly, we found that school-aged children within the 25(OH)D3 deficiency cohort exhibit lower R-series and C-series ages than their peers (Figure 1D). In summary, our research findings indicate that a deficiency in 25(OH)D3 during the school-age period is a significant risk factor for delayed growth and development.

3.3. The value of BMI, TC, TG, Ca, ALP, and bone age in predicting 25(OH)D3 deficiency in school-aged children

We further constructed the receiver operating characteristic (ROC) curve to assess whether BMI, TC, TG, Ca, ALP, and bone age could be utilized for forecasting 25(OH)D3 deficiency in school-aged children. The AUC for each parameter was BMI (AUC: 0.879), TC (AUC: 0.785), TG (AUC: 0. 872), Ca (AUC: 0. 839), ALP (AUC: 0.688), and Bone age (AUC: 0. 809), respectively, all of which presented a significance level of P<0.05 (Table 2). The results confirmed that a vast majority of clinical Indicators have a significant diagnostic value (Figure 2).

3.4. Analysis of the relationship between 25(OH)D3 levels and BMI, TC, TG, Ca, ALP, and bone age

To further analyze whether there is a direct correlation between 25(OH)D3 levels and BMI, BMI, TC, TG, Ca, ALP, and bone age. We selected 56 children from the 25(OH)D3 deficiency cohort and used Spearman's correlation analysis to assess whether there is an association between their serum 25(OH)D3 levels and BMI, TC, TG, Ca, ALP, and bone age. The outcomes illustrated that there was a negative correlation between 25(OH)D3 levels in the children’s serum and BMI (R²=-0.6234, P<0.0001), TC (R²=-0.5998, P<0.0001), TG (R²=-0.6125, P<0.0001), and ALP (R²=-0.6019, P<0.0001) (Figure 3 A-D), whereas a positive correlation was observed with Ca (R²=0.5920, P<0.0001) and bone age (R²=0.6729, P<0.0001) (Figure 3 E-F). These correlations were statistically significant with P<0.05, as presented in Table 3.

Over the last several years, with the improvement in people’s quality of life, childhood obesity has become increasingly prominent. As opposed to healthy children, this group shows a dramatic elevation in BMI, and the risk of cardiovascular and metabolic diseases is also vigorously heightened (13-15). 25(OH)D3, as a common indicator for evaluating vitamin D, plays a crucial role in regulating Ca levels and influencing cell proliferation and differentiation, which are of great significance in the body’s growth and development. Therefore, this research seeks to probe the relationship between 25(OH)D3 and BMI, TC, and TG in school-aged children, observing the impact of alterations in 25(OH)D3 levels on childhood obesity. In addition, Ca, ALP, and bone age are important indicators of bone metabolism. Actively investigating the influence of 25(OH)D3 changes on Ca, ALP, and bone age may provide a theoretical basis for understanding the abnormalities in Ca, ALP, and bone age caused by vitamin D deficiency in school-aged children.

The findings of this study suggested that the 25(OH)D3 deficiency cohort had substantially heightened BMI, TC, and TG levels compared to the non-deficiency cohort, which meant that 25(OH)D3 deficiency could culminate in childhood obesity. In a preceding study, researchers have ascertained that 25(OH)D3 in obese children is vigorously lowered vis-à-vis normal-weight children. In this scenario, the BMI of obese children abnormally increases. They have also pointed out that with the increasing age of obese children, the 25(OH)D3 deficiency worsens, which can mutually support the findings of this study (16). TC and TG are both commonly utilized clinical indicators for assessing the lipid content within the blood. The former reflects the total cholesterol contained in lipoproteins in the blood, while the latter reflects the total triglycerides contained in lipoproteins. An uplift in their levels denotes fat accumulation within the body (17, 18). 25(OH)D3 assumes a function in augmenting calcium ion levels within fat cells and fatty acid synthetase activity, making itself an indispensable inhibitor during the process of fat cell differentiation. When there is a deficiency of 25(OH)D3 in school-aged children, the inhibitory effect of 25(OH)D3 is affected, resulting in fat accumulation within the body and abnormally elevated BMI, TC, and TG levels (19, 20). It is worth noting that in the current research, FBG and HbA1c serum levels in both cohorts did not exhibit remarkable disparities, revealing that 25(OH)D3 deficiency in school-aged children might not have a huge impact on glucometabolic. Nonetheless, in prior research, Safarpour (21) and others have unraveled that vitamin D supplementation can achieve FBG and HbA1c modulation. Corica (22) and colleagues have also confirmed that vitamin D deficiency in obese children can bring about impaired glucose metabolism and elevated blood glucose levels. The divergences between the above-mentioned reports and the findings of this study may be attributed to factors such as differences in the age and geographical location of the study subjects.

Our research also unveiled that the 25(OH)D3 deficiency cohort had significantly lower levels of Ca, ALP, and bone age vis-a-vis the non-deficiency cohort, suggesting that 25(OH)D3 insufficiency impinged on the bone growth and development of school-aged children. Vitamin D is an essential humoral factor that modulates bone metabolism and sustains normal development in the body. It can be obtained through sunlight exposure, UV radiation, and dietary intake. On one hand, vitamin D stimulates the production of intestinal calcium-binding proteins, augments blood Ca levels, and boosts bone mineralization. On the other hand, vitamin D induces the maturation and differentiation of osteoblasts, facilitating the formation and maturation of bone matrix (23-25). In cases of vitamin D deficiency, only 10-15% of dietary calcium can be absorbed due to the lack of calcium within the serum, giving rise to an imbalance in the calcium-phosphorus ratio, which disrupts normal epiphyseal cartilage growth and mineralization, leading to growth retardation and bone deformities. Thus, in situations of vitamin D deficiency, the supplementation of calcium alone has minimal effect on growth and development and may even cause bone deformities such as epiphyseal protrusion and rib beading (26). ALP is an enzyme present in multiple tissues throughout the body, originating from the liver, bones, intestines, or kidneys. However, bone ALP and liver ALP account for approximately 95% of the total ALP activity in human serum. Research has unveiled that the most common cause of heightened ALP levels in the blood is related to liver or bone diseases (27). ALP exerts a critical function in modulating calcium absorption and utilization through its involvement in mineral transformation in the bones and the activation of vitamin D. In bones, ALP steps up the release of phosphate ions and forms minerals in combination with calcium ions, maintaining bone structure and strength. Furthermore, the activity level of ALP can reflect alterations in calcium and phosphorus metabolism. When there is an imbalance in calcium and phosphorus metabolism, such as inadequate calcium absorption or excessive excretion, the activity of ALP often undergoes changes. Therefore, by monitoring ALP activity, the status of calcium and phosphorus metabolism can be assessed, providing further insights into bone health. This study further demonstrated that the 25(OH)D3 deficiency cohort displayed a dramatic elevation in ALP, and the reason for this is associated with the high bone turnover state resulting from vitamin D insufficiency. Due to the impact of vitamin D deficiency, there is an imbalance in the calcium-phosphorus proportion, culminating in impaired bone growth and development. In this state, osteoblasts become more active, which can cause a rise in the ALP level. Bellastella (28) and others have also pinpointed in their research that serum ALP profile is modulated by vitamin D, denoting a close correlation between the two.

In our research, the value of BMI, TC, TG, Ca, ALP, and bone age in forecasting 25(OH)D3 insufficiency in school-aged children was observed through ROC analysis. It was discovered that BMI≥24.50 kg/m2, TC≥4.08 mmol/L, TG≥1.39 mmol/L, Ca≤2.18 mmol/L, ALP≤306.26 U/L, and bone age≤7.25 years are indicators with high sensitivity for predicting 25(OH)D3 deficiency. Actively monitoring these indicators may provide assistance in early identification of 25(OH)D3 deficiency in school-aged children. Additionally, this research investigated the correlation between 25(OH)D3 levels and BMI, TC, TG, Ca, ALP, and bone age in school-aged children through the assistance of Spearman coefficients. It was confirmed that 25(OH)D3 levels in school-aged children were negatively associated with BMI, TC, TG, and ALP but positively correlated with Ca and bone age. This unveiled a close relationship between 25(OH)D3 deficiency and childhood obesity as well as bone growth and development. In clinical practice, particular attention should be devoted to monitoring the fluctuations in 25(OH)D3 levels among school-aged children, ensuring their optimal growth and development during this critical period.

In conclusion, it can be inferred that insufficiency of 25(OH)D3 may contribute to school-age children's obesity. Furthermore, this deficiency exerts an impact on bone growth and development in these children, leading to reduced levels of calcium, delayed bone maturation, and ALP levels. When conducting clinical work, prioritizing the screening for vitamin D deficiency in school-age children is particularly crucial.

Author Contributions

Y.X., L.S., and L.Z. designed and initiated the study. Y.X., L.S., and L.Z. discussed results and provided important intellectual content throughout the study. Y.X. wrote the manuscript. L.S., and L.Z. revised, edited, and supervised this paper. All authors participated in data interpretation.

Funding

This study did not receive funding support.

Declaration of interest

No potential conflicts of interest were disclosed.

Data availability

The data that support the findings of this study are available on request from the corresponding author.

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Table1. Baseline characterization of participation
Item	25-(OH) D3 deficiency group (n=56)	Non-25-(OH) D3 deficiency group (n=103)	x²/t	P
Gender (n)			0.01	0.88
Male [n (%)]	38 (67.86)	71 (68.93)
Female [n (%)]	18 (32.14)	32 (31.07)
Age (years)	9.24±2.06	9.30±2.11	0.17	0.86
BMI (kg/m²)	25.41±1.86	23.16±1.08	9.65	<0.001
TC (mmol/L)	4.92±1.88	3.18±1.07	7.44	<0.001
TG (mmol/L)	1.62±0.39	1.23±0.14	9.14	<0.001
FBG (mmol/L)	4.23±1.01	4.24±1.06	0.05	0.95
HbA1c (%)	4.90±0.67	4.88±0.63	0.18	0.85
Ca (mmol/L)	1.94±0.15	2.64±0.21	22.05	<0.001
ALP (U/L)	241.50±61.27	212.72±46.85	3.31	<0.001
Bone age (years)	6.18±1.36	7.58±1.51	5.77	<0.001

Note: data expressed as mean and standard deviation and frequency (percentage); BMI: Body Mass Index; TC: Total cholesterol; TG: Triglyceride; ALP: Alkaline phosphatase; Ca: Serum calcium.

Table 2. The value of BMI, TC, TG, Ca, ALP, and bone age in predicting 25-(OH) D3 deficiency in school-aged children
Index	AUC	SE	P	95%IC	Optimum cutoff value	Sensitivity	Specificity
BMI	0.879	0.815～0.943	0.682	24.50 kg/m²	0.932	0.750	0.879
TC	0.785	0.700～0.868	0.530	4.08 mmol/L	0.816	0.714	0.785
TG	0.872	0.797～0.948	0.698	1.39 mmol/L	0.913	0.785	0.872
Ca	0.839	0.762～0.915	0.704	2.18 mmol/L	0.884	0.821	0.839
ALP	0.688	0.598～0.778	0.297	306.26 U/L	0.922	0.375	0.688
Bone age	0.809	0.736～0.881	0.545	7.25 years	0.777	0.768	0.809

Note: BMI: Body Mass Index; TC: Total cholesterol; TG: Triglyceride; ALP: Alkaline phosphatase; Ca: Serum calcium; SE: standard error

Table 3. Analysis of the relationship between 25-(OH) D3 levels and outcomes
Index	R²	P
BMI	-0.530	<0.001
TC	-0.678	<0.001
TG	-0.653	<0.001
Ca	0.447	<0.001
ALP	-0.625	0.009
Bone age	0.521	<0.001

Note: BMI: Body Mass Index; TC: Total Cholesterol; TG: Triglyceride; ALP: Alkaline Phosphatase; Ca: Serum Calcium.

No competing interests reported.

The Association of Vitamin D Insufficiency with the Prevalence of Obesity in Children: Implications for Serum Calcium Levels, Alkaline Phosphatase Activity, and Bone Maturation

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Abstract

Figures

1. Introduction

2. Materials and methods

3. Results

4. Discussion

5. Conclusion

Declarations

References

Tables

Additional Declarations

Status:

Version 1