Vitamin D Nutritional Status And Its Association With Bone And Cardiovascular Health Among Children And Adolescents In Six Chinese Cities

[Background]Nowadays,evidence on the prevalence of vitamin D deficiency from general Chinese children and adolescents with a wide age span in recent years is limited.The heightened prevalence of obesity among Chinese children and adolescents was reported in recent years.Nevertheless,data are lacking regarding the associations of vitamin D with adiposity and body fat distribution.Vitamin D plays a significant role in bone and mineral metabolism.Childhood and adolescence are critical periods in skeletal development,which will determine an individual’s peak bone mass.Most previous studies have shown a positive correlation between vitamin D levels and bone mineral density(BMD)in children,but the results varied by ethnicity,region,gender,and age,and no consistent conclusions have been reached yet.In addition,there are fewer studies on the relationship between vitamin D and bone metabolism-related indicators such as parathyroid hormone(PTH)and osteocalcin in children.Besides,vitamin D has also shown to play an essential role in the optimal function of various organs and tissues,including the cardiovascular system.Both vitamin D deficiency and cardiometabolic risk factors pose great health risks to children,and cardiometabolic risk factors in childhood may contribute to cardiovascular disease in adulthood.Nevertheless,few studies have addressed these associations between them in Chinese pediatric population.Furthermore,since most previous studies were performed in Caucasians and in adults,whether the suggested current widely used cutoff point may not be suitable for other populations,especially in children with darker skin and different lifestyles,such as Asians.According to the metabolism of vitamin D,the BMD,circulating PTH levels,and cardiometabolic indexes may be useful indicators in determine optimal vitamin D status.[Objective](1)to describe the vitamin D nutritional status and distribution characteristics in Chinese children and adolescents;(2)to clarify the relationship between adposity and vitamin D nutritional status;(3)to assess association between vitamin D and skeletal and cardiovascular health;(4)to explore the optimal vitamin D levels for skeletal and cardiovascular health in children.[Methods]Study population from the China Child and Adolescent Cardiovascular Health(CCACH)study.This study was a large,nationwide,and multicenter observational study conducted between 2013 and 2015,10,696 pediatric participants(51.2%boys)aged 6-18 years were included.The following information was collected:(1)Demographic and sociological information,life habits,disease history,and family history;(2)Anthropometric measurement:height,weight,waist circumference,systolic blood pressure,diastolic blood pressure;(3)Dual-energy X-ray absorptiometry(DXA)assessed total and regional body composition:body fat,lean body mass,bone mineral density,further calculate body mass index(BMI),fat mass percentage(FMP),total and regional body fat mass index(FMI)and fat ratio;(4)Hematologic examination:25-hydroxyvitamin D(25[OH]D)and PTH,OC,blood calcium,phosphorus,fibroblast growth factor-23(FGF-23),lipid(total cholesterol[TC],low density lipoprotein cholesterol,[LDL-C],triglyceride,[TG],high density lipoprotein cholesterol,[HDL-C],Non-high density lipoprotein cholesterol,[Non-HDL-C]),and fasting plasma glucose(FPG).Obesity,hypertension,hyperlipidemia,impaired fasting glucose(IFG),and metabolic syndrome(MS)were diagnosed.Vitamin D nutritional status was assessed by 25(OH)D concentration as "deficiency"(<30 nmol/L),"inadequacy"(30 to<50 nmol/L)and "sufficiency"(≥50 nmol/L)according to the Institute of Medicine(IOM).Vitamin D insufficiency(<50 nmol/L)includes inadequacy and deficiency.Appropriate statistical analysis methods were used based on data distribution.Multi-variables linear regression,binomial logistic regression,multiple Logistic regression,generalized additive models,ROC analysis,and segmented regression were used.In all regression models,adiposity indicators and BMD were used on their sex-and age-specific z-scores.[Results]1.Vitamin D nutritional status and its related factors among children and adolescents in six Chinese citiesThe average level of 25(OH)D in the total population was 39.20±15.51 nmol/L,and 78.2%had vitamin D insufficiency,Among the six study cities,the highest level of 25(OH)D was 44.23 ± 16.54 nmol/L in Jinan,and the lowest level was 30.59 ± 13.12 nmol/L in Chongqing.In four seasons of blood collection,the highest level of 25(OH)D was 47.39±16.17 nmol/L in summer,and the lowest level was 36.68 ± 14.34 nmol/L in spring.The level of 25(OH)D in boys was higher than that in girls(40.60±15.45 nmol/L vs.37.72±15.44 nmol/L,P<0.001).Additionally,an L-shape curve with a threshold age of 14 years was observed in the relationship between 25(OH)D and age in both genders.The lowest rates of vitamin D deficiency and insufficiency were found among participants aged 6-8 years,but the highest among those aged 12-14 years(85%).After adjusted for age,sex,geographic location,BMI,season of blood collection,and other life behavior,multivariate regression models showed that the risks of having vitamin D deficiency in the high intake frequency group were 17%and 27%less than the low intake frequency of eggs and aquatic products children,respectively,with P values<0.05.2.Association of adiposity indicators with vitamin D nutritional statusThere was an inverted U-shaped relationship between BMI z-scores and 25(OH)D levels.Multivariate regression models showed that 25(OH)D levels in slim,overweight,obese,and severely obese children were 0.94 nmol/L,0.57 nmol/L,0.89 nmol/L,and 1.98 nmol/L lower than that in normal BMI group,respectively,P values<0.05.In stratified analyses by sex,consistent results were observed among boys rather than girls.Different from BMI,FMI z-score was linear negatively correlated with 25(OH)D levels in both boys and girls,but the association more robust in boys.Multivariate linear regression analysis showed that the regression coefficient of FMI z-score and 25(OH)D levels in boys was-0.86(P<0.001),while that of girls was-0.27(P=0.23 1).Analyses that used FMP instead of FMI gave similar results.In addition,ROC analysis showed that the AUCs of FMI or FMP in crude and multivariable models were greater than that of BMI models in both sexes,all P<0.05.For body fat distribution,fat in different regions exhibited differential vitamin D insufficiency risk.Among boys,after adjustment for multiple variables,including other regional FMI,higher trunk-FMI,and Android-FMI were associated with a greater likelihood of vitamin D insufficiency[OR(95%CI):2.14(1.58～2.89)and 1.87(1.41-2.48),respectively].In comparison,extremity-FMI and gynoid-FMI were associated with protection from vitamin D insufficiency[OR(95%CI):0.63(0.47～0.83)and 0.71(0.55～0.92),respectively],all P values<0.05.Among girls,the associations of regional fat with vitamin D were weaker than those in boys,and most analyses did not reach statistical significance.3.The relation of vitamin D nutritional status with bone mineral density and bone metabolic biomarkersIn the overall study population,linear regression models adjusted for age,sex,geographic location,season of blood collection,living habits,total body muscle mass,and body fat mass,25(OH)D concentrations were positively associated with BMD of the whole body and all regions,and the BMD z-scores increased by 0.041～0.065 for per 10nmol/L change of 25(OH)D.There was an interaction between vitamin D and BMI with BMD,and all P values<0.05 except for lumbar BMD.Furthermore,25(OH)D levels were negatively correlated with PTH,phosphorus,and OC,but positively associated with calcium and FGF-23.For per 10nmol/L change in 25(OH)D,Log-PTH,phosphorus,and OC decreased by 0.056pg/mL,0.011mmol/L,and 4.149ng/mL,while calcium and Log-FGF-23 increased by 0.002mmol/L and 0.018pg/mL,respectively.Similar trends and results were observed in stratified analyses by sex,but the effect sizes were mostly greater in boys than that in girls.Based on segmented regression analysis,the break-points of 25(OH)D for TBLH BMD z-scores were estimated to be 51.6 nmol/L,50.8 nmol/L,and 36.8 nmol/L in the overall study participants,boys,and girls,respectively.Also,the break-points for BMD z-scores at the arms,legs,ribs,thoracic spine,lumbar spine,and pelvic were similar to TBLH BMD z-scores.Moreover,the estimations of the break-points on PTH were 46.4 nmol/L,47.2 nmol/L,and 29.6 nmol/L in the overall,boys and girls,respectively.4.The relationships between vitamin D nutrition status and cardiometabolic indicatorsIn the overall study population,after adjusted for confounding factors,multivariate binomial logistic regression showed 25(OH)D negatively associated with IFG,high TG,high Non-HDL-C,and MS.For per 10nmol/L increased in 25(OH)D,the risk of IFG,high TG,high Non-HDL-C,and MS decreased by 12%,12%,10%,and 9%,respectively,P<0.05.Similar results were observed in stratified analyses by sex.In addition,there was an interaction between vitamin D and obesity on the IFG(P=0.034),with an excess relative risk of interaction of 33%and an attribution ratio of 21%among the overall population.Consistent results were observed only in boys when analysed by sex.Based on segmented regression analysis,the break-points of 25(OH)D for high TG,high Non-HDL-C,IFG,and MS were estimated to be 39.4 nmol/L,77.3 nmol/L,42.4 nmol/L,and 45.7nmol/L in the overall study participants,and 52.7 nmol/L,65.9 nmol/L,45.8 nmol/L,and 59.6 nmol/L in boys.Among girls,36.9 nmol/L,73.8 nmol/L,41.8 nmol/L,and 43.3nmol/L were estimated,respectively.[Conclusions](1)Vitamin D insufficiency is common among children aged 6-18 years in six Chinese cities,and is significantly more prevalent among girls and senior children.(2)Children with adiposity or central fat distribution tended to have a poor vitamin D nutritional status.(3)Vitamin D levels are positively associated with BMD,and are closely related to bone metabolic indicators.Vitamin D insufficiency has a synergistic effect on BMD with obesity.(4)Vitamin D insufficiency is associated with increased odds of various cardiometabolic disorders.In the future,research on vitamin D and cardiovascular disease should consider the influence of obesity.(5)The optimal break-points of 25(OH)D levels based on BMD is about 50nmol/L～55nmol/L in boys and 35nmol/L～40nmol/L in girls,higher break-points of 25(OH)D may be suitable for cardiometabolic health.