Vitamin D deficiency is common in healthy children, the main reasons include lack of outdoor activities, sunlight and vitamin D intake[12], and it is also related to race, season, age and body mass index[13–15]. In school students, the number of girls with vitamin D deficiency is more than that of men[16]. In winter, the 25(OH)D of black and white children decreased significantly, but the decrease of 25(OH)D of black children was smaller than that of white children, because the collagen type 1 cross-linked C-telopeptide (CTX) of black children increased significantly in winter, which could promote the vitamin D resorption rate[17]. In Danish school-age children, vitamin D level is negatively correlated with low-density lipoprotein, triglyceride and blood pressure, and this correlation has nothing to do with body fat and physical activity except blood pressure[18]. A study in China shows that the nutritional status of Nanjing Children in winter is relatively good, and the serum 25(OH)D level is 20–24 ng/ml[19]. In this study, OI children and healthy children in Lanzhou area were selected for comparison. Because of the higher dimension, vitamin D deficiency may be more common than that in Nanjing area. This study found that orthostatic intolerance was more common in school-age children, the median age was 11 years old, and the serum 25(OH)D level was significantly lower in OI children, especially in girls. Although we did not evaluate the growth environment, eating habits and daily activities of the children, but because this study is limited to Lanzhou area, there is little difference in the living environment and related eating habits of the children here, and such a large difference in vitamin D levels between healthy children and oi group can also reflect that there is a more serious vitamin D deficiency in OI children.
Vitamin D deficiency may be associated with cardiovascular disease in children [20]. Mann et al. found that low level of 25(OH)D (< 20ng/ml) can inhibit the activity of vagus nerve and increase the risk of cardiovascular disease[6]. Mustafa et al. found that the lack of 25(OH)D was significantly related to the impairment of cardiac autonomic nerve function through heart rate variability (HRV) parameter evaluation, and the cardiac autonomic nerve dysfunction was improved after 25(OH)D replacement therapy[21]. A study on cardiovascular autonomic function in patients with type 2 diabetes shows that 25(OH)D deficiency is associated with decreased parasympathetic function[22]. Vitamin D supplementation can prevent and delay the occurrence of cardiovascular autonomic dysfunction[23].
Vascular endothelial dysfunction may be another important cause of OI[1]. Vitamin D receptor (VDR) is expressed in endothelial cells, vascular smooth muscle and myocardial cells. After binding with VDR, vitamin D can stimulate the production of no by activating endothelial NO synthase (eNOS), thus mediating vasodilation[24]. In addition, cell and animal experiments in vitro also show that 25(OH)D is very important for VSMC proliferation and growth, and normal VSMC function is a necessary condition for good arterial compliance. Low 25(OH)D level inhibits the proliferation of vascular smooth muscle cells through acute calcium influx, increases the calcification of smooth muscle cells, and thus reduces arterial compliance[25, 26]. In addition, 25(OH)D is a negative endocrine regulator of RAAS system. Vitamin D can also inhibit the expression of paraglomerular cells and renin, thereby inhibiting the proliferation of VSMCs, thereby affecting blood pressure[27]. At present, studies have found that low serum 25(OH)D (≤ 25 ng/ml) level is earlier than the onset of OH, and low serum 25(OH)D can promote the onset of OH[28]. We hypothesize that vitamin D deficiency may cause or promote orthostatic intolerance related symptoms in OI children, but this needs further study.
Although there is no significant correlation between serum 25(OH)D and PTH concentration[29], most clinical studies show that serum 25(OH)D is negatively correlated with PTH. The parathyroid hormone level of children with 25(OH)D deficiency was higher than that of children without 25(OH)D deficiency[30], and this negative correlation had nothing to do with season and race[31], when the serum 25(OH)D level was lower than 30 ng/ml, PTH release was significantly promoted[15]. Amini, Z. et al. Believed that the serum 25(OH)D level of overweight or obese children would increase when it was lower than 12.4 ng/ml and 17.0 ng/ml[32]. However, Kang et al. Believe that when the25(OH)D level is less than 18.0 ng/ml, the PTH level in children's body will increase, the blood calcium level will decrease, and the possibility of hyperparathyroidism will also increase[33]. Maguire, J. L. and others believe that there is a nonlinear relationship between 25(OH)D and PTH. When 25(OH)D is 42.8ng/ml, PTH level is the lowest. When 25(OH)D is less than 42.8ng/ml, PTH will decrease significantly with the decrease of 25(OH)D. When 25(OH)D is more than 42.8ng/ml, PTH will increase slowly with the increase of 25(OH)D[34]. Some studies suggest that parathyroid hormone (PTH) supplementation can increase the expression of endothelial nitric oxide synthase (eNOS) and play a role in reducing age-related aortic endothelial dysfunction[35]. In our study, we found that the PTH level of girls was higher than that of boys in both healthy group and oi group. However, the comparison between groups found that although OI group had lower 25(OH)D level, it did not seem to change significantly in PTH level compared with normal group. Based on previous studies, we hypothesized that the PTH level of OI children would be higher than that of the normal group.
Whether vitamin D supplementation can improve the symptoms of orthostatic intolerance in children with OI needs further study.
A study in Brazil shows that 25(OH)D has a good ability to predict cardiac metabolic risk. When the concentration of 25(OH)D is higher than 32 ng/ml, the prevalence of cardiac metabolic risk in children will be reduced by 49%[36]. It has been found that increasing circulating 25(OH)D concentration can reduce the fat tissue (IMAT) between forearm muscles and increase the cross-sectional area (MCSA) of forearm and calf skeletal muscles[37], which may improve the contractility of lower limb muscles in OI children and avoid reflex hypotension due to upright. Chaudhari reported a case of 1-hydroxylase deficient POTS patients with improved palpitation symptoms after oral vitamin D treatment, suggesting that this kind of patients can be treated with calcitriol[38], but this still needs larger sample clinical trials to verify. However, in view of vitamin D deficiency in OI children, we still suggest that children should eat more foods rich in vitamin D, such as fish and dairy products, and increase light and outdoor activities. In addition, ROC curve shows that serum 25(OH)D at 19.49ng/ml has moderate sensitivity and specificity in the diagnosis of OI, which can be used for the diagnosis of OI.