Study on the Relationship of 25-hydroxyvitamin D and Intact Parathyroid Hormone in Chinese Adults

DOI: https://doi.org/10.21203/rs.2.21603/v1

Abstract

Background:Vitamin D plays an important role in bone health and other diseases, however, there is no consensus over the optimal serum 25-hydroxyvitamin D (25(OH)D) concentration. Many studies consider that the 25(OH)D concerntration which maximally inhibit serum intact parathyroid hormone (iPTH) might be the optimal status for vitamin D sufficiency. This study was performed to study the relationship between 25(OH)D concentration and intact parathyroid hormone (iPTH) concentration in the Chinese non-clinical population aged 18-44y. Methods: The serum samples of adults aged 18-44 years old were selected from the established serum bank of Chinese Chronic Diseases and Nutrition Survey (CCDNS, 2015-2018). The serum 25(OH)D concentration was determined by high performance liquid chromatography tandem mass spectrometer, and the iPTH was determined by electronic chemiluminescence method. The relationship of 25(OH)D and iPTH were analyzed by correlation analysis, segmented linear regression and the confidence interval was determined by bootstrap method. Results: 623 serum samples (293 male, 330 female) of 25(OH)D concentration and iPTH concentration were analyzed. Significant higher 25(OH)D concentration was found in male than female. And the samples from the southern China had higher 25(OH)D concentration than those from the northern China. Samples from autumn had higher 25(OH)D concentration than those from spring and winter. The inversely relationship between 25(OH)D concentration and iPTH concentration was observed in both male and female. The concentration of 25(OH)D was 19.2 (10.1-27.2) ng/mL (P=0.02) when iPTH entered the plateau in women and no plateau for iPTH was found in men. Conclusions: The relationship between 25(OH)D and iPTH differs by sex among Chinese adults aged 18-44y. Further study is needed to evaluate the sex-specific ranges of optimal vitamin D. Trial registration: Not applicable. Keywords: 25-hydroxyvitamin D; parathyroid hormone; plateau; Chinese adults

Background

Vitamin D is one of the essential micronutrients in human body. Vitamin D can stimulate the synthesis of osteopontin and alkaline phosphatase in osteoblasts and inhibit the apoptosis of osteoblasts, which is beneficial to bone formation [1]. Recent studies have found that Vitamin D nutritional status is not only related to bone health, but also to cell metabolism, immune system, respiratory system and other human functions [2,3]. On the other hand, Vitamin D excess can lead to hypercalcemia [4], therefore it is very important to accurately evaluate the nutritional status of human Vitamin D for early prevention and treatment of related diseases.

25-hydroxyvitamin D [25(OH)D] is the main circulation form of Vitamin D in blood with a half-life of 2–3 weeks [5]. It is recognized as a reliable indicator for evaluating Vitamin D status in human body [6]. However, there are still controversies about the threshold of 25(OH)D in serum for judging the nutritional status of Vitamin D. There are two main popular perspectives of thresholds for Vitamin D deficiency recommended by the American Institute of Medicine (IOM) and the Endocrine Society (TES), respectively [5,7]. The Institute of Medicine (IOM) of America considered that a serum 25(OH)D level of at least 20 ng/mL (50 nmol/L), meet the requirements of at least 97.5% of the population. And it defined VitD deficiency as < 12 ng/ml (30 nmol/L) 25(OH)D and considered levels between 12–20 ng/ml (30–50 nmol/L) as insufficient VitD [6,8]. TES issued serum 25(OH)D level of 30 ng/mL (75 nmol/L) was considered sufficient. Serum 25(OH)D level that was lower than 20 ng/mL (50 nmol/L) as VitD deficiency and serum 25(OH)D level between 20–30 ng/mL (50–75 nmol/L) as VitD insufficiency [5].

Intact Parathyroid hormone (iPTH) is a calcium-regulated hormone and it mainly acts on kidney and bone tissues. iPTH concentration has been reported inversely associated with serum 25(OH)D concentrations until a threshold, and then the iPTH concentration reaches its plateau at a minimum level above the threshold[9]. This threshold and above is often suggested as Vitamin D sufficiency[10–11]. There are a number of cross-sectional and randomized controlled trialsreport on the inversely relationship between 25(OH)D concentration and iPTH concentration in different coutries and ethnicities [10–11]. There was no consistency in the threshold values of serum 25(OH)D that varies from 25 nmol/L (10 ng/mL) to 50 nmol/L (125 ng/mL) [10]. There are still some studies in which such threshold or the negative correlation was not found.

This study is to analyze the relationship between serum 25(OH)D concentration and iPTH concentration in Chinese adults aged 18-44y based on the Chinese Chronic Diseases and Nutrition Survey (CCDNS) 2015–2018. We try to understand if there is such a threshold for this specific group of Chinese population.

Methods

Study population

650 samples of adults aged 18-44y were collected from the Chinese population serum bank established from the CCDNS 2015–2018 by the method of simple random sampling. CCDNS is a cross-sectional survey of the civilian non-institutionalized population of China, conducted by the National Institute of Nutrition and Health and the Center for the Prevention and Control of Chronic Non-communicable Diseases, Chinese Center for Disease Control and Prevention (NINH & CPC, China CDC). All the participants of this survey were selected by using a stratified proportional random cluster sampling. All the participants and their guardians gave their informed consent in writing to participate in the CCDNS survey.

25(OH)D and iPTH detection

Both serum 25(OH)D and serum iPTH were detected in this study. 2 mL of fasting venous blood was collected and centrifuged at 1500 × g for 15 min, 20–30 min after the blood was taken. The serum was aliquot and stored in a brown vessel at − 20℃ in the laboratory where the investigation area was located. All the serum specimens from all the investigation areas were transported to the serum bank located in NINH by cold chain. All the blood samples were preserved at -70℃ in a freezer before detection. The High Performance Liquid Chromatography Tandem Mass Spectrometer (AB Sciex Pte. Ltd. USA) was used to analyze serum 25(OH)D concentration. The calibration of the assay was verified by using the NIST standard reference material SRM 972. The average bias was 2.3% for 25(OH)D2 and 1.7% for 25(OH)D3 comparing with Nist SRM 972. The iPTH concentration was measured by electronic chemiluminescence immunoassay (Roche e601, F Hoffmann-La Roche Ltd. Switzerland). The CV was 4.9% in the 51.5–53.9 pg/mL range, and 4.2% in the 186–191 pg/ml range.

Variables

A national project workgroup was established in China CDC to develop a unified survey and questionnaires to carry out the investigation by using unified equipments and methods. The basic information of the subjects (including age, sex, region type, etc.) was collected by questionnaire. China’s Qinling Mountains and Huaihe River are recognized as the boundary to divide the north and the south. The region type are classified according to the level and type of economic development and the population size [12]. Body Mass Index (BMI) was calculated according to bodyweight and height. Body weight was measured by uniform electronic scale, and standing height was measured by a metal column type height meter.

Statistical Analysis. Serum 25(OH)D and iPTH concentrations were recorded by using P50 (P25–P75) because they were not compliant with the normal distribution according to the normality test, and then they were compared by the Kruskal–Wallis test in different subgroups. The partial correlation analysis adjustment by age, BMI and season. The liner regression were used to assess the correlation between the 25(OH)D concentration and the iPTH concentration. The locally weighted regression smooth scatterplot (LOESS) procedure is a nonparametric method for fitting a smooth curve that best characterizes the relationship between 2 continuous variables [13]. Given the reported non-linear association between iPTH and 25(OH)D, the LOESS curve was then utilized to characterize the association between them. The threshold estimate for 25(OH)D was calculated by using segmented liner regression and non-liner regression model [14] by R version 3.6.1 statistical software. The optimal threshold value was chosen based on adjusted R2 and associated P value for the threshold variable. All the other analyses were performed by SAS version 9.4 statistical software (SAS Institute Inc., Cary, NC, USA). Two tailed P < 0.05 was considered as statistically significant.

Results

Sample characteristics

Samples of poor blood quality or those with incomplete information were excluded, and the serum 25(OH)D concentration and iPTH concentration of 623 blood samples (293 male and 330 female) aged 18-44y were included in this study (Table 1). The samples were collected from all 31 provincial administrative regions in China. The male samples covered 209 survey areas, and the female samples covered 196 survey areas. The median age was 31(25–39) years old. The median BMI was 23.1(20.9–25.6) kg/m2, and female had a statistally lower BMI than male (P = 0.009). The median iPTH concentration was 24.2(18.1–31.7) pg/mL with the range of 5.5–96.4 pg/mL, and no statistical difference was found between male and female in all age groups. No statistical difference was found in all age groups in terms of iPTH and 25(OH)D concentration in both sex. The distribution of iPTH by sex was showed in Fig. 1. The median 25(OH)D concentration was 19.1(13.2–26.1) ng/mL with the range of 3.2–57.8 ng/mL. Male had a significant higher 25(OH)D concentration than that of female in all age groups and both region types. The distribution of 25(OH)D by sex was showed in Fig. 2. The 25(OH)D concentration of the serum samples from the north was significantly lower than those from the south in both sexes. No statistical difference was found in different region types in both sexes. As CCDNS did not conduct the investigation on a seasonal basis, our samples did not cover all the seasons. In this study, the 25(OH)D level was highest in autumn. No significant difference was found in spring, autumn and winter in terms of the median iPTH concentration.

Table 1
25 hydroxyvitamin D and intact parathyroid hormone concentration of Chinese adults aged 18-44y.
Characteristic
Total
Male
Female
Pa
Sample size(n,%)
623
293(47%)
330(53%)
 
Age(y)
31(25–39)
30(24–38)
31(25–39)
0.37
BMI(kg/m2)
23.1(20.9–25.6)
23.7(21.4–26.3)
22.8(20.7–25.0)
0.009
iPTH(pg/mL)
24.2(18.1–31.7)
24.0(18.0-30.2)
24.3(18.2–32.4)
0.30
Age group (iPTH, pg/mL)
       
18-25y
23.7(18.6–29.9)
23.9(17.8–29.3)
23.6(18.8–31.8)
0.46
26-35y
24.2(17.2–31.6)
23.9(17.7–30.4)
24.3(17.1–32.1)
0.82
36-44y
24.8(18.8–32.3)
24.1(18.2–31.6)
25.1(19.8–33.6)
0.42
Latitude (iPTH, pg/mL)
       
North
24.9(18.2–32.3)
23.7(17.8–31.1)
25.2(18.7–33.5)
0.09
South
23.8(17.8–30.4)
24.2(18.2–29.9)
23.1(17.6–31.5)
0.76
Region type (iPTH, pg/mL)
       
Urban
25.0(19.1–31.8)
24.9(19.5–31.6)d
23.4 (17.1–29.0)
0.83
Rural areas
23.8(17.5–31.0)
25.2(19.1–31.9)
24.7(17.7–33.6)
0.74
Season (iPTH, pg/mL)
       
Spring
25.3(19.0-31.8)
24.8(17.7–31.8)
25.7(19.5–31.7)
0.88
Autumn
23.9(18.2–30.4)
23.8(18.3–29.9)
23.9(17.8–31.5)
0.97
Winter
24.4(17.8–32.5)
24.0(17.5–31.2)
25.0(18.1–33.5)
0.17
25(OH)D(ng/mL)b
19.0(13.2–26.1)
20.9(15.4–28.2)
17.2(12.2–23.6)
< 0.001
Age group (25(OH)D, ng/mL)
       
18-25y
18.1(12.2–24.9)
19.4(14.0-27.7)
16.6(11.7–22.6)
0.02
26-35y
18.3(13.3–26.1)
20.5(15.1–27.8)
17.1(12.5–24.2)
0.007
36-44y
20.7(14.5–28.0)
21.9(16.6–30.2)
18.2(12.8–25.6)
0.001
Latitude (25(OH)D, ng/mL)
       
North
14.4(10.6–20.4)c
17.6(11.9–23.5)c
12.7(10.1–17.4)c
< 0.001
South
23.6(17.4–29.9)
25.0(18.4–32.9)
22.4(17.1–28.3)
0.01
Region type (25(OH)D, ng/mL)
       
Urban
18.3(12.5–24.9)
20.5(14.2–27.1)
16.2(11.7–22.7)
0.004
Rural areas
19.2(13.7–26.8)
21.2(15.8–29.0)
17.4(12.8–25.2)
< 0.001
Seasons (25(OH)D, ng/mL)
       
Spring
17.4(11.8–26.1)
18.4(11.8–27.1)
15.9(11.8–21.6)
0.36
Autumn
20.9(15.2–28.3)e
22.3(15.9–30.4)e
19.9(14.4–26.2)e
0.01
Winter
17.2(11.9–23.8)
19.4(14.3–25.7)
15.0(10.7–21.5)
< 0.001
1 Age, BMI, 25(OH)D concentration and iPTH concentration were all recorded by using P50 (P25–P75) due to not compliant with normal distribution. a Difference between sexes; b To convert to nmol/L, multiply ng/mL by 2.5; c Significant different from the south, P < 0.05; d Significant different from the rural areas, P < 0.05; e Significant different from the other seasons, P < 0.05.

Serum 25(OH)D and its correlation with iPTH

The results of age, BMI and season adjusted partial correlation analysis showed that the serum 25(OH)D was inversely associated with the serum iPTH concentration in both sexes (male, rs=-0.18, P = 0.002 female, rs=-0.19, P < 0.001). The results of linear regression showed that the serum iPTH concentration was not liner related with the serum 25(OH)D concentration in both sexes owing to very low R-square (male, adjusted R2 = 0.04; female, adjusted R2 = 0.02).

The scatter plot of iPTH concentration by 25(OH)D concentration and corresponding LOESS curve for each sex was showed in Fig. 3. The negative correlation between iPTH concentration and 25(OH)D concentration was apparent according to the scatter plot. The threshold analysis showed the 25(OH)D concentration was 15.8 ng/mL (P = 0.001) when the concentration of iPTH entering into its plateau, which means serum 25(OH)D maximally inhibited the iPTH concentration. As for female, the threshold was 19.2 (10.1–27.2) ng/mL (P = 0.02). The threshold analysis showed that the threshold was 9.1 (8.3–40.9) ng/mL for male, however the P value was above 0.05 (P = 0.19). Therefore, there was not clear threshold for male within the range of 5.2 ~ 57.8 ng/mL.

Discussion

As early as 1987, researchers began to study the relationship between Vitamin D and iPTH by cross-sectional studies or randomized controlled trials to search the plateau period of iPTH inhibition by supplementing Vitamin D during different groups, including the elderly, female, healthy adults, Vitamin D-deficient people, etc [15–16]. Survey data from NHANES 2003–2004 and 2004–2005 shows that the relationships among 25(OH)D, BMD and PTH in American adults vary according to race/ethnicity. Significant inverse relationship between 25(OH)D and iPTH values was only observed when 25(OH)D concentrations were below 26 ng/ml among blacks, while inverse relationship was observed above and below a 25(OH)D level of 20 ng/ml in whites and Mexican-Americansin [15]. Aloia et al. [17] found that iPTH reached plateau stage when the serum 25(OH)D concentration was between 40–50 nmol/L (16–20 ng/mL) of African American women. In addition to the above studies, there are also studies that failed to find the threshold [10, 18]. Different races and genetic backgrounds might explain the phenomenon, and it is necessary to study whether the same cutoffs are suitable for different ethnicity.

This is the first national cross-sectional study on the threshold of 25(OH)D among Chinese population. In our study, we analyzed the threshold of iPTH reaching plateau stage by sex, because of the significant difference in the distribution of 25(OH)D levels between male and female. We found that the concentration of 25(OH)D was 19.2 ng/mL (48 nmol/L) when iPTH entered into its plateau in Chinese women aged 18-44y. It is close to the threshold of 50.8 nmol/L (20.3 ng/mL) in adult of both sex aged 20-45y in Shanghai city, China reported by Yao et al [19]. The threshold for deficiency could be better explored and analyzed with more relevant indicators, such as bone health indicators, endocrine indicators, etc. The 25(OH)D concentration was inversely associated with iPTH concentration through out the 25(OH)D range with no apparent threshold for male in our study. The sex differences in our study may be owing to the limited sample size and the distribution of 25(OH)D concentration in males samples. Similar results were also reported by a cross-sectional study conducted among adolescents aged 12-15y in North Ireland, where the researchers found a threshold at 60 nmol/L (24 ng/mL) in girls, and no cutoff was found in boy [20]. Although 25(OH)D level of male was significantly higher than that of female, iPTH did not differ significantly. This might also indicate that the corresponding iPTH was no longer increased when the level of 25(OH)D increases to a certain range. The secretion of sex hormones and growth hormone might also be associated with the sex difference. The results from different studies is controversial regarding the relationships of 25(OH)D concentration with levels of sex hormones and gonadotropins [21]. Further study should also be made to reveal the difference between sexes. We also found the disparity of 25(OH)D concentration in different seasons. Though no samples for summer in our study, the seasonal distribution of 25(OH)D concentration is consistent with the report from Kroll et al. in the United States [22]. In their study, they found the lowest concentration of iPTH occurs 3.5 weeks after the 25(OH)D3 reaches its highest concentration and vice versa. We can hardly tell the impact of relationship between iPTH concentration and 25(OH)D concentration, because our samples are limited and not distributed to every month of a year. Further study should also be made to explore the impact of seasonal factor on the relationship between iPTH and 25(OH)D.

The VitD insufficiency and deficiency of Chinese adults aged 18-44y was 34.5% and 19.4%, respectively, according to IOM’s recommendation. The VitD insufficiency and deficiency reached to 30.7% and 53.9%, respectively, and only 15.4% was sufficient when adopting TES’s recommendation. The median 25(OH)D concentration was 19.1(13.2–26.1) ng/mL, and it is apparently lower than 10 years ago [23]. Haze weather, less outdoor time, the use of sunscreen might explain the reduction of 25(OH)D concentration. Significant lower 25(OH)D concentration in female than that of male might mainly owing to less sun exposure. Higher 25(OH)D concentration in southern area attributes to stronger ultraviolet radiation in southern area than in the northern area. We suggest to explore sex specific thresholds by taking into consideration potential impact of physiological differences between male and female. Although there are significant differences in 25(OH)D levels between the northern and southern populations in Chinese adults, it is difficult to distinguish individuals strictly according to regions due to population mobility, topographic differences, and etc. For these reasons, we do not recommend setting different boundaries for different regions.

We acknowledge several limitations. First, the limited samples size. Although samples in this study covered all the provincial administrative regions in China, the sample size was only up to 623 cases. In particular, there were only 10 samples in April, which may also lead to the deviation of results. Since this study is an exploratory study in this field of China, the sample size was small in deed, and we will increase the sample size in subsequent studies. Secondly, the dietary sources of Vitamin D and calcium intake [24], bone health indicators, inflammatory factors, and other factors that may influence the relationship between iPTH and 25(OH)D, were not included in this study. Due to the above factors, it may lead to bias in the relationship or threshold between iPTH and 25(OH)D in this study.

Conclusions

In summary, although the present study was hindered by some limitations, we still find a threshold for Chinese women aged 18-44y at 19.2 ng/mL, above which we consider the Vitamin D status is sufficient. The value was consistent with current IOM recommendations of sufficiency. No apparent threshold was found in Chinese men aged 18-44y.

Abbreviations

25(OH)D, 25-hydroxyvitamin D; iPTH, intact parathyroid hormone; CCDNS, Chinese Chronic Diseases and Nutrition Survey; NINH, National Institute of Nutrition and Health; CPC, the Center for the Prevention and Control of Chronic Non-communicable Diseases; China CDC,Chinese Center for Disease Control and Prevention; BMI, Body Mass Index; LOESS, locally weighted regression smooth scatterplot;

Declarations

Ethics approval and consent to participate

The data of this study was from the Chinese Chronic Diseases and Nutrition Survey 2015-2018. The CNNHS 2015-2018 was given ethical approval by Ethics Review Board of Chinese Center for Disease Control and Prevention (No. 201519-A).

Consent for publication

The data of this study did not include personal information (i.e., name or address). All participants were adults.

Not applicable.

Availability of data and materials

The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.

Competing interests

The authors declare that they have no competing interests.

Funding

This research was funded by the Chinese National Natural Science Foundation Project: Study on defining physiologically "normal" vitamin D in apparent healthy Chinese childbearing women (No. 81872627).

Author's Contributions

All authors have read and agree to the published version of the manuscript. Conceptualization, Yichun Hu and Lichen Yang; Data curation, Yichun Hu; Investigation, Yichun Hu and Siran Li; Methodology, Yichun Hu and Lichen Yang; Software, Yichun Hu; Supervision, Lichen Yang and Xiaoguang Yang; Validation, Yichun Hu and Zhen Liu; Writing – original draft, Yichun Hu; Writing – review & editing, Yichun Hu, Lichen Yang and Xiaoguang Yang.

Acknowledgments

We thank all the participants in our study and all the staff working for the Chinese Chronic Diseases and Nutrition Survey (CCDNS 2015-2018). We thank Dr. Tianjin Chen for language improvement and Zhijun Chen for statistical analysis.

Authors' information

Key Laboratory of Trace Element Nutrition of National Health Commission, National Institute for Nutrition and Health, China Chinese Center for Disease Control and Prevention (China CDC), Beijing 100050, PR China.

References

  1. Morales O, Samuelsson MK, Lindgren U, et a1.Effects of alpha 25-dihydroxy-vitamin D3 and growth hormone on apoptosis and proliferation in UMR 106 oste--oblast-like cells[J].Endocrinology, 2004, 145: 87-94.
  2. Holick MF. Sunlight and Vitamin D for bone health and prevention of autoimmune diseases, cancers, and cardiovascular disease[J]. American Journal of Clinical Nutrition, 2004, 80(6 Suppl):16785-16885.
  3. Martineau AR, Jolliffe DA, Hooper RL, et al. Vitamin D supplementation to prevent acute respiratory tract infections: systematic review and meta-analysis of individual participant data[J]. Bmj, 2017, 356(Suppl 3):i6583.
  4. Araki T, Holick MF, Alfonso BD, et al. Vitamin D Intoxication with Severe Hypercalcemia due to Manufacturing and Labeling Errors of Two Dietary Supplements Made in the United States[J]. The Journal of clinical endocrinology and metabolism, 2011, 96(12): 3603-3608.
  5. Holick MF, Binkley NC, Bischoffferrari H A, et al. Evaluation, treatment, and prevention of vitamin D deficiency: an Endocrine Society clinical practice guideline[J]. The Journal of Clinical Endocrinology & Metabolism,2011, 96(7), 1911–1930.
  6. Heaney RP. Serum 25-hydroxyvitamin D is a reliable indicator of vitamin D status. American Journal of Clinical Nutrition, 2011 , 94 (2) :619
  7. Ross AC, Taylor CL, Yaktine AL, et al. Tolerable Upper Intake Levels: Calcium and Vitamin D - Dietary Reference Intakes for Calcium and Vitamin D - NCBI Bookshelf[J]. 2012, 130(5):1427.
  8. Ross AC, Manson JAE, Abrams SA, et al. The 2011 Report on Dietary Reference Intakes for Calcium and Vitamin D From the Institute of Medicine: What Clinicians Need to Know[J]. Obstetrical & Gynecological Survey, 2011, 66(6):356-357.
  9. Rosen CJ, Abrams SA , Aloia JF , et al. IOM Committee Members Respond to Endocrine Society Vitamin D Guideline[J]. Obstetrical & Gynecological Survey, 2012, 67(8):479-480.
  10. Sai AJ, Walters RW, Fang X, et al. Relationship between vitamin D, parathyroid hormone, and bone health.[J]. Journal of Clinical Endocrinology & Metabolism, 2011, 96(3):436-46.
  11. Aloia JF , Chen DG , Chen H . The 25(OH)D/PTH Threshold in Black Women[J]. The Journal of Clinical Endocrinology & Metabolism, 2010, 95(11):5069-5073.
  12. National Health Commission of China. Report on Nutrition and Chronic Diseases of Chinese Residents (2015). People's Medical Publishing House, Beijing, 2015.
  13. Cleveland WS, Devlin ST. Locally weighted regression: an approach to regression analysis by local fitting. J Am Stat Assoc. 1988;83:596–610.
  14. Fong Y , Huang Y , Gilbert PB , et al. chngpt: Threshold regression model estimation and inference[J]. BMC Bioinformatics, 2017, 18: 454.
  15. Gutiérrez OM, Farwell WR , Kermah D , et al. Racial differences in the relationship between vitamin D, bone mineral density, and parathyroid hormone in the National Health and Nutrition Examination Survey[J]. Osteoporosis International, 2011, 22(6):1745-1753
  16. Moslehi N, Shabbidar S, Mirmiran P, et al. Determinants of parathyroid hormone response to vitamin D supplementation: a systematic review and meta-analysis of randomised controlled trials.[J]. British Journal of Nutrition, 2015, 114(9):1360-1374.
  17. Aloia JF, Talwar SA, Pollack S, et al. Optimal vitamin D status and serum parathyroid hormone concentrations in African American women.[J]. American Journal of Clinical Nutrition, 2006, 84(3):602
  18. Jean W , Lam CWK , Jason L, et al. Very high rates of vitamin D insufficiency in women of child-bearing age living in Beijing and Hong Kong[J]. British Journal of Nutrition, 2008, 99. 1330-1334.
  19. Yao P, Lu L, Hu Y, et al. A dose-response study of vitamin D3 supplementation in healthy Chinese: a 5-arm randomized, placebo-controlled trial.[J]. European Journal of Nutrition, 2016, 55(1): 383-392.
  20. Hill TR , Cotter AA , Mitchell S , et al. Vitamin D status and parathyroid hormone relationship in adolescents and its association with bone health parameters: analysis of the Northern Ireland Young Heart’s Project[J]. Osteoporosis International, 2010, 21(4):695-700.
  21. Rafiq R, van Schoor NM, Sohl E, et al. Associations of vitamin D status and vitamin D-related polymorphisms with sex hormones in older men. J Steroid Biochem Mol Biol. 2016, 164:11-17.
  22. Kroll MH , Bi C , Garber CC , et al. Temporal Relationship between Vitamin D Status and Parathyroid Hormone in the United States[J]. PLoS ONE, 2015, 10(3):
  23. Piao JH, Huo JS. Report on Nutrition and Health Status of Chinese Residents Part II: Physical and Nutritional Status of Residents from 2010 to 2013, People's Medical Publishing House, Beijing. 2019.
  24. Tsugawa N , Uenishi K , Ishida H , et al. Association between vitamin D status and serum parathyroid hormone concentration and calcaneal stiffness in Japanese adolescents: sex differences in susceptibility to vitamin D deficiency[J]. Journal of Bone and Mineral Metabolism, 2016, 34(4):464-474.