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Associations between serum calcium, 25(OH)D level and bone mineral density in adolescents

Associations between serum calcium, 25(OH)D level and bone mineral density in adolescents Backgrounds: It is important to improve our understanding of the roles of calcium and vitamin D in bone health for preventing osteoporosis. We aimed at exploring the associations between serum calcium, vitamin D level, and bone mineral density (BMD) in adolescents included in the National Health and Nutrition Examination Survey (NHANES) 2001–2006. Methods: Weighted multivariate linear regression models were used to estimate the associations of serum calcium, 25(OH)D level with total BMD. Smooth curve fitting was used to explore the potential non-linear relationship. Results: A total of 5990 individuals aged between 12 and 19 years were included in this study. The fully-adjusted model showed serum calcium positively correlated with total BMD. However, an inverted U-shaped relationship was found when we performed the smooth curve fitting method, and the inflection point was calculated at 9.6 mg/dL using the two-piecewise linear regression model. In contrast, there was a positive correlation between serum 25(OH)D and total BMD after adjusting for potential confounders. Conclusions: The present study revealed a positive correlation between serum 25(OH)D level and total BMD, and an inverted U-shaped relationship between serum calcium and total BMD. Keywords: Calcium, Vitamin D, Bone health, Adolescent, NHANES Introduction way to maintain bone health in adulthood and pre- Osteoporosis is a global health problem that is vent osteoporosis in older age [5]. reported to originate during childhood or adolescence Calcium is an essential nutrient for skeletal [1]. Adolescence is a critical period of skeletal devel- development and maintenance [6]. Calcium supple- opment and peak bone mass (PBM) may be reached mentation is recommended for improving bone in late adolescence [2]. Evidence indicates that when health in older adults. However, the effect of cal- PBM increases by 5% during childhood and adoles- cium supplementation on bone mineral density cence, the risk of osteoporotic fracture reduces by (BMD) remains controversial [7], and it is uncer- 40%, while when PBM increases by 10%, this risk tain whether an elevated serum calcium level is decreases by 50% [3, 4]. Therefore, increased bone beneficial to bone health [8, 9]. Moreover, vitamin mass accumulation during this period is an effective D is known to play an essential role in maintaining normocalcaemia, thus permitting normal skeletal mineralization [10]. In individuals with a low BMD * Correspondence: orthozzx@163.com or those at a high risk of osteoporotic fractures, Department of Osteoporosis Care and Control, Xiaoshan Affiliated Hospital of Wenzhou Medical University, Hangzhou 311200, Zhejiang, China calcium and vitamin D supplementation are Clinical Research Center, Xiaoshan Affiliated Hospital of Wenzhou Medical suggested as adjuncts to osteoporosis therapies University, Hangzhou 311200, Zhejiang, China [11]. However, their effect on fracture risk is Full list of author information is available at the end of the article © The Author(s). 2021 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. Pan et al. Advances in Rheumatology (2021) 61:16 Page 2 of 9 unclear [12]. Furthermore, whether serum calcium, 5990 individuals aged 12–19 years with available data on and vitamin D independently correlate with BMD serum calcium, and 25(OH)D levels, and total BMD in the general population or certain population were included. The NHANES protocols were approved groups remains unclear [13, 14]. To the best of by the Institutional Review Board of the National Center our knowledge, no large-sample study has been for Health Statistics, and participants or their proxies (< performed in adolescents. Moreover, the beneficial 18 years) provided informed consent [19]. effect of vitamin D on bone health was reported to be associated with serum 25(OH)D level and not Variables (1,25(OH)2D) [15], and serum 25(OH)D level has In this study, the dependent variable was total BMD, been used to assess vitamin D status [16, 17]. and the independent variables were serum calcium Therefore, in this study, we examined the associa- and 25(OH)D levels. All subjects included in the tions of serum calcium, and 25(OH)D level with present study received dual-energy X-ray absorpti- total BMD among US adolescents using samples ometry (DXA) total body scans. For the 2001–2006 from a database of a multiracial population. cycles, total BMD was measured using the DXA scans obtained from a QDR-4500A fanbeam densitometer Methods (Hologic, Inc., Bedford, Massachusetts) by trained and Study population certified radiologic technologists. The Beckman Syn- As a nationally representative survey, the National chron LX20 (Beckman Coulter, Brea, CA) was used Health and Nutrition Examination Survey (NHANES) to determine serum calcium, and a radioimmunoassay collected health examination data from the non- kit (DiaSorin, Stillwater, Minnesota, USA) was used to institutionalized US population [18]. These data are re- determineserum 25(OH)Dfor the2001–2006 cycles. leased on a two-year cycle. We used the data from three The following variables were selected as potential con- cycles of NHANES 2001–2006 in this study. A total of founders: age, gender, race/ethnicity, physical activity Table 1 Participant characteristics Characteristic Boys (n = 3086) Girls (n = 2904) P value Age, mean ± SD (years) 15.46 ± 2.26 15.35 ± 2.23 0.0551 Race/Ethnicity (%) 0.9754 Non-Hispanic White 62.87 63.15 Non-Hispanic Black 14.47 14.48 Mexican American 11.50 11.13 Other race/ethnicity 11.16 11.25 BMI, mean ± SD (kg/m ) 23.31 ± 5.50 23.55 ± 5.78 0.1073 Income to poverty ratio, mean ± SD 2.64 ± 1.62 2.57 ± 1.62 0.0912 Physical activity (%) < 0.0001 Sedentary 2.95 4.85 Low 7.72 11.63 Moderate 6.51 8.47 High 22.05 16.20 Not recorded 60.77 58.85 Calcium supplementation (%) < 0.0001 Not use 87.21 83.80 < 0.4 g/d 10.94 12.99 ≥ 0.4 g/d 1.84 3.21 Serum calcium, mean ± SD (mg/dL) 9.80 ± 0.30 9.64 ± 0.30 < 0.0001 Serum vitamin D, mean ± SD (ng/mL) 24.23 ± 8.63 23.32 ± 10.02 0.0002 Total BMD, mean ± SD (g/cm ) 1.10 ± 0.14 1.06 ± 0.10 < 0.0001 Mean ± SD for continuous variables: P value was calculated by weighted linear regression model % for categorical variables: P value was calculated by weighted chi-square test Abbreviation: BMI, body mass index, BMD bone mineral density Pan et al. Advances in Rheumatology (2021) 61:16 Page 3 of 9 Table 2 Associations of serum calcium, 25(OH)D with total bone mineral density Model 1 Model 2 Model 3 β (95% CI) β (95% CI) β (95% CI) Serum calcium −0.0157 (−0.0257, −0.0058) −0.0003 (− 0.0083, 0.0077) 0.0084 (0.0007, 0.0160) Serum calcium (quartile) Q1 Reference Reference Reference Q2 −0.0065 (− 0.0163, 0.0033) 0.0072 (− 0.0003, 0.0148) 0.0088 (0.0017, 0.0160) Q3 0.0008 (−0.0087, 0.0103) 0.0136 (0.0062, 0.0211) 0.0141 (0.0070, 0.0212) Q4 −0.0144 (− 0.0233, − 0.0055) 0.0032 (− 0.0040, 0.0103) 0.0098 (0.0030, 0.0166) P for trend 0.004 0.484 0.008 Serum 25(OH)D −0.0005 (− 0.0009, − 0.0002) 0.0001 (− 0.0003, 0.0003) 0.0006 (0.0003, 0.0008) Serum 25(OH)D (quartile) Q1 Reference Reference Reference Q2 −0.0415 (− 0.0532, − 0.0298) −0.0051 (− 0.0145, 0.0044) 0.0050 (− 0.0040, 0.0139) Q3 −0.0475 (− 0.0581, − 0.0369) 0.0046 (− 0.0046, 0.0138) 0.0166 (0.0079, 0.0254) Q4 −0.0384 (− 0.0483, − 0.0284) 0.0030 (− 0.0062, 0.0122) 0.0202 (0.0113, 0.0291) P for trend < 0.001 0.181 < 0.001 Model 1: no covariates were adjusted Model 2: age, gender, race/ethnicity were adjusted Model 3: age, gender, race/ethnicity, body mass index, income to poverty ratio, physical activity, and calcium supplementation use were adjusted (based on suggested metabolic equivalent rank) [20], in- square test for categorical variables, and the come to poverty ratio, body mass index, and calcium weighted linear regression model for continuous supplementation use. Detailed information on serum variables. The weighted multivariate linear regression calcium, and 25(OH)D levels, total BMD, and other vari- model was used to investigate whether serum ables can be found at www.cdc.gov/nchs/nhanes/. calcium and 25(OH)D levels independently corre- lated with total BMD. We used generalized additive Statistical analysis models and smooth curve fitting to explore potential We used sample weights in all analyses according to non-linear relationships. We further calculated the the stratified, multistage probability sampling design. inflection points using the two-piecewise linear The P-value was calculated using the weighted chi- regression model. All analyses were conducted using Table 3 Total bone mineral density by quartiles of serum calcium, stratified by race/ethnicity and age Quartiles of White Black Mexican American Other race serum calcium Total BMD g/cm (95% Confidence Interval) 12 to 15 years Lowest quartile 1.012 (0.994, 1.029) 1.069 (1.055, 1.083) 1.015 (1.000, 1.031) 1.015 (0.983, 1.047) 2nd 1.011 (0.996, 1.026) 1.068 (1.055, 1.081) 1.008 (0.995, 1.021) 1.024 (1.000, 1.048) 3rd 1.011 (0.998, 1.025) 1.065 (1.052, 1.077) 1.010 (0.998, 1.023) 1.027 (1.002, 1.052) Highest quartile 1.006 (0.995, 1.017) 1.062 (1.052, 1.072) 0.994 (0.983, 1.005) 0.998 (0.978, 1.018) P for trend 0.540 0.383 0.031 0.200 16 to 19 years Lowest quartile 1.132 (1.118, 1.146) 1.207 (1.195, 1.220) 1.120 (1.109, 1.131) 1.139 (1.116, 1.162) 2nd 1.137 (1.124, 1.151) 1.203 (1.190, 1.216) 1.117 (1.105, 1.128) 1.164 (1.139, 1.189) 3rd 1.140 (1.127, 1.152) 1.214 (1.202, 1.225) 1.117 (1.105, 1.129) 1.132 (1.108, 1.156) Highest quartile 1.137 (1.126, 1.148) 1.207 (1.196, 1.219) 1.113 (1.102, 1.125) 1.152 (1.127, 1.176) P for trend 0.598 0.722 0.485 0.883 Gender, body mass index, income poverty ratio, physical activity, and calcium supplement use were adjusted Pan et al. Advances in Rheumatology (2021) 61:16 Page 4 of 9 Fig. 1 The association between serum calcium and total bone mineral density. a Each black point represents a sample. b Solid rad line represents the smooth curve fit between variables. Blue bands represent the 95% of confidence interval from the fit. Adjusted for age, gender, race/ethnicity, income to poverty ratio, education, physical activity, body mass index, calcium supplementation use R (version 3.5.3) and EmpowerStats software (http:// existed in boys, Whites and Blacks (Figs. 3 and 4), www.empowerstats.com). P-value < 0.05 was consid- whereas the serum calcium level positively correlated ered statistically significant. with total BMD in girls, Mexican Americans and other race/ethnicity. In addition, we calculated that Results the inflection points were 9.6 mg/dL in boys and The weighted characteristics of the study population ac- Whites, and 9.2 mg/dL in Blacks. cording to gender are presented in Table 1. Most of the participants were racially/ethnically classified as “non- Association between serum 25(OH)D level and total BMD Hispanic white”. A total of 3086 boys and 2904 girls The serum 25(OH)D level negatively correlated with were included in this study: For boys and girls, respect- total BMD in the unadjusted model [0.0005 (− 0.0009, ively, the mean age was 15.46 ± 2.26 and 15.35 ± 2.23 − 0.0002)] (Table 2). This association became positive years, mean serum calcium was 9.80 ± 0.30 mg/dL and after adjusting for all potential confounders [0.0006 9.64 ± 0.30 mg/dL, mean serum 25(OH)D was 24.23 ± (0.0003, 0.0008)] (Table 2,Fig. 2). Compared to par- 8.63 ng/mL and 23.32 ± 10.02 ng/mL, and mean total ticipants with the lowest serum 25(OH)D level in Q1, 2 2 BMD was 1.10 ± 0.14 g/cm and 1.06 ± 0.10 g/cm . participants in the other groups had a higher total BMD. The trend test remained significant (P < 0.001). Association between serum calcium level and total BMD The results of total BMD by quartiles of serum There was a negative correlation between the serum 25(OH)D, stratified by race/ethnicity and age. Are calcium level and total BMD in the unadjusted model showninTable 5. In the subgroup analysis stratified [− 0.0157 (− 0.0257, − 0.0058)] (Table 2), while after by gender and race/ethnicity, we found a U-shaped adjusting for all potential confounders, a positive cor- relationship in boys, and an inverted U-shaped rela- relation was found [0.0084 (0.0007, 0.0160)]. Com- tionship in girls and Whites (Figs. 3 and 4). The re- pared to participants with the lowest serum calcium sults of the inflection points are shown in Table 4. level in Q1, participants in other groups had a higher total BMD. The results of total BMD by quartiles of Discussion the serum calcium level, stratified by race/ethnicity The aim of this study was to explore whether there are and age, are shown in Table 3.Furthermore,we independent correlations between serum calcium, and found an inverted U-shaped relationship between the 25(OH)D levels and total BMD among adolescents aged serum calcium level and total BMD using the smooth 12–19 years. The results showed that serum 25(OH)D curve fitting method (Fig. 1). We subsequently calcu- was positively correlated with total BMD, and the rela- lated that the inflection point was 9.6 mg/dL using tionship of serum calcium with total BMD assumed an the two-piecewise linear regression model (Table 4). inverted U-shaped (inflection point: 9.6 mg/dL). In the subgroup analysis stratified by gender and Calcium plays an important role in many biological race/ethnicity, this inverted U-shaped relationship systems, most notably in bones. Thus, it is essential to Pan et al. Advances in Rheumatology (2021) 61:16 Page 5 of 9 Table 4 Threshold effect analysis of serum calcium and 25(OH)D on total bone mineral density by using two-piecewise linear regression Adjusted ß (95% CI), p-value Serum calcium Total Fitting by standard linear model 0.0084 (0.0007, 0.0160) 0.0317 Fitting by two-piecewise linear model Inflection point 9.6 Serum calcium < 9.6 (mg/dL) 0.0348 (0.0165, 0.0530) 0.0002 Serum calcium > 9.6 (mg/dL) −0.0051 (− 0.0164, 0.0063) 0.3824 Log likelihood ratio 0.002 Boy Fitting by standard linear model 0.0034 (−0.0076, 0.0143) 0.5446 Fitting by two-piecewise linear model Inflection point 9.6 Serum calcium < 9.6 (mg/dL) 0.0447 (0.0128, 0.0765) 0.0060 Serum calcium > 9.6 (mg/dL) −0.0109 (− 0.0260, 0.0042) 0.1564 Log likelihood ratio 0.007 White Fitting by standard linear model 0.0129 (−0.0017, 0.0276) 0.0843 Fitting by two-piecewise linear model Inflection point 9.6 Serum calcium < 9.6 (mg/dL) 0.0465 (0.0091, 0.0839) 0.0148 Serum calcium > 9.6 (mg/dL) −0.0025 (− 0.0240, 0.0191) 0.8218 Log likelihood ratio 0.055 Black Fitting by standard linear model 0.0053 (−0.0080, 0.0187) 0.4353 Fitting by two-piecewise linear model Inflection point 9.2 Serum calcium < 9.2 (mg/dL) 0.1074 (0.0200, 0.1949) 0.0161 Serum calcium > 9.2 (mg/dL) −0.0011 (− 0.0155, 0.0133) 0.8780 Log likelihood ratio 0.020 Serum 25(OH)D Boy Fitting by standard linear model 0.0013 (0.0009, 0.0018) < 0.0001 Fitting by two-piecewise linear model Inflection point 24 Serum 25(OH)D < 24(ng/mL) 0.0024 (0.0015, 0.0034) < 0.0001 Serum 25(OH)D > 24(ng/mL) 0.0007 (0.0000, 0.0014) 0.0400 Log likelihood ratio 0.008 Girl Fitting by standard linear model 0.0003 (−0.0000, 0.0007) 0.0565 Fitting by two-piecewise linear model Inflection point 26 Serum 25(OH)D < 26(ng/mL) 0.0011 (0.0005, 0.0018) 0.0006 Serum 25(OH)D > 26(ng/mL) −0.0003 (− 0.0008, 0.0003) 0.3218 Pan et al. Advances in Rheumatology (2021) 61:16 Page 6 of 9 Table 4 Threshold effect analysis of serum calcium and 25(OH)D on total bone mineral density by using two-piecewise linear regression (Continued) Adjusted ß (95% CI), p-value Log likelihood ratio 0.004 White Fitting by standard linear model 0.0003 (−0.0002, 0.0009) 0.1945 Fitting by two-piecewise linear model Inflection point 23 Serum 25(OH)D < 23(ng/mL) 0.0035 (0.0018, 0.0052) < 0.0001 Serum 25(OH)D > 23(ng/mL) −0.0005 (− 0.0011, 0.0002) 0.1629 Log likelihood ratio < 0.001 age, gender, race/ethnicity, body mass index, income to poverty ratio, physical activity, and calcium supplementation use were adjusted In the analysis for boy/girl, white/black, the model is not adjusted for gender or race/ethnicity, respectively ensure adequate calcium intake throughout life for may have deleterious effects on bone. The above evi- building and maintaining bones [21]. However, a lower- dence suggested that calcium intake is required to im- than-recommended calcium intake has been reported prove BMD in subjects with low serum calcium levels. for European and Brazilian populations [22, 23]. Several It has been shown that a low serum 25(OH)D level trials have suggested that supplementing by oral calcium has an adverse effect on bone health [29]. Several cross- salts is notably associated with bone attenuation [24, 25]. sectional studies reported a positive association between Some recent studies showed either no significant correl- serum 25(OH)D level and BMD in adults [30–32]. Vita- ation or a negative association between serum calcium min D deficiency has been a global health problem in level with BMD [8, 9, 13]; our results suggested an the general population, with a distinct lack of data in inverted U-shaped relationship in adolescents aged 12– children and adolescents [33]. Recent studies showed 19 years. There are some biological explanations for the that hypovitaminosis D is a common disease in children, findings of this study. It was found that a high calcium and studies in an adult population regarding the aeti- intake or an intake exceeding the optimal level, could re- ology of osteoporosis have somewhat linked the evidence duce osteoblast differentiation and mineralization to vitamin D deficiency during childhood and adoles- in vitro [26, 27] and in some animals [28]. Thus, there cence [34]. The results of a cross-sectional study of 100 may be a narrow range of optimal calcium levels that Indian healthy school-age children showed that the promote bone growth, whereas elevated calcium levels serum 25(OH)D level positively related to BMD [35]. Fig. 2 The association between serum 25(OH)D level and total bone mineral density. a Each black point represents a sample. b Solid rad line represents the smooth curve fit between variables. Blue bands represent the 95% of confidence interval from the fit. Adjusted for age, gender, race/ethnicity, income to poverty ratio, education, physical activity, body mass index, calcium supplementation use Pan et al. Advances in Rheumatology (2021) 61:16 Page 7 of 9 Table 5 Total bone mineral density by quartiles of serum 25(OH)D level, stratified by race/ethnicity and age Quartiles of White Black Mexican American Other race 25(OH)D level 2 Total BMD g/cm (95% Confidence Interval) 12 to 15 years Lowest quartile 0.975 (0.929, 1.022) 1.064 (1.054, 1.074) 0.996 (0.979, 1.013) 1.027 (0.996, 1.058) 2nd 0.994 (0.973, 1.015) 1.068 (1.056, 1.079) 0.994 (0.982, 1.007) 0.993 (0.970, 1.016) 3rd 1.013 (1.001, 1.025) 1.061 (1.048, 1.075) 1.012 (1.002, 1.023) 1.000 (0.981, 1.020) Highest quartile 1.011 (1.002, 1.020) 1.071 (1.052, 1.090) 1.014 (1.000, 1.027) 1.050 (1.026, 1.074) P for trend 0.134 0.780 0.024 0.079 16 to 19 years Lowest quartile 1.106 (1.073, 1.139) 1.212 (1.204, 1.220) 1.107 (1.094, 1.120) 1.135 (1.107, 1.162) 2nd 1.126 (1.106, 1.146) 1.203 (1.191, 1.215) 1.109 (1.098, 1.119) 1.153 (1.128, 1.178) 3rd 1.127 (1.115, 1.140) 1.198 (1.182, 1.215) 1.115 (1.104, 1.125) 1.136 (1.115, 1.157) Highest quartile 1.144 (1.136, 1.152) 1.210 (1.188, 1.232) 1.140 (1.128, 1.152) 1.160 (1.136, 1.185) P for trend 0.003 0.262 < 0.001 0.347 Gender, body mass index, income poverty ratio, physical activity, and calcium supplement use were adjusted Our results also showed a positive association between To the best of our knowledge, this is the largest the serum 25(OH)D level and total BMD. We performed study investigating the relationships between serum subgroup analyses to describe the data in more detail calcium, and 25(OH)D levels and BMD in adoles- following the STROBE guidelines [36]. A non-linear re- cents, and this representative sample of a multiracial lationship between the 25(OH)D level and total BMD population may be used as a general investigation of was found, and the inflection points were detected. the whole population. Some limitations are worth These findings suggest a potentially optimal serum vita- noting. First, accurate data on puberty status were min D level for BMD, while elevated 25(OH)D levels not included in our study. Although age was adjusted (beyond the turning point) may lead to a lower BMD in as a covariate in this study, the possible bias related girls and Whites. The heterogeneity among these stud- to the unmeasured puberty status remained a limita- ies, including differences in participant selection, study tion. Second, due to its cross-sectional design, this re- size, study design, and controlled confounders, may pro- search had less power regarding the determination of vide a possible explanation for these conflicting causal relationships between serum calcium, and conclusions. 25(OH)D levels and BMD. Fig. 3 The associations between serum calcium (a), serum 25(OH)D (b) and total bone mineral density stratified by gender. Adjusted for age, race/ethnicity, income to poverty ratio, education, physical activity, body mass index, calcium supplementation use Pan et al. Advances in Rheumatology (2021) 61:16 Page 8 of 9 Fig. 4 The associations between serum calcium (a), serum 25(OH)D (b) and total bone mineral density stratified by race/ethnicity. Adjusted for age, gender, income to poverty ratio, education, physical activity, body mass index, calcium supplementation use Conclusions Center, Xiaoshan Affiliated Hospital of Wenzhou Medical University, Hangzhou 311200, Zhejiang, China. 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Associations between serum calcium, 25(OH)D level and bone mineral density in adolescents

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Abstract

Backgrounds: It is important to improve our understanding of the roles of calcium and vitamin D in bone health for preventing osteoporosis. We aimed at exploring the associations between serum calcium, vitamin D level, and bone mineral density (BMD) in adolescents included in the National Health and Nutrition Examination Survey (NHANES) 2001–2006. Methods: Weighted multivariate linear regression models were used to estimate the associations of serum calcium, 25(OH)D level with total BMD. Smooth curve fitting was used to explore the potential non-linear relationship. Results: A total of 5990 individuals aged between 12 and 19 years were included in this study. The fully-adjusted model showed serum calcium positively correlated with total BMD. However, an inverted U-shaped relationship was found when we performed the smooth curve fitting method, and the inflection point was calculated at 9.6 mg/dL using the two-piecewise linear regression model. In contrast, there was a positive correlation between serum 25(OH)D and total BMD after adjusting for potential confounders. Conclusions: The present study revealed a positive correlation between serum 25(OH)D level and total BMD, and an inverted U-shaped relationship between serum calcium and total BMD. Keywords: Calcium, Vitamin D, Bone health, Adolescent, NHANES Introduction way to maintain bone health in adulthood and pre- Osteoporosis is a global health problem that is vent osteoporosis in older age [5]. reported to originate during childhood or adolescence Calcium is an essential nutrient for skeletal [1]. Adolescence is a critical period of skeletal devel- development and maintenance [6]. Calcium supple- opment and peak bone mass (PBM) may be reached mentation is recommended for improving bone in late adolescence [2]. Evidence indicates that when health in older adults. However, the effect of cal- PBM increases by 5% during childhood and adoles- cium supplementation on bone mineral density cence, the risk of osteoporotic fracture reduces by (BMD) remains controversial [7], and it is uncer- 40%, while when PBM increases by 10%, this risk tain whether an elevated serum calcium level is decreases by 50% [3, 4]. Therefore, increased bone beneficial to bone health [8, 9]. Moreover, vitamin mass accumulation during this period is an effective D is known to play an essential role in maintaining normocalcaemia, thus permitting normal skeletal mineralization [10]. In individuals with a low BMD * Correspondence: orthozzx@163.com or those at a high risk of osteoporotic fractures, Department of Osteoporosis Care and Control, Xiaoshan Affiliated Hospital of Wenzhou Medical University, Hangzhou 311200, Zhejiang, China calcium and vitamin D supplementation are Clinical Research Center, Xiaoshan Affiliated Hospital of Wenzhou Medical suggested as adjuncts to osteoporosis therapies University, Hangzhou 311200, Zhejiang, China [11]. However, their effect on fracture risk is Full list of author information is available at the end of the article © The Author(s). 2021 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. Pan et al. Advances in Rheumatology (2021) 61:16 Page 2 of 9 unclear [12]. Furthermore, whether serum calcium, 5990 individuals aged 12–19 years with available data on and vitamin D independently correlate with BMD serum calcium, and 25(OH)D levels, and total BMD in the general population or certain population were included. The NHANES protocols were approved groups remains unclear [13, 14]. To the best of by the Institutional Review Board of the National Center our knowledge, no large-sample study has been for Health Statistics, and participants or their proxies (< performed in adolescents. Moreover, the beneficial 18 years) provided informed consent [19]. effect of vitamin D on bone health was reported to be associated with serum 25(OH)D level and not Variables (1,25(OH)2D) [15], and serum 25(OH)D level has In this study, the dependent variable was total BMD, been used to assess vitamin D status [16, 17]. and the independent variables were serum calcium Therefore, in this study, we examined the associa- and 25(OH)D levels. All subjects included in the tions of serum calcium, and 25(OH)D level with present study received dual-energy X-ray absorpti- total BMD among US adolescents using samples ometry (DXA) total body scans. For the 2001–2006 from a database of a multiracial population. cycles, total BMD was measured using the DXA scans obtained from a QDR-4500A fanbeam densitometer Methods (Hologic, Inc., Bedford, Massachusetts) by trained and Study population certified radiologic technologists. The Beckman Syn- As a nationally representative survey, the National chron LX20 (Beckman Coulter, Brea, CA) was used Health and Nutrition Examination Survey (NHANES) to determine serum calcium, and a radioimmunoassay collected health examination data from the non- kit (DiaSorin, Stillwater, Minnesota, USA) was used to institutionalized US population [18]. These data are re- determineserum 25(OH)Dfor the2001–2006 cycles. leased on a two-year cycle. We used the data from three The following variables were selected as potential con- cycles of NHANES 2001–2006 in this study. A total of founders: age, gender, race/ethnicity, physical activity Table 1 Participant characteristics Characteristic Boys (n = 3086) Girls (n = 2904) P value Age, mean ± SD (years) 15.46 ± 2.26 15.35 ± 2.23 0.0551 Race/Ethnicity (%) 0.9754 Non-Hispanic White 62.87 63.15 Non-Hispanic Black 14.47 14.48 Mexican American 11.50 11.13 Other race/ethnicity 11.16 11.25 BMI, mean ± SD (kg/m ) 23.31 ± 5.50 23.55 ± 5.78 0.1073 Income to poverty ratio, mean ± SD 2.64 ± 1.62 2.57 ± 1.62 0.0912 Physical activity (%) < 0.0001 Sedentary 2.95 4.85 Low 7.72 11.63 Moderate 6.51 8.47 High 22.05 16.20 Not recorded 60.77 58.85 Calcium supplementation (%) < 0.0001 Not use 87.21 83.80 < 0.4 g/d 10.94 12.99 ≥ 0.4 g/d 1.84 3.21 Serum calcium, mean ± SD (mg/dL) 9.80 ± 0.30 9.64 ± 0.30 < 0.0001 Serum vitamin D, mean ± SD (ng/mL) 24.23 ± 8.63 23.32 ± 10.02 0.0002 Total BMD, mean ± SD (g/cm ) 1.10 ± 0.14 1.06 ± 0.10 < 0.0001 Mean ± SD for continuous variables: P value was calculated by weighted linear regression model % for categorical variables: P value was calculated by weighted chi-square test Abbreviation: BMI, body mass index, BMD bone mineral density Pan et al. Advances in Rheumatology (2021) 61:16 Page 3 of 9 Table 2 Associations of serum calcium, 25(OH)D with total bone mineral density Model 1 Model 2 Model 3 β (95% CI) β (95% CI) β (95% CI) Serum calcium −0.0157 (−0.0257, −0.0058) −0.0003 (− 0.0083, 0.0077) 0.0084 (0.0007, 0.0160) Serum calcium (quartile) Q1 Reference Reference Reference Q2 −0.0065 (− 0.0163, 0.0033) 0.0072 (− 0.0003, 0.0148) 0.0088 (0.0017, 0.0160) Q3 0.0008 (−0.0087, 0.0103) 0.0136 (0.0062, 0.0211) 0.0141 (0.0070, 0.0212) Q4 −0.0144 (− 0.0233, − 0.0055) 0.0032 (− 0.0040, 0.0103) 0.0098 (0.0030, 0.0166) P for trend 0.004 0.484 0.008 Serum 25(OH)D −0.0005 (− 0.0009, − 0.0002) 0.0001 (− 0.0003, 0.0003) 0.0006 (0.0003, 0.0008) Serum 25(OH)D (quartile) Q1 Reference Reference Reference Q2 −0.0415 (− 0.0532, − 0.0298) −0.0051 (− 0.0145, 0.0044) 0.0050 (− 0.0040, 0.0139) Q3 −0.0475 (− 0.0581, − 0.0369) 0.0046 (− 0.0046, 0.0138) 0.0166 (0.0079, 0.0254) Q4 −0.0384 (− 0.0483, − 0.0284) 0.0030 (− 0.0062, 0.0122) 0.0202 (0.0113, 0.0291) P for trend < 0.001 0.181 < 0.001 Model 1: no covariates were adjusted Model 2: age, gender, race/ethnicity were adjusted Model 3: age, gender, race/ethnicity, body mass index, income to poverty ratio, physical activity, and calcium supplementation use were adjusted (based on suggested metabolic equivalent rank) [20], in- square test for categorical variables, and the come to poverty ratio, body mass index, and calcium weighted linear regression model for continuous supplementation use. Detailed information on serum variables. The weighted multivariate linear regression calcium, and 25(OH)D levels, total BMD, and other vari- model was used to investigate whether serum ables can be found at www.cdc.gov/nchs/nhanes/. calcium and 25(OH)D levels independently corre- lated with total BMD. We used generalized additive Statistical analysis models and smooth curve fitting to explore potential We used sample weights in all analyses according to non-linear relationships. We further calculated the the stratified, multistage probability sampling design. inflection points using the two-piecewise linear The P-value was calculated using the weighted chi- regression model. All analyses were conducted using Table 3 Total bone mineral density by quartiles of serum calcium, stratified by race/ethnicity and age Quartiles of White Black Mexican American Other race serum calcium Total BMD g/cm (95% Confidence Interval) 12 to 15 years Lowest quartile 1.012 (0.994, 1.029) 1.069 (1.055, 1.083) 1.015 (1.000, 1.031) 1.015 (0.983, 1.047) 2nd 1.011 (0.996, 1.026) 1.068 (1.055, 1.081) 1.008 (0.995, 1.021) 1.024 (1.000, 1.048) 3rd 1.011 (0.998, 1.025) 1.065 (1.052, 1.077) 1.010 (0.998, 1.023) 1.027 (1.002, 1.052) Highest quartile 1.006 (0.995, 1.017) 1.062 (1.052, 1.072) 0.994 (0.983, 1.005) 0.998 (0.978, 1.018) P for trend 0.540 0.383 0.031 0.200 16 to 19 years Lowest quartile 1.132 (1.118, 1.146) 1.207 (1.195, 1.220) 1.120 (1.109, 1.131) 1.139 (1.116, 1.162) 2nd 1.137 (1.124, 1.151) 1.203 (1.190, 1.216) 1.117 (1.105, 1.128) 1.164 (1.139, 1.189) 3rd 1.140 (1.127, 1.152) 1.214 (1.202, 1.225) 1.117 (1.105, 1.129) 1.132 (1.108, 1.156) Highest quartile 1.137 (1.126, 1.148) 1.207 (1.196, 1.219) 1.113 (1.102, 1.125) 1.152 (1.127, 1.176) P for trend 0.598 0.722 0.485 0.883 Gender, body mass index, income poverty ratio, physical activity, and calcium supplement use were adjusted Pan et al. Advances in Rheumatology (2021) 61:16 Page 4 of 9 Fig. 1 The association between serum calcium and total bone mineral density. a Each black point represents a sample. b Solid rad line represents the smooth curve fit between variables. Blue bands represent the 95% of confidence interval from the fit. Adjusted for age, gender, race/ethnicity, income to poverty ratio, education, physical activity, body mass index, calcium supplementation use R (version 3.5.3) and EmpowerStats software (http:// existed in boys, Whites and Blacks (Figs. 3 and 4), www.empowerstats.com). P-value < 0.05 was consid- whereas the serum calcium level positively correlated ered statistically significant. with total BMD in girls, Mexican Americans and other race/ethnicity. In addition, we calculated that Results the inflection points were 9.6 mg/dL in boys and The weighted characteristics of the study population ac- Whites, and 9.2 mg/dL in Blacks. cording to gender are presented in Table 1. Most of the participants were racially/ethnically classified as “non- Association between serum 25(OH)D level and total BMD Hispanic white”. A total of 3086 boys and 2904 girls The serum 25(OH)D level negatively correlated with were included in this study: For boys and girls, respect- total BMD in the unadjusted model [0.0005 (− 0.0009, ively, the mean age was 15.46 ± 2.26 and 15.35 ± 2.23 − 0.0002)] (Table 2). This association became positive years, mean serum calcium was 9.80 ± 0.30 mg/dL and after adjusting for all potential confounders [0.0006 9.64 ± 0.30 mg/dL, mean serum 25(OH)D was 24.23 ± (0.0003, 0.0008)] (Table 2,Fig. 2). Compared to par- 8.63 ng/mL and 23.32 ± 10.02 ng/mL, and mean total ticipants with the lowest serum 25(OH)D level in Q1, 2 2 BMD was 1.10 ± 0.14 g/cm and 1.06 ± 0.10 g/cm . participants in the other groups had a higher total BMD. The trend test remained significant (P < 0.001). Association between serum calcium level and total BMD The results of total BMD by quartiles of serum There was a negative correlation between the serum 25(OH)D, stratified by race/ethnicity and age. Are calcium level and total BMD in the unadjusted model showninTable 5. In the subgroup analysis stratified [− 0.0157 (− 0.0257, − 0.0058)] (Table 2), while after by gender and race/ethnicity, we found a U-shaped adjusting for all potential confounders, a positive cor- relationship in boys, and an inverted U-shaped rela- relation was found [0.0084 (0.0007, 0.0160)]. Com- tionship in girls and Whites (Figs. 3 and 4). The re- pared to participants with the lowest serum calcium sults of the inflection points are shown in Table 4. level in Q1, participants in other groups had a higher total BMD. The results of total BMD by quartiles of Discussion the serum calcium level, stratified by race/ethnicity The aim of this study was to explore whether there are and age, are shown in Table 3.Furthermore,we independent correlations between serum calcium, and found an inverted U-shaped relationship between the 25(OH)D levels and total BMD among adolescents aged serum calcium level and total BMD using the smooth 12–19 years. The results showed that serum 25(OH)D curve fitting method (Fig. 1). We subsequently calcu- was positively correlated with total BMD, and the rela- lated that the inflection point was 9.6 mg/dL using tionship of serum calcium with total BMD assumed an the two-piecewise linear regression model (Table 4). inverted U-shaped (inflection point: 9.6 mg/dL). In the subgroup analysis stratified by gender and Calcium plays an important role in many biological race/ethnicity, this inverted U-shaped relationship systems, most notably in bones. Thus, it is essential to Pan et al. Advances in Rheumatology (2021) 61:16 Page 5 of 9 Table 4 Threshold effect analysis of serum calcium and 25(OH)D on total bone mineral density by using two-piecewise linear regression Adjusted ß (95% CI), p-value Serum calcium Total Fitting by standard linear model 0.0084 (0.0007, 0.0160) 0.0317 Fitting by two-piecewise linear model Inflection point 9.6 Serum calcium < 9.6 (mg/dL) 0.0348 (0.0165, 0.0530) 0.0002 Serum calcium > 9.6 (mg/dL) −0.0051 (− 0.0164, 0.0063) 0.3824 Log likelihood ratio 0.002 Boy Fitting by standard linear model 0.0034 (−0.0076, 0.0143) 0.5446 Fitting by two-piecewise linear model Inflection point 9.6 Serum calcium < 9.6 (mg/dL) 0.0447 (0.0128, 0.0765) 0.0060 Serum calcium > 9.6 (mg/dL) −0.0109 (− 0.0260, 0.0042) 0.1564 Log likelihood ratio 0.007 White Fitting by standard linear model 0.0129 (−0.0017, 0.0276) 0.0843 Fitting by two-piecewise linear model Inflection point 9.6 Serum calcium < 9.6 (mg/dL) 0.0465 (0.0091, 0.0839) 0.0148 Serum calcium > 9.6 (mg/dL) −0.0025 (− 0.0240, 0.0191) 0.8218 Log likelihood ratio 0.055 Black Fitting by standard linear model 0.0053 (−0.0080, 0.0187) 0.4353 Fitting by two-piecewise linear model Inflection point 9.2 Serum calcium < 9.2 (mg/dL) 0.1074 (0.0200, 0.1949) 0.0161 Serum calcium > 9.2 (mg/dL) −0.0011 (− 0.0155, 0.0133) 0.8780 Log likelihood ratio 0.020 Serum 25(OH)D Boy Fitting by standard linear model 0.0013 (0.0009, 0.0018) < 0.0001 Fitting by two-piecewise linear model Inflection point 24 Serum 25(OH)D < 24(ng/mL) 0.0024 (0.0015, 0.0034) < 0.0001 Serum 25(OH)D > 24(ng/mL) 0.0007 (0.0000, 0.0014) 0.0400 Log likelihood ratio 0.008 Girl Fitting by standard linear model 0.0003 (−0.0000, 0.0007) 0.0565 Fitting by two-piecewise linear model Inflection point 26 Serum 25(OH)D < 26(ng/mL) 0.0011 (0.0005, 0.0018) 0.0006 Serum 25(OH)D > 26(ng/mL) −0.0003 (− 0.0008, 0.0003) 0.3218 Pan et al. Advances in Rheumatology (2021) 61:16 Page 6 of 9 Table 4 Threshold effect analysis of serum calcium and 25(OH)D on total bone mineral density by using two-piecewise linear regression (Continued) Adjusted ß (95% CI), p-value Log likelihood ratio 0.004 White Fitting by standard linear model 0.0003 (−0.0002, 0.0009) 0.1945 Fitting by two-piecewise linear model Inflection point 23 Serum 25(OH)D < 23(ng/mL) 0.0035 (0.0018, 0.0052) < 0.0001 Serum 25(OH)D > 23(ng/mL) −0.0005 (− 0.0011, 0.0002) 0.1629 Log likelihood ratio < 0.001 age, gender, race/ethnicity, body mass index, income to poverty ratio, physical activity, and calcium supplementation use were adjusted In the analysis for boy/girl, white/black, the model is not adjusted for gender or race/ethnicity, respectively ensure adequate calcium intake throughout life for may have deleterious effects on bone. The above evi- building and maintaining bones [21]. However, a lower- dence suggested that calcium intake is required to im- than-recommended calcium intake has been reported prove BMD in subjects with low serum calcium levels. for European and Brazilian populations [22, 23]. Several It has been shown that a low serum 25(OH)D level trials have suggested that supplementing by oral calcium has an adverse effect on bone health [29]. Several cross- salts is notably associated with bone attenuation [24, 25]. sectional studies reported a positive association between Some recent studies showed either no significant correl- serum 25(OH)D level and BMD in adults [30–32]. Vita- ation or a negative association between serum calcium min D deficiency has been a global health problem in level with BMD [8, 9, 13]; our results suggested an the general population, with a distinct lack of data in inverted U-shaped relationship in adolescents aged 12– children and adolescents [33]. Recent studies showed 19 years. There are some biological explanations for the that hypovitaminosis D is a common disease in children, findings of this study. It was found that a high calcium and studies in an adult population regarding the aeti- intake or an intake exceeding the optimal level, could re- ology of osteoporosis have somewhat linked the evidence duce osteoblast differentiation and mineralization to vitamin D deficiency during childhood and adoles- in vitro [26, 27] and in some animals [28]. Thus, there cence [34]. The results of a cross-sectional study of 100 may be a narrow range of optimal calcium levels that Indian healthy school-age children showed that the promote bone growth, whereas elevated calcium levels serum 25(OH)D level positively related to BMD [35]. Fig. 2 The association between serum 25(OH)D level and total bone mineral density. a Each black point represents a sample. b Solid rad line represents the smooth curve fit between variables. Blue bands represent the 95% of confidence interval from the fit. Adjusted for age, gender, race/ethnicity, income to poverty ratio, education, physical activity, body mass index, calcium supplementation use Pan et al. Advances in Rheumatology (2021) 61:16 Page 7 of 9 Table 5 Total bone mineral density by quartiles of serum 25(OH)D level, stratified by race/ethnicity and age Quartiles of White Black Mexican American Other race 25(OH)D level 2 Total BMD g/cm (95% Confidence Interval) 12 to 15 years Lowest quartile 0.975 (0.929, 1.022) 1.064 (1.054, 1.074) 0.996 (0.979, 1.013) 1.027 (0.996, 1.058) 2nd 0.994 (0.973, 1.015) 1.068 (1.056, 1.079) 0.994 (0.982, 1.007) 0.993 (0.970, 1.016) 3rd 1.013 (1.001, 1.025) 1.061 (1.048, 1.075) 1.012 (1.002, 1.023) 1.000 (0.981, 1.020) Highest quartile 1.011 (1.002, 1.020) 1.071 (1.052, 1.090) 1.014 (1.000, 1.027) 1.050 (1.026, 1.074) P for trend 0.134 0.780 0.024 0.079 16 to 19 years Lowest quartile 1.106 (1.073, 1.139) 1.212 (1.204, 1.220) 1.107 (1.094, 1.120) 1.135 (1.107, 1.162) 2nd 1.126 (1.106, 1.146) 1.203 (1.191, 1.215) 1.109 (1.098, 1.119) 1.153 (1.128, 1.178) 3rd 1.127 (1.115, 1.140) 1.198 (1.182, 1.215) 1.115 (1.104, 1.125) 1.136 (1.115, 1.157) Highest quartile 1.144 (1.136, 1.152) 1.210 (1.188, 1.232) 1.140 (1.128, 1.152) 1.160 (1.136, 1.185) P for trend 0.003 0.262 < 0.001 0.347 Gender, body mass index, income poverty ratio, physical activity, and calcium supplement use were adjusted Our results also showed a positive association between To the best of our knowledge, this is the largest the serum 25(OH)D level and total BMD. We performed study investigating the relationships between serum subgroup analyses to describe the data in more detail calcium, and 25(OH)D levels and BMD in adoles- following the STROBE guidelines [36]. A non-linear re- cents, and this representative sample of a multiracial lationship between the 25(OH)D level and total BMD population may be used as a general investigation of was found, and the inflection points were detected. the whole population. Some limitations are worth These findings suggest a potentially optimal serum vita- noting. First, accurate data on puberty status were min D level for BMD, while elevated 25(OH)D levels not included in our study. Although age was adjusted (beyond the turning point) may lead to a lower BMD in as a covariate in this study, the possible bias related girls and Whites. The heterogeneity among these stud- to the unmeasured puberty status remained a limita- ies, including differences in participant selection, study tion. Second, due to its cross-sectional design, this re- size, study design, and controlled confounders, may pro- search had less power regarding the determination of vide a possible explanation for these conflicting causal relationships between serum calcium, and conclusions. 25(OH)D levels and BMD. Fig. 3 The associations between serum calcium (a), serum 25(OH)D (b) and total bone mineral density stratified by gender. Adjusted for age, race/ethnicity, income to poverty ratio, education, physical activity, body mass index, calcium supplementation use Pan et al. Advances in Rheumatology (2021) 61:16 Page 8 of 9 Fig. 4 The associations between serum calcium (a), serum 25(OH)D (b) and total bone mineral density stratified by race/ethnicity. Adjusted for age, gender, income to poverty ratio, education, physical activity, body mass index, calcium supplementation use Conclusions Center, Xiaoshan Affiliated Hospital of Wenzhou Medical University, Hangzhou 311200, Zhejiang, China. We found that serum calcium level had an inverted U-shaped relationship with total BMD, while serum Received: 1 October 2020 Accepted: 2 March 2021 25(OH)D level positively correlated with total BMD. Further studies are needed to assess whether in- References creased serum 25 (OH) D or calcium levels may have 1. Yang X, Zhai Y, Zhang J, Chen JY, Liu D, Zhao WH. Combined effects of a beneficial effect on BMD in adolescents with low physical activity and calcium on bone health in children and adolescents: a serum 25 (OH) D or calcium levels. systematic review of randomized controlled trials. WJP. 2020;16(4):356-65. 2. Baxter-Jones AD, Faulkner RA, Forwood MR, Mirwald RL, Bailey DA. Bone Acknowledgements mineral accrual from 8 to 30 years of age: an estimation of peak bone mass. The authors appreciate the time and effort given by participants during the J Bone Miner Res. 2011;26(8):1729–39. data collection phase of the NHANES project. 3. van der Sluis IM, de Muinck Keizer-Schrama SM. 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Published: Mar 10, 2021

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