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Low vitamin D status adversely affects bone health parameters in adolescents^1,2,3

¹ From the Departments of Food and Nutritional Sciences (TRH, AAC, AF, MK, and KDC) and Medicine (KDC), University College, Cork, Ireland; the Northern Ireland Centre for Food and Health (JW, PR, and JJS) and the Systems Biology Research Group (WD), University of Ulster, Coleraine, United Kingdom; the University College Dublin Institute for Sport and Health, University College, Dublin, Ireland (CB), and the Department of Epidemiology and Public Health, Queens University, Belfast, United Kingdom (LM)

² Supported by the Higher Education Authority (HEA) under the Strand 1: North/South Programme for Collaborative Research and by the Northern Ireland Department of Health, Social Services and Public Safety.

³ Reprints not available. Address correspondence to KD Cashman, Department of Food and Nutritional Sciences, and Department of Medicine, University College, Western Road, Cork, Ireland. E-mail: k.cashman{at}ucc.ie.

	ABSTRACT

TOP ABSTRACT INTRODUCTION SUBJECTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Background: The effects of subclinical vitamin D deficiency on bone mineral density (BMD) and bone turnover in adolescents, especially in boys, are unclear.

Objective: We aimed to investigate the relations of different stages of vitamin D status and BMD and bone turnover in a representative sample of adolescent boys and girls.

Design: BMD was measured by dual-energy X-ray absorptiometry at the nondominant forearm and dominant heel in a random sample of 12- (n = 260) and 15-y-old (n = 239) boys and 12- (n = 266) and 15-y-old (n = 250) girls. Serum 25-hydroxyvitamin D, parathyroid hormone, osteocalcin, and type I collagen cross-linked C-telopeptide were assessed by using enzyme-linked immunoassays. Relations between vitamin D status and bone health indexes were assessed by using regression modeling.

Results: Using multivariate regression to adjust for potential physical, lifestyle, and dietary confounding factors, we observed that 12- and 15-y-old girls with high vitamin D status (74.1 nmol/L) had significantly greater forearm (but not heel) BMD (β = 0.018; SE = 0.008; P < 0.05 for each age group) and lower serum parathyroid hormone concentrations and bone turnover markers than did those with low vitamin D status. These associations were evident in subjects sampled throughout the year and in winter only. There was no significant relation between vitamin D status and BMD in boys.

Conclusions: Maintaining serum 25-hydroxyvitamin D concentrations above 50 nmol/L throughout the year may be a cost-effective means of improving bone health. Increased emphasis on exploring strategies for improving vitamin D status in adolescents is needed.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION SUBJECTS AND METHODS RESULTS DISCUSSION REFERENCES

 
It is well-established that prolonged and severe vitamin D deficiency [represented as serum 25-hydroxyvitamin D (25(OH)D) concentrations < 10–25 nmol/L] leads to rickets in children and osteomalacia in adults (1, 2). In contrast, the effect of subclinical vitamin D deficiency [also refered to as vitamin D insufficiency (3-5)] on skeletal health is less clear.

A number of studies in adolescents have shown a high prevalence of subclinical vitamin D deficiency in Europe (6-12), the United States (13-17), Lebanon (18), New Zealand (19, 20), and Tasmania (21), especially during the winter months. It is well-recognized that, in elderly subjects, low vitamin D status elevates parathyroid hormone (PTH) concentrations, which, in turn, increases bone turnover and bone loss, contributes to mineralization defects, and increases risk of hip and other fractures (22), but the effects in children and adolescents are unclear. Elevated PTH concentrations may not be driven by the same mechanism in adolescents as in adults, and they may not necessarily be detrimental to bone health. For example, serum PTH concentrations are normally higher during adolescence (23, 24), when the rate of bone remodeling and consolidation is at a peak. Even though the relation between vitamin D status and PTH during adolescence remains unclear, the findings from a limited number of studies in adolescent girls provide evidence of a possible adverse effect of low vitamin D status for bone mineral acquisition and bone remodeling in adolescence (6, 9, 10). Those 3 studies were conducted in winter; therefore, the serum 25(OH)D cutoffs to define low vitamin D status were within a tight range—typically, <50 nmol/L.

There is a lack of consensus on the serum 25(OH)D concentration that reflects optimal vitamin D status, but it has been suggested that serum 25(OH)D concentrations > 80 nmol/L are needed to plateau PTH concentration (25). However, Viljakainen et al (26) recently showed in Finnish girls that vitamin D supplementation significantly increased bone mineral augmentation of the femur and lumbar spine, and that a serum 25(OH)D concentration > 50 nmol/L was sufficient to promote bone acquisition. Furthermore, whereas there are some data on the effect of low vitamin D status on bone health in girls, no study has been conducted in boys, despite the prevalence of low vitamin D status in this subgroup (7, 8, 14, 20, 27).

Therefore, the main objective of the present study was to investigate the relations among different stages of vitamin D status and bone mineral density (BMD) of the forearm and heel in a representative sample (n = 1015) of 12- and 15 y-old adolescent boys and girls living at 54–55°N in the United Kingdom, in whom our group (27) recently showed that low vitamin D status is prevalent. In addition, we investigated the relations among vitamin D status, serum PTH, and biochemical markers of bone turnover.

	SUBJECTS AND METHODS

TOP ABSTRACT INTRODUCTION SUBJECTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Design
The Young Hearts 2000 (YH2000) survey is the second in a series of cross-sectional studies examining a representative sample of adolescents from Northern Ireland. Details of subject recruitment and the inclusion and exclusion criteria were reported elsewhere (28-30). Eleven percent, 16%, 16%, 6%, 2%, 7%, 10%, 11%, 11%, and 11% of the group were sampled during January, February, March, April, May, June, September, October, November, and December, respectively. None of the subjects were sampled during July or August because of the summer vacation. Complete records were available for 1015 adolescents who had provided a blood sample and for whom data on pubertal status, anthropometry, BMD, habitual physical activity, and food intakes were also available.

Written informed consent was obtained from the subjects and from each subject's parent or guardian. Ethical approval was obtained from the Research Ethics Committee of the Queen's University of Belfast.

Anthropometric and lifestyle data
Standing height and body weight was measured as described previously (29). Pubertal status of each subject was assessed by a pediatrician using visual signs such as nongenital secondary hair growth, vocal timbre, body habitus, general muscular development, and (in girls) overall breast development. Lifestyle and physical activity data were obtained from questionnaires, as described previously (29, 31). Dietary data were collected via a nutritionist-administered 7-d diet history method (32).

Assessment of bone mineral density
BMD of the nondominant forearm (distal radius) and dominant heel (os calcis) was measured by dual-energy X-ray absorptiometry with a Norland Lunar peripheral instantaneous X-ray imager bone densitometer (PIXI; Lunar Corporation, Madison, WI), which has a precision of 0.5%. Before each scan, the densitometer was calibrated by using quasi-anthropomorphic phantoms according to the manufacturer's recommendations. The results of the scan were expressed as BMD (g calcium hydroxyapatite/cm²).

Collection and preparation of samples
Nonfasting blood samples were collected by venipuncture into an evacuated tube with no additive. They were then processed to serum, which was immediately stored at –80 °C until required for analysis.

Experimental techniques
Serum 25-hydroxyvitamin D
Concentrations of 25(OH)D were measured in serum samples by using an enzyme-linked immunosorbent assay [(ELISA) OCTEIA 25-Hydroxy Vitamin D; Immuno Diagnostic Systems, Ltd, Boldon, United Kingdom]. The intraassay and interassay CVs for the ELISA method were 5.9% and 6.6%, respectively. The quality and accuracy of serum 25(OH)D analysis in our laboratory is ensured on an ongoing basis by participation in the Vitamin D External Quality Assessment Scheme (DEQAS) from Charing Cross Hospital (London, United Kingdom). This ELISA is used for the quantitative determination of 25(OH)D. It has 100% cross-reactivity with 25(OH)D₃, and, whereas 75% cross-reactivity with 25(OH)D₂ was also reported, Carter et al (33) reported that the assay did not underestimate 25(OH)D₂ in the DEQAS samples. A comparison of the performance of our ELISA with that of a commonly used radioimmunoassay in relation to the DEQAS samples shows very good correlation (ELISA = 1.2238 x radioimmunoassay – 5.5514; r = 0.96).

Serum intact parathyroid hormone
Intact PTH concentrations were measured in serum by using an ELISA (MD Biosciences Inc, St Paul, MN). The intraassay and interassay CVs were 3.4% and 3.8%, respectively.

Serum type 1 collagen cross-linked C-telopeptides
Type 1 collagen cross-linked C-telopeptide (CTx) was measured in the serum samples by using an ELISA (Nordic Bioscience Diagnostics A/S, Herlev, Denmark). The intraassay and interassay CVs were 6% and 5%, respectively.

Serum osteocalcin
Osteocalcin concentrations were measured in serum samples by using an ELISA (Metra Osteocalcin EIA Kit; Quidel Corporation, San Diego, CA). The intraassay and interassay CVs were 6.0% and 7.6%, respectively.

Statistical analysis
The statistical analyses were performed by using SPSS for WINDOWS software (version 12; SPSS Inc, Chicago, IL). Data that were not normally distributed were logarithmically [natural log (ln)] transformed before statistical analysis, to achieve near-normal distributions. Tests for independence were used to compare demographic variables such as age grouping, sex, season of sampling, and pubertal status and to compare dietary factors between the subjects included in the current analysis (n = 1015) and the complete YH2000 dataset (n = 2017). Age x sex interactions for height, weight, forearm BMD, heel BMD, serum 25(OH)D, PTH, osteocalcin, CTx, physical activity, and dietary vitamin D and calcium were examined by using 2-factor analysis of variance. Serum 25(OH)D concentrations were grouped into tertiles. Regression analyses, for each age-sex group, were then undertaken to assess the extent of the association between vitamin D status and BMD and bone turnover marker concentrations. The tertiles of serum 25(OH)D were coded by using a dummy variable–coding scheme, which allowed comparisons to be made between the high-status group and the moderate-status group and between the high-status group and the low-status group. Univariate models were constructed with nondominant forearm BMD or dominant heel BMD as the dependent variable and 3 categories of vitamin D status (ie, low, moderate, and high) as the explanatory variables. Multivariate models were then constructed to include adjustment for potential physical, dietary, and lifestyle confounders, including height, weight, pubertal status, alcohol drinking, smoking habits, physical activity, supplement use, and intake of calcium and fruit [fruit intake was previously shown to influence BMD in this cohort of adolescents (29)]. The same approach was used for serum PTH, osteocalcin, and CTx concentrations. Finally, age x sex x vitamin D status interactions were investigated.

	RESULTS

TOP ABSTRACT INTRODUCTION SUBJECTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Baseline characteristics of adolescents
Characteristics of the adolescents included in the current analysis (n = 1015) were compared with those of all participants in the YH2000 study (n = 2017), which was a representative sample of adolescents in Northern Ireland. There was no significant difference in the percentage distribution of sex, age, Tanner scores, and proportion sampled during summer or winter between these 2 groups (data not shown). Similarly, there was no significant difference in height, weight, BMI, or the intake of vitamin D and calcium between these 2 groups (data not shown).

Subject characteristics, BMD measurements, biochemical markers of bone turnover, vitamin D status, and selected nutritional information for the sample by age and sex group are presented in Table 1. Boys 12 y old had greater forearm and heel BMD, were more physically active, had higher concentrations of serum CTx and osteocalcin, and had higher intakes of calcium and vitamin D than did their female counterparts. Girls 12 y old were taller and heavier and had higher serum PTH concentrations than did their male counterparts. There was no difference in serum 25(OH)D concentrations between 12-y-old boys and girls. Boys aged 15 y were taller and heavier; were more physically active; had greater heel BMD; had higher serum 25(OH)D, PTH, CTx, and osteocalcin; and had higher intakes of calcium and vitamin D than did their female counterparts. Girls aged 15 y had greater forearm BMD than did their male counterparts.

Table 2

Table 3

	DISCUSSION

TOP ABSTRACT INTRODUCTION SUBJECTS AND METHODS RESULTS DISCUSSION REFERENCES

 
The findings of the present study in a large, representative sample of healthy adolescents show that 12- and 15-y-old girls with low vitamin D status had lower BMD of the forearm and higher PTH and bone turnover marker concentrations than did those with high vitamin D status. Whereas there were significant associations in similarly aged boys between vitamin D status and serum PTH and osteocalcin, no significant association was evident between vitamin D status and BMD or serum CTx.

In the entire group of girls, sampled throughout the year, the group with low vitamin D status had serum 25(OH)D concentrations (<46.3 nmol/L) that broadly encompassed the range of values between vitamin D deficiency and insufficiency [<25–50 nmol/L (9, 10)], whereas the group with high vitamin D status had concentrations (>74.1 nmol/L) that were close to one suggested definition of optimal vitamin D status [80 nmol/L (25, 34)]. In 12- and 15-y-old girls, there was no significant difference between those with moderate (46.4–74.0 nmol/L) and high vitamin D status. These findings may suggest that serum 25(OH)D concentrations > 46.3 nmol/L are needed for adequate BMD accrual and rate of bone remodeling in adolescent girls.Viljakainen et al (26) recently suggested, on the basis of their findings that improving the vitamin D status of adolescent Finnish girls via vitamin D supplementation for 12 mo significantly increased bone mineral augmentation of the femur and lumbar spine, that serum 25(OH)D concentrations of >50 nmol/L may be optimal. Lehtonen-Veromaa et al (6) reported that none of the girls in their study who had baseline serum 25(OH)D concentrations of >50 nmol/L lost BMD at the lumbar spine. It is also notable that, unlike BMD of the femur or lumbar spine, which appears to be responsive to the serum 25(OH)D concentration in more sexually mature girls (6, 26), BMD of the forearm was influenced by the serum 25(OH)D concentration in 12- and 15-y old girls. This finding is in line with the findings of 2 studies that vitamin D status influenced forearm BMD in prepubertal (10) and peripubertal (9) girls.

The mechanism underlying the association between BMD of the forearm and vitamin D status is unclear, but that association may be related to our findings that serum PTH and bone turnover marker concentrations were higher in girls with low vitamin D status than in those with high vitamin D status. Lehtonen-Veromaa et al (6) found a significant inverse correlation between serum 25(OH)D and CTx, but not osteocalcin, in girls 9–15 y old. In general, there were no differences in bone marker concentrations between girls in the moderate and high vitamin D status groups in the present study, which, again, suggests that it is those with low vitamin D status (ie, <46.3 nmol/L) who show changes in bone turnover. It is interesting that PTH was higher in girls with moderate vitamin D status than in those with high vitamin D status, which is in line with findings of some studies suggesting that, in adolescents, serum PTH either does not plateau with increasing serum 25(OH)D (9) or plateaus at serum 25(OH)D concentrations of >80 nmol/L (27). The effect of low vitamin D status on bone health in boys has received very little research emphasis to date. In the present study, whereas a lack of association was found between tertiles of vitamin D status and BMD of the forearm in 12- or 15-y-old males, there were significant differences in serum osteocalcin and PTH. The reasons for the lack of BMD associations in males are unclear, and they require further investigation.

In a complementary approach, regression analysis models were run only in those subjects sampled in winter, and, thus, they provide a more refined comparison of stages of vitamin D status within the lower range of serum 25(OH)D concentrations. Whereas there was in that analysis no association between vitamin D status and BMD in boys, the girls with low (<43.0 nmol/L) and moderate (43.1–57.0 nmol/L) vitamin D status had lower BMD of the forearm than did the girls with high (>57.1 nmol/L) vitamin D status. Thus, serum 25(OH)D concentrations of >57 nmol/L may be required to optimize BMD of the forearm, which agrees closely with the concentrations suggested for lumbar spine and femur, ie, >50 nmol/L (6, 26).

We previously showed that 36% of these adolescents had 25(OH)D concentrations < 50 nmol/L throughout the year (27). The prevalence of vitamin D inadequacy was much higher (50%) in subjects sampled during the winter, because of the northerly latitude (54–55°N) of Northern Ireland (27). Thus, the possible adverse effect of low vitamin D status on bone health measures during adolescence is of concern for a large proportion of that population. We also previously reported that, in this cohort during winter, low vitamin D intake (<1.7 µg/d) and being female were significant predictors of having a serum 25(OH)D concentration of <50 nmol/L (27). Thus, for persons living at latitudes above 37°N in Ireland or the United Kingdom, elsewhere in Europe, and North America, low intakes of vitamin D may take on increased importance during the winter, when sunlight is of insufficient intensity to stimulate dermal vitamin D synthesis. Determination of the dietary intake of vitamin D that will support the year-round maintenance of serum 25(OH)D concentrations of >50 nmol/L is important and worthy of urgent scientific research.

There was no relation between BMD of the heel and the tertile of vitamin D status in any sex or age group in the present study. To our knowledge, there has been no other report of the effect of vitamin D status on BMD of the heel. It has been suggested previously that the effect of vitamin D on the skeleton may be site-specific (6), but the reasons for this possibility are not clear. They may have to do with a modulatory effect of body weight on the influence of vitamin D on BMD, and effects were evident in the present study in the forearm but not the heel, which would experience much more load than would the forearm. In addition, it may be that differences exist in the metabolic activity in these 2 skeletal sites. It is interesting that McGartland et al (29) showed, in the same YH2000 cohort, that high fruit intake in 12- and 15-y-old girls was associated with higher BMD of the heel, but no association was observed with BMD of the forearm. Thus, the site-specific effects of nutrition on BMD may also depend on the nutritional factor in question.

The main strength of the present study is that it was conducted in a large, representative sample of adolescents, both male and female, in Northern Ireland. The limitations of the study include the lack of data on bone mineral content and fractures. Furthermore, whereas the use of a peripheral instantaneous X-ray imager to assess BMD is a convenient and acceptable method for large studies, less is known about the precision and accuracy of that method, especially among youth, as compared with the use of axial (central) dual-energy X-ray absorptiometry measurements of the hip and spine. It would be interesting to see whether the results generated in the current study would be replicated in a study that included axial measurements.

In conclusion, whereas there is no consensus about the serum 25(OH)D concentration that defines either low or optimal vitamin D status in adolescents (6, 9, 10, 25, 26, 33), we found a positive association between high vitamin D status and forearm BMD in 12- and 15-y-old girls after adjustment for potential confounders. This association likely arises because of the lower serum PTH and markers of bone remodeling seen with higher vitamin D status. With the observed associations between vitamin D status and bone heath measures, a recommendation that adolescents maintain their serum 25(OH)D concentration above an agreed cutoff (possibly >50 nmol/L) may be a cost-effective means of improving bone health. Greater emphasis should be given to exploring strategies for improving vitamin D status in adolescents.

	ACKNOWLEDGMENTS

 
The authors' responsibilities were as follows—AF, LM, MK, JMWW, PJR, JJS, WD, CAB and KDC: the conception of the work and awardees of funding for the study; PJR, JJS, CAB, and LM: contributions to the execution of the Young Hearts Project; TRH, AAC, MK, and KDC: sample analysis; and TRH, AAC, AF, LM, MK, JMWW, PJR, JJS, WD, CAB, and KDC: data analysis and the writing of the manuscript. None of the authors had a personal or financial conflict of interest.

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