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University of Tennessee Health Science Center, Memphis, TN 38112 and * University of Jyväskylä, Jyväskylä, Finland
5To whom correspondence should be addressed. E-mail: ftylavsky{at}utmem.edu
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ABSTRACT |
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 TOP ABSTRACT LITERATURE CITED |
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KEY WORDS: • vitamin D • adolescents • bone density • bone accrual • parathyroid hormone
The Institute of Medicine released recommendations for vitamin D intake for adolescents in 1997 (1). Serum 25 hydroxyvitamin D [25(OH)D]6 was set as the criterion for determining vitamin D adequacy. Although during puberty, the metabolism of 25(OH)D to 1,25dihydroxyvitamin D [1,25(OH)2D] increases, there are few studies that lend support to or refute this fact. Based on available studies, the deficiency level was set at <27 nmol/L (1). At the time of the report, there was a lack of data on vitamin D’s ability to maintain normal calcium metabolism or its effect on peak bone mass. Since the publication of this report there has been additional information to shed light on the relationship between intake, sunlight exposure, and deficiency of 25(OH)D in adolescents. This article provides an overview of factors related to serum vitamin D in adolescents.
Prevalence of serum 25(OH)D deficiency in adolescents
The production of 25(OH)D in the liver is dependent on vitamin D obtained from the diet and from exposure to ultraviolet light. Ultraviolet rays stimulate the conversion of pro-vitamin D in skin to vitamin D, making it available to the liver for hydroxylation to 25(OH)D. Thus, the circulating concentrations of 25(OH)D are considered to be reflective of the person’s total vitamin D exposure (2,3). Yet there is no consensus on the concentration of serum 25(OH)D that would yield the most benefit for bone health (4–6). The definition for vitamin D deficiency based on serum 25(OH)D varies between studies, with the majority consensus setting the level at 25 nmol/L (Table 1). The prevalence of 25(OH)D deficiency ranged from 0% to 32%, depending on the season measured and the latitude of the population under study. In those studies that reported higher cut-points for serum 25(OH)D insufficiency, the prevalence rates increased upward to 75% for some populations. Of the 3 studies that included boys and girls, 2 found a gender difference in the prevalence of vitamin D deficiency dependent upon the season in which they were measured. Decline in 25(OH)D stores from summer to winter have been well documented by numerous groups for adolescent males and females (7–13). In general, the prevalence of vitamin D deficiency was 5–14% higher for those assessed during the winter months compared with the summertime. Ethnic differences are prominent in the U.S.-based studies. African Americans have the highest prevalence, with progressively decreasing prevalence for Mexican Americans, Asians, and then Caucasians. In the third cycle of the National Health and Nutrition Examination Survey (NHANES III), northern latitudes were assessed in the summer and southern latitudes in the winter season. At first glance there appeared to be a seasonal difference in 25(OH)D status; however, the sample from the South contained a higher proportion of African Americans and Mexican Americans. The apparent seasonal difference could be explained by differences in ethnic composition of the 2 regions. Because of differences in study design, variability in different 25(OH)D assays (14), geographic latitude of the population under study, and the age range, ethnicity, and gender of the sample makes comparing studies difficult. However, these data underscore the importance of considering ethnic composition, gender, and regional and seasonal differences in sample selection, and/or the analysis phase of research studies focusing on vitamin D status.
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During puberty, the conversion of 25(OH)D to 1,25 dihydroxyvitamin D [1,25(OH)2-D] increases to meet the demands of growth. A concomitant decrease in 25(OH)D stores has been supported by some (11,15) but not all studies (16). Aksnes and Aarskog (15) provide longitudinal data on 104 girls and boys as support for decreased serum 25(OH)D during puberty. Lehtonen-Veromaa and colleagues (11) from Finland provided support for declines in 25(OH)D during rapid growth by classifying females with regard to the onset of menarche. The authors reported that 2 y or more prior to the onset of menarche, serum 25(OH)D levels were 10 nmol/L higher than serum 25(OH)D within 2 y of menarche. Although the data were not statistically compared by pubertal status and the prepubertal groups were smaller than the older girls’ groups, the data does provide substance for thought. In contrast, cross-sectional data from NHANES III suggests the prevalence of 25(OH)D deficiency for adolescent boys and girls ages 12 to 19 y old was lower than was reported for the other age groups (7). The classification of chronological age from 12 to 19 y old as an identifier for the pubertal years prevents NHANES III data from refuting or supporting that 25(OH)D are compromised during the rapid growth period. Longitudinal studies underway or completed have the opportunity to provide insight into the importance of 25(OH)D stores during a time when demands for maximal height velocity and mineralization are occurring.
Serum 25(OH)D and fractional absorption of calcium
Vitamin D demands during adolescence are a function of dietary intake and growth velocity. The primary function of vitamin D during puberty is to increase the absorption of calcium to meet the demands of bone mineralization. Lee and colleagues (17) reported a negative association between serum 25(OH)D and fractional absorption of calcium in 12 girls between the ages of 9 to 17 y. The study was performed with Chinese girls whose average calcium intake was 591 mg/d. In contrast, Abrams and colleagues (18,19) did not find a correlation between serum 25(OH)D levels and fractional absorption in Caucasians, Mexican Americans, or African Americans. The average calcium intake in the children was between 821 and 1110 mg/d (19,20). In adults, serum 25(OH)D has been associated with fractional absorption of calcium (21). Thus, it is reasonable to pose a few questions: 1) Is the association dependent on adequacy of serum 25(OH)D or solely a function of dietary calcium intake, and, most importantly, 2) is the lower serum 25(OH)D reflective of the increased conversion of 25(OH)D to 1,25(OH)2-D to meet the demands for growth and mineralization of the skeleton?
Serum 25(OH)D and parathyroid hormone
The negative or curvilinear relationship between serum 25(OH)D and parathyroid hormone (PTH) during puberty has been shown in many cross-sectional studies (8,10,22,23). The focus of these efforts has been on defining the level of serum 25(OH)D that suppresses PTH. This inflection point is considered by some as the criteria for defining 25(OH)D deficiency (4,5). A graph of the relationship between serum PTH and 25(OH)D, published by Cheng et al. (24), is shown in Figure 1. The relationship reported by Cheng is very similar to that published by others (8,10,22,23). Examining the lower end of the reference range for serum 25(OH)D demonstrates much variability in PTH, with only a small sample number having above normal PTH levels. Further examination indicates that individuals are near the upper limit for normal PTH (65 nmol/L) across all 25(OH)D concentrations. The data should be scrutinized to identify those who have abnormal PTH, at low 25(OH)D concentrations, to evaluate those with high normal PTH regardless of 25(OH)D concentrations, and to determine the impact on bone accrual. Cross-sectional data can help to answer these questions, but only a longitudinal study can begin to untangle this complex and not well understood relationship during a period of rapid growth.
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The evaluation of the association between serum 25(OH)D and bone health during puberty, using bone assessment techniques, has shown varying results. Much of the variability between studies is due to differences in study design, sexual maturity of the sample studied, serum 25(OH)D concentrations defined as deficient, and bone assessment modality. Outila and colleagues (23) reported that females with serum 25(OH)D concentrations above 40 nmol/L had greater radial bone mineral density (BMD) (P < 0.05) and ulna BMD (P = 0.08). Using the same cut-points for serum 25(OH)D concentrations, Cheng and colleagues (24) clearly showed that a progressive increase in cortical BMD with increasing serum 25(OH)D concentrations at both the distal radius and the tibia shaft using peripheral quantitative computed tomography (pQCT). However, no differences based on serum 25(OH)D concentrations were found in the total femur, the lumbar spine, or whole body BMD as assessed by dual energy X-ray absorptiometry (DXA). Lehtonen-Veromaa’s data showed that the relationship between 25(OH)D status and BMD of femoral neck and spine was dependent on the length of time prior to the onset of menarche (25). These findings raise important questions that are not easily answered: 1) are these different findings due to differential growth patterns for the selected skeletal sites, and 2) are the different observations due to different bone assessment techniques? Answers to the questions can be obtained with the availability of pQCT in longitudinal studies.
Serum 25(OH)D and food intake
Gordon and colleagues (10) evaluated a multi-ethnic group of adolescents attending a medical clinic in Boston. They found that those who selected soft drinks were at higher risk for vitamin D deficiency, while the consumption of milk or cold cereal was protective against deficiency. This is the first multifactorial study that presents food selection as having a role on vitamin D deficiency. However, a discerning investigation is warranted to determine whether the 25(OH)D status was preserved due to the adequacy of calcium intake and/or vitamin D intake. It should be noted that milk and dairy products contain phosphorus, potassium, and magnesium, which are also beneficial for bone metabolism, and that may not be easily replicated by fortifying foods with vitamin D and calcium alone.
Vitamin D supplementation, serum 25(OH)D, and bone assessment
The effects of vitamin D supplementation on serum 25(OH)D has been extensively examined in adults (6). In contrast, there have been only a few studies investigating the effect in adolescents. Due to differences in populations, use of vitamin D-2 or cholecalciferol, the dosing regimen, and the duration of the study, the findings could be instructive for planning future studies. Guillemant and colleagues (13) evaluated the effect of vitamin D supplementation during the winter on serum 25(OH)D in white males in France. This study administered 2.5 mg (10,000 IU) cholecalciferol to participants at the end of September, November, and January. Serum 25(OH)D levels were the same at baseline and March for those receiving the supplements, while serum 25(OH)D levels fell 40 nmol/L for those individuals who did not receive supplements. PTH remained the same in the supplemented group and increased in the nontreated group. Bone assessments were not performed. Lehtonen-Veromaa and colleagues (26) made a baseline assessment of 171 females during the winter and summer months prior to starting a vitamin D supplementation study. The supplementation regimen included 10 µg of vitamin D-2 taken daily from October to February for 2 y; in addition, girls with <1000 mg of calcium intake were provided with daily supplements of 500 mg of calcium. At the end of the 2 y there was no increase in serum 25(OH)D levels. For the 3rd y of the study the researchers increased the dose to 20 µg of vitamin D-2 daily. After 6 mo on the 20 µg dose, serum 25(OH)D concentrations were higher than those obtained during the winter baseline period, but did not reach concentrations observed during the summer months. There was a positive trend for a gain in spinal BMD (P = 0.01) and greater BMD at the femoral neck (P = 0.15) with greater vitamin D baseline stores. There were no results presented on the changes in bone area and bone mineral content, thus making it difficult to determine if differential growth was due to baseline bone size. As this study focused on the effect of vitamin D supplementation on vitamin D status, data were not provided on the effect of change in serum 25(OH)D in relation to bone status. Clearly, there is a need for more studies to evaluate the latter.
In summary, the paucity of research relating vitamin D nutrition to bone accrual in adolescents provides a wealth of opportunity for researchers to investigate the factors that impact serum 25(OH)D from the laboratory to population-based studies. The real challenge for performing free-living human studies is incorporating ethnicity, gender, sunlight exposure, diet, and stage of puberty into the study design. If the outcome measure is bone accrual, the studies should have a comprehensive assessment using DXA, pQCT, and other modalities that can provide information on the quality of bone mass. Calcium isotope studies may provide important information about the net effect on bone mineralization without the use of longitudinal studies.
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FOOTNOTES |
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2 Guest Editor Disclosure: Michael F. Holick, Academic Associate Nichols Institute; Christel Lamberg-Allardt, no relationships to disclose; Lisa A. Spence, Director of Nutrition Research for the National Dairy Council.
3 Author Disclosure: no relationships to disclose.
4 Supported by Lebonheur Health Systems and GlaxoSmithKline.
6 Abbreviations used: 1,25(OH)2-D, 1,25 dihydroxyvitamin D; 25(OH)D, 25 hydroxy-vitamin D; BMD, bone mineral density; DXA, dual energy xray absorptiometry; NHANES III, third cycle of the National Health and Nutrition Examination Survey; pQCT, peripheral quantitative computed tomography; PTH, parathyroid hormone.
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