To determine the vitamin D status (serum 25-hydroxyvitamin D; S-25OHD) in adolescent girls and elderly community-dwelling women living in four countries of northern Europe and to explain differences in S-25OHD concentrations between and within the countries.
A cross-sectional observational study conducted in a standardised way during February–March. S-25OHD was analysed by high-performance liquid chromatography. Vitamin D and calcium intake was calculated using a standardised food composition database.
Denmark, Finland, Ireland, and Poland.
A total of 199 girls (mean (s.d.) age 12.6 (0.5) y) and 221 women (mean (s.d.) age 71.8 (1.4) y).
The median (inter quartiles) concentration of S-25OHD was 29.4 (20.3, 38.3) nmol/l for the girls and 40.7 (28.0, 54.2) nmol/l for the women. S-25OHD below 25 nmol/l was found in 37% of the girls and 17% of the women, and S-25OHD below 50 nmol/l was found in 92% of the girls and 37% of the women. Positive significant determinants for S-25OHD in girls were use of vitamin D supplements, and in women sun habits, dietary vitamin D intake, use of vitamin D and calcium supplements. Body mass index and smoking were negative determinants in women. For women predictors could explain the differences between countries (Pcountry=0.09, R2=0.39), but for girls the difference remained significant even after including predictors (Pcountry=0.03, R2=0.15).
Vitamin D status is low in northern Europe during winter. More than one-third of the adolescent girls have vitamin D status below 25 nmol/l and almost all are below 50 nmol/l. Two-thirds of the elderly community-dwelling women have vitamin D status below 50 nmol/l. Use of vitamin D supplements is a significant positive determinant for S-25OHD for both girls and women (P=0.001).
The European Fifth Framework Programme (Contract No. QLK1-CT-2000-00623).
The number of hip fractures in the European Union has increased by more than 25% over 4 years (Read, 2003). Low vitamin D status contributes to declining bone mass by elevating PTH leading to increased bone resorption and thereby increased incidence of hip fractures in elderly (Dawson-Huges et al, 1991; Chapuy et al, 1992; Heihinheimo et al, 1992; Ooms et al, 1995; Papadimitropoulus et al, 2002; Zittermann, 2003). Vitamin D status is also very important during adolescence, as there is a high rate of skeletal growth and bone mass accumulation. Increased bone resorption and decreased bone formation due to lack of vitamin D during the growth period may lead to a reduced peak bone mass, and a higher risk of postmenopausal osteoporosis (Bonjour et al, 1991; Ribot et al, 1995; Sabatier et al, 1996; Weaver et al, 1999; Lehtonen-Veromaa et al, 2002; Wang et al, 2003).
To assess vitamin D status, the concentration of serum 25-hydroxyvitamin D (S-25OHD) is considered as an accurate and integrative measure reflecting an individual's intake and cutaneous production of vitamin D (Hollis, 1996; Heaney, 1999; Ovesen et al, 2003; Zittermann, 2003). However, it is difficult to compare vitamin D status across borderlines, since S-25OHD values from different laboratories cannot be assumed to be comparable unless a cross-calibration has been performed (Lips et al, 1999).
Controversy exists regarding which circulating level of S-25OHD is appropriate (McKenna & Freaney, 1998; Heaney, 2003; Holick, 2004; Lips, 2004). The index disease for vitamin D deficiency is rickets/osteomalacia (Heaney, 2003), which is prevented by S-25OHD concentration above 10–25 nmol/l (Parfitt, 1990; Vieth, 1999; Wharton & Bishop, 2003). However, this level does not acknowledge the importance of vitamin D associated long-latency disorders (non-index diseases), including osteoporosis (Parfitt, 1990; Heaney, 2003). The limit for optimal S-25OHD concentrations with respect to osteoporosis is still unclear with levels ranging from 40 and up to 100 nmol/l (Docio et al, 1998; Outila et al, 2001; Heaney, 2003; Zittermann, 2003; Holick, 2004; Lips, 2004). In this study, we have chosen to operate with limits of 25 and 50 nmol/l. The limit of 50 nmol/l is a careful choice, since we cannot be confident that concentrations between 25 and 50 (or higher) nmol/l have similar negative effects in adolescents and elderly.
The aim of this study was to determine the vitamin D status in healthy Caucasian adolescent girls and elderly community-dwelling women from four northern European countries in a standardised way and to explain differences in S-25OHD concentrations between as well as within the four countries.
Subjects and methods
The study is the baseline part of a 1-y long observational study involving four European countries (Denmark, Finland, Ireland and Poland). Two age groups, adolescent girls and elderly women, had S-25OHD measured in a standardised way during February and March 2002 in all four countries.
The ethic committees in each country approved the study protocol. The study was carried out in accordance with the Declaration of Helsinki. Written informed consent was obtained from all participants, as well as from the parents/guardians of the girls.
In Denmark, the subjects were randomly selected from the Danish National Central Offices of Civil Registrations. Among a total of 3380 girls and 8671 women living in the Copenhagen and Frederiksberg municipality (55.4°N), 235 girls and 346 women were randomly selected by use of date of birth and invited by letter to participate in the study. Among the invited, 59 of the girls and 54 of the women accepted. In Poland, the subjects were randomly selected from the Polish National Central Offices of Civil Registrations, and among a total of 360 girls and 670 women living in the Sadyba region of Warsaw (52.1°N), 130 girls and 130 women were randomly selected and invited by letter to participate. Among the invited, 61 of the girls and 68 of the women accepted. In Finland, the women were randomly selected by the Finnish National Population Register. A total of 200 women living in the Porvoo area (60.1°N) were invited to participate by letter, and the first 60 accepting the invitation were included. The Finnish girls were recruited from schools in the Porvoo area. The girls were invited to participate by letter distributed in the classes, and the first 60 accepting the invitation were included. In Ireland, the subjects were recruited from the Cork area (51.9°N). The girls were recruited from local schools and the women from voluntary organisations for the elderly in the community, adverts in local papers, and posters in relevant places (Ireland does not have Civil Registers). All subjects were Caucasians.
The goal was to recruit 50 women and 50 girls from each country, which allows multiple regression analysis with about 20 explanatory variables. More subjects were recruited from Denmark, Finland and Poland, and fewer from Ireland. The sample was selected randomly but in limited regions within each country and, therefore may not be representative for the country as a whole. The representativeness of the sample could not be assessed due to lack of information about the non-acceptors. However, we expect such a selection to be equally strong in all countries, thereby not affecting the comparison between countries and the relationship between vitamin D status and various predictors.
Subjects taking medication (except dietary supplements) known to affect S-25OHD concentrations were excluded. Therefore two women (one Danish and one Polish) taking antiepileptics and two women (both Polish) taking active vitamin D metabolites were excluded. Nine women and nine girls with incomplete data in one of the explanatory variables were excluded in the multiple regression analysis. In total, 190 girls and 212 women were included in the multiple regression analysis. The subjects excluded did not differ from the rest of the population with respect to S-25OHD and the explanatory variables.
Biochemical sampling and measurement
Morning blood samples were taken by venipuncture after an overnight fast. Local anaesthetic patches were offered to the girls to reduce the discomfort of venipuncture. Blood samples were centrifuged (approx. 3000 × g) within 2 h of sampling, and serum was frozen and stored at −80°C. All serum samples were sent on dry ice to Denmark where they were stored at −80°C and analysed by the Danish Institute for Food and Veterinary Research.
S-25OHD concentrations were analysed by High Performance Liquid Chromatography (HPLC). Serum proteins were precipitated with ethanol, and deproteinised serum was subsequently applied to an MFC18 solid-phase extraction column (Isolute®, International Sorbent Technology, Mid Glamorgan, UK) for elution of the S-25OHD fraction with ethylacetate:n-heptane (10:90). The extracted S-25OHD was injected into an HPLC-system (Waters, Milford, MA, USA) equipped with a 600 controller and pump, a refrigerated 717PLUS Autosampler, a cyano column (Luna, Phenomenex, Torrance, CA, USA), a 996 Diode Array Detector set at 220–320 nm for detection and a 2487 Absorbance Detector set at 265 nm for quantification. Mobile phase consisted of a mixture of 2-propanol and n-heptane (1.5:98.5). Participation in the Vitamin D External Quality Assessment Scheme (DEQAS, Charing Cross Hospital, London, UK) secured the HPLC-method was in agreement with commercially available assays. The inter-assay CV is 6.3% and the intra-assay CV is 4.3%.
At the same day of blood sampling, all the subjects answered a standardised questionnaire that ascertained demographic characteristics, chronic diseases, self-report of difficulty with task of daily life (women only), smoking habits (women only), menarche status (girls only), use of medication, use of dietary supplements, sun habits, holidays and other lifestyle variables. Regular use (daily or every other day) of all vitamin D and calcium containing dietary supplements (multivitamins, pure supplements, some other mix) were recorded in the standardised questionnaire and it was recorded whether the supplements contained vitamin D (yes/no) and/or calcium (yes/no).
Weight and height were recorded without shoes. The body mass index (BMI) was calculated (weight/height2) and recorded (kg/m2). The age of the subjects is the age on the date of blood sampling and interview.
The subjects answered a standardised food frequency questionnaire (FFQ) that ascertained the foods (incl. fortified foods) contributing to 95% of the vitamin D intake and 75% of the calcium intake determined from the most recent dietary intake studies in the respective countries. However, the questionnaire used in Finland had open frequencies instead of the predetermined nine possible frequencies used in Denmark, Ireland and Poland (ranging from ‘less than one time per month’ to ‘4–5 times per day or more’).
In order to avoid systematic differences between the national food composition data sets, a standardised food composition database (based on biological assays for vitamin D) was built upon data from each country's food composition databases. In addition, the same nutrient calculation system was used to calculate the vitamin D and calcium intake from all the countries. The Danish Institute for Food and Veterinary Research (DFVF) performed the intake calculations using the General Intake Estimation System (GIES), a system developed at DFVF (Christensen, 2001). GIES is capable of working with multiple data scenarios, as the intake model in GIES operates with three separate data layers: the recorded food intake, recipes and food composition data. The three data layers in GIES communicate through interface tables. GIES is developed in Delphi version 6 (Borland Software Corporation) and accesses data in standard database management system (DBMS). For these calculations, data were stored in a Paradox version 7 database (Corel Corporation). For the intake estimation food model recipes matching the FFQ are used. The food model recipes are constructed for each country. The portion sizes, the recipes, the water and fat yield have, however, been standardised as much as possible, and yet national habits are still accounted for.
Data handling and statistical analysis
The biochemical data, the intake data, the background data, and the height and weight were gathered from all four countries, and statistically handled as one data set using SAS v8. Analyses included standard descriptive statistics. The countries were compared using ANOVA for the normally distributed variables (weight, height and BMI) and nonparametric ANOVA for the non-normally distributed variables (S-25OHD, dietary vitamin D and calcium intake).
Multiple regression analyses were performed for women and girls separately in order to describe the relation between (logarithmically transformed) S-25OHD and the possible explanatory variables. The following categorical variables were included: vitamin D supplements (coded as: 0=no supplements, 1=taking supplements regularly), calcium supplements (coded as: 0=no supplements, 1=taking supplements regularly), pubertal status (girls only, coded as: 0=period not started, 1=period started), sun habits (‘how do you prefer to stay outside during summer season: avoid sun, sometimes in sun or prefer sun (reference group)’), smoking habits (women only: smoker, ex-smoker or nonsmoker (reference group)), and country (Denmark, Finland, Ireland and Poland (reference group)). The following continuous numerical variables were included: age (y), BMI (kg/m2), dietary vitamin D intake (μg/day), dietary calcium intake (mg/day), post menarche time (girls only, if period has started, months since start of menarche) and package year (women only, if smoker or ex-smoker, ‘number of cigarettes smoked per day in number of years'/20). The dietary vitamin D and calcium intakes were logarithmically transformed in order to achieve linearity. The significance level was chosen as 0.05.
Regarding calculation of interpreted ratio estimates, see Appendix A.
Vitamin D status
The S-25OHD concentrations are shown in Table 1, and the percentages of girls and women with S-25OHD concentrations below 25 and 50 nmol/l are shown in Table 2. The percentiles for each country are shown in Figures 1 and 2.
The median concentration of S-25OHD for all girls was 29.4 nmol/l, and 37% had vitamin D status below 25 nmol/l and almost all the girls (92%) had vitamin D status below 50 nmol/l. Irish girls had a significantly higher concentration of S-25OHD compared to the other girls (P<0.01). The median concentration of S-25OHD for all women was 40.7 nmol/l, and 17% had vitamin D status below 25 nmol/l and 67% below 50 nmol/l. Polish women had a significantly lower concentration of S-25OHD compared to the other women (P<0.0001). The coefficient of variation for S-25OHD was 43% for all girls and 52% for all women.
Determinants of S-25OHD concentrations in the girls
To explain the differences in S-25OHD concentrations between the countries multiple regression analysis was performed, and effects are quantified in Table 3. Only use of vitamin D supplements (P=0.001) had a positive association with S-25OHD for girls. The other explanatory variables had non-significant associations (P>0.05) with S-25OHD. The studied variables did not explain the difference in S-25OHD concentrations between the countries, since the P-value for country is significant (P=0.03). Only 15% of the total variation in S-25OHD concentrations within countries are explained (R2=0.15) and the remaining variation amounts to a coefficient of variation of 41%.
Determinants of S-25OHD concentrations in the women
For the women (log) vitamin D dietary intake (P=0.0001), use of vitamin D supplements (P=0.001), use of calcium supplements (P=0.02) and staying outside in sun (P=0.049) all had a positive association with S-25OHD. BMI (P=0.0003) and smoking (P=0.045) had a negative association with S-25OHD (quantifications in Table 4). The studied variables explained part of the difference in S-25OHD concentrations between the countries, since the P-value for country became non-significant (P=0.09). Approximately 40% of the total variation in S-25OHD concentrations within countries are explained (R2=0.39) by the included explanatory variables, thereby reducing the coefficient of variation to 42%.
Interpreted ratio estimates
The estimated regression coefficients are not directly comparable due to different units in the explanatory variables and interpreted ratio estimates (Appendix A) are therefore calculated for both girls and women (Tables 3 and 4). The interpreted ratio estimates indicate how differently the various explanatory variables affect the S-25OHD concentration.
In this study, low vitamin D status was found among adolescent girls and elderly women from northern Europe during the late winter season. Of the adolescent girls, 37% had vitamin D status (defined by S-25OHD) below 25 nmol/l and 92% were below 50 nmol/l. Corresponding figures for the elderly women were 17 and 67%.
The biological differences between teenage girls and elderly women make the comparison of vitamin D status between the age groups problematic. Still, it is worth noticing that the girls have a median vitamin D status about 10 nmol/l lower than the women. But can it really be true that almost all of the girls have a critically low vitamin D status during winter? Or should the cutoff limits be different for young girls and elderly women? Can recurring low winter vitamin D status among young girls lead to long-latency diseases like osteoporosis later in life if summer status is high? Significant higher bone accretion was found in a 3-y long study among 9–15 y girls with normal vitamin D status (defined as S-25OHD>37.5 nmol/l) compared with the severely deficient girls (S-25OHD<20 nmol/l) (Lehtonen-Veromaa et al, 2002). More studies are needed to clarify the optimal vitamin D status for girls and to answer the questions above.
Large differences in vitamin D status have been found between countries both for girls and women (McKenna, 1992; Chapuy et al, 1996, 1997; Kristinsson et al, 1998; Melin et al, 1999; Carnevale et al, 2001; Du et al, 2001; Fuleihan et al, 2001; Pasco et al, 2001; Vieth et al, 2001; Looker et al, 2002; Kudlacek et al, 2003); however, conclusions on regional differences based on comparisons of S-25OHD concentrations are often questionable because of the lack of standardisation between methods (Lips et al, 1999; Heaney, 2000; Ovesen et al, 2003; Lips, 2004). In our study all blood samples were measured in the same laboratory, which allows comparison between countries.
One could argue that the dissimilarities in selection of subjects in our study are a limitation for making statements on the differences in S-25OHD concentration between the countries. However, the representativeness of the sample could not be assessed due to the lack of information about the non-acceptors. While this is a limitation of the study, the selection will possibly not influence the relation between S-25OHD and the various predictors.
Different lifestyle parameters are included in the statistical analysis (Table 1). Both the Finnish women and girls have a higher vitamin D intake compared to the other countries due to a high fish intake in Finland. Danes take more supplements than the other countries. Most Danish women smoke, but the Polish women smoke more (greater package year). Polish women and girls have a greater avoidance of sun.
Apart from the present study, the only other multi-European-country study determining S-25OHD concentrations in a standardised way is the SENECA study (van der Wielen et al, 1995). In SENECA, the elderly women (age: 70–75 y) had average S-25OHD concentrations ranging from 21 to 48 nmol/l (in Greece and Norway, respectively) and 47% were below 30 nmol/l (winter measurements). In comparison, 30% of the women in our study had S-25OHD concentration below 30 nmol/l. However, the different methods used to measure S-25OHD, HPLC in our study and competitive protein-binding in the SENECA study, and lack of intercomparison studies, preclude direct comparison of vitamin D status between studies.
We found that the dietary vitamin D intake, the use of vitamin D and calcium supplements, and staying outside in sun had a positive association with S-25OHD concentration for the elderly women, and that BMI and smoking had a negative association with S-25OHD (P<0.05).
In comparison, the SENECA study found that use of vitamin D supplements and/or use of sunlamps (P<0.001) as well as activities of daily living score, clothing attitudes, tertiles of body weight, energy intake, going outside during sunny periods, calcium intake, meat and fish intake (P<0.10) were associated with S-25OHD. In SENECA, fish and meat intake was included instead of dietary vitamin D intake, which could not be calculated due to a lack of a standardised European food composition database (van der Wielen et al, 1995; Schroll et al, 1997). A standardised database for the included countries was constructed in our study, and the vitamin D and calcium intakes were therefore included in our multiple regression analyses.
Similarities in determinants of S-25OHD concentrations between the SENECA study and our study are: use of vitamin D supplements, vitamin D dietary intake (calculated as nutrient intake in our study and fish/meat intake in SENECA) and calcium intake (use of calcium supplements in our study and calculated as nutrient intake in SENECA). Dietary calcium intake was not a significant determinant in our study, and use of calcium supplements was not included in the regression model of SENECA. Staying outside in the sun was directly associated with S-25OHD concentration in both studies. In SENECA, smoking was not included in the multiple regression model. None of the women in our study used sunlamps.
The inverse relation between BMI and S-25OHD found in our study was not found in SENECA, but it has been demonstrated in other studies, and different explanations have been proposed (Bell et al, 1984, 1985; Liel et al, 1988; Need et al, 1993; Wortsman et al, 2000; Nesby-O'Dell et al, 2002; Rucker et al, 2002; Arunabh et al, 2003). The mechanism of variations in S-25OHD concentrations in both non-obese and obese persons appears to be related to availability of adipose tissue leading to excessive storage of the precursor in the fat tissue (Arunabh et al, 2003). Studies of the association between a high BMI and low vitamin D status have mostly been performed in obese persons, but a recent study (Arunabh et al, 2003) showed the same inverse relation in healthy lean to mildly obese women, with the specification that it was the percentage of body fat, which correlated strongest with S-25OHD compared to BMI and body weight. In contrast, probably through other mechanisms, gaining weight reduces women's risk of hip fracture, and loosing weight increases risk (Cummings et al, 1995; Salamone et al, 1999).
In order to target the improvement of vitamin D status in Europe, it is necessary to investigate the determinants that have the largest effect on S-25OHD concentration. The interpreted ratio estimates shown in Tables 3 and 4 indicate that the determinants have different effects on S-25OHD. Increasing women's dietary vitamin D intake by 50% only increases the S-25OHD 7%, while taking a vitamin D supplement increases S-25OHD by 27%. We can however not be certain, that the associations found in this cross-sectional study can be directly interpreted as longitudinal (ie. interventional) effects. From the rather large residual variation between individuals (CV: 41 and 42% for girls and women, respectively), we may suspect that additional significant predictors may be discovered in future investigations. Nevertheless, the interpreted ratio estimates could indicate that it might not be a simple matter to increase the S-25OHD concentration of a specific population group to a given concentration by rather substantial lifestyle changes. Supplementation may not be realistic on population basis and adequate food fortification with vitamin D should be considered.
The only significant determinant of S-25OHD we found for the adolescent girls was the use of vitamin D supplements. 15% of the variation in S-25OHD among the girls is explained (vs 39% for women) by the variables included. Development of a higher peak bone mass during adolescent years may protect against postmenopausal osteoporosis (Bonjour et al, 1991; Sabatier et al, 1996; Weaver et al, 1999); however, it is difficult to follow the effects of adolescent nutrition into adulthood (Weaver et al, 1999). It has not been established whether the same cutoff limit is suitable for both children and the elderly; however, we find it worrying that more than one-third of the girls in our study have S-25OHD concentrations below 25 nmol/l. With the increasing occurrence of osteoporosis, more focus on nutrient and lifestyle interventions during the pubertal growth phase is important. To our knowledge, no other standardised European multi-country studies with adolescents exist. In comparison, the postmenopausal phase is a much more studied phenomenon.
In conclusion, our results show low vitamin D status among adolescent girls and elderly community-dwelling women in northern Europe during the late winter season. The consequences for peak bone mass in girls and the risk of developing osteoporosis later in life should be further investigated in longitudinal intervention studies. Additional vitamin D intake is necessary to prevent low winter vitamin D status in northern Europe. Studies to determine the efficacy of vitamin D fortification on vitamin D status in population groups at risk are needed.
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Karin Hess Ygil, Tue Christensen and Anders Møller are acknowledged for the dietary intake calculations. The study is part of the OPTIFORD-project ‘Towards a strategy for optimal vitamin D fortification’, financed by EU, the 5th Framework Programme (QLK1-CT-2000-00623).
Guarantor: R Andersen.
Contributors: RA wrote the manuscript and undertook the statistical analyses with advice from LTS, CM and LO. CB, KDC, JC, AF, CL-A, OM, CM and LO designed the study. JC undertook the standardised protocol. RA, EC, MKä, MKi, AMN, MO'B and MR-N collected the data. JJ undertook the measurements of S-25OHD. All contributed to the manuscript.
Estimated regression coefficients (β) represent the effect on outcome for a one unit increase in the respective covariate. Since outcome (S-25OHD) was logarithmic transformed, we transformed the coefficients to ratio estimates (10β), indicating a multiplicative increase in outcome corresponding to one unit increase in the covariate. This is done for the following covariates: vitamin D and calcium supplements, sun habits, pubertal status, smoking habits, BMI, post menarche time, package year and country.
Logarithmic transformation of outcome:
Taking the antilogarithm:
One unit increase in outcome:
For the covariates that were themselves logarithmic transformed (vitamin D and calcium dietary intake), this ratio corresponds to the effect of a one unit increase on logarithmic scale, that is, a 10-fold increase on the original scale. Since it is unrealistic to increase the vitamin D and calcium intake 10-fold, we instead calculated and present effects corresponding to a 50% increase for vitamin D and calcium intake (1.5β).
Logarithmic transformation of outcome and covariate:
Taking the antilogarithm:
10-fold increase in outcome:
50% increase in outcome:
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Andersen, R., Mølgaard, C., Skovgaard, L. et al. Teenage girls and elderly women living in northern Europe have low winter vitamin D status. Eur J Clin Nutr 59, 533–541 (2005). https://doi.org/10.1038/sj.ejcn.1602108
- hypovitaminosis D
- vitamin D status
- 25-hydroxyvitamin D
- elderly women
- adolescent girls
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