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How Much Vitamin D₃ Do the Elderly Need?

Calcium Research Unit, Department of Applied Chemistry and Microbiology, University of Helsinki, Helsinki, FINLAND
Danish Institute for Food and Veterinary Research, Søborg, DENMARK

Address reprint requests to: Christel Lamberg-Allardt, Ph.D., Department of Applied Chemistry and Microbiology, P.O. Box 66, FIN-00014 University of Helsinki, FINLAND. E-mail: christel.lamberg-allardt{at}helsinki.fi

	ABSTRACT

TOP FOOTNOTES ABSTRACT INTRODUCTION SUBJECTS AND METHODS RESULTS CONCLUSIONS REFERENCES

 
Background: Vitamin D insufficiency poses a problem in many parts of the world, the elderly being an especially vulnerable group. This insufficiency results from an inadequate amount of sunshine and a low dietary intake of vitamin D. Typically, insufficiency is accompanied with high intact parathyroid hormone, (S-iPTH) concentrations.

Aims of the Study: We studied how serum 25-hydroxy vitamin D (S-25-OHD) concentrations respond to different doses of vitamin D₃ supplementation. Secondly to determine the smallest efficient dose to maintain serum 25-OHD concentration above the insufficiency level. We also studied which dose would be efficient in decreasing S-iPTH concentration in these subjects.

Subjects and Methods: Forty-nine 65- to 85-year-old women participated. The women were randomly assigned into one of four groups receiving 0 (placebo), 5, 10 or 20 µg of vitamin D₃ daily for 12 weeks. Fasting morning blood was drawn at the beginning of the study, and thereafter every second week. Calciotropic variables were assessed from serum and urine samples.

Results: The S-25-OHD concentration increased significantly (p < 0.001) in all supplemented groups [5 µg: by 10.9 (8.5) nmol/L, 10 µg: by 14.4 (6.9) nmol/L, 20 µg: by 23.7 (11.9) nmol/L], whereas it decreased in the placebo group by 8.3 (13.2) nmol/L. Equilibrium in S-25-OHD concentration was reached in all groups after 6 weeks of supplementation at 57.7 (8.9) nmol/L, 59.9 (8.9) nmol/L and 70.9 (8.9) nmol/L in the groups with increasing vitamin D supplementation. The dose-response to supplementation decreased with increasing vitamin D status at baseline, r = –0.513, p = 0.002. S-iPTH tended to decrease in those with highest dose response to supplementation.

Conclusions: A clear dose response was noted in S-25-OHD to different doses of vitamin D₃. The recommended dietary intake of 15 µg is adequate to maintain the S-25-OHD concentration around 40–55 nmol/L during winter, but if the optimal S-25-OHD is higher than that even higher vitamin D intakes are needed. Interestingly, subjects with lower vitamin D status at baseline responded more efficiently to supplementation than those with more adequate status.

Key words: elderly, vitamin D₃ supplementation, 25-hydroxyvitamin D, parathyroid hormone, dose-response

	INTRODUCTION

TOP FOOTNOTES ABSTRACT INTRODUCTION SUBJECTS AND METHODS RESULTS CONCLUSIONS REFERENCES

 
Vitamin D deficiency is typically found in countries receiving no or hardly any UV-light during the winter months, when people must rely on the diet as their main source of the vitamin D [1–3]. Secondary hyperparathyroidism, presenting especially among the elderly, is a consequence of long-term vitamin D deficiency [4] and may promote bone loss. In the summer, cutaneous synthesis of vitamin D, under the influence of UVB light, increases body stores of vitamin D [1,5]. However, with ageing, production of vitamin D may decrease [6]. In addition, a malfunction of the kidney may change vitamin D metabolism in the elderly [7]. Interestingly, a recent study [8] has concluded that intestinal absorption of vitamin D is not decreasing with age, as earlier thought [9].

Optimal vitamin D status, in addition to its role in bone health, may support the quality of life of the elderly by increasing muscle strength, preventing falls and decreasing the risk of infections [10,11]. Several studies have suggested that aged individuals benefit from larger vitamin D intakes than those recommended by the Food and Nutrition Board [4,12].

The optimal level for S-25-OHD has puzzled researchers for years, but currently a consensus was reached in a round table meeting concluding that S-25-OHD concentration of 75–80 nmol/L would be optimal for bone health [13]. At the same time, Lips [14] reported that S-25-OHD concentration above 50 nmol/L is adequate. Yet, it is suspected that the S-iPTH might not decrease with increasing 25-OHD concentration at all, [7] and highest S-25-OHD concentrations do not sustain bone health [10], especially in the elderly subjects.

The aim of this study was to define, in a controlled setting, how serum 25-OHD concentrations respond to different doses of vitamin D₃ which are considered safe and close to the dietary reference intake, DRI [15] for the elderly. In addition, we wanted to find the smallest efficient dose to maintain serum 25-OHD concentration above the insufficiency level (50 nmol/L) [14] and optimal level (70 nmol/L) [13]. We also studied which dose would be efficient in decreasing S-iPTH concentration in those subjects with increased S-iPTH concentration.

	SUBJECTS AND METHODS

TOP FOOTNOTES ABSTRACT INTRODUCTION SUBJECTS AND METHODS RESULTS CONCLUSIONS REFERENCES

 
Subjects
Women, aged 65–85 years, were recruited from the Helsinki area (60°N) by an announcement in a local paper in Helsinki, Finland. The study protocol was approved by the Ethics Committees of the hospital districts of Helsinki and Uusimaa. All subjects gave written informed consent in accordance with the Helsinki declaration.

Fifty-two women participated in the intervention trial, which lasted 12 weeks, from the beginning of January to April 2002, when uvb radiation is scarce in Finland. Of the 52 enrolled subjects, three subjects dropped out due to the strict schedule of the study, thus 49 completed the study. According to the protocol travelling to sunny places was not allowed during the study. None of the subjects used tanning salons. The subjects were randomly assigned into four groups receiving placebo, 5 µg, 10 µg or 20 µg vitamin D₃ a day. Scanpharm Ltd (Birkerød, Denmark) supplied the vitamin D₃ tablet used in the groups receiving placebo, 5 µg and 10 µg supplementation per day. Ferrosan Ltd (Espoo, Finland) supplied the vitamin D₃ drops used in the 20-µg group and this group was not double-blinded.

The first fasting blood sample was taken between 8.00 and 9.30 a.m. at the start of the intervention in January 2002. Fasting blood samples were then collected every other week at 8:00–9:30 am. Twenty-four-hour urine samples were collected three times; at the beginning, in the middle and at the end of the study. The subjects filled in a form containing questions about their medical history, the frequency and dose of vitamin D and calcium supplements, physical activity, and sun bathing. Dietary vitamin D and calcium intake were evaluated using a validated food frequency questionnaire, FFQ, which is a semi-quantitative questionnaire covering over 70 foods [16]. The nutrient content of foods were calculated using the Finnish national food composition database, Fineli®, version 2001, which is maintained by the National Public Health Institute of Finland, Nutrition unit. The forms were checked by the researchers, and if needed additional information was requested. Vitamin D supplement users (n = 17) were accepted to participate, as supplements were considered as a source of dietary vitamin D.

Assays
The fasting serum samples were collected between 8:00 and 9:30 a.m. and stored at –20°C before analysis. S-25-OHD concentration (S-25-OHD₂ and S-25-OHD₃) in the samples were measured with HPLC-analysis at the Danish Institute for Food and Veterinary Research, Søborg, Denmark [17]. The coefficients of variation (CV) for the intra- and interassay were 4.3% and 6.3%, respectively. Serum intact parathyroid hormone (S-iPTH) was measured with a commercial OCTEIA assay (IDS, Boldon, UK) with intra- and interassay CVs of 2.3% and 4.0%, respectively. Serum and urinary concentrations of calcium, phosphate and creatinine (S-Ca, S-Pi, U-Ca, and U-Crea) were analyzed using an automated KoneLab spectrophotometer (Thermo Clinical Labsystems Ltd, Espoo, Finland) at the Department of Applied Chemistry and Microbiology, University of Helsinki, following routine methods. The intra- and interassay CVs for these analyses were less than 5%, except for U-Ca and U-Crea, which were less than 10%. The U-Ca and U-Pi concentrations were expressed as mmol/mmol Crea.

Statistical Analyses
Statistical analyses were performed using SPSS version 10.0 for Windows (SPSS Inc, Chicago, 60606, USA, 2000). Pearson correlation characterises the association between variables. Repeated measures ANOVA were used to study the effect of supplementation at different time-points as well as differences between groups. For two group comparison independent samples t-test was applied, and for several groups ANOVA. Post-hoc tests were performed with Tukey’s honestly significant difference (HSD) and least significant difference (LSD). If the variables were not normally distributed, the Friedman, Kruskal-Wallis or Mann-Whitney U test were employed. Results are presented as the mean values and standard deviation, SD, in parenthesis. Results were considered statistically significant when p < 0.05, p-values between 0.05 and 0.1 were considered as trends.

	RESULTS

TOP FOOTNOTES ABSTRACT INTRODUCTION SUBJECTS AND METHODS RESULTS CONCLUSIONS REFERENCES

 
Baseline Characteristics
The baseline characteristics of the groups are shown in Table 1. The mean 25-OHD concentration was 47.2 (14.7) nmol/L at baseline. The groups did not differ from one another. Neither the users of hormone replacement therapy (HRT) nor the users of supplements differed from non-users in any way (data not shown).

View larger version (13K): [in this window] [in a new window]   Fig. 1. The correlation between the dietary intake of vitamin D (calculated by FFQ) and S-25-OHD concentration at baseline. Line presents Pearson correlation, r = 0.415, p = 0.003.

View larger version (11K): [in this window] [in a new window]   Fig. 2. S-25-OHD concentrations for the four study groups are presented with separate lines. Symbols (•) 0, (*) 5, () 10 and () 20 µg/d represent mean values at each time-point and the error bars 1 SEM. At two weeks time-point all supplemented groups differed from the placebo (repeated measures ANOVA; p < 0.001). The plateau was reached after six weeks in every supplemented group and the concentration did not increase any further. All reached plateaus differed from the placebo group (ANOVA; p < 0.001).

View larger version (26K): [in this window] [in a new window]   Fig. 3. The box-plot figure of the final 25-OHD concentration in each sub-group. The grey boxes present the lower subgroup which initial 25-OHD was 35.4 (7.9) nmol/L. The white boxes are for higher sub-group which initial 25-OHD was 58.5 (10.2) nmol/L. Subjects in the higher sub-group reached higher final 25-OHD concentration with each supplementation when compared to lower sub-group; p at least 0.03.

View larger version (9K): [in this window] [in a new window]   Fig. 4. The correlation between the S-25-OHD concentration at baseline and dose-response. Line presents Pearson correlation, r = –0.513, p = 0.002.

View larger version (8K): [in this window] [in a new window]   Fig. 5. S-iPTH concentration is presented for each of the four subject groups. Symbols (•) 0, (*) 5, () 10 and () 20 µg/d represent mean values at each time-point and the error bars 1 SEM.

Urinary calcium and phosphate excretions were adjusted for creatinine, because the urinary creatinine content changed on average 12.7 (11.1)%, which indicates incomplete 24 hour urinary collection. After adjustment supplementation had no effect either on urinary calcium or on phosphate excretion.

	DISCUSSION

 
We found that the elderly women responded efficiently to supplementation, with a significant increase in S-25-OHD already after two weeks in every vitamin D₃-supplemented group. After six weeks of supplementation a plateau was reached in the S-25-OHD concentration which is believed to indicate equilibrium between the production and degradation of S-25-OHD [18] or there could be an increased turnover of S-25-OHD in response to a higher intake. To our knowledge, this is the first study trying to solve the relationship between dietary intake of vitamin D and serum 25-OHD concentration among the elderly with sampling scheme, in which samples were taken in two week intervals during the 12 week period.

Is a Plateau in the S-25-OHD Concentration Reached?
Recently was shown with a set of high vitamin D doses that a dose-dependent plateau in the S-25-OHD concentration could be reached [5]. In the present study the plateaus were reached after six week at 58, 60 and 71 nmol/L in the groups receiving 5, 10 and 20 µg of vitamin D₃ per day, respectively. However, the mean total vitamin D intakes were 16, 21 and 30 µg/d in these groups, respectively. The S-25-OHD concentration continually decreased in the placebo group, in which the mean dietary intake of vitamin D intake was 11 µg/d.

Heaney et al. [5] proposed that vitamin D-deficient persons respond more efficiently to supplementation than healthy subjects with an adequate vitamin D status. Our results support this, as higher dose-response was related to the lower initial S-25-OHD concentration. The question is why the dose-response was poorer in subjects with initially higher vitamin D status? We suggest that in these elderly the production of 1,25(OH)₂-vitamin D was enhanced due to elevated S-iPTH concentration. It is shown in some studies that 1,25(OH)₂-vitamin D could down-regulate the liver 25-hydroxylases [19,20]. This regulation is thought to be intermittent, but we suggest that higher 1,25(OH)₂-vitamin D concentration could be the reason for lower response in S-25-OHD. Although we did not measure 1,25(OH)₂-vitamin D, and thus we cannot draw any definite conclusions.

We noted that the final S-25-OHD concentrations reached were higher in subjects who started at higher level which is in accordance with speculation that the plateau attained with supplementation is related to the initial S-25-OHD concentration [21]. However, the 12 week supplementation period was not long enough to overcome the effect of basal S-25-OHD concentration, although we expected it to be as the biological half-life for the 25-OHD concentration is 20–30 days [22].

The increments in S-25-OHD concentrations from the baseline to the end of the study were 11, 14 and 24 nmol/L, in the groups receiving 5, 10 and 20 µg of vitamin D3, respectively. Our results are consistent with those of Patel et al. [23], Harris & Dawson-Hughes [8], who marked similar changes in S-25-OHD concentrations in groups receiving 10 µg and 20 µg vitamin D₃/d. Yet, some studies [24–27] have reported greater increments which refer to stronger response to supplementation. This could be due to different vitamin D status at baseline e.g. impaired kidney function.

Searching for the Lowest Efficient Dose
We think that the circulating 25-OHD concentration reflects the body stores of vitamin D. In the optimal situation the S-25-OHD concentration is maintained stable throughout the year. This would prevent the deleterious increase of the S-PTH concentration, which is known to occur with seasonal variation of S-25-OHD [1,28].

All subjects in the vitamin D supplemented groups had a final S-25-OHD concentration higher than 40 nmol/L, and this clearly means that supplementation is advantageous in winter. However, when focusing on the final S-25-OHD concentrations we will have to make our estimation based on the daily total vitamin D intake, instead of the supplemented dose. Our results implicate that 10 µg/d is not enough to maintain S-25-OHD above 40 nmol/L in winter. With 15 µg/d vitamin D status is maintained around 40–55 nmol/L. To keep up the summer S-25-OHD concentration of ambulatory elderly in Finland (= 60 nmol/l) [1,29], the elderly would require on average 23.8 µg/d of vitamin D.

Effect of Vitamin D₃ Supplementation on S-iPTH Concentration
Aged people have been speculated to need larger vitamin D doses to keep the S-iPTH concentration normal [7]. Our results showed, however, that over a 12-week vitamin D supplementation with a dose as high as 20 µg/d, S-iPTH concentration was not normalised. The supplementation period may possibly have been too short, as longer supplementation periods are known to affect PTH secretion [23,24,26]. There was a trend to a decrease in S-iPTH in subjects with lower vitamin D status at baseline.

A low calcium intake could increase S-iPTH concentration [30,31], as well, but that is not probably the case in our study, because the mean dietary intake of calcium was 1030 (400) mg/d which agrees with the current recommendation for this age group [15]. Other factors might have influenced S-iPTH concentration; for example, in this age group, primary hyperparathyroidism is relatively common and could not be ruled out.

	CONCLUSIONS

TOP FOOTNOTES ABSTRACT INTRODUCTION SUBJECTS AND METHODS RESULTS CONCLUSIONS REFERENCES

 
Supplementation with doses 5, 10, and 20 µg/d increased the 25-OHD concentration. A plateau in the 25-OHD concentration was marked in all supplemented groups after six weeks. However, in the placebo group the S-25-OHD concentration continually decreased.

A higher dose-response was noted in subjects with lower S-25-OHD concentration at baseline, but those who started with higher initial 25-OHD concentration reached higher final concentration and 12 week intervention may not be long enough to overcome the initial difference between these subgroups.

This is an attempt to estimate adequate vitamin D intake in relation to S-25-OHD concentration for elderly subjects during winter. We conclude that 10 µg/d is not enough to keep up S-25-OHD above 40 nmol/L in winter. However, with 15 µg/d a S-25-OHD concentration of 40–55 nmol/L is maintained. To maintain the summer S-25-OHD concentration of 60 nmol/l which is seen among ambulatory elderly in Finland, the elderly would require on average 24 µg/d of vitamin D.

Vitamin D supplementation had no effect on PTH secretion, calcium and phosphate concentrations in serum or urine. If the main goal is to suppress PTH secretion, a longer supplementation period, higher doses of vitamin D or accompanied calcium supplementation may have been needed, after first ruling out other causes of elevated S-iPTH.

	FOOTNOTES

TOP FOOTNOTES ABSTRACT INTRODUCTION SUBJECTS AND METHODS RESULTS CONCLUSIONS REFERENCES

 
This study is financed by the European Fifth Framework Programme (Contract No. QLK1-CT-2000-00623).

Received April 20, 2005. Accepted February 10, 2006.

	REFERENCES

TOP FOOTNOTES ABSTRACT INTRODUCTION SUBJECTS AND METHODS RESULTS CONCLUSIONS REFERENCES

 

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This Article Abstract Figures Only Full Text (PDF) Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Viljakainen, H. T. Articles by Lamberg-Allardt, C. Search for Related Content PubMed PubMed Citation Articles by Viljakainen, H. T. Articles by Lamberg-Allardt, C.