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The Effect of Oral Supplementation of Vitamin D3 on Serum Levels of Vitamin D: A Review | OMICS International
ISSN: 2161-1165
Epidemiology: Open Access

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The Effect of Oral Supplementation of Vitamin D3 on Serum Levels of Vitamin D: A Review

Francesca Jarrett1, Gloria Michelle Ducasa2, David B Buller3 and Marianne Berwick4*

1Special Student, University of New Mexico, Albuquerque, New Mexico, USA

2PREP Program, University of New Mexico, Albuquerque, New Mexico, USA

3Klein Buendel, Golden, Colorado, USA

4Professor, Department of Internal Medicine and Dermatology, University of New Mexico, Albuquerque, New Mexico, USA

Corresponding Author:
Marianne Berwick
Distinguished Professor
Department of Internal Medicine and Dermatology
University of New Mexico, Albuquerque, NM 87131, USA
Tel: 505-272-4369
Fax: 505-272-2570
E-mail: [email protected]

Received Date: December 29, 2013; Accepted Date: February 10, 2014; Published Date: February 12, 2014

Citation: Jarrett F, Ducasa GM, Buller DB, Berwick M (2014) The Effect of Oral Supplementation of Vitamin D3 on Serum Levels of Vitamin D: A Review. Epidemiol 4:148. doi:10.4172/2161-1165.1000148

Copyright: © 2014 Jarrett F, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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Abstract

Due to the strong interest in the role of vitamin D in health, we tried to find data to illustrate the relationship between oral supplementation and change in serum levels of vitamin D. We reviewed the literature of randomized, placebo-controlled trials of oral supplementation and serum levels of vitamin D through 2014. We found 25 informative studies which showed a significant dose-response between oral supplementation and serum levels of vitamin D with an r2 of 0.61.These data are consistent with single studies and meta-analyses.In conclusion, the data show a consistent relationship that appears to be independent of multiple confounders.

Keywords

Ultraviolet radiation; Cholecalciferol; Serum levels

Introduction

Recently there has been a resurgence of interest in the role of vitamin D3, or cholecalciferol, supplementation in disease prevention and health maintenance. Systematic reviews have recently been published with a focus on specific groups, such as those over 50 [1] or by body mass index [2]. Studies have been carried out on serum vitamin D levels to evaluate the role of supplementation on risk for multiple health conditions, ranging from bone health to cancer.

However, the benefits and risks of cholecalciferol supplementation are under debate after the publication of a 2010 Institute of Medicine Report that recommended supplementary and dietary reference levels for Vitamin D [3]. From an epidemiological perspective, cholecalciferol is unique, as it can be obtained not only through food and supplementation, but also from ultraviolet radiation, specifically UVB (280-320 nm) [4]. Thus, some groups have suggested that people increase time in the sun and forgo sunscreen in an effort to increase their serum 25-(OH)D levels [5]. However, because over exposure to UVB rays can also lead to an increase in skin cancer incidence, the health effects associated with UV exposure may be problematic.

Oral supplementation of Vitamin D3 may be a safe alternative to UVB and should be easy to regulate to achieve optimum dosage [6]. Unfortunately, outside of single studies, there is little research that evaluates the dose-response relationship between oral intake of cholecalciferol and subsequent serum levels of vitamin D.Because of this knowledge gap, we conducted a literature review to gain perspective on current knowledge about the dose-response of serum vitamin D with supplementation.

Methods

We reviewed studies identified through a combination of personal archives and the National Library of Medicine database PubMed using the search terms “vitamin D supplementation,” “vitamin D serum” “randomized trials of vitamin D” and “25-(OH)D.” The earliest eligible study available was from 1991 and the most recent was from 2013. Studies were excluded for incomplete, or inaccessible data, leaving 36 studies that were included in this review. Of these 36 studies, 25 were analyzed (Table 1) and evaluated through graphical analysis (Figure 1), and 11 were listed separately (Table 2) because of irregular dose patterns, such as a one-time bolus intervention.

Study Number and Author Location Subjects [number, age, and sex] Length of Study Amount of Supplemental Vitamin D Given Serum levels – Baseline and After [nmol/L] Change in serum level [nmol/L]
Biancuzzo RM et al. [7] Boston, Massachusetts 34 healthy adults, 18-79 11 weeks 1000 IU/D Baseline: 53.2
After: 83.9
30.7
Al-Shaar L et al. [8] Lebanon 336 healthy adolescents 1 year 200 IU/D
2000 IU/D
200 Baseline: 37.4
200 After:  46.4
2000 Baseline:  37.4
2000 After:  90.6
200:  8.9
2000: 53.2
Ng K et al. [9] Boston, Massachusetts 328 African American, 30-80 years old 3 months 1000 IU/D
2000 IU/D
4000 IU/D
1000 Baseline: 40.4
1000 After: 74.1
2000 Baseline: 34.7
2000 After: 86.9
4000 Baseline:  39.2
4000 After: 114.6
1000:  26.9
2000:  48.2
4000:  75.6
Ala-Houhala MJet al. [10] Tampere, Finland 33 healthy hospital employees 4 weeks 800 IU/D Baseline:  53.5
After: 73.7
20.2
Holmlund-Suila Eet al.
[11]
Helsinki, Finland 113 healthy newborn infants from a single hospital 10 Weeks 400, 1200. Or 1600 IU/D 400 Baseline: 53
400 After: 88
1200 Baseline: 53
1200 After: 124
1600 Baseline: 53
1600 After: 153
400: 35
1200: 71
1600: 100
Gepner A Det al. [12] Madison, Wisconsin 114 healthy post-menopausal women mean age 63.9, 4 Months 2500 IU/D Baseline: 78.1
After: 117.3
39.2
Holvik Ket al. [13] Oslo, Norway 55 subjects. Healthy adults], average age 28 years, 63.6% women] 4 weeks 400 IU/D Baseline: 44.3
After: 78.4
34.1
Toss Get al. [14] Linköping, Sweden 45 subjects of which 32 were female, aged 55-84 1 Year 1600 IU/D Baseline: 50.4
After: 84.2
33.8
Dong Yet al. [15] Augusta, Georgia 49 Normotensive African American boys and girls, mean age 16.3 16 Weeks 400 IU/D or 2000 IU/D 400 Baseline: 34
400 After: 59.8
2000 Baseline: 33.1
2000 After: 85.7
400: 25.8
2000: 52.6
Pfeifer Met al. [16] Bad Prymont, Germany
Graz, Austria
114 healthy men and women, 70+ years 1 year 400 IU/D Baseline: 55
After: 84
29
Holick M Fet al. [17] Boston, Massachusetts 68 healthy, different racial/ethnic groups, 18-84 years old 11 weeks 1000 IU/D Baseline:  48.9
After:  72.1
23.2
Heany R Pet al. [18] Omaha, Nebraska 67 healthy men, average age 38.7 20 weeks 1,000, 5,000 or 10,000 IU/D 1000 baseline: 72.1
1000 after: 84.1
5,000 Baseline: 69.3
5,00 After: 161.2
10,000 Baseline: 65.6
10,000 After:  225.0
1000: 12
5,000: 91.9
10,000: 159.4
Trang H Met al. [19] Toronto, Canada 72 subjects, mean age 38 14 days 4000 IU/D Baseline: 41.3
After: 64.6
23.3
Lips Pet al. [20] Amsterdam, Netherlands 2578 people, including 1916 women and 662 men, mean age 80, with no major health problems 3.5 years 4000 IU/D Baseline: 23
After: 60
37
Chapuy MCet al. [21] Lyon, France 142 Healthy, ambulatory women aged 84 ± 6 years 18 months 800 IU/D Baseline: 39.9
After: 104.8
64.9
Dawson-Hughes Bet al. [22] Massachusetts 333 healthy, postmenopausal women, mean age 61.4 1 year 400 IU/D Summer baseline:  81.6
Post summer:  97
Winter baseline:  60.6
Post winter: 92.1
Summer:  15.4 Winter:  31.5
Gallagher JCet al. [23]   Omaha, Nebraska 163 postmenopausal white females with vitamin D insufficiency, mean age 67, divided into 8 study groups of 20 or 21 participants 1 year 400, 800, 1600, 2400, 3200, 4000, or 4800 IU/D 400 Baseline: 37.8
400 After: 60.9
800 Baseline: 39.0
800 After: 74.4
1600 Baseline: 37.4
1600 After: 87.9
2400 Baseline: 38.2
2400 After: 95.8
3200 Baseline: 39.8
3200 After: 101.3
4000 Baseline: 37.2
4000 After: 105.8
4800 Baseline: 38.6
4800 After: 109.3
400: 23.1
800: 35.4
1600: 50.5
2400: 57.6
3200:  61.5
4000: 68.6
4800: 70.7
Bogh MKet al. [24] Malmö, Sweden 32 vitamin D deficient patients from a primary care center in Malmö, Sweden, mean age of 32 6 weeks 1600 IU/D Baseline: 23.3
After: 60.6
37.7
Al-Daghri NMet al. [25] Riyadh, Kingdom of Saudi Arabia 92 total, 58 women, median age 56.6 and 34 men, medial age 51.2.
All had Diabetes Mellitus Type 2
18 Months 2000 IU/D Baseline: 32.2
After: 54.7
22.5
Harris SSet al. [26] Boston, Massachusetts 89, Overweight or obese African Americans with prediabetes or diabetes 12 Weeks 4000 IU/D Baseline: 40
After: 81
41
Yiu  Yet al. [27] Hong Kong, China 100 type 2 DM patients with 25[OH]D concentration <30 ng.mL 12 weeks 5000 IU/D Baseline: 54.9
After: 152.4
97.5
Pierrot-
Deseilligny Cet al. [28]  
Paris, France 156 Relapsing-remitting multiple sclerosis patients under first line immunomodulatory therapy and initial serum levels less than 100 nmol/L 29.1 Months 3010 IU/D Baseline: 49
After: 110
61
Garrett-Mayer Eet al. [29] Columbia, South Carolina 47 patients, 12 African American [mean age 63.2] and 35 White men [mean age 65.3] with early-stage low-risk prostate cancer 1 year 4000 IU/D Caucasian Baseline: 91.6
Caucasian After: 167.9
African American Baseline: 53.4
African American After: 168.9
Caucasian: 76.3
African American: 115.5
Bischoff-Ferrari HAet al. [30] Zurich, Switzerland 173 patients with previous hip fracture age > 65 [average age 84 years] 79% Women 1 year 800 IU/D or 2000 IU/D 800 Baseline: 31.5
800 After: 92.0
2000 Baseline: 34.1
2000 After: 116.21
800:  60.6
2000:  82.2
Suzuki Met al. [31] Tokyo, Japan 114 patients with Parkinson’s Disease, aged 45-85 1 year 1200 IU/D Baseline: 56.2
After: 104.1
47.9

Table 1: Randomized studies of daily vitamin D [IU/D] with change in serum level [nmol/L] over baseline.

epidemiology-oral-supplementation

Figure 1: Change in serum vitamin D [nmol/L] with oral supplementation [IU/D] in 25 studies.

Study Number and Author Location of Study Subjects [number, age, and sex] Length of Study Amount of Supplemental Vitamin D Given Serum levels- Baseline and After [nmol/L] Change in serum level [nmol/L]
Matias PJet al. [32] Portugal 158 Hemodialysis Patients 6 months 50,000 IU/week [25[OH]D<15 ng/mL]
10,000 IU/week [25[OH] 16-30 ng/mL]
2,700 IU/week [25[OH]D > 30ng/mL
Baseline: 55.7
After: 104.8
49.1
Goswami Ret al. [33] New Delhi, India 173 Healthy Asian Indian females with a mean age of 21.7 6 Months 60,000 IU/ week Baseline: 57.9
After: 186.2
128.3
Alvarez JAet al. [34] Atlanta, GA 46 patients with stage 2 & 3 CKD 18-90 years 12 months 50,000 IU/week for 12 weeks
50,000 IU/ every other week for 40 weeks
Baseline: 67.4
After: 116.6
49.2
Markmann Pet al. [35] Odense, Denmark 52 Chronic Kidney Disease patients, male and female, mean age 71 8 Weeks 40,000 IU/ week Baseline: 23.8
After: 141.6
117.8
Armas LAet al. [36] Omaha, Nebraska Patients with Stage 5 Chronic Kidney Disease 15 Weeks 10,333 IU/ week Baseline: 33.2
After: 92.1
58.9
Lips Pet al. [37] Subjects came from Mexico Washington, Indiana, Nebraska, Netherlands, Germany, and, Canada 226 men and women, mean age 78.5, who were vitamin D deficient 16 Weeks 8400 IU/ week Baseline: 34.7
After: 65.4
30.7
Tokmak Fet al. [38] North Rhine-Westphalia, Germany 64 haemodialysis patients 9 months 20,000 IU/ week Baseline: 16.7
After: 79.5
62.8
Jakopin Eet al. [39] Slovenia 101 Hemodialysis patients [52 men, 49 women] Average age 63.3 years 24 months 40,000 IU/month Baseline: 28.6
After: 54.9
26.3
Witham MCet al. [40] Dundee, United Kingdom 74 subjects with a history of myocardial infarction, average age 66 years 6 months 100,000 IU Bolus every two months Baseline: 49
After: 62
13
Grossman  REet al. [41] Atlanta, Georgia 30 Adults in the hospital for Cystic Fibrosis Pulmonary Exacerbation, mean age 24.9, both male and female, all Caucasian 12 Weeks One time 250,000 IU Bolus Baseline: 76.4
After: 91.6
15.2
Tran Bet al. [42] Australia 615 population-based, 60-84 years old  1 year 30,000 IU/month
60,000 IU/month
30,000 Baseline: 41.6
30,000 After: 63.9
60,000 Baseline: 41.7
60,000 After: 77.9
30,000: 22.3 60,000: 36.1

Table 2: Randomized studies of vitamin D [IU] that gave weekly, monthly or bolus supplementation [nmol/L].

The studies we reviewed were chosen from available literature addressing vitamin D and met pre-determined criteria for involvement.These criteria included information as to the dose of oral supplementation of cholecalciferol (vitamin D3) and serum levels of 25-(OH)D at baseline and post-intervention and included placebo groups for comparison (Tables 1 and 2). We found that many studies looked at the effect of vitamin D supplementation and dietary intake on disease outcome. Sixteen studies meeting our criteria evaluated healthy individuals [7-22]. Nine studies meeting our criteria evaluated individuals with disease included individuals with vitamin D deficiency [23,24], individuals with diabetes [25-27], relapsing multiple sclerosis patients [28], individuals with early stage prostate cancer [29], patients with previous hip fractures [30], and Parkinson Disease [31]. The number of studies that included the necessary information on serum levels pre- and post-supplementation were limited, and only a few addressed serum vitamin D levels exclusively in response to oral supplementation.

Although we wished to perform a meta-analysis, we found that the data were too heterogeneous for valid statistical evaluation. Some of the factors that contributed to the heterogeneity included varying geographical latitude, age, pre-existing medical conditions, dose size, and calcium supplementation, frequency of dose, follow-up time, and overall quality of the study. In addition, we found that several studies did not include crucial information, such as standard deviation or baseline levels, because vitamin D was not the primary focus of their research. Studies that were not placebo-controlled, randomized, or had an inadequate sample size (i.e., fewer than 20) were eliminated from our main analysis. It should be noted that seven of the studies gave weekly doses of cholecalciferol (Table 2) while three others administered onetime only bolus doses. These two groups were evaluated separately and not included in the daily dose results.

In order to determine the change in serum vitamin D per amount of oral supplementation, we subtracted the baseline serum level from the post-intervention serum level and correlated that with the amount of oral vitamin D given. This information was calculated by linear regression using change from baseline serum vitamin D and with duration included as both a quadratic and linear term using SAS 9.3 (Carr, NC).

Results

Analyses of the best available data show a clear trend. Figure 1, which shows the data from the twenty most reliable and homogeneous studies [7-26], exhibits a positive correlation between amounts of oral vitamin D administered and change in serum vitamin D levels. Figure 1 shows the change in vitamin D serum levels from the most rigorous studies that gave daily doses of cholecalciferol. These values are highly significantly correlated with a P-value<0.001 and an r2 of 0.61. We did not analyze the data from Table 2 statistically because the data were too few for meaningful analysis.

Discussion

These results demonstrate the overall coherence of the more generalizable studies, all of which were double blind and had an adequate sample size. Interestingly, our simple model is quite robust. There is a relatively strong dose-response between the amount of supplement and the change in serum vitamin D status.Surprisingly, results did not change significantly when we restricted them to studies of healthy individuals or to studies with intervention of 6 months or more. From the large scatter noted in Figure 1, it is clear that a great deal more information needs to be evaluated regarding the appropriate dose if vitamin D3 to raise serum vitamin D to a specific level. In addition, there is a clear need for additional placebo-controlled, double-blind studies to be conducted on the effects of serum 25-(OH)D levels in response to oral supplementation. One of the main limitations to our research was the fact that there are actually few randomized studies of cholecalciferol supplementation. To be useful for study of the effect of cholecalciferol on health and disease outcomes as well as clinical utility, it is important to know how different doses of vitamin D change serum vitamin D. Thus more studies need to be conducted on the oral supplementation of cholecalciferol before the scientific community can understand the importance of vitamin D supplementation to health.

Limitations include the heterogeneous nature of the studies and the fact that our analysis did not take into account the climate zone in which a person lives, or the role of age, body mass index, activity and diet in determining serum levels of vitamin D. In addition, the linear regression and slope determined using Figure 1, do not account for the “plateau” of serum vitamin D levels at high concentrations (e.g., 23). However, as a beginning, our study provides a baseline from which develop a more precise evaluation. This is especially important in light of the aging US population, the recent increase in interest in the role of vitamin D in disease prevention and the urgent need to carefully understand the role of vitamin D in health-whether it is a symptom of poor health or a means to better health.

Acknowledgements

This work was supported by the National Cancer Institute at the National Institutes of Health (K05 CA131675 to M.B).

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