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*
'Special Student, University of New Mexico, Albuquerque, New Mexico, USA
2 PREP Program, University of New Mexico, Albuquerque, New Mexico, USA
3 Klein Buendel, Golden, Colorado, USA
4 Professor, 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, mberwick at salud.unm.edu
Received December 29, 2013; Accepted February 10, 2014; Published February 12, 2014
Table of contents
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  or by body mass index . 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 . 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) . 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 . 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 . 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.
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.
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 , individuals with early stage prostate cancer , patients with previous hip fractures , and Parkinson Disease . 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).
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.
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.
This work was supported by the National Cancer Institute at the National Institutes of Health (K05 CA131675 to M.B).
- Autier P, Gandini S, Mullie P (2012) A systematic review: influence of vitamin D supplementation on serum 25-hydroxyvitamin D concentration. J Clin Endocrinol Metab 97: 2606-2613.
- Zittermann A, Ernst JB, Gummert JF, Borgermann J (2013) Vitamin D supplementation, body weight and human serum 25-hydroxyvitamin D response: a systematic review. Eur J Nutr.
- IOM (Institute of Medicine) (2011) Dietary Reference Intakes for Calcium and Vitamin D. The National Academies Press, Washington, DC.
- McDonnell SL, French CB, Heaney RP (2013) Quantifying the non-food sources of basal vitamin D input. J Steoid Biochem Mol Biol.
- Lagunova Z, Porojnicu AC, Aksnes L, Holick MF, Iani V, et al. (2013) Effect of vitamin D supplementation and ultraviolet B exposure on serum 25-hydroxyvitamin D concentrations in healthy volunteers: a randomized, crossover clinical trial. Br J Dermatol 169: 434-440.
- Ashwell M, Stone EM, Stolte H, Cashman KD, Macdonald H, et al. (2010) UK Food Standards Agency Workshop Report: an investigation of the relative contributions of diet and sunlight to vitamin D status. Br J Nutr 104: 603-611.
- Biancuzzo RM, Clarke N, Reitz RE, Travison TG, Holick MF (2013) Serum concentrations of 1,25-dihydroxyvitamin D2 and 1,25-dihydroxyvitamin D3 in response to vitamin D2 and vitamin D3 supplementation. J Clin Endocrinol Metab 98: 973-979.
- Al-Shaar L, Mneimneh R, Nabulsi M, Maalouf J, Fuleihan GE (2013) Vitamin D3 dose requirement to raise 25-hydroxyvitamin D to desirable levels in adolescents: Results from a randomized controlled trial. J Bone Miner Res.
- Ng K, Scott JB, Drake BF, Chan AT, Hollis BW, et al. (2013) Dose response to vitamin D supplementation in African Americans: results of a 4-arm, randomized, placebo-controlled trial. Am J ClinNutr.
- Ala-Houhala MJ, Vahavihu K, Hasan T, Kautiainen H, Ylianttila L, et al. (2012) Comparison of narrowband ultraviolet B exposure and oral vitamin D substitution on serum 25-hydroxyvitamin D concentration. Br J Dermatol 167: 160-164.
- Holmlund-Suila E, Viljakainen H, Hytinantti T, Lamberg-Allardt C, Andersson S, et al. (2012) High-dose vitamin d intervention in infants--effects on vitamin d status, calcium homeostasis, and bone strength. J Clin Endocrinol Metab 97: 4139-4147.
- Gepner AD, Ramamurthy R, Krueger DC, Korcarz CE, Binkley N, et al. (2012) A prospective randomized controlled trial of the effects of vitamin D supplementation on cardiovascular disease risk. PLoS One 7: e36617.
- Holvik K, Madar AA, Meyer HE, Lofthus CM, Stene LC (2012) Changes in the vitamin D endocrine system and bone turnover after oral vitamin D3 supplementation in healthy adults: results of a randomised trial. BMC Endocr Disord 12: 7.
- Toss G, Magnusson P (2012) Is a daily supplementation with 40 microgram vitamin D3 sufficient? A randomised controlled trial. Eur J Nutr 51: 939-945.
- Dong Y, Stallmann-Jorgensen IS, Pollock NK, Harris RA, Keeton D, et al. (2010) A 16-week randomized clinical trial of 2000 international units daily vitamin D3 supplementation in black youth: 25-hydroxyvitamin D, adiposity, and arterial stiffness. J Clin Endocrinol Metab 95: 4584-4591.
- Pfeifer M, Begerow B, Minne HW, Suppan K, Fahrleitner-Pammer A, et al. Effects of a long-term vitamin D and calcium supplementation on falls and parameters of muscle function in community-dwelling older individuals. Osteoporos Int 20: 315-322.
- Holick MF, Biancuzzo RM, Chen TC, Klein EK, Young A, et al. (2008) Vitamin D2 is as effective as vitamin D3 in maintaining circulating concentrations of 25-hydroxyvitamin D. J Clin Endocrinol Metab 93: 677-681.
- Heaney RP, Davies KM, Chen TC, Holick MF, Barger-Lux MJ (2003) Human serum 25-hydroxycholecalciferol response to extended oral dosing with cholecalciferol. Am J Clin Nutr 77: 204-210.
- Trang HM, Cole DE, Rubin LA, Pierratos A, Siu S, et al. (1998) Evidence that vitamin D3 increases serum 25-hydroxyvitamin D more efficiently than does vitamin D2. Am J ClinNutr 68: 854-858.
- Lips P, Graafmans WC, Ooms ME, Bezemer PD, Bouter LM (1996) Vitamin D supplementation and fracture incidence in elderly persons. A randomized, placebo-controlled clinical trial. Ann Intern Med 124: 400-406.
- Chapuy MC, Arlot ME, Duboeuf F, Brun J, Crouzet B, et al. (1992) Vitamin D3 and calcium to prevent hip fractures in the elderly women. N Engl J Med 327: 1637-1642.
- Dawson-Hughes B, Dallal GE, Krall EA, Harris S, Sokoll LJ, et al. (1991) Effect of vitamin D supplementation on wintertime and overall bone loss in healthy postmenopausal women. Ann Intern Med 115: 505-512.
- Gallagher JC, Sai A, Templin T 2nd, Smith L (2012) Dose response to vitamin D supplementation in postmenopausal women: a randomized trial. Ann Intern Med 156: 425-437.
- Bogh MK, Gullstrand J, Svensson A, Ljunggren B, Dorkhan M (2012) Narrowband ultraviolet B three times per week is more effective in treating vitamin D deficiency than 1600 IU oral vitamin Da,/ per day: a randomized clinical trial. Br J Dermatol 167: 625-630.
- Al-Daghri NM, Alkharfy KM, Al-Othman A, El-Kholie E, Moharram O, et al. (2012) Vitamin D supplementation as an adjuvant therapy for patients with T2DM: an 18-month prospective interventional study. Cardiovasc Diabetol 11: 85.
- Harris SS, Pittas AG, Palermo NJ (2012) A randomized, placebo-controlled trial of vitamin D supplementation to improve glycaemia in overweight and obese African Americans. Diabetes ObesMetab 14: 789-794.
- Yiu YF, Yiu KH, Siu CW, Chan YH, Li SW, et al. (2013) Randomized controlled trial of vitamin D supplement on endothelial function in patients with type 2 diabetes. Atherosclerosis 227: 140-146.
- Pierrot-Deseilligny C, Rivaud-Pechoux S, Clerson P, de Paz R, Souberbielle JC (2012) Relationship between 25-OH-D serum level and relapse rate in multiple sclerosis patients before and after vitamin D supplementation. Ther Adv Neurol Disord 5: 187-198.
- Garrett-Mayer E, Wagner CL, Hollis BW, Kindy MS, Gattoni-Celli S (2012) Vitamin D3 supplementation (4000 lU/d for 1 y) eliminates differences in circulating 25-Hydorxyvitamin D between African American and white men. Am J Clin Nutr 96: 332-336.
- Bischoff-Ferrari HA, Dawson-Hughes B, Platz A, Orav EJ, Stahelin HB, et al. Effect of high-dosage cholecalciferol and extended physiotherapy on complications after hip fracture: a randomized controlled trial. Arch Intern Med 170: 813-820.
- Suzuki M, Yoshioka M, Hashimoto M, Murakami M, Noya M, et al. (2013) Randomized, double-blind, placebo-controlled trial of vitamin D supplementation in Parkinson disease. Am J Clin Nutr 97: 1004-1013.
- Matias PJ, Jorge C, Ferreira C, Borges M, Aires I, et al. (2010) Cholecalciferol supplementation in hemodialysis patients: effects on mineral metabolism, inflammation, and cardiac dimension parameters. Clin J Am Soc Nephrol 5: 905-911.
- Goswami R, Vatsa M, Sreenivas V, Singh U, Gupta N, et al. (2012) Skeletal muscle strength in young Asian females after vitamin D and calcium supplementation: A double-blind randomized controlled clinical trial. J Clin Endocrinol Metab 97: 4709-4716.
- Alvarez JA, Zughaier SM, Law J, Hao L, Wasse H, et al. (2013) Effects of high-dose cholecalciferol on serum markers of inflammation and immunity in patients with early chronic kidney disease. Eur J Clin Nutr 67: 264-269.
- Marckmann P, Agerskov H, Thineshkumar S, Bladbjerg EM, Sidelmann JJ, et al. (2012) Randomized controlled trial of cholecalciferol supplementation in chronic kidney disease patients with hypovitaminosis D. Nephrol Dial Transplant 27: 3523-3531.
- Armas LA, Andukuri R, Barger-Lux J, Heaney RP, Lund R (2012) 25-Hydroxyvitamin D response to cholecalciferol supplementation in hemodialysis. Clin J Am Soc Nephrol 7: 1428-1434.
- Lips P, Binkley N, Pfeifer M, Recker R, Samanta S, et al. (2010) Once-weekly dose of 8400 IU vitamin D(3) compared with placebo: effects on neuromuscular function and tolerability in older adults with vitamin D insufficiency. Am J Clin Nutr 91: 985-991.
- Tokmak F, Quack I, Schieren G, Sellin L, Rattensperger D, et al. (2008) High- dose cholecalciferol to correct vitamin D deficiency in haemodialysis patients. Nephrol Dial Transplant 23: 4016-4020.
- Jakopin E, PecovnikBalon B, Ekart R, Gorenjak M (2011) High-dose cholecalciferol supplementation for vitamin D deficiency in haemodialysis patients. J Int Med Res 39: 1099-1106.
- Witham MD, Dove FJ, Khan F, Lang CC, Belch JJ, et al. (2013) Effects of Vitamin D supplementation on markers of vascular function after myocardial infarction--a randomised controlled trial. Int J Cardiol 167: 745-749.
- Grossmann RE, Zughaier SM, Kumari M, Seydafkan S, Lyles RH, et al. (2012) Pilot study of vitamin D supplementation in adults with cystic fibrosis pulmonary exacerbation: A randomized, controlled trial. Dermatoendocrinol 4: 191-197.
- Tran B, Armstrong BK, Carlin JB, Ebeling PR, English DR, et al. (2012) Recruitment and results of a pilot trial of vitamin D supplementation in the general population of Australia. J Clin Endocrinol Metab 97: 4473-4480.
PDF is attached at the bottom of this page
- How Much Vitamin D Category listing with associated searches
- Endocrine Society Guideline should be raised to 2 ng per 100 IU of vitamin D – March 2013
- How to predict response to a vitamin D dose – RCT April 2014
- Toward predicting vitamin D levels without a blood test.
- Overview Vitamin D Dose-Response
- Dose response equations for Vitamin D
- All items in category Predict Vitamin D
- All items in category How Much Vitamin D
- Dose response equations for Vitamin D
The TOP articles in How Much Vitamin D are listed here:
- At least 1,200 IU of Vitamin D if you consume 3,000 calories daily (FDA) – 2018
- Vitamin D needed to treat: 10 ng thru 40 ng – Dec 2013
- Vitamin D - at least 4,000 IU to achieve 40-60 ng and reduce risk of early death – Holick June 2018
- Vitamin D recommendations by Italian Endocrinologists – 40 ng if pregnant, 30 ng if high risk – April 2018
- US govt. notices new Vitamin D proof, will wait years for large trials to end – Dec 2017
- US admits math mistake was made in 2010 in estimating Vitamin D, but will not change recommendations – Nov 2017
- 1000 IU should be the new vitamin D RDA (if you think 20 ng is enough) - May 2017
- Much more than 2,000 IU of vitamin D is needed daily (Middle East studies agree) – meta-analysis Nov 2016
- 2000 IU of vitamin D- doctors trained that it was too much, but it is often too little
- Vitamin D levels are dropping rapidly – what you need to do
- 200 IU needed to increase vitamin D levels by 1 ng (not 100 IU) – summary of 25 studies – Feb 2014
- Vitamin D needs in 2004:1000 IU, 10 years later same author says 3,500 IU
- One pill every two weeks gives you all the vitamin D most adults need
- FDA considering raising adult Vitamin D, but not for adults who are senior or pregnant- Feb 2014
- Vitamin D Deficiency: Time for Inaction (question mark)– Jan 2014
- 5,000 IU recommended by Vitamin D Council - Dec 2013
- 2 out of 3 people think that they get enough vitamin D, but only 1 in 3 get even the absolute minimum – Oct 2013
- Obese need 2.5 IU of vitamin D per kg to increase 1 ng (about 3.4 X more) – RCT Sept 2013
- Huge variation in taking vitamin D supplements with age of female, less than 1000 IU not help much – July 2013
- Hyperbaric Oxygen – spectrum of benefits (what about hyperdose of vitamin D) - June 2013
- Vitamin D level can be high, but little benefit: due to kidney, genes, low Magnesium etc.
- Huge increase in UK vitamin D prescriptions by July 2012
- Let 1000 die from vitamin D deficiency rather than incur 1 lawsuit
- Vitamin D DRI for children lowered to 200 IU in Korea – Jan 2013
- Even taking as much as 4200 IU vitamin D 43 percent had less than 30 ng in blood – RCT Jan 2013
- Rickets cured for 3 months with 10,000 IU per kg vitamin D (600,000 IU max) – Sept 2012
- 30 percent of vitamin D sold now has more than 2000 IU - Dec 2012
- Best heart geometry associated with vitamin D of 30-37 ng – Oct 2012
- How often might 50000 IU vitamin D be taken - results of clinical trials
- NASA thinks spacestation personnel only need 800 IU of vitamin D – Sept 2012
- European adults can take 4000 IU of vitamin D – July 2012
- With just 200 IU vitamin D in intravenous feeds, deficiency results
- 400 iu of vitamin D is like 24 seconds of sun in a swimsuit in Los Angeles
- Reasons for low response to vitamin D
- Vitamin D Recommendations around the world - IU and ng
7297 visitors, last modified 02 Aug, 2014, URL:
- All items in category How Much Vitamin D