Food-Fortified Vitamin D3 More Effective than D2 at Raising Serum 25(OH)D Levels | Blog | Metagenics18/7/2019  by Ashley Jordan Ferira, PhD, RDN
A food fortification trial demonstrated that 600 IU of daily vitamin D3 had a significantly greater impact than 600 IU of daily vitamin D2 in elevating serum blood levels of 25-hydroxyvitamin D [25(OH)D].1-2 Vitamin D is essential for skeletal health and many emerging extraskeletal physiological processes, but remains one of the most common micronutrient dietary gaps, resulting in widespread hypovitaminosis D globally. Understanding how much vitamin D the body needs daily, in what form, and from what sources is still being discovered. There are two forms of vitamin D: plant-based ergocalciferol (vitamin D2) and animal-based cholecalciferol (vitamin D3). D2 can be found in UV-irradiated mushrooms, certain fortified foods (breakfast cereals, margarine, and milk), dietary supplements, and vitamin D prescription medications. D3 is found in oily fish, egg yolks, fortified milk, and dietary supplements.4 Chemically, D2 and D3 are almost identical except for key side chain differences, with D2 having an additional double bond. D3 has been shown to have a higher affinity to the vitamin D binding protein, hepatic 25-hydroxylase (enzyme that converts vitamin D to the circulating 25(OH)D form) and vitamin D receptor. Whether these chemical and cellular differences translate into differential abilities in raising serum 25(OH)D, the clinical measure of vitamin D status, has been a hotly debated topic since the early 20th century.5 Research literature to date demonstrates a robust case gaining momentum for vitamin D3 and against vitamin D2 for supplementation. In particular, a 2012 systematic review and meta-analysis by of randomized controlled vitamin D supplementation trials in humans explored a head-to-head comparison of vitamin D2 vs. D3 in raising serum 25(OH)D; vitamin D3 was clearly shown to be more efficacious at raising and maintaining serum 25(OH)D levels than vitamin D2.4 Authors concluded that vitamin D3 may be considered the preferred choice for supplementation.4 Since natural sources of vitamin D (dietary input and UVB exposure from the sun) are limited, and a daily vitamin D supplementation regimen is a personal health decision, vitamin D fortification of the food supply is an important, strategic public health measure to help increase dietary vitamin D intake and improve status in the general population.6 Clarity is needed to elucidate whether D2 and D3 are equally effective sources for food fortification, since both forms are currently utilized in the food supply.6 A study by Tripkovic et al. helps to shed light on key differences.1 Results were published in The American Journal of Clinical Nutrition by Dr. Laura Tripkovic and colleagues from a randomized, double-blind, placebo-controlled food fortification trial that included 335 healthy South Asian and white European women aged 20–64 years.1 Participants were randomized to one of five groups: 1) Placebo: Placebo juice with placebo biscuit 2) D2J: Juice supplemented with 15 mcg vitamin D2 with placebo biscuit 3) D2B: Placebo juice with biscuit supplemented with 15 mcg vitamin D2 4) D3J: Juice supplemented with 15 mcg vitamin D3 with placebo biscuit 5) D3B: Placebo juice with biscuit supplemented with 15 mcg vitamin D3 Fifteen mcg of vitamin D is equivalent to 600 IU of vitamin D, which is the US Recommended Daily Allowance (RDA) for ages 1-70 years.7 The daily food-fortified intervention was 12 weeks long during the winter, and serum total 25(OH)D levels were collected at baseline, week 6 and week 12. Data analysis combined ethnic groups. D3-fortified consumption was shown to be twice as effective as D2 in raising 25(OH)D serum levels in the body.1 While the placebo group experienced a 25% reduction in serum 25(OH)D levels over the course of the study, the D2J and D2B groups saw 25(OH)D increases of 33% and 34%, respectively. Most effective, however, were the D3 groups, with 25(OH)D increases in the D3J and D3B groups of 75% and 74%, respectively. The D3J group induced higher incremental increases in 25(OH)D levels: 16.9 nmol/L higher than the D2J group, 16.0 nmol/L higher than the D2B group, and 42.9 nmol/L higher than the placebo group.1 Both juice- and biscuit-supplemented vitamin D3 groups demonstrated similar results, with no statistical differences seen between D3J and D3B groups.1 Compared to white European women, the South Asian women demonstrated a greater increase in 25(OH)D levels in response to both D2 and D3, which was likely caused by their lower baseline vitamin D status.1 This study shows that modest supplementation levels (600 IU daily) of D3 in food and beverage sources twice as effective at raising serum levels of 25(OH)D than vitamin D2.1 This study and previous supplementation studies may impact future policy and practice for vitamin D supplementation source. Additional research addressing dose response, bioactivity of D3 versus D2 and the impact of foods with high levels of vitamin D3 is needed.2 Why is this Clinically Relevant?
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 by Ashley Jordan Ferira, PhD, RDN
Vitamin D is essential- it helps absorb calcium, supports nervous and muscle tissue, and the immune system. Compared to normal-weight counterparts, vitamin D deficiency is more prevalent in those with obesity. In the US over one-third of adults meet obesity criteria.1 A study in The Journal of Clinical Endocrinology and Metabolism2 examined cellular mechanisms of vitamin D trafficking in metabolically dysfunctional adipose tissue as compared to normal adipocytes in conjunction with a vitamin D supplementation intervention in a randomized, controlled trial. Ninety-seven male subjects completed the vitamin D intervention study. Fifty-four normal-weight and 67 obese males were initially randomized to receive either 50 mcg/week of 25-hydroxyvitamin-D3 [25(OH)D3] (2,000 IU/week equivalent) or 150 mcg/week of vitamin D3 (6,000 IU/week equivalent) for one year. Vitamin D sufficiency was defined as a 25(OH)D blood level > 20 ng/ml. This serum concentration is aligned with the National Academy of Medicine’s cutoff for vitamin D sufficiency.3 Vitamin D uptake, conversion and release were investigated in control (non-insulin-resistant) and insulin-resistant 3T3-L1 adipocytes, as well as in subcutaneous adipose tissue (SAT) samples from lean and obese participants. The release of vitamin D and its metabolites were induced with the addition of adrenaline. Expression of the vitamin D receptor and vitamin D conversion enzymes, 25-hyroxylase and 1α-hydroxylase, was also examined. The research team elucidated key differences in cellular vitamin D trafficking effects and supplementation effects:
Why is this Clinically Relevant?
References
 by Ashley Jordan Ferira, PhD, RDN
Autism spectrum disorder (ASD) is a complex neurodevelopmental syndrome with significant social, communication and behavioral deficits and challenges.1 No cure exists for ASD, although early interventions (birth to 3 years) can yield developmental improvements.1 ASD impacts approximately 1 in 68 children in the US and is 4.5 times more common in boys (1 in 42) than girls (1 in 189).2 Vitamin D’s extraskeletal roles are numerous, including its role as a neurosteroid, impacting both brain development and connectivity, and likely synaptic plasticity as well.3 Vitamin D is also one of the most common micronutrient deficiencies. Previous research has revealed associations between gestational and early childhood vitamin D insufficiency and ASD.4 This suggests that hypovitaminosis D represents a modifiable risk factor for ASD.4 Furthermore, preliminary evidence demonstrates that gene variants related to vitamin D metabolism play a role in the pathophysiology of ASD.5 Robustly designed intervention trials have been scant. The first double-blind randomized controlled trial (RCT) utilizing vitamin D3 supplementation in children with ASD was published in The Journal of Child Psychology and Psychiatry in 2018.6 The study included 109 Egyptian children (85 boys; 24 girls) 3-10 years of age with confirmed ASD diagnosis. The children were randomized to receive vitamin D3drops (300 IU D3/kg/day; not to exceed 5,000 IU/day) or matching placebo drops daily for 4 months.6 Serum 25-hydroxyvitamin D (25[OH]D) levels were measured at baseline and 4-months. For ethical reasons, children who were identified to have vitamin D deficiency (25[OH]D <20ng/mL) were excluded from the study and administered vitamin D supplementation by the study authors.6 Autism symptoms were assessed using validated measures completed by two different psychologists and a senior psychiatrist.6 Four months of daily vitamin D3 supplementation at 300 IU/kg/day:6
Following 4 months of vitamin D3 supplementation, improvements (all p <0.05, most p <0.01; as compared to placebo) were demonstrated in many core manifestations of ASD, including:6
This rigorously designed RCT is the first of its kind to demonstrate safety and efficacy of vitamin D3supplementation in children with ASD.6 Two previous open-label vitamin D3 supplementation studies also demonstrated improvements in ASD symptoms.7-8 Wide-scale studies are warranted to continue to critically ascertain the effects of vitamin D on ASD. Why is this Clinically Relevant?
References
 Food first, but fill the gap: The case for vitamin D supplementation
Ashley Jordan Ferira, PhD, RDN If you can have a favorite nutrient, mine would be vitamin D. Historically famous for its essential, classical role in calcium and phosphorus homeostasis and bone physiology (think rickets prevention), the past few decades of research have unveiled diverse, extraskeletal health roles for vitamin D, including but not limited to the immune system, cardiometabolic pathophysiology, cancer, pregnancy, etc. Whether consuming vitamin D2 or D3 (FYI, the latter more potently impacts vitamin D status),1 vitamin D ultimately circulates in the 25-hydroxyvitamin D [25(OH)D] form (the clinical biomarker used to measure vitamin D status) and acts throughout the body as a pleiotropic hormone in its active form, 1,25-dihydroxyvitamin D [1,25(OH)2D]. Unlike other nutrients, this fat-soluble vitamin is obtainable via several unique routes: the skin with adequate UVB exposure, a handful of natural food sources, a few fortified foods, dietary supplements, and even prescription drugs. The problem is that few foods naturally contain vitamin D (e.g., egg yolk, certain fatty fish, fish liver oil, and certain species of UV-irradiated mushrooms), and fortified foods offer relatively small amounts (e.g., 100 IU vitamin D per 8 oz cup of fortified milk or orange juice),2 so vitamin D supplementation becomes a strategic solution. In the eloquent words of pediatrician and vitamin D researcher, Carol Wagner, MD: “Something so simple- vitamin D supplementation- could improve the health status of millions and so becomes an elegant solution to many of our health problems today.” If it’s possible to be defensive of a micronutrient, I am protective of vitamin D. Non-evidence-based rumors and negative media attention targeting vitamin D are common. Some of the misinformation is hype from anti-supplement camps who make broad, sweeping statements that lack scientific substantiation. But not all of the vitamin D myths originate from bias or lack of intellectual rigor. After all, who has time to keep up with the impressive, daily output of new vitamin D research? Clinicians certainly do not have the luxury of time, not in the current healthcare paradigm. Nevertheless, when inaccurate conclusions are propagated to patients about vitamin D and their health, that’s more harm than good. So, let me help out. This blog series explores some of the most common vitamin D myths. Let’s tackle just 1 myth today: Myth: I get enough vitamin D from food, so I don’t need a vitamin D supplement. Can you meet your vitamin D needs from food alone? Well, that depends on how you define “needs.” Let’s talk about the 2 major (and quite different) sets of vitamin D recommendations. First, the National Academy of Medicine (NAM), formerly known as the Institute of Medicine, provided vitamin D Recommended Dietary Allowances (RDAs) in 2010.3 Here’s how much vitamin D NAM says that we (Americans and Canadians) need based on bone health research (think rickets and osteomalacia prevention, calcium absorption, etc.):3
But I have a bone to pick (pun intended) with NAM’s vitamin D recommendations. I find them to be problematic, if not contradictory at times, for a few key reasons. To start with, the RDA is by definition “the average daily level of intake sufficient to meet the nutrient requirements of nearly all (97-98%) healthy people.”4 Well, that misses the unhealthy people. Since 2/3rd of the country are overweight or obese5 and heart disease and cancer are the #1 and #2 causes of mortality in the US, respectively,6 one can extrapolate that the vitamin D RDAs do not apply to a decent chunk of the gen pop. In fact, research indicates that overweight and obese individuals require more vitamin D than their lean counterparts,7 but the NAM recommendations fail to consider adiposity. Second, lumping a toddler and 68-year-old grandmother in the same RDA category (i.e., ages 1-70 years) seems to lack nuance. Skeletal health is critical throughout life, but you cannot tell me that the vitamin D needs for the rapidly accruing skeleton in childhood and adolescence are no different than an adult or older adult’s skeletal needs. Third, the RDAs for daily vitamin D intake are simply incongruent with the serum 25(OH)D cutoffs NAM also published in 2010. They provided the following 25(OH)D ranges:
The somewhat ironic problem is that the overly conservative vitamin D RDAs won’t get you into the 25(OH)D range that NAM defines for sufficiency. Regular UVB sun exposure (with adequate skin surface area, right latitude, right time of year, etc.) can raise serum D levels into sufficiency, except cutaneous vitamin D synthesis from sun is highly variable and limited for many. But 400-800 IU/day of vitamin D simply won’t do the trick. It’s like asking someone to fill up an 30-gallon fish tank and giving them a few cups of water to do the trick. In the sage words of the late Bob Heaney, MD: “We’ve been able to show that the (vitamin D) RDA barely budges the blood 25-hydroxyvitamin D level.”8 Thanks to Dr. Heaney, who made invaluable research contributions to the field of vitamin D, we know that 100 IU/day of vitamin D increases serum 25(OH)D concentrations by approximately 1 ng/mL.9That means that 1,000 IU/day of vitamin D would raise 25(OH)D by about 10 ng/mL. Although weight status, age, and the patient’s baseline vitamin D status can variably impact the supplementation response, this “rule of thumb” can be used to roughly calculate vitamin D supplementation needs. For example, let’s take a patient: me. I have limited UVB sun exposure and consume some foods that contain vitamin D (e.g., milk, eggs, salmon) but irregularly. My daily 5,000 IU vitamin D3 supplement has my serum 25(OH)D at 54 ng/mL. It stays between 50-60 ng/mL, which is in the sufficient range. But I’m an anomaly. Nationally representative research backs up the fact that Americans are not getting adequate vitamin D from their diets.10-11 First, 93% of Americans 2 years and older are failing to consume at least 400 IU/day of vitamin D from diet alone, and this estimate includes fortified food sources.10 Even when diet plus sun exposure are both thrown into the mix, about 1/3rd of the US population has serum 25(OH)D levels associated with vitamin D insufficiency or deficiency.11 For more details on vitamin D deficiency and why it persists, check out this blog. Dietitians (I am one) and other clinicians love to preach “food first.” That slogan is true but ignores research on key nutrient gaps. I prefer to say, “food first, then fill the gaps.” And in the case of vitamin D, the gap is practically guaranteed, except for the outlier patient who’s knocking back fish liver oils and irradiated mushrooms. Lastly, a more current and scientifically and clinically nuanced set of guidelines exist. One year after the NAM recommendations were released, several of the world’s leading vitamin D researchers convened to review the evidence to date, resulting in the 2011 publication: Evaluation, Treatment, and Prevention of Vitamin D Deficiency: An Endocrine Society Clinical Practice Guideline.12 The US Endocrine Society’s conclusions are harmonious with the mindset of a clinician, who is tasked with addressing the vitamin D needs of unique patients. The guideline recommends higher daily vitamin D levels than NAM, with a different and logical purpose in mind: Raising serum 25(OH)D levels into the sufficient range (≥ 30 ng/ml):12
The guidelines even differentiate vitamin D needs based on adiposity: Children and adults who are obese may need 2-3 times more vitamin D daily than normal-weight individuals.12 Finally, the US Endocrine Society provides clear guidance for correcting vitamin D deficiency in all age groups, with repletion and maintenance dosing information, which is a topic that I will cover in a future blog. Individual genetic differences for the vitamin D receptor (VDR) (i.e., gene polymorphisms like Cdx2, Apa1, Fok1, Taq1) are another important facet to weave into each patient’s unique vitamin D story, underscoring the prudence of a personalized lifestyle medicine approach to treat the individual. Takeaway: No, you cannot satisfy your vitamin D needs from food alone. If you plan to raise and maintain your serum 25(OH)D level (the biomarker that indicates vitamin D status) in the sufficient range for skeletal and extraskeletal health, that will require daily vitamin D supplementation. Remember, 30 ng/mL is not the goal. It’s the cutoff for insufficiency. Here’s a sneak peak at some of the additional vitamin D myths that will be covered in future blogs:
Do you have a question about the science and clinical application for vitamin D? Let me know by commenting below! References
Ashley Jordan Ferira, PhD, RDN is Manager of Medical Affairs and Metagenics Institute, where she specializes in nutrition and medical communications and education. Dr. Ferira’s previous industry and consulting experiences span nutrition product development, education, communications, and corporate wellness. Ashley completed her bachelor’s degree at the University of Pennsylvania and PhD in Foods & Nutrition at The University of Georgia, where she researched the role of vitamin D in pediatric cardiometabolic disease risk. Dr. Ferira is a Registered Dietitian Nutritionist (RDN) and has served in leadership roles across local and statewide dietetics, academic, industry, and nonprofit sectors. |
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