Vitamin D2 Is Much Less Effective than Vitamin D3 in Humans

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For those wanting the more scientific explanation, here is a journal study. (The

Journal of Clinical Endocrinology and Metabolism)

http://jcem.endojournals.org/cgi/content/full/89/11/5387

Vitamin D2 Is Much Less Effective than Vitamin D3 in Humans

A. G. Armas, Bruce W. Hollis and P. Heaney

Creighton University (L.A.G.A., R.P.H.), Omaha, Nebraska 68131; and Medical

University of South Carolina (B.W.H.), ton, South Carolina 29425

Address all correspondence and requests for reprints to: P. Heaney, M.D.,

Creighton University, 601 North 30th Street, Suite 4841, Omaha, Nebraska 68131.

E-mail: rheaney@....

Abstract

Top

Abstract

Introduction

Subjects and Methods

Results

Discussion

References

Vitamins D2 and D3 are generally considered to be equivalent in humans.

Nevertheless, physicians commonly report equivocal responses to seemingly large

doses of the only high-dose calciferol (vitamin D2) available in the U.S.

market.

The relative potencies of vitamins D2 and D3 were evaluated by administering

single doses of 50,000 IU of the respective calciferols to 20 healthy male

volunteers, following the time course of serum vitamin D and 25-hydroxyvitamin D

(25OHD) over a period of 28 d and measuring the area under the curve of the rise

in 25OHD above baseline.

The two calciferols produced similar rises in serum concentration of the

administered vitamin, indicating equivalent absorption. Both produced similar

initial rises in serum 25OHD over the first 3 d, but 25OHD continued to rise in

the D3-treated subjects, peaking at 14 d, whereas serum 25OHD fell rapidly in

the D2-treated subjects and was not different from baseline at 14 d. Area under

the curve (AUC) to d 28 was 60.2 ng·d/ml (150.5 nmol·d/liter) for vitamin D2 and

204.7 (511.8) for vitamin D3 (P < 0.002). Calculated AUCindicated an even

greater differential, with the relative potencies for D3:D2 being 9.5:1.

Vitamin D2 potency is less than one third that of vitamin D3. Physicians

resorting to use of vitamin D2 should be aware of its markedly lower potency and

shorter duration of action relative to vitamin D3.

Introduction

Top

Abstract

Introduction

Subjects and Methods

Results

Discussion

References

VITAMIN D DEFICIENCY IS a common problem, especially in older and sick

individuals (1, 2). Because most people get most of their vitamin D from sun

exposure (3) with a small amount obtained from food and supplements, those at

risk for vitamin D deficiency are those with little sun exposure and/or poor

dietary intake. Older people are especially at risk because aging lowers the

amount of 7-dehydrocholesterol in the skin and the capacity for vitamin D

production (4).

Hypovitaminosis D is associated with increased PTH secretion, increased bone

turnover, osteoporosis, histological osteomalacia and increased risk of hip and

other fractures (5, 6), and, in its most severe expression, clinical

osteomalacia (5). Vitamin D deficiency is increasingly being recognized by

clinicians and treated, but the treatment guidelines are unclear and available

preparations limited. The current adult vitamin D intake recommendation from the

Food and Nutrition Board (7) is 200 IU/d up to age 50, 400 IU up to age 70, and

600 IU thereafter. However, it now appears that, if total input were confined to

these amounts, only the most severe degrees of vitamin D deficiency would be

prevented (3). In any event, these recommendations apply to both ergocalciferol

(vitamin D2) and cholecalciferol (vitamin D3).

Since the 1930s it has been generally assumed that vitamin D2 and vitamin D3 are

equally effective in humans. This conclusion was based mainly on anti-rachitic

bioassays. With acceptance of serum 25-hydroxyvitamin D concentration as the

appropriate functional indicator of vitamin D status (7), it has become

important to reevaluate this assumption of equivalence. Only a few studies have

directly compared vitamins D2 and D3 using contemporary analytic methods. The

limited evidence available indicates that vitamin D3 is substantially more

efficacious than vitamin D2 (8, 9).

Because ergocalciferol is the only high-dose calciferol on the U.S. market,

patients who are severely vitamin D deficient have usually been treated in the

U.S. with this form of the vitamin, in a dose of 50,000 IU orally or (in the

past) im. Dosing frequencies have varied from one or three times weekly to once

every 2 months. Physicians frequently find that such a regimen produces little

or no change in serum 25-hydroxyvitamin D (25OHD) concentrations (10). Whether

this is because of disease-related abnormalities of vitamin D metabolism in such

patients, because of problems with the assay measuring serum 25OHD, or because

of nonequivalence of ergocalciferol and cholecalciferol (vitamin D3) has been

unclear. Our sole purpose in this study was to evaluate the relative potency of

the two calciferols using research-level assay methods.

Subjects and Methods

Top

Abstract

Introduction

Subjects and Methods

Results

Discussion

References

Subjects

The subjects were 30 men, between ages 20 and 61, in good general health, who

habitually consumed less than 16 oz of milk per day and had less than 10 h of

sun exposure per week. We excluded those with granulomatous conditions, liver

disease, kidney disease, or diabetes and those taking anticonvulsants,

barbiturates, or steroids in any form. (There were four subjects who took a

multivitamin occasionally, averaging one time per week. They agreed to stop

taking this supplement 1 wk before and throughout the study.) Mean (± SD) age

was 33.06 ± 11.47, weight was 89.36 ± 11.59 kg, and body mass index was 27.14 ±

2.77 kg/m2. All subjects were from Omaha, Nebraska, and surrounding communities.

The project was approved by the Institutional Review Board of Creighton

University, and all subjects gave written informed consent.

Design

The project was conducted during the month of July, 2003. Subjects were randomly

assigned to receive 1) no supplement (the seasonal effect, control group), 2)

one tablet labeled to contain 50,000 IU (1.25 mg) ergocalciferol (the vitamin D2

group), or 3) 10 tablets labeled to contain 5,000 IU (125 µg)/tablet

cholecalciferol (the vitamin D3 group). Because the vitamin D3 preparation was

not a marketed product, we asked the supplier to provide a certificate of

analysis. [The 50,000-IU D2 tablet preparation was supplied by Sidmak

Laboratories, Inc. (High Point, NC). The 5,000-IU D3 tablet preparation was

supplied by Tishcon Corp. (Salisbury, MD). The product was assayed on June 12,

2003, and found to contain 5,513 IU/capsule.]

For the control group receiving no vitamin D supplement, serum samples were

obtained at d 0 and 28, so as to quantify the midsummer rise in 25OHD that would

be expected in all groups. For the two groups receiving a vitamin D supplement,

serum samples were obtained at d 0, 1, 3, 5–7, 14, and 28. At the initial visit,

each subject's weight and height were measured. Height was measured using a

Harpenden stadiometer (Seritex, Inc., Carlstadt, NJ). Blood was obtained for

measurement of serum vitamin D and 25OHD. After the baseline blood was obtained,

the subjects were observed while they took the assigned vitamin D supplement

dose. At each subsequent visit, the subject's weight was measured and blood

obtained for measurement of serum vitamin D and 25OHD. The subjects were asked

to recall their sun exposure since the previous visit. The subjects were given

supplies of sun block lotion, sun protection factor (SPF) 15, to use during

out-of-the-ordinary sun exposure.

Analytical methods

Serum ergo- and cholecalciferol concentrations were determined by reversed-phase

HPLC, as described elsewhere (11). Serum 25OHD was determined by RIA, using the

IDS kit (Nichols Institute, San Clemente, CA). Because it has been reported (12)

that the antibody in this kit reacts poorly with 25OHD2, we measured the samples

from the vitamin D2-treated subjects using both the IDS and the DiaSorin kits

(DiaSorin, Stillwater, MN). However, in this group of subjects, there were no

significant differences in analyzed 25OHD increments above baseline between the

values produced by the two antibodies. Hence, for the values in the D2-treated

participants that we report here, we averaged the results obtained with the two

RIAs. Finally, to be certain that the RIAs were adequately detecting both 25OHD2

and 25OHD3, aliquots of the serum samples obtained at 0, 3, and 28 d were

assayed by HPLC (10) for both 25OHD2 and 25OHD3. The mean increment in total

25OHD by HPLC at 3 and 28 d was virtually identical with the mean increment

measured by RIA.

Statistical methods

The 25OHD signal produced by the 50,000-IU calciferol dose was analyzed as the

increment in total 25OHD concentration above baseline, adjusted for the mean

rise in serum 25OHD observed in the untreated controls (0.259 nmol/liter·d).

Area under the curve (AUC) of serum 25OHD increments at 14 and 28 d was

calculated by the trapezoidal method individually for each subject. AUC was

calculated using pharmacokinetic, biexponential models (PK Solutions, Summit

Research Services, Ashland, OH) fitted to the mean 25OHD values at each time

point. Mean values for AUC14 and AUC28 for the two calciferols were compared by

the usual t test for independent samples.

Results

Top

Abstract

Introduction

Subjects and Methods

Results

Discussion

References

Serum calciferol concentrations were measured at d 0, 1, and 3. The results are

shown in Fig. 1. Baseline values of both calciferols were low, with the D3

concentration higher than the D2, as would be expected. However, the rise by d 1

was essentially identical for both calciferols, and at d 3 the serum levels of

the two had fallen close to baseline and were virtually identical. This behavior

indicates that absorption of the two calciferols was approximately equivalent.

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FIG. 1. Time course of serum concentrations of vitamin D after a single oral

dose of 50,000 IU of cholecalciferol (vitamin D3) or ergocalciferol (vitamin

D2,) in healthy male subjects (n = 10 for each group). The error bars are 1 SEM.

[Copyright P. Heaney, 2004. Used with permission.]

The time course for the increment in serum 25OHD is shown in Fig. 2, which

presents the mean changes in values at each visit for total 25OHD (i.e. the sum

of 25OHD2 and 25OHD3). These values were corrected for the change we measured in

25OHD levels in our control population because of summer sun exposure. Both

vitamin D2 and vitamin D3 produced initial rises in 25OHD levels during the

first 3 d that did not differ significantly from one another. The mean 25OHD

concentration in the D2-treated subjects then began to fall until, by d 14, it

was not different from baseline. By contrast, 25OHD concentration in the

D3-treated subjects continued to rise through d 14 and by d 28 was still higher

than the peak value for the D2-treated group.

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FIG. 2. Time course of the rise in serum 25OHD after a single oral dose of

50,000 IU of either cholecalciferol (vitamin D3) or ergocalciferol (vitamin D2)

to two groups of 10 normal men each. Error bars are 1 SEM. The zero-change line

incorporates a correction for the seasonal rise in 25OHD occurring at the time

this study was performed. (To convert from nmol/liter to ng/ml, multiply by

0.4.) [Copyright P. Heaney, 2004. Used with permission.]

The best measure of total exposure of the organism to an administered agent is

given by AUC of the serum concentration against time. Here the greater potency

of D3 was dramatically evident. AUC28 was 60.2 ± 23.4 ng·d/ml (150.5 ± 58.5

nmol·d/liter) for D2 and 204.7 ± 32.4 ng·d/ml (511.8 ± 80.9 nmol·dl) for D3 (P <

0.002). This is a more than 3-fold difference in potency. AUC is actually the

preferable pharmacokinetic measure of total exposure, and if AUC is used

instead, the values for D2 and D3 are, respectively, 112.8 and 1072.8 ng·d/ml

(282 and 2682 nmol·d/liter), for a nearly 10-fold difference in potency.

Because, as it turned out, 28 d was not long enough to get a firm estimate of

the elimination phase in the D3-treated subjects, the AUC for D3 must be

considered uncertain. In any event, it is clear that the AUC28 values understate

the contrast and that the potency difference must lie somewhere between 3- and

perhaps 10-fold.

An initially unanticipated finding was the decline in 25OHD3 concentration in

the ergocalciferol-treated men, as shown by HPLC (Fig. 3). Whereas 25OHD3 in the

untreated control group rose by 3 ng/ml (7.5 nmol/liter), presumably because of

ongoing sun exposure, the vitamin D2-treated group experienced a fall in 25OHD3

of nearly 4 ng/ml (10 nmol/liter) (P < 0.01).

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FIG. 3. Changes in serum 25OHD3 in the subjects treated with vitamin D2 and in

those in the untreated control group over the 28 d of follow-up after a single

oral dose of 50,000 IU vitamin D2. The error bars are 1 SEM. The mean 28-d value

in the D2-treated subjects was significantly lower than both their own baseline

values and the corresponding values in the control group (which exhibited the

expected summer rise in serum 25OHD). (To convert from nmol/liter to ng/ml,

multiply by 0.4.) [Copyright P. Heaney, 2004. Used with permission.]

Discussion

Top

Abstract

Introduction

Subjects and Methods

Results

Discussion

References

To our knowledge, this is the first study comparing vitamins D3 and D2 by

mapping the time course of serum 25OHD after a single dose. We showed that

vitamin D3 raises and maintains 25OHD levels to a substantially greater degree

than does vitamin D2, with a differential potency of at least 3-fold, and more

likely closer to 10-fold.

The two treated groups had the same baseline 25OHD levels. With the dose of

50,000 IU of vitamin D2 and vitamin D3, the respective vitamin D levels rose in

parallel, showing that both forms of vitamin D were absorbed comparably. And the

rise in serum 25OHD was virtually the same for the first 3 d of the study for

both vitamins D2 and D3, indicating comparable conversion to the 25-hydroxy

metabolite. The much more rapid decline of serum 25OHD in the vitamin D2-treated

subjects after 3 d would seem to reflect substantially more rapid metabolism or

clearance of the vitamin D2 metabolite. Other studies (13, 14) have suggested

either differences in affinity of the vitamin D-binding protein (DBP) for the

two calciferols or higher affinity of the hepatic 25-hydroxylase for vitamin D3

than vitamin D2. The latter seems improbable from our data, because the initial

rise in 25OHD concentration was the same for the two calciferols. The former

offers a more plausible explanation. 25OHD2 has been shown to have a lesser

affinity for DBP than does 25OHD3 (15), which would result in a shorter

circulating half-life for 25OHD2 vs. 25OHD3. The relative binding of vitamin D

and its metabolites to DBP determines the circulating half-lives of these

substances (16). [That is why vitamin D and 1,25(OH)2D possess much shorter

circulating half-lives than 25OHD (17). Similarly, the reason birds cannot use

vitamin D2 as a feed supplement is because 25OHD2 will not bind to the avian DBP

and is thus rapidly eliminated from the circulation (18).]

This study complements the findings of Trang et al. (9) who, using daily dosing

of 4000 IU for 2 wk, reported an increase in 25OHD 70% greater with vitamin D3

than for vitamin D2. (After adjustment for concomitant changes in the control

group, the difference between the two groups can be shown to have been

approximately 2-fold.) The reason for the larger differential found in our study

is unclear. In any case, both studies show that there is a substantial

difference in serum 25OHD achieved by the same dose of the two calciferols.

There can be little doubt that the demonstrated lower potency of vitamin D2 is

physiologically/pharmacologically meaningful. Serum 25OHD is the recognized

functional status indicator for vitamin D nutrition (7). Recent studies have

shown that raising serum 25OHD improves calcium absorption (19), reduces fall

frequency (20), and lowers osteoporotic fracture risk (6). Furthermore, lower

extremity muscle function improves across virtually the entire range of

prevailing serum 25OHD concentrations (21).

It would be desirable to have long-term dosing data as well, because such

information would more closely approximate the situation of actual treatment.

However, such information would serve only to define more precisely the

magnitude of the difference. It would not be expected to alter the finding of a

substantial differential in potency between the two calciferols, because by

standard pharmacokinetics, the concentration achieved by multiple doses of a

short half-life substance is virtually always lower than the concentration

achieved by comparable doses with a long half-life compound. Continuous dosing

studies would need to be of several months' duration because Heaney et al. (3)

have shown, at least for vitamin D3, that time to equilibrium is approximately 5

months. At 14 d of continuous dosing, Tjelleson et al. (8) found a potency

difference of nearly three times, which, for the reason just given, must

understate the differential.

The fall in 25OHD3 that we observed in the D2-treated subjects has been reported

previously. Using a design similar to that of Trang et al. (9), Tjellesen et al.

(8) described a nearly 70% drop in 25OHD3 in subjects treated for 2 wk with 4000

IU/d of vitamin D2. This fall may reflect either competition by D2 for the

25-hydroxylase or increased metabolic degradation of 25OHD3 by the mechanisms

up-regulated to metabolize vitamin D2 and its metabolites (or both).

It is worth noting in passing that our subjects were all healthy young men with

some sun exposure (not homebound as a nursing home resident or elderly person

might be). Their mean baseline 25OHD level was 31.7 ng/ml ± 8.45 (79.19

nmol/liter ± 21.13), nearly at the optimal level of 32 ng/ml (80 nmol/liter) or

higher [where calcium absorption plateaus and PTH levels become minimal (22)].

Even so, individual baseline 25OHD levels ranged from 15.2–58.7 ng/ml

(37.9–146.8 nmol/liter). Thus, approximately half of the subjects, who would not

usually be considered at risk for vitamin D deficiency, nevertheless exhibited

suboptimal vitamin D status during the summer. Presumably, their vitamin D

levels would be even lower at midwinter. The finding of suboptimal vitamin D

levels in those without obvious risk is consistent with other studies that

report high prevalence of vitamin D deficiency in general medicine patients at

no particular risk for vitamin D deficiency (23).

It is important to note that even in those subjects with high baseline serum

25OHD values, one large dose of vitamin D3 produces serum 25OHD values well

within the safe range of 25OHD [i.e. <88 ng/ml (220 nmol/liter) (1)]. The mean

rise was only approximately 7 ng/ml (18 nmol/liter), and the highest observed

25OHD rise was 10.4 ng/ml (26 nmol/liter); the latter produced a value of 69.2

ng/ml (173 nmol/liter) and occurred in the subject with the highest starting

value.

As the medical community is becoming more aware of vitamin D deficiency and its

effects, both on bones and other body tissues (24, 25, 26), there will be more

testing of vitamin D levels and interest in treating the deficiency. The goal

should be standardized methods of testing and clear recommendations on the level

of 25OHD that should be achieved and what form of vitamin D to use, in what

amount, and how often (27).

This study addresses some of these issues. Clearly, vitamin D3 is the preferable

form of vitamin D. This is in contrast to the long-held belief that vitamin D2

and vitamin D3 are seen by the body as identical. This nonequivalence makes

sense, because the two calciferols are known not to be equivalent in other

species, and vitamin D3 is the form that animals make in response to sunlight.

There are several barriers to the clinician in treating vitamin D-deficient

patients. Most published studies were performed using vitamin D3, and

application of their results to patients using vitamin D2 is not easily

possible, as we have shown here. This is not to suggest that vitamin D2, in the

50,000-IU dosage form, is not efficacious in treating severe vitamin D

deficiency. A large body of experience indicates that it can be quite effective.

But, as the unitage of the two forms of the vitamin is clearly not equivalent,

thinking about dosing must be adjusted to match the product used. The data

presented in this paper indicate that the 50,000-IU dosage form of vitamin D2

should be considered to be equivalent to no more than 15,000 IU of vitamin D3

and perhaps closer to only 5,000 IU. In any event, the tolerable upper intake

level, 2,000 IU/d, published for vitamin D3 (7), and already judged to be set

too low (3), ought not be applied to vitamin D2.

Another barrier is the lack of a high-potency therapeutic vitamin D3 preparation

in the United States. In Europe, several high-potency preparations are

available, some used for " stoss " therapy in clinical trials (6, 28, 29). With

the vitamin D3 that is available mainly by special order in the United States,

it would require 25–50 pills (of 1,000 or 2,000 IU each) to achieve a 50,000-IU

dose, a regimen that would not be practical or acceptable to most patients.

More needs to be done both to standardize methods of testing 25OHD and to

provide a high-potency vitamin D3 preparation available for clinical use (27).

Additional studies are also needed to establish optimal dosing recommendations.

Footnotes

This work was supported by research funds of Creighton University and the

Medical University of South Carolina.

Abbreviations: AUC, Area under the curve; DBP, vitamin D-binding protein; 25OHD,

25-hydroxyvitamin D.

Received February 25, 2004.

Accepted August 13, 2004.

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Abstract

Introduction

Subjects and Methods

Results

Discussion

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