We have long advocated for the potential benefits of supplementation with vitamin D3, not D2, in persons with musculoskeletal pain. While some authors claim the formulation of vitamin D does not make that much difference, recent feedback from an UPDATES reader, plus a research summary by two experts, point toward D3 as the definite choice. In fact, prescribing D2 supplements should be reconsidered.
First, the letter, e-mailed to us from Susan Gray of Little Rock, Arkansas [name used with permission]:
“Dr. Leavitt, I have read your 50-page report on Vitamin D [PDF available here] several times and consider it an excellent reference. After almost 3 years of absolutely unbelievable pelvic/hip/thigh pain, I finally found a doctor who checked my blood level of vitamin D. I thought this would be waste of time, as I was regularly taking about 1800-2000 IU/day in supplements plus drinking milk, eating yogurt, etc. It turned out that my vitamin D blood level was 29 ng/mL. This doctor said he sees plenty of people who are deficient and in pain, as well as many who are also in pain when their blood levels seem normal. He likes to get people to about the 75 ng/mL level of vitamin D [measured as 25(OH)D].”
“He prescribed for me vitamin D2 at 100,000 IU/week for 8 weeks and the pain reduction was remarkable. Then he put me on vitamin D3, 2000 IU/day for maintenance. Over the next 8 weeks, the pain returned, so I dug out my remaining D2 prescription and began taking those again. However, the pain just got worse and, after another 6 weeks, I was in agony.”
“I did some homework and learned that D2 doesn't have anywhere near the shelf-life that D3 has. The old D2 I was taking probably was worthless, and I was in worse shape than ever. I began a regimen of vitamin D3 4000 IU/day and the pain went away again, so I have maintained that ever since. I tried once to reduce the maintenance dose to 2500-3000 IU/day of D3, but noticed the pain returning. I’ve had my blood levels of vitamin D checked several times since and have remained between 60 and 80 ng/mL.”
“So, three big things I've learned from this and want share: 1) some people need more than 2000 IU/day of D3 for proper maintenance, 2) patients should not keep their old high-dose D2 and revert back to it if necessary, it may have gone bad, and 3) don't listen to the vitamin D recommendations of the Institute of Medicine [discussed in UPDATE here] regarding daily doses of Vitamin D, especially when it comes to pain.”
This letter arrived soon after we wrote a recent UPDATE [here] on vitamin D, suggesting that D3 is preferred over D2; although, some authors are still saying the two forms are equivalent if properly dosed. We also noted that our original recommendation of 2000+ IU/day of D3 in persons with pain might be overly conservative; however, for many persons there might be concerns about nephrolithiasis (kidney stones) or hypercalcemia at high doses on a regular basis.
We looked into this further and discovered a very important article published in 2006, titled “The case against ergocalciferol (vitamin D2) as a vitamin supplement” [Houghton and Vieth 2006]. Writing in the American Journal of Clinical Nutrition, the authors (both distinguished experts in the field) carefully review available research and note that vitamin D3 has proven to be the more potent form of vitamin D in all primate species, including humans.
They observe that vitamin D2, if given in high enough doses, does prevent infantile rickets and is capable of healing adult osteomalacia; however, the superiority of vitamin D3 over D2 at increasing 25(OH)D levels is now well documented. As for the stability and toxicity of D2 compared with D3, they state the following…
“Synthetic production of vitamin D3 is manufactured in a similar manner to that which occurs naturally in human and animal skin, via the production of 7-dehydrocholesterol from cholesterol and subsequent irradiation to its active D3 form. Conversely, vitamin D2 is synthetically produced from irradiation of ergosterol derived from the mold ergot. In addition to its lower bioactivity, the poor stability of vitamin D2 is worrisome, particularly upon exposure of crystalline D2 powder to varying temperatures, humidity, or even storage containers. In contrast, vitamin D3 powder is not as labile. As a result, the vitamin D content by various manufacturers has been found to differ substantially from that of the labeled claim. …. The poorer stability of and greater impurities in vitamin D2 powders may also lead to a higher risk of toxicity than that associated with the vitamin D3 metabolites.”
Houghton and Vieth  further observe that, despite an emerging body of evidence suggesting the greater efficacy of vitamin D3, prescription formulations of vitamin D in North America are the D2 form. Reasons for this are unclear; however, the mere fact that D2 is indeed a prescription product, whereas D3 is readily available over-the-counter (OTC) or by mail order (at least in the U.S.), may lead practitioners to rely on prescribed high-dose D2 to correct vitamin D deficiency.
For one thing, many patients expect practitioners to provide written prescriptions for medicinal products, rather than advice to merely purchase inexpensive OTC versions on their own. Secondly, there is a perception that prescription products are of higher quality and purity, which might have some merit since some brands of OTC vitamin products (and especially those available via the Internet from unfamiliar sources) could be of uncertain dosage and quality.
Still, Houghton and Vieth  point out that prescribed vitamin D2 may not have the potency and half-life that practitioners think it does. They comment on research that found high-dose D2 raised the serum levels of 25(OH)D rapidly during the first few days but concentrations then fell toward baseline by day 14 and were below baseline by day 28. Whereas, comparable dosing with D3 produced a steady rise in 25(OH)D that peaked by day 14 and remained above baseline at 28 days. Further analyses showed a 3-fold greater potency of vitamin D3, such that 50,000 IU D2 should be considered equivalent to 15,000 IU D3, and likely closer to only 5000 IU D3.
Further complicating the clinical picture, Houghton and Vieth propose that the production of 25(OH)D2 resulting from D2 supplementation hampers the accurate laboratory assessment of total circulating 25(OH)D. They state, “common assay systems used for clinical purposes have either a diminished capacity or do not detect 25(OH)D2 with the same efficiency as 25(OH)D3.” Therefore, with D2 supplementation, laboratory tests might yield an erroneous underestimation of actual vitamin D status, which may lead to excessive high-dose D2 supplementation and potentially adverse consequences, such as hypercalcemia.
While a single research review, such as this by Houghton and Vieth, might not be the last word on this subject, the authors clearly conclude that “vitamin D2 should no longer be regarded as a nutrient appropriate for supplementation or fortification of foods.” And, it raises important points for further consideration:
- Past research on vitamin D for pain conditions might have been biased by using D2 rather than D3, resulting in inaccurate 25(OH)D assessments and understated trial outcomes. This should be taken into account when examining prior research studies and designing new ones.
- When vitamin D2 is prescribed, should there be concerns about limited shelf-life of the product affecting potency, and can followup laboratory tests for 25(OH)D levels be trusted as accurate?
- In view of the concerns, there is a question as to whether healthcare providers should continue prescribing high-dose vitamin D2 — such as 50,000 or 100,000 once weekly — to correct inadequacies of 25(OH)D, or should readily available vitamin D3 supplements be considered instead? Various dosages of D3 are commercially available without prescription via many retail and online outlets, including 400, 1000, 2500, 5000, 10,000, 25,000 and even 50,000 IU tablets and gel capsules.
- Considering the many available dosage formulations of D3, is it really necessary to start patients on once-weekly high doses (eg, 50,000 IU) for a period of time? Or, would it be just as effective, and possibly more biologically sound, to have patients start with, say, 5,000 IU D3 daily and later taper up or down as necessary to achieve desired 25(OH)D levels and pain relief?
At the least, when vitamin D supplementation is prescribed or recommended for patients, there should be a discussion about the potential harms of self-treating with OTC products without medical consultation. For example, a patient who was previously treated with prescribed 50,000 IU D2 might later take it upon themselves to self-treat with store-bought 50,000 IU D3 tablets that are unknowingly of considerably greater potency. It also might be appropriate for practitioners to identify sources of vitamin D3 supplements in their locales, or from online outlets, that they believe are of good quality and reasonable cost for recommending to patients.
REFERENCE: Houghton LA, Vieth R. The case against ergocalciferol (vitamin D2) as a vitamin supplement. Am J Clin Nutr. 2006;84(4):694-697 [access full article here].