An extensive review and analysis of research studies proposes that over-the-counter vitamin D3 is preferred rather than prescribed forms of vitamin D2. Although, an excellent paper offering guidelines for clinicians suggests that either D2 or D3 is acceptable, provided supplementation is sufficient to adequately raise deficient levels of the vitamin.
In an ongoing series of Pain-Topics UPDATES [here], we have discussed the importance of adequate vitamin D for possibly preventing or ameliorating certain chronic pain conditions, particularly musculoskeletal pain, such as back aches. The question of which form of vitamin D supplementation is best for this purpose frequently arises and has been the subject of considerable debate and equivocal research findings.
Vitamin D3 Found to Reduce Mortality
Researchers conducted a Cochrane Systematic Review and Meta-analysis to asses the potential benefits of vitamin D for preventing death in adults [Bjelakovic et al. 2011]. They included all randomized controlled trials that compared vitamin D at any dose, duration, and route of administration versus placebo or no intervention. Vitamin D could have been administered as supplemental vitamin D3 (cholecalciferol) or vitamin D2 (ergocalciferol), or as an active metabolite of vitamin D, such as alfacalcidol or calcitriol.
The investigators discovered 50 trials for analysis, half of which were of good quality, with 94,148 participants in all trials. Most studies focused on elderly women (>70 years of age) who had been taking vitamin D for a median of 2 years. Overall, vitamin D in any form decreased mortality by about 3%; however, when the different forms of vitamin D were assessed separately, only vitamin D3 decreased mortality significantly, by 6% (this analysis included 74,789 participants in 32 trials; Relative Risk=0.94; 95% Confidence Interval, 0.91 to 0.98), whereas vitamin D2, alfacalcidol, or calcitriol did not significantly reduce deaths. Other findings of importance include:
- The NNT (number-needed-to-treat) for vitamin D3 was 161. That is, for every 161 persons treated with D3 one additional death was prevented in this population.
- Vitamin D3 combined with calcium increased the risk of nephrolithiasis (kidney stones) by 17% (RR=1.17, 95% CI 1.02 to 1.34). However, this combination did benefit survival in persons who also were calcium deficient, possibly due to fall/facture prevention.
- Supplementation with the active metabolite of vitamin D — alfacalcidol and calcitriol — had no significant effect on mortality but increased the risk of hypercalcemia (excessive calcium in the blood) by more than 200% (RR=3.18, 95% CI 1.17 to 8.68).
- Daily oral administration of vitamin D3 appeared to be more beneficial than weekly or monthly dosing of any vitamin D formulation.
The authors conclude that there is good evidence that vitamin D3 may significantly benefit survival of mainly elderly women living independently or in institutional care, who were likely to be vitamin D deficient and with significant risk of falls and fractures. These findings might generalize to all adults of any age but further research is needed as confirmation.
New Guideline Tells More About Vitamin D
We recommend a new research-review and guideline for practitioners and patients interested in the latest data and thinking on vitamin D. Writing in the Journal Clinical Endocrinology & Metabolism, Michael F. Holick, MD, and a Task Force of distinguished experts provide a comprehensive discussion of vitamin D and guidelines for clinicians on the evaluation, treatment, and prevention of its deficiency [Holick et al. 2011]. There is an emphasis on the care of patients who currently have or are at risk for deficiency [which might include a majority of persons in most clinical practices – ed], including discussions of vitamin D for certain pain conditions and to prevent falls/fractures in the elderly.
Considering that vitamin D deficiency is very common in all age groups and that few foods contain vitamin D, the Task Force recommends supplementation at daily intake and tolerable upper limit levels that are generally higher than those of the most recent IOM report on this subject [discussed in UPDATE here]. The Task Force also suggests the measurement of serum 25-hydroxyvitamin D (25[OH]D) levels by reliable assays as an initial diagnostic test in patients at risk for deficiency. At the present time, however, there is insufficient evidence to recommend screening all individuals who are not at risk for deficiency or to prescribe vitamin D to attain noncalcemic benefits for cardiovascular protection. In somewhat of a contradiction to the evidence cited above by Bjelakovic et al., treatment with either vitamin D3 or D2 is recommended for deficient patients.
If There is a Choice, Take D3
Bjelakovic et al. observe that some, but not all, clinical trials have found evidence that vitamin D3 increases serum 25(OH)D more efficiently than vitamin D2. One rationale is that the plasma half-life of vitamin D3 is longer and it has a higher affinity to the vitamin D binding protein, hepatic vitamin D hydroxylase, and vitamin D receptors. Furthermore, D3 is the only form of vitamin D produced naturally in our body (eg, historically from daily exposure to sunshine), while vitamin D2 can only be obtained from certain plant or mushroom sources in the diet. Additionally, some evidence suggests that vitamin D2 may upregulate several enzymes that degrade administered vitamin D2 and endogenous D3.
Availability of vitamin D3 and D2 supplements seems to vary worldwide. In the United States, D3 (cholecalciferol) is readily available and inexpensive over-the-counter. Whereas, various brands of supplemental, high-dose vitamin D2 (ergocalciferol) and active metabolites (1,25[OH]2D, alfacalcidol, calcitriol) are generally available only by prescription. Other countries have different practices and, from previous UPDATES-reader comments, it seems that access to vitamin D in any form and in significant doses can be difficult in some locales.
The review/analysis by Bjelakovic appears to support our contention that, if there is a choice, oral vitamin D3 taken daily would be preferred. Combinations with supplemental calcium probably should be avoided — to limit chances of nephrolithiasis or hypercalcemia — unless laboratory tests confirm insufficient calcium is being obtained from dietary sources.
In balance, we also must note that, in their guidelines, Hollick et al. recommend that adults who are vitamin D deficient could be prescribed 50,000 IU of vitamin D3 or D2 once a week for 8 weeks — or its equivalent of 6,000 IU D3 or D2 per day — to achieve a blood level of 25(OH)D >30 ng/mL. This would be followed by maintenance therapy of 1,500 to 2,000 IU/day, they write.
Neither of the articles mentioned above thoroughly discusses the vitamin D needs of persons with pain conditions. This has been considered more completely in our full 50-page report [PDF here] and in other UPDATES in this series [here]. Although, in most cases, our dosing recommendations have erred on the side of being conservative and individual patients with pain may benefit from either more or less vitamin D3 supplementation than indicated.
> Bjelakovic G, Gluud LL, Nikolova D, et al. Vitamin D supplementation for prevention of mortality in adults. Cochrane Database Syst Rev. 2011;6(7):CD007470 [abstract here].
> Holick MF, Binkley NC, Bischoff-Ferrari HA, et al. Evaluation, Treatment, and Prevention of Vitamin D Deficiency: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab (JCEM). 2011(Jul);96(7):1911-1930 [abstract here and free PDF here (temporarily)].