Thursday, February 28, 2013

Winter 2013: Vitamin D & Pain Research Roundup

Vitamin D ResearchTherapeutic effects of vitamin D supplementation continue to be a research subject of intense interest. Recent studies investigated possible benefits of vitamin D for painful colitis and in bone fracture prevention. Additional research trials examined whether brief daily exposure to the sun is sufficient for synthesizing adequate vitamin D, or whether periodic megadoses of oral or injected supplements would be better. Some results are surprising.

Low Vitamin D & Painful Colitis Linked

Researchers from the University of Pennsylvania, Philadelphia, PA, conducted a cross-sectional study to examine the relationship between vitamin D levels and clinical disease activity in patients with ulcerative colitis [Blanck and Aberra 2013]. According to background information — which appeared in an early online edition of the journal Digestive Diseases and Sciences — inflammatory bowel diseases (IBD) are chronic, inflammatory, autoimmune disorders of the gastrointestinal tract, and prior research has suggested a role of vitamin D in affecting disease severity.

There are two different forms, Crohn’s disease and ulcerative colitis. IBD affects significant numbers of persons globally; in the United States, an estimated 436,000 persons have Crohn’s disease and 512,000 have ulcerative colitis, with a lower prevalence in southern states compared with other parts of the country.

The researchers examined 34 patients with an ulcerative colitis diagnosis; 53% female, mean age 46 years. Study results indicated that 15 patients had normal vitamin D levels and 19 were deficient; that is, with serum 25(OH)D < 30 ng/mL, including 12 with 25(OH)D <20 ng/mL. Vitamin D-deficient patients were statistically more likely to have increased disease activity than patients with normal levels (P=0.04), with 68% of deficient patients displaying active disease compared with only a third (33%) in the sufficient group.

There was also a statistically significant association between vitamin D status and the need for treatment with steroid medications, with a higher percentage of vitamin D-deficient patients (47%) requiring such treatment compared with only 7% in the sufficient group (P=0.02). There was no association between season of visit and disease activity.

CONCLUSION/COMMENTARY: The researchers conclude that vitamin D deficiency is common among patients with active ulcerative colitis, particularly those requiring corticosteroids. However, further investigation is needed to determine the clinical utility of vitamin D monitoring in these patients and whether there is a role for vitamin D supplementation as a treatment for the condition.

It should be noted that this was a small, underpowered, nonrandomized, observational study. Cause-effect relationships cannot be assumed and much larger trials are needed to define a possible role of vitamin D.

Still, in an article [here] about this study, John Cannell, MD, founder of the Vitamin D Council, observes it is likely that ulcerative colitis (UC) may be another autoimmune disorder that vitamin D supplementation may help. “As it can be a serious disease,” he says, “I recommend adults with UC, keep their 25(OH)D in the high natural range, about 70-80 ng/mL, and that may require 10,000 IU/day of vitamin D3 [emphasis added]. I recommend higher natural levels and doses of vitamin D in those who have a serious illness linked to vitamin D for simple common sense reasons: higher doses are safe and they may help more than lower doses.”

Cannell, who has specialized in studying and writing about vitamin D for many years, has consistently advocated for daily vitamin D3 supplement doses and 25(OH)D levels that are much higher than most guidelines or studies recommend, or would be comfortable for most practitioners to prescribe for their patients. At the same time, however, research is lagging far behind in providing definitive guidance when it comes to dosing and serum levels of vitamin D that are optimal for persons with painful conditions of any type.

REFERENCE: Blanck S, Aberra F. Vitamin D Deficiency Is Associated with Ulcerative Colitis Disease Activity. Dig Dis Sci. 2013(Jan); epub ahead of print [abstract].


Vitamin D/Calcium Not Recommended for Fracture Prevention?

A newly published recommendation statement from the U.S. Preventive Services Task Force (USPSTF) concludes that there is insufficient evidence to support the use of vitamin D and calcium supplements to prevent fractures among community-dwelling men and premenopausal women [Moyer et al. 2013]. Concurrently, the task force recommends against daily vitamin D and calcium supplementation as beneficial in preventing fractures in postmenopausal women.

For reaching its conclusions, the USPSTF performed 2 systemic reviews and a meta-analysis of the effects of vitamin D supplementation with or without calcium on bone health among community-dwelling adults. In pooled trials, vitamin D and calcium supplementation had no effect on the frequency of bone fractures (pooled Relative Risk [RR]=0.89; 95% Confidence Interval [CI], 0.76–1.04). Furthermore, there was no significant evidence of an effect of vitamin D alone on fracture risk (pooled RR=1.03; 95% CI, 0.84–1.26).

A meta-analysis of persons ≥65 years of age determined that fracture risk may be reduced by supplementation with higher doses of vitamin D (≥800 IU daily), but these effects were not significant in subgroup analyses. One large trial — the Women's Health Initiative (WHI), including 36,282 healthy postmenopausal women — reported a slightly increased risk for nephrolithiasis (ie, kidney stones) associated with vitamin D and calcium supplementation (Hazard Ratio=1.17; 95% CI, 1.02–1.34), with a NNH (number needed to harm) of 273, but the magnitude of this harm was considered small by the USPSTF.

COMMENTARY: The USPSTF’s cautious approach, based on a lack of ample high-quality evidence, seems understandable; however, further research is needed on this issue of vitamin D and fracture prevention. There are still many fundamental questions regarding benefits versus risks of vitamin D gained via sun exposure, food fortification, or daily supplements, as well as the hormone’s many roles in body function beyond bone mineralization.

For most individuals there is some question as to the prudence of calcium supplementation along with vitamin D, unless the person is assessed as being calcium deficient. Additionally, few studies have examined beneficial effects of high-dose supplementation to achieve serum 25(OH)D well above 30 ng/mL that some authorities consider more optimal (see Cannell note above).

For example, the USPSTF found that doses ≥800 IU D3/day did reduce fracture risk in select patients. This raises the question of what might be achieved via 2,000 or 4,000 IU D3/day and/or 25(OH)D3 levels in the ±50 ng/mL range — but this has not been adequately tested in clinical trials.

In its statement — which appeared in a prepublication edition of the Annals of Internal Medicine — the task force concedes that physicians should use more than evidence alone in their decision-making. “Clinicians should understand the evidence but individualize decision making to the specific patient or situation,” the authors note. Similarly, they suggest that policy and insurance coverage decisions should involve considerations in addition to the currently available evidence of clinical benefits and harms. Finally, the recommendations apply to noninstitutionalized or community-dwelling asymptomatic adults without a history of fractures, and they do not apply to persons with osteoporosis or vitamin D deficiency (which may encompass a vast majority of older adults).

REFERENCE: Moyer VA on behalf of the U.S. Preventive Services Task Force. Vitamin D and Calcium Supplementation to Prevent Fractures in Adults: U.S. Preventive Services Task Force Recommendation Statement. Ann Intern Med. 2013(Feb); online ahead of print [article here].


Is Vitamin D from Brief Sun Exposure Sufficient?

Some authors have suggested that the body can make the vitamin D it needs from relatively brief sun exposure on a regular basis. Is this true?

To find out, researchers from the Ajou University School of Medicine in South Korea studied the effect of brief sun exposure on vitamin D levels in 20 young women for 4 weeks [Lee et al. 2012]. The women were volunteers, without a condition that might influence vitamin D status, such as chronic liver or renal disease or hypo/hyper-parathyroidism, or use of vitamin D supplements due to osteoporosis or osteomalacia.

The study was conducted between October and November at latitude 37 degrees north, about the latitude of San Francisco, Washington DC, Lisbon, or Tehran. The women were told to get 20 minutes of midday sun (noon-1pm) exposure on their hands, forearms, and faces every weekday for 4 weeks. During the trial period, subjects were instructed not to take vitamin D supplements or eat foods rich in the vitamin.

Initially, all of the women had deficient vitamin D levels: average serum 25(OH)D was ≈11 ng/mL and no woman had levels greater than 20 ng/mL to begin the study. However, after a month of daily sun exposure 25(OH)D levels did not increase significantly at all; mean change pre- and post-exposure was merely +0.62 ng/mL. In fact, overall, there was a negative correlation between mean change in serum 25(OH)D and weekly sunlight exposure (r= –0.469, P=0.037).

CONCLUSION/COMMENTARY: The researchers conclude that change of serum 25(OH)D concentration after 4 weeks of sunlight exposure was not statistically significant in women with vitamin D deficiency. In fact, the vitamin D status in many of the women became even more deficient.

Of additional interest and concern, all of the women — who were employees at the medical center and volunteered for the study, but were not chosen randomly — were deficient in vitamin D at the outset. At the same time, however, this was a very small observational study, so the results need to be considered in that context; plus, there are some other potentially confounding factors that might have affected results.

It is possible that the women did not expose themselves to the sun as often as instructed, and there were no adjustments made for variations in skin type that might affect vitamin D synthesis. Also of importance, the time of year — October-November — probably marks the beginning of “vitamin D winter” even in moderately northern latitudes, when UVB rays from the sun begin to weaken and remain so until late spring.

Most of all, and contrary to prior advice, such brief sun exposure of only hands, forearms, and face is probably insufficient for the body to produce adequate amounts of vitamin D at any time of year. And, other research has shown that persons deficient in vitamin D need considerable amounts of the vitamin to raise their levels. Yet, more extensive sunbathing, with prolonged exposure of large body surfaces — and without sunscreen, which would block UVB rays — raises questions of dermatologic safety.

Although further research in larger, randomized, controlled trials would be helpful, this preliminary study supports our contention that the sun is generally an unreliable source of adequate vitamin D in modern society. A more dependable approach is via daily supplements of vitamin D3, with periodic 25(OH)D assessments as necessary to assure adequacy.

REFERENCE: Lee SH, Park SJ, Kim KM, et al. Effect of sunlight exposure on serum 25-hydroxyvitamin d concentration in women with vitamin d deficiency: using ambulatory lux meter and sunlight exposure questionnaire. Korean J Fam Med. 2012 Nov;33(6):381-389 [article here].


Are Large Oral or Injected Vitamin D3 Doses Better for Treating Deficiency?

Researchers at Tehran University of Medical Sciences, Iran, recently reported a randomized controlled trial assessing the effectiveness and practicality of oral vitamin D3 supplements compared with intramuscular vitamin D3 supplement injections in the treatment of vitamin D deficiency [Zabihiyeganeh et al. 2013]. They randomized 92 patients with vitamin D deficiency — described as <30 ng/mL 25(OH)D — to receive 300,000 IU of vitamin D3, either intramuscularly as a single injection or orally in 6 divided doses during a 3 month period (about the equivalent of 3,300 IU D3/day). Serum 25(OH)D was assessed at baseline, 3 months, and 6 months.

The researchers found that both treatment regimens significantly increased vitamin D blood levels. However, at 3 months, Vitamin D status was significantly higher in the oral than in the injection group; mean 25(OH)D was 36 ng/mL vs 23.5 ng/mL, respectively (P=0.03). At 6 months, 25(OH)D levels were statistically comparable; mean 20.8 ng/mL and 24.9 ng/mL, respectively (P=0.32). There was a marginally significant trend in favor of oral dosing in the proportion of subjects who sustained vitamin D adequacy at 6 months (P=0.06); but 15% of all patients still remained at <20 ng/mL 25(OH)D.

CONCLUSION/COMMENTARY: The researchers conclude that both regimens are safe, effective, and practical. However, while the short-term superiority of the oral route seems evident, they note, the preferred treatment modality may depend on patient choice, adherence with a dosing regimen, and availability of vitamin D dosage forms in particular regions.

It should be noted that both of the approaches in this study — a single 300,000 IU injection, or six 50,000 IU oral doses — might be considered a megadose supplementation strategy, and it seems of concern that 25(OH)D was not sustained over time at more adequate levels (>30 ng/mL) by either approach. It is unfortunate that the researchers did not also test a daily dose of oral vitamin D3 at, say, 4,000 IU/day (or more).

Although the body can store vitamin D as 25(OH)D for a limited time, the disposition of megadoses is still being investigated; much of a very large dose may go unused. The human organism evolved under conditions of daily sun exposure, synthesizing vitamin D each day to meet its needs. Therefore, daily oral supplementation of vitamin D3 would fit a more naturalistic scheme and potentially better satisfy the body’s requirements. This would be of special concern in persons with musculoskeletal-associated pain conditions, who may require 25(OH)D levels well above 30 ng/mL (as noted above).

REFERENCE: Zabihiyeganeh M, Jahed A, Nojomi M. Treatment of hypovitaminosis D with pharmacologic doses of cholecalciferol, oral vs intramuscular; an open labeled RCT. Clinical Endocrinology. 2013(Feb);78(2):210–216 [abstract here].

eNotifications Don’t Miss Out. Stay Up-to-Date on Pain-Topics UPDATES!
Register [here] to receive a once-weekly e-Notification of new postings.