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BRUCE ROSEMAN, M.D.
NICOLE LIVESCU, R.N.
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VITAMIN D UPDATE FROM AMERICAN HEART ASSOCIATION 2011 MEETING


November 18, 2011 (Orlando, Florida) — Data from a prospective, randomized, placebo-controlled trial has cast real doubt on the alleged cardioprotective benefits of vitamin D. Researchers performing the small study report that treatment with vitamin D for four months had no significant effect on endothelial function, vascular stiffness, or inflammation in healthy postmenopausal women.

"At this point in time, from the standpoint of heart-disease prevention, we have no evidence to prescribe vitamin D to patients, and we have no evidence not to give it," senior investigator Dr James Stein (University of Wisconsin School of Medicine and Public Health, Madison, WI) told heartwire. "We have other agents that have been proven effective to lower the risk of cardiovascular disease. In the US, with many patients taking the supplement and many physicians prescribing it, some of whom are megadosing it, what we really have going on is a massive, uncontrolled experiment."

The study, led by Dr Adam Gepner (University of Wisconsin School of Medicine and Public Health), was presented here this week at the American Heart Association 2011 Scientific Sessions. It included 114 postmenopausal women with serum 25-OH vitamin-D concentrations > 10 and < 60 ng/mL. The women were randomized to 2500 IU of vitamin D3 or placebo for four months.

Confirming several previous observational studies, the patients in the study with low levels of vitamin D were more likely to have a multitude of cardiovascular risk factors compared with patients with significantly higher levels at baseline. Stein acknowledged his study has limitations--it was small and only four months long and did not look at hard cardiovascular events--but the group saw no evidence of change across multiple surrogate end points, including endothelial function, arterial stiffness, C-reactive protein (CRP) levels, and blood pressure.

"I am concerned that vitamin D has become the new vitamin C or vitamin E," Stein told heartwire. "It has been touted as a panacea for all sorts of conditions, including muscle aches, mood disorders, and fatigue, and is now being used by many physicians as a way to prevent heart disease."

The 20 000-patient Vitamin D and Omega-3 Trial (VITAL) study is currently ongoing, but results of the study won't be available until 2016 or 2017. The study, which is led by researchers from the Brigham and Women's Hospital in collaboration with the National Cancer Institute and the National Health, Lung, and Blood Institute, is a randomized clinical trial investigating whether taking 2000 IU of vitamin D3 daily or 1 g of omega-3 fatty acids reduces the risk of developing cancer, heart disease, and stroke in people who do not have a prior history of these illnesses.

Other vitamin-D studies at the AHA meeting

Other observational, cross-sectional, and retrospective studies presented at the AHA meeting also addressed the vitamin-D issue. In one study, led by Dr Mahir Karakas (University of Ulm, Germany), researchers found there was 68% lower risk of coronary heart disease among women with higher levels of vitamin D compared with subjects with lower levels of vitamin D. The data, from 298 patients enrolled in the MONICA/KORA cohort study, did not show a reduction in coronary heart disease risk in men. Despite the results, Karakas said that "there is a real vitamin hype going on right now, and we should await the results of the VITAL study" before prescribing vitamin D to patients.

Another study, led by Dr Jonathan Emberson (University of Oxford, UK), showed that there was a 17%, 24%, and 21% lower risk of vascular death, nonvascular death, and all-cause mortality in individuals with high serum 25(OH) vitamin D3 compared with subjects with low serum levels enrolled in the Whitehall study. When the results of Whitehall were included with other studies in a meta-analysis the group also performed, they observed a 30% reduction in the risk of all-cause mortality among those with high levels of vitamin D. Presenting the results at the AHA meeting, Emberson was cautious in his interpretation of the data, stating that the data do not show causality and that while the association is statistically real, it is nonspecific. While he said that there "could be something real going on here," the results could still be caused by unmeasured residual confounding variables.

And finally, researchers, including lead author Dr Nikoo Cheraghi (Children's Mercy Hospitals and Clinics, Kansas City, MO) reported that serum 25(OH) vitamin D3 deficiency was associated with decreased carotid arterial distensibility but not increased intima-media thickness among high-risk children.
VITAMIN D DISCUSSION FROM NATIONAL INSTITUTE OF HEALTH
VITAMIN D
 
Can Vitamin D Treat Pain?

Pauline Anderson

February 27, 2012 — Women with dysmenorrhea who take a single high dose of vitamin D suffer much less menstrual pain and have no need of pain medications for any reason for up to 2 months, a new study has found.

“To our knowledge, this is the first study investigating the effect of a single high dose of vitamin D in primary dysmenorrhea,” wrote the study authors, led by Antonino Lasco, MD, from the Department of Internal Medicine, University of Messina, Italy.

“Our data support the use of cholecalciferol in these patients, especially when exhibiting low plasmatic levels of 25(OH)D [25-hydroxyvitamin D],” they write.

The study is published February 27 in the Archives of Internal Medicine.

Pain Trigger

Dysmenorrhea affects almost one half of menstruating women. The pelvic pain is believed to be triggered by excessive uterine production of prostaglandins, synthesized from omega-6 fatty acids before menses, that control vasoconstriction and uterine contractions.

According to the study authors, vitamin D may act as an anti-inflammatory and may regulate the expression of key genes involved in the prostaglandin pathway, causing decreased biological activity of prostaglandins.

The study included 40 women aged 18 to 40 years who had experienced at least 4 consecutive painful menstrual periods in the past 6 months and had a 25(OH)D serum level below the upper limit of the lowest quartile (<45 ng/mL). They were not taking calcium, vitamin D, oral contraceptives, or other medications, and they had not used an intrauterine contraceptive device during the previous 6 months.

The participants could use other means of birth control, however. They were also allowed to use nonsteroidal anti-inflammatory drugs (NSAIDs) as needed, but they had to record their use of these agents.

The women were randomly assigned to receive a single oral dose of 300,000 IUs of vitamin D (cholecalciferol) or placebo 5 days before the time they expected to begin their next menstrual period.

The primary outcome was intensity of menstrual pain as measured by a visual analog scale. The secondary outcome was use of NSAIDs.

After 2 months, baseline pain scores decreased 41% among women in the vitamin D group; there was no difference in scores among women taking placebo (P < .001). The greatest reduction in pain was among women in the vitamin D group who had the most severe pain at baseline (r = -0.76; P < .001)

During the study, none of the women in the vitamin D group needed NSAIDs to manage pain at 1 and 2 months, whereas 40% of those taking placebo used an NSAID at least once (P = .003).

Implications for Chronic Pain?

In an accompanying commentary, Elizabeth R. Bertone-Johnson, ScD, from the Division of Biostatistics and Epidemiology, University of Massachusetts, Amherst, and JoAnn E Manson, MD, from the Division of Preventive Medicine, Department of Epidemiology, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, said the study provides support for larger randomized trials of vitamin D for treating pain-related conditions in women.

Chronic widespread pain and fibromyalgia syndromes are more prevalent in women, "likely owing to the influence of sex steroid hormones," they write.

This future research, they write, must address several key issues.

"First, it is important to know how long reductions in pain associated with a single high-dose vitamin D therapy would persist and how often treatment would need to be repeated," the editorialists write. They point out that each dose would need to be effective for a lengthy period for average daily intake to remain below recommended upper limits.

Because many women will experience dysmenorrhea for several years until menopause, follow-up of participants in vitamin D trials must be extended to better evaluate adverse effects and to compare risks and benefits, they note.

The editorialists also note that it remains unknown whether vitamin D would improve dysmenorrhea pain in women with higher 25(OH)D levels.

"If these findings are confirmed in future randomized trials, vitamin D supplementation may become an important new treatment option for women who experience menstrual pain disorders," they conclude. "In the meantime, encouraging all women to obtain the recommended dietary allowance for vitamin D (?600 IU/d for women of reproductive age), as well as screening for low serum 25(OH)D levels among women with other risk factors for vitamin D deficiency, would be a rational interim approach."

Pain Site

Approached for comment, Clifford Lo, MD, PhD, Director, Harvard Human Nutrition Program, and Medical Education Coordinator, Harvard Medical School Division of Nutrition, said that although the numbers were small, there was a convincing difference between the placebo and vitamin D groups in the study.

However, although it is plausible that vitamin D affects prostaglandins, the study did not specify which prostaglandin or which pain site might be involved, said Dr. Lo, whose research interests include vitamin D metabolism.

The study proposes an interesting possible mechanism, "but that's certainly not good enough for me to say that this is a good treatment for pain," said Dr. Lo. "It's very premature to say it's something we should use."

Pain associated with dysmenorrhea is generally subjective and not easily measured, he added. It is difficult to make conclusions about the effect an agent will have on pain when there is "no convincing biomarker" for the pain, as was the case with this study, said Dr. Lo.

The 300,000 IU dose of vitamin D used in the study is probably harmless if taken every month or 2, and even perhaps every week, but it could cause hypercalcemia if taken daily, said Dr. Lo. The typical vitamin D dose is 400 to 1000 IU/day.

Dr. Lo pointed out that because the participants in the study had vitamin D levels below 45 ng/mL, they were not exactly deficient in vitamin D to begin with. "Most people would say that you're not deficient until you're below 20 ng/ml," he said. "I would say that half the American population is below 30 ng/mL."

The study authors and editorialists have disclosed no relevant financial relationships.

Arch Intern Med. 2012;172:366-367, 367-369.

Medscape Medical News © 2012 WebMD, LLC