Thursday, October 4, 2012

New Research on Vitamin D, Pain, & Mortality

Vitamin D ResearchBenefits of Vitamin D continue to be featured in the news and medical journals. Some of the latest reports suggest that if you have a loved one who is afflicted with painful rheumatoid arthritis or multiple sclerosis, or is elderly and frail, make sure they get plenty of vitamin D — they may have less pain or disability and live longer as a result. Here is a roundup of the research.

Vitamin D Reduces RA Risk
Writing in an early online edition of Clinical Rheumatology, researchers report a systematic review and meta-analysis examining the association between vitamin D intake and the development of rheumatoid arthritis (RA) and between serum vitamin D levels and RA severity [Song et al. 2012]. Their literature search revealed 3 cohort studies including 215,757 participants and 874 incident (ie, newly developed) cases of RA, as well as 8 studies on the association between serum vitamin D levels and RA activity involving 2,885 RA patients and 1,084 controls.

The meta-analysis showed a significant association between total dietary vitamin D intake and development of RA (Relative Risk [RR] of the highest vs. the lowest group = 0.758, 95% Confidence Interval [CI] 0.577-0.937; P=0.047). That is, individuals in the group with highest total vitamin D intake from food (and/or sunshine) had roughly a 24% lower risk of developing RA than those in the lowest vitamin D group. Subgroup meta-analysis also showed a similarly significant association between greater intake from vitamin D supplements and lower RA incidence (RR=0.764, 95% CI 0.628-0.930, P=0.007).

As for disease severity, 7 of 8 studies found that higher vitamin D levels were associated with lower RA disease activity. A single, small study found no correlation between vitamin D levels and disease activity among 85 RA patients, but these patients exhibited a high prevalence of vitamin D deficiency that might have influenced the study outcome.

Vitamin D Lowers Severity of MS Activity & Disability
Research reported in the Annals of Neurology found that low blood levels of vitamin D were strongly associated with an increased number of brain lesions and signs of a more active disease state in people with multiple sclerosis (MS) [Mowry et al. 2012]. This suggests a potential link between vitamin D and the risk of longer-term disability from the autoimmune disorder.

A characteristic of MS is that the body's immune system attacks the coating of nerve fibers in the brain and spinal cord. This coating, made of myelin, insulates the nerves and helps them to send electrical signals that control movement, speech, and other functions. When myelin is attacked, inflammation interferes with message transmission activity, which shows up on an MRI as lesions that look like white spots. There is currently no cure for the disease, but there are medications to help reduce the number of attacks, which can be acutely or chronically painful, and to help reduce lingering symptoms of an attack.

In their research report, Mowry and colleagues used data from a 5-year study at the University of California at San Francisco of 469 people with MS. Each year, researchers assessed vitamin D levels — 25-hydroxyvitamin D, or 25(OH)D — and performed MRIs on the brains of study participants, looking for both new lesions and active spots of disease. The investigators found that each 10 ng/mL increase in 25(OH)D was associated with a 15% lower risk of new lesions (P=0.004) and a 32% lower risk of spots indicating active disease (P=0.002), which would require treatment with medication to reduce the likelihood of permanent nerve damage.

Furthermore, each 10 ng/mL increase in vitamin D level also was significantly associated with lower subsequent disability (P=0.037). In all cases, the significant impact of vitamin D levels remained evident, even after other factors that can affect disease progress were accounted for, including smoking status, current MS treatment, age, and gender.

Low Vitamin D Affects Mortality in the Elderly
Previous Pain-Topics UPDATES have variously reported on the importance of adequate vitamin D for musculoskeletal heath, as well as overall health, and in fall and painful fracture prevention. Beneficial effects might be especially pronounced in elderly persons, affecting longevity, as two recent studies in the United States suggest.

  • In the first study, Ellen Smit of Oregon State University and colleagues conducted a prospective investigation on the effects of frailty and vitamin D status on mortality in older Americans [Smit et al. 2012]. As reported in the European Journal of Clinical Nutrition, participants included 4,731 persons aged ≥60 years with 12 years of follow-up in the Third National Health and Nutrition Examination Survey. Frailty was defined as meeting 3 or more criteria and pre-frailty as meeting up to 2 of 5 criteria: a) low body mass index (BMI), b) slow walking, c) weakness, d) exhaustion, and/or e) low physical activity. Vitamin D status was assessed by serum 25(OH)D and categorized into quartiles. Analyses were adjusted for other comorbid conditions, gender, race, age, smoking, education, and latitude (affecting sunlight exposure).

    Results indicated that serum 25(OH)D concentrations were lowest in participants with frailty, intermediate in participants with pre-frailty, and highest in participants without frailty. The odds of frailty in the lowest quartile of serum 25(OH)D was nearly twice (1.94) the odds in the highest quartile (95% CI, 1.09–3.44). Mortality was positively associated with frailty, with the risk among participants who were frail and had low serum 25(OH)D nearly 3 times greater than in those who were not frail and who had high concentrations of serum 25(OH)D (Hazard Ratio = 2.98; 95% CI, 2.01–4.42).

  • In the second study, reported in an early online edition of the Journal of Clinical Endocrinology and Metabolism (JCEM), 2,638 well-functioning, community-dwelling Caucasians and African-Americans aged 71 to 80 years — 49% male, 39% black — were asked to fast for 12-hours, after which a blood sample was collected to determine levels of vitamin D and parathyroid hormone [Kritchevsky et al. 2012]. Every 6 months during more than 8 years of followup study participants were contacted to determine their medical condition. This was part of Health ABC, a prospective cohort study conducted in Memphis, TN, and Pittsburgh, PA.

    During the study, there were 691 deaths from all causes and, overall, lower 25(OH)D and high parathyroid hormone concentrations were associated with increased mortality rates in Black and white older adults. The researchers observed vitamin D insufficiency — defined as blood levels <20 ng/mL 25(OH)D — in one third of study participants, and this was associated with nearly a 50% increase in mortality rate. Overall, mean 25(OH)D concentrations were lower in Blacks than in whites, as might be expected, and this affected mortality rates among African Americans. Parathyroid hormone levels followed a similar pattern and higher levels were significantly associated with mortality.

COMMENTARY: All of these well-conducted studies were of considerable size (ie, well-powered) to produce valid results, but they were observational in design — utilizing cross-sectional and longitudinal methodologies — so cause-effect relationships cannot be assumed. For example, it is not known with certainty whether the particular conditions of interest influenced development of low vitamin D status in some way or the other way around.

This is a common problem in much of the research on vitamin D. While the evidence to date generally supports the benefits of maintaining adequately high levels of 25(OH)D in the elderly and in patients with a number of pain-related conditions — and we have been an advocate of vitamin D in these UPDATES — prospective randomized controlled clinical trials are generally lacking. The optimal 25(OH)D levels and the necessary supplementation of vitamin D3 to achieve and maintain those levels for preventing or ameliorating specific pain-related conditions, and in benefitting elderly populations, are still largely undetermined by a substantial body of high-quality research.

Technically, since vitamin D — 25(OH)D and its active metabolite, calcitriol — acts as a hormone in the body, an argument might be made that it should meet standards of efficacy and safety required of any pharmaceutical product. However, since vitamin D3 is a generic, over-the-counter, inexpensive agent, it seems unlikely that the necessary clinical trials will ever be conducted. And, there appears to be no clinical evidence to date favoring advantages of more expensive, prescription vitamin D2 or calcitriol analog products.


  • Kritchevsky SB, Tooze JA, Neiberg RH, et al. 25-Hydroxyvitamin D, Parathyroid Hormone, and Mortality in Black and White Older Adults: The Health ABC Study. JCEM. 2012(Oct); online ahead of print [abstract].
  • Mowry EM, Waubant E, McCulloch CE, et al. Vitamin D status predicts new brain magnetic resonance imaging activity in multiple sclerosis. Ann Neurol. 2012(Aug);72(2):234-240 [abstract].
  • Smit E, Crespo CJ, Michael Y, et al. The effect of vitamin D and frailty on mortality among non-institutionalized US older adults. Eur J Clin Nutrition. 2012(Sep);66:1024-1028 [abstract].
  • Song GG, Bae SC, Lee YH. Association between vitamin D intake and the risk of rheumatoid arthritis: a meta-analysis. Clin Rheumatol. 2012(Sep 2); online ahead of print [abstract].

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