Dr. Ron’s Research Review – July 25, 2012

This week’s research review focuses on Vitamin D.

The incidence of vitamin D deficiency is rising worldwide, yet it often remains undiagnosed and untreated. To achieve this sufficiency (>30 ng/mL), most people need 600 to 2000 IU/day; consumption up to of 5000 IU per day of vitamin D is reported as safe. (Wimalawansa 2012)

Metabolic activation and inactivation of vitamin D results in a plethora of metabolites, of which only 25-hydroxyvitamin D (calcifediol) and 1,25-dihydroxyvitamin D (calcitriol) are clinically relevant. (Hollis 2010)

In breast cancer MCF-7 cells, aromatase gene expression and estradiol production were decreased, while production of androgens was markedly increased by vitamin D3. In NCI-H295R (adrenal) cells, 1alpha,25-dihydroxyvitamin D(3) stimulated aromatase expression and decreased dihydrotestosterone production. In prostate cancer LNCaP cells, aromatase expression increased after the same treatment, as did production of testosterone and dihydrotestosterone. (Lundqvist, Norlin et al. 2011)

Combating vitamin D deficiency may reduce the incidence of autoimmune disease. (Kinder and Hagaman 2011)

Vitamin D3 is more efficacious at raising serum 25(OH)D concentrations than is vitamin D2. (Tripkovic, Lambert et al. 2012)

Myositis-myalgia is the most common cause of statin intolerance, leading to cessation of statin use. Vitamin D can reverse myositis-myalgia in vitamin D deficient, statin intolerant, hypercholesterolemic patients. (Glueck, Abuchaibe et al. 2011)

Dr. Ron


Articles

Symptomatic myositis-myalgia in hypercholesterolemic statin-treated patients with concurrent vitamin D deficiency leading to statin intolerance may reflect a reversible interaction between vitamin D deficiency and statins on skeletal muscle

            (Glueck, Abuchaibe et al. 2011) Download

Myositis-myalgia is the most common cause of statin intolerance, leading to cessation of statin use, with consequent failure to lower LDL cholesterol to target levels for primary and secondary prevention of cardiovascular disease (CVD). We hypothesize that symptomatic myositis-myalgia in hypercholesterolemic statin-treated patients with concurrent 25 (OH) vitamin D deficiency and statin intolerance may reflect a reversible interaction between vitamin D deficiency and statins on skeletal muscle. In hypercholesterolemic, vitamin D deficient patients, intolerant to statins because of myositis-myalgia, three non-blinded clinical case series have uniformly demonstrated that after supplementation with oral vitamin D2 which normalizes serum 25 (OH) vitamin D levels, statins can be successfully re-instituted in >90% of patients, without recurrent myositis-myalgia, with reduction of LDL cholesterol to target levels. Empirically, in 68 hypercholesterolemic patients, unable to tolerate>/=1 statin because of myositis-myalgia, selected by low (<32 ng/ml) serum 25 (OH) vitamin D, we have prospectively assessed whether resolution of vitamin D deficiency would result in statin tolerance, free of myositis-myalgia. On no statins, 50,000 units of vitamin D2 was given twice/week for 3 weeks, and was then continued once/week. After 3 weeks on vitamin D supplementation, statins were restarted, and patients were re-assessed after 3 months on statins while continuing vitamin D supplementation. At 3 months follow-up, on vitamin D supplementation and re-instituted statins, 62 of 68 (91%) previously statin-intolerant patients now tolerated statins well and were asymptomatic without myositis-myalgia. In these 68 patients, on vitamin D supplementation and statins, mean+/-SD vitamin D rose from 22+/-7 to 43+/-13 ng/ml (p<0.0001), and LDL cholesterol fell from 162+/-55 to 101+/-35 mg/dl (p<0.0001). Despite published and new empirical evidence, the medical establishment has refused to accept the hypothesis, requiring placebo-controlled, double-blind studies, none having been reported to date. A placebo-controlled, double-blind study is needed to document that normalization of serum 25 (OH) vitamin D levels in vitamin D deficient, statin intolerant patients would facilitate re-introduction of statins with concurrent freedom from myositis-myalgia. The ability to reverse myositis-myalgia in vitamin D deficient, statin intolerant, hypercholesterolemic patients by vitamin D supplementation would be extraordinarily valuable, facilitating reinstitution of statins to lower LDL cholesterol to reduce risk of CVD events. We hypothesize that symptomatic myositis-myalgia in hypercholesterolemic statin-treated patients with concurrent vitamin D deficiency producing statin intolerance may reflect a reversible interaction between vitamin D deficiency and statins on skeletal muscle.

Assessment and interpretation of circulating 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D in the clinical environment

            (Hollis 2010) Download

The unique cis-triene structure of vitamin D and related metabolites makes it susceptible to oxidation, ultraviolet (UV) light-induced conformational changes, heat-induced conformational changes, and attacks by free radicals. Vitamin D(2) is much less bioactive than vitamin D(3) in humans. Metabolic activation and inactivation of vitamin D are well characterized and result in a plethora of metabolites, of which only 25-hydroxyvitamin D (25(OH)D) and 1,25-dihydroxyvitamin D (1,25(OH)(2)D) provide any clinically relevant information. 25(OH)D(2) and 25(OH)D(3) are commonly known as calcifediol and the 1,25(OH)(2)D metabolites as calcitriol. In this review the current state of the science on the clinical assessment of circulating 25(OH)D and 1,25(OH)(2)D is described.

Could combating vitamin D deficiency reduce the incidence of autoimmune disease?

            (Kinder and Hagaman 2011) Download

1alpha,25-Dihydroxyvitamin D3 exerts tissue-specific effects on estrogen and androgen metabolism

            (Lundqvist, Norlin et al. 2011) Download

It is well-known that 1alpha,25-dihydroxyvitamin D(3) and analogs exert anti-proliferative and pro-differentiating effects and these compounds have therefore been proposed to be of potential use as anti-cancer agents. Due to its effects on aromatase gene expression and enzyme activity, 1alpha,25-dihydroxyvitamin D(3) has been proposed as an interesting substance in breast cancer treatment and prevention. In the present study, we have examined the effects of 1alpha,25-dihydroxyvitamin D(3) on estrogen and androgen metabolism in adrenocortical NCI-H295R cells, breast cancer MCF-7 cells and prostate cancer LNCaP cells. The NCI-H295R cell line has been proposed as a screening tool to study endocrine disruptors. We therefore studied whether this cell line reacted to 1alpha,25-dihydroxyvitamin D(3) treatment in the same way as cells from important endocrine target tissues. 1alpha,25-Dihydroxyvitamin D(3) exerted cell line-specific effects on estrogen and androgen metabolism. In breast cancer MCF-7 cells, aromatase gene expression and estradiol production were decreased, while production of androgens was markedly increased. In NCI-H295R cells, 1alpha,25-dihydroxyvitamin D(3) stimulated aromatase expression and decreased dihydrotestosterone production. In prostate cancer LNCaP cells, aromatase expression increased after the same treatment, as did production of testosterone and dihydrotestosterone. In summary, our data show that 1alpha,25-dihydroxyvitamin D(3) exerts tissue-specific effects on estrogen and androgen production and metabolism. This is important knowledge about 1alpha,25-dihydroxyvitamin D(3) as an interesting substance for further research in the field of breast cancer prevention and treatment. Furthermore, the observed cell line-specific effects are of importance in the discussion about NCI-H295R cells as a model for effects on estrogen and androgen metabolism.

Comparison of vitamin D2 and vitamin D3 supplementation in raising serum 25-hydroxyvitamin D status: a systematic review and meta-analysis

            (Tripkovic, Lambert et al. 2012)  Download

BACKGROUND: Currently, there is a lack of clarity in the literature as to whether there is a definitive difference between the effects of vitamins D2 and D3 in the raising of serum 25-hydroxyvitamin D [25(OH)D]. OBJECTIVE: The objective of this article was to report a systematic review and meta-analysis of randomized controlled trials (RCTs) that have directly compared the effects of vitamin D2 and vitamin D3 on serum 25(OH)D concentrations in humans. DESIGN: The ISI Web of Knowledge (January 1966 to July 2011) database was searched electronically for all relevant studies in adults that directly compared vitamin D3 with vitamin D2. The Cochrane Clinical Trials Registry, International Standard Randomized Controlled Trials Number register, and clinicaltrials.gov were also searched for any unpublished trials. RESULTS: A meta-analysis of RCTs indicated that supplementation with vitamin D3 had a significant and positive effect in the raising of serum 25(OH)D concentrations compared with the effect of vitamin D2 (P = 0.001). When the frequency of dosage administration was compared, there was a significant response for vitamin D3 when given as a bolus dose (P = 0.0002) compared with administration of vitamin D2, but the effect was lost with daily supplementation. CONCLUSIONS: This meta-analysis indicates that vitamin D3 is more efficacious at raising serum 25(OH)D concentrations than is vitamin D2, and thus vitamin D3) could potentially become the preferred choice for supplementation. However, additional research is required to examine the metabolic pathways involved in oral and intramuscular administration of vitamin D and the effects across age, sex, and ethnicity, which this review was unable to verify.

Vitamin D in the New Millennium

         (Wimalawansa 2012) Download

The incidence of vitamin D deficiency is rising worldwide, yet in the vast majority of patients, the condition remains undiagnosed and untreated. Current evidence overwhelmingly indicates that supplemental doses greater than 800 IU/day have beneficial effects on the musculoskeletal system, improving skeletal homeostasis, thus leading to fewer falls and fractures. Evidence is also accumulating on the beneficial effects of vitamin D on extraskeletal systems, such as improving immune health, autoimmune disorders, cancer, neuromodulation, diabetes, and metabolic syndrome. The cause-effect relationship of vitamin D deficiency with increasing incidences of nonskeletal disorders is being investigated. Published reports support the definition of sufficiency, serum levels of 25-hydroxyvitamin D [25(OH)D] greater than 30 ng/mL (75 nmol/L). To achieve this, most people need vitamin D supplementation ranging from 600 to 2000 IU/day; consumption up to of 5000 international units (IU) per day of vitamin D is reported as safe. Although light-skinned individuals need 1000 IU/day of vitamin D, elderly and dark-skinned individuals are likely to need approximately 2000 IU/day to maintain serum 25(OH)D levels greater than 30 ng/mL. Other vulnerable patients, such as the obese, those who have undergone bariatric surgery, and those with gastrointestinal malabsorption syndromes, may require higher doses of vitamin D to maintain normal serum levels and be healthy.


Research

Glueck, C. J., C. Abuchaibe, et al. (2011). "Symptomatic myositis-myalgia in hypercholesterolemic statin-treated patients with concurrent vitamin D deficiency leading to statin intolerance may reflect a reversible interaction between vitamin D deficiency and statins on skeletal muscle." Med Hypotheses 77(4): 658-61.

Hollis, B. W. (2010). "Assessment and interpretation of circulating 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D in the clinical environment." Endocrinol Metab Clin North Am 39(2): 271-86, table of contents.

Kinder, B. W. and J. T. Hagaman (2011). "Could combating vitamin D deficiency reduce the incidence of autoimmune disease?" Expert Rev Clin Immunol 7(3): 255-7.

Lundqvist, J., M. Norlin, et al. (2011). "1alpha,25-Dihydroxyvitamin D3 exerts tissue-specific effects on estrogen and androgen metabolism." Biochim Biophys Acta 1811(4): 263-70.

Tripkovic, L., H. Lambert, et al. (2012). "Comparison of vitamin D2 and vitamin D3 supplementation in raising serum 25-hydroxyvitamin D status: a systematic review and meta-analysis." Am J Clin Nutr 95(6): 1357-64.

Wimalawansa, S. J. (2012). "Vitamin D in the new millennium." Curr Osteoporos Rep 10(1): 4-15.