Several more Vitamin D analyses fail to consider dose size, duration, etc. – Dec 2013

Proof that Vitamin D Works has the following summary of typical errors of Trials and Meta-analysis
Many Clinical Trials have not found a benefit because of one or more of the following failures:

1. Fails to use a large enough dose of vitamin D (often < 1,100 IU)
   The Even larger dose needed if: 1) obese, 2) poor gut, 3) sick (many diseases consume lots of vitamin D)
2. Fails to have given vitamin D for a long enough time (a few RCT lasted less than 5 weeks)
3. Fails to have given Vitamin D frequently enough. At least every 2 months for D3) - and at least weekly for D2
   Note: Infrequent dosing also causes unbalancing of the body's chemistry
4. Fails to provide a loading dose, or had too short a duration to restore the vitamin D levels
5. Fails to use D3 form, instead uses the less effective D2 form
6. Fails to have a healthy range of Calcium or other important cofactors (especially for bone-related trials
   Also, differences in Magnesium can result in 30% change in response to vitamin D
   Magnesium is dependent on water, food, supplements
7. Fails to notice the pre-existing vitamin D levels - only those who are low will likely show a benefit
8. Fails to notice how/when the vitamin D was taken (which can change the response by as much as 2X)
9. Fails to report on compliance (in one case 40% of the participants did not take the supplements consistently)

Many Meta-Analyses also do not find a benefit because one or more of the above failures
In addition, many meta-analysis average together ALL of the trials
Imagine a story about a meta-analysis of aspirin (which has never been done)
   There would be scores of RCT for aspirin not working with 3 mg doses
   There would be a many RCT of aspirin not working with 30 mg doses
   There would be a few studies of aspirin WORKING with 300+ mg doses
   There would be many studies of small amounts of Willow bark (Vitamin D2 instead of Vitamin D3)
   Then there would be a meta-analysis of aspirin and Willow Bark
   - That meta-analysis would conclude that aspirin and Willow bark do not work.

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Vitamin, Mineral, and Multivitamin Supplements for the Primary Prevention of Cardiovascular Disease and Cancer, A Systematic Evidence Review for the U.S. Preventive Services Task Force

Evidence Syntheses, No. 108

Investigators: Stephen P Fortmann, MD, Brittany U Burda, MPH, Caitlyn A Senger, MPH, Jennifer S Lin, MD, MCR, Tracy L Beil, MS, Elizabeth O'Connor, PhD, and Evelyn P Whitlock, MD, MPH.
Kaiser Permanente Research Affiliates Evidence-based Practice Center
Rockville (MD): Agency for Healthcare Research and Quality (US); November 2013.
Report No.: 14-05199-EF-1

In the United States, dietary supplements are commonly used to prevent chronic diseases, including cardiovascular disease (CVD) and cancer.

Purpose: To systematically review evidence for the use of multivitamins or single nutrients and functionally related nutrient pairs for the prevention of CVD and cancer in the general population (primary prevention).

Methods: We searched MEDLINE, EMBASE, Cochrane Database of Systematic Reviews, the Database of Abstracts of Reviews of Effects, and Cochrane Central Register of Controlled Trials to identify literature that was published between 2005 and January 29, 2013. We also examined the references from the previous reviews and other relevant reviews to identify additional studies; we also searched Web sites of government agencies and other organizations for grey literature. Two investigators independently reviewed identified abstracts and full-text articles against a set of a priori inclusion and quality criteria. One investigator abstracted data into an evidence table and a second investigator checked these data. We qualitatively and quantitatively synthesized the results for the four key questions and grouped the included studies by study supplement. We conducted meta-analyses using Mantel-Haenzel fixed effects models for overall cancer incidence, CVD incidence, and all-cause mortality.

Results: We included 103 articles representing 26 unique studies. Very few studies examined the use of multivitamin supplements. Two trials showed a protective effect against cancer in men; only one of these trials included women and found no effect. No effects of treatment were seen on CVD or all-cause mortality. Beta-carotene showed a negative effect on lung cancer incidence and mortality among individuals at high risk for lung cancer at baseline (i.e., smokers and asbestos-exposed workers); this effect was persistent even when combined with vitamin A or E. Trials of vitamin E supplementation showed mixed results and altogether had no overall effect on cancer, CVD, or all-cause mortality. Only one of two included selenium trials showed a beneficial effect for colorectal and prostate cancer; however, this trial included a small sample size. The few studies addressing folic acid, vitamin C, and vitamin A showed no effect on CVD, cancer, and mortality. Vitamin D and/or calcium supplementation also showed no overall effect on CVD, cancer, and mortality. Harms were infrequently reported and aside from limited paradoxical effects for some supplements, were not considered serious.

Conclusions: There are a limited number of trials examining the effects of dietary supplements on the primary prevention of CVD and cancer; the majority showed no effect in healthy populations. Clinical heterogeneity of included studies limits generalizability of results to the general primary care population. Results from trials in at-risk populations discourage additional studies for particular supplements (e.g., beta carotene); however, future research in general primary care populations and on other supplements is required to address research gaps.
(We see many of the RCT errors mentioned above)

Note: WHI study used just 400 IU of vitamin D

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Vitamin D status and ill health: a systematic review

The Lancet Diabetes & Endocrinology, Early Online Publication, 6 December 2013
doi:10.1016/S2213-8587(13)70165-7Cite or Link Using DOI
Prof Philippe Autier MD a b philippe.autier at i-pri.org, Prof Mathieu Boniol PhD a b, Cécile Pizot MSc a, Prof Patrick Mullie PhD a c

Low serum concentrations of 25-hydroxyvitamin D (25[OH]D) have been associated with many non-skeletal disorders. However, whether low 25(OH)D is the cause or result of ill health is not known. We did a systematic search of prospective and intervention studies that assessed the effect of 25(OH)D concentrations on non-skeletal health outcomes in individuals aged 18 years or older. We identified 290 prospective cohort studies (279 on disease occurrence or mortality, and 11 on cancer characteristics or survival), and 172 randomised trials of major health outcomes and of physiological parameters related to disease risk or inflammatory status. Investigators of most prospective studies reported moderate to strong inverse associations between 25(OH)D concentrations and cardiovascular diseases, serum lipid concentrations, inflammation, glucose metabolism disorders, weight gain, infectious diseases, multiple sclerosis, mood disorders, declining cognitive function, impaired physical functioning, and all-cause mortality. High 25(OH)D concentrations were not associated with a lower risk of cancer, except colorectal cancer. Results from intervention studies did not show an effect of vitamin D supplementation on disease occurrence, including colorectal cancer. In 34 intervention studies including 2805 individuals with mean 25(OH)D concentration lower than 50 nmol/L at baseline supplementation with 50 μg per day or more did not show better results. Supplementation in elderly people (mainly women) with 20 μg vitamin D per day seemed to slightly reduce all-cause mortality. The discrepancy between observational and intervention studies suggests that low 25(OH)D is a marker of ill health. Inflammatory processes involved in disease occurrence and clinical course would reduce 25(OH)D, which would explain why low vitamin D status is reported in a wide range of disorders. In elderly people, restoration of vitamin D deficits due to ageing and lifestyle changes induced by ill health could explain why low-dose supplementation leads to slight gains in survival.
Clipped from Press Release
“If the health benefits of high vitamin D concentrations shown by data from observational studies are not reproduced in randomised trials (the gold standard method for assessing a causal relation between an exposure and an outcome) then the relation between vitamin D status and disorders are probably the result of confounding or physiological events involved in these disorders”*, explains lead author Professor Philippe Autier from the International Prevention Research Institute in Lyon, France.

Autier and colleagues analysed data from 290 prospective observational studies and 172 randomised trials examining the effects of vitamin D levels on non-bone health outcomes up to December 2012.

They found that the benefits of high vitamin D concentrations from observational studies— including reduced risk of cardiovascular events (up to 58%), diabetes (up to 38%), and colorectal cancer (up to 34%)—were not confirmed in randomised trials. Indeed, meta-analyses of recent randomised trials failed to identify any effect of raising vitamin D concentrations with supplementation on disease occurrence, severity, or clinical course.

According to Autier, “What this discrepancy suggests is that decreases in vitamin D levels are a marker of deteriorating health. Ageing and inflammatory processes involved in disease occurrence and clinical course reduce vitamin D concentrations, which would explain why vitamin D deficiency is reported in a wide range of disorders.”*

Publisher wants $31.50 for the PDF, but comments are free__

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See also VitaminDWiki

• Overview Meta-analysis of Vitamin D
• Why randomized controlled trials of calcium and vitamin D sometimes fail – June 2012
• All items in category Meta-analysis 667 items
• No association between Multiple Sclerosis relapses and being treated with vitamin D–meta-analysis May 2013
• No weight loss when average over trials lasting 6 weeks and only 200 IU of vitamin D – meta-analysis July 2013
• Yet another meta-analysis ignores vitamin D dose and serum level – Autoimmune disease – Dec 2012
• Vitamin D may prevent falls and fractures without Calcium – an overview of 9 meta-analysis – Oct 2012
• Omega-3 does not help heart patients – meta-analysis Sept 2012
• Example of a vitamin D meta-analysis which ignored the data – June 2012
• Proof that Vitamin D Works 71 health problems prevented/treated - as of Oct 2016
• Why many vitamin D trials fail to find benefits - Nov 2016