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How to Understand, Refute, and Plan Studies Using Vitamin D - Feb 2017

 

The following is a copy from the website of International College of Human Nutrition and Functional Medicinehttp://www.ichnfm.org/dWebsite includes many other studies and videos by Alex Vasquez Posted 12 Feb updated 19 Feb 2017 by Alex Vasquez DC ND DO FACNThe PDF (download) of this article is considered the final version.

 

Defining the problems
  1. The (primary) problem: Most doctors and researchers have zero expert-level training in Nutrition (let alone Clinical Nutrition, Therapeutic/Interventional Nutrition, Functional Nutrition) and therefore the studies they design using vitamin D are methodologically flawed, as described below. 
  2. The (secondary) problem: Too many studies using vitamin D (cholecalciferol) have used vitamin D in 1) doses that are inadequate, 2) for durations that are inadequate, and thus these studies are therapeutically underpowered, tending to lead to lackluster or negative (inefficacious) results, thereby leading to the false conclusion that vitamin D is ineffective when in fact it either is or might be effective.
  3. The (tertiary) problem: As a result of therapeutically underpowered studies, too many research articles paint a false picture of inefficacy when in fact vitamin D is or may be highly efficacious; as a result, patients are denied a safe and effective therapeutic route that offers low-cost efficacy, high safety, and numerous collateral benefits. 
  4. The (quaternary) problem: Another major problem is that too many doctors and researchers are unaware of the major paradigm-shifting studies that should have resulted in major acceptance of vitamin D utilization in preventive public health and clinical medicine; as a result of this ignorance, too many research projects are essentially starting from zero or a very shallow foundation rather than progressively building on a foundation of good science and appropriate pattern recognition. Researchers who have not studied the history of nutrition and the decades of literature are essentially ignorant of the history and direction of the field into which they enter; one can be amused by the prospect of a researcher placed in a position of authority to shape and define the direction of a field which he/she has never studied, ie, many researchers wear no clothes. 

I already addressed and potentially solved these problems more than 10 years ago: In 2004 and 2005, I was the principal author on several publications published in peer-reviewed journals, and in each of these I listed criteria for the design and therefore evaluation of studies using vitamin D; I will list these publications here with hyperlinks to their full text and then describe these criteria with any updates. Also listed here is a CME monograph that I wrote in 2008 and review article that I published in 2011 in a professional journal; this article (excerpted from my recent textbook Inflammation Mastery (2016)* to provide necessary updates) also describes the clinical use of vitamin D within the context of a foundation clinical nutrition protocol. 

  1. Vasquez, Manso, Cannell. The clinical importance of vitamin D (cholecalciferol): a paradigm shift with implications for all healthcare providers. Altern Ther Health Med 2004 Sep: PDFPMID 15478784
  2. Vasquez, Cannell. Calcium and vitamin D in preventing fractures: data are not sufficient to show inefficacy. British Medical Journal 2005 Jul: PDFPMID 16002891
  3. Vasquez. Subphysiologic doses of vitamin D are subtherapeutic: comment on the study by the Record Trial Group. TheLancet.com 2005 May PDF

According to the pioneering clinical trial by Heaney et al (Am J Clin Nutr 2003 Jan), “Healthy men seem to use 3000–5000 IU cholecalciferol/d”; a daily dose of 3,000–5,000 IU cholecalciferol/d corresponds to a serum 25-OH-vitamin D of 60 ng/ml (150 nmol/L). However, serum 25-OH-vitamin D should be equal to or greater than 80 ng/ml (200 nmol/L) in order to alleviate secondary relative hyperparathyroidism; the daily dose of vitamin D3 required to lower/normalize serum parathyroid hormone (PTH) is 10,000 IU (250 mcg) per day. Therefore, we can conclude that a reasonable daily dose of vitamin D ranges from 4,000–10,000 IU per day, and that the lowest acceptable serum 25-OH-vitamin D levels corresponding with adequate supplementation is 60 ng/ml (150 nmol/L) whereas a level of 80 ng/ml (200 nmol/L) is required to alleviate secondary (relative) hyperparathyroidism. Several of my publications (listed as #4 and #5 below) have also included a description of the minimal values and optimal therapeutic ranges for serum 25-OH-vitamin D; the perhaps obvious importance of these ranges is to define effective treatment (ie, sufficient vitamin D supplementation/nutriture) and to therefore differentiate adequate from inadequate supplementation dosages. 4. Vasquez. Musculoskeletal Pain: Expanded Clinical Strategies, commissioned and published by the Institute for Functional Medicine 2008 PDF*5. Vasquez. Revisiting the five-part nutritional wellness protocol: the supplemented Paleo Mediterranean diet. Nutritional Perspectives 2011 Jan PDF*Past and Future Vitamin D Studies: Critique and Design: A large percentage of published clinical trials have suffered from flawed design, including inadequate dosing, inadequate duration, wrong type of vitamin D (ie, ergocalciferol, D2), failure to test serum vitamin D levels, and/or failure to ensure that serum vitamin D levels entered into the optimal range. The following guidelines have been provided for clinicians and researchers using vitamin D in clinical practice and research to improve the quality of research and patient care.

  1. Dosages of vitamin D must reflect physiologic requirements and natural endogenous production and should therefore be in the range of 3,000–10,000 IU per day: The physiologic requirement for vitamin D is 3,000–5,000 IU per day in adult males. Full-body exposure to ultraviolet light (eg, sunshine) can produce the equivalent of 10,000–25,000 IU of vitamin D3 per day. Therefore, intervention trials with supplemental vitamin D should use between 4,000 IU/day, which is presumably sufficient to meet physiologic demands, and 10,000 IU/day, which is the physiologic dose attained naturally via full-body sun exposure within a short period of time outdoors. Also, the higher dose of 10,000 IU/day is necessary in some patients who have absorption defects and therefore need a higher oral dose to "force absorption" and/or who are obese and therefore need a higher dose to achieve tissue saturation for a larger body mass. Based on these physiologic criteria, we see that the majority of intervention studies in adults have used inadequate, subphysiologic doses of vitamin D. Therefore, many studies that failed to identify therapeutic benefits from vitamin D supplementation were flawed due to insufficient therapeutic intervention—the dose of vitamin D was too low. This insight also illuminates a double-standard in research: whereas no legitimate drug study would use a subtherapeutic dose of a pharmaceutical agent and then (falsely) assert inefficacy, poorly designed and therapeutically underpowered (eg, using 10% of the known effective dose) nutrition studies are published and make headlines and shape policy (mostly by maintaining the status quo of nutritional inaction and ignorance) on weekly basis. For example, a study using an antibiotic or antiseizure drug that failed to administer a therapeutic dosage or achieve a therapeutic serum level would never be accepted for publication in a headlining medical journal; yet, underdosed nutrition studies are commonly published in headlining journals and then reported to mainstream media as proof of the inefficacy of nutritional intervention.
  2. Vitamin D supplementation must be continued for at least 5-9 months for maximum benefit: Since serum 25(OH)D levels do not plateau until after 3-4 months of supplementation, and we would expect clinical and biochemical changes to become optimally apparent some time after the attainment of peak serum levels, any intervention study of less than 5-9 months is of insufficient duration to determine either maximum benefit or inefficacy of vitamin D supplementation. Conversely, since vitamin D supplementation can alter intracellular metabolism within minutes of administration, benefits seen in short-term studies should not be inaccurately attributed to statistical error or placebo effect. The vitamin D trial does not begin with the initiation of supplementation but rather the study beginsafter the achievement of vitamin D sufficiency (defined below).
  3. Supplementation should be performed with D3 rather than D2: Although cholecalciferol (vitamin D3) and ergocalciferol (vitamin D2) are both used as sources of vitamin D, D3 is the human nutrient and is much more efficient in raising and sustaining serum 25OHD levels. Vitamin D2 is a fungal metabolite and has been associated with adverse effects due to contamination and altered pharmacokinetics/dynamics. The type of vitamin D must always be clearly stated in published research reports.
  4. Supplements should be tested for potency: Some products do not contain their claimed amount. This problem was illustrated in the study by Heaney et al (2003 Jan) who found that the vitamin D supplement they used in their study, although produced by a well-known company, contained only 83% of its stated value. To ensure accuracy and consistency of clinical trials, actual dosages must be known.
  5. Effectiveness of supplementation must include evaluation of serum vitamin D levelsSupplementation does not maximize therapeutic efficacy unless it raises serum 25(OH)D levels into the optimal range. To assess absorption, compliance, and safety, serum 25(OH)D levels must be monitored in clinical trials involving vitamin D supplementation. Assessment of serum levels is important also to determine the relative dose-effectiveness of different preparations of vitamin D, as some evidence suggests that emulsification facilitates absorption of fat-soluble nutrients. Measurement of 1,25-dihydroxyvitamin (calcitriol) is potentially misleading and is not recommended for the evaluation of vitamin D status; however, measurement of calcitriol levels is increasingly used clinically to evaluate for the severity or presence of inflammatory and malignant diseases, as discussed in 


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How to Understand, Refute, and Plan Studies Using Vitamin D - Feb 2017        

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