Remember that you can have this article read aloud to you by using the Substack app:
Background: Today I was looking for a different citation when I found the original post from 2005 which was my “rapid response” to the British Medical Journal to their bogus and bungled publication “Randomised controlled trial of calcium and supplementation with cholecalciferol (vitamin D3) for prevention of fractures in primary care”BMJ 2005;330 doi:https://doi.org/10.1136/bmj.330.7498.1003 published 28 April 2005. During that era of the BMJ up until 2004/2005, the editor was Richard Smith, who probably was not perfect but was certainly much better than those who would follow him and convert the journal into a drug-marketing tabloid that published “research” and “editorials” from paid drug-company representatives, as I have also noted at the website of the BMJ and in other publications in other journals:
My 2005 reply is available at the following link and is archived below in text and PDF:
https://www.bmj.com/rapid-response/2011/10/30/subphysiologic-doses-vitamin-d-are-subtherapeutic-comment-study-porthouse-
Of important note, the Editors of the BMJ invited me to write a formal paper-published reply that was also published separately per the citation and PDF below:
Vasquez A, Cannell J. Calcium and vitamin D in preventing fractures: data are not sufficient to show inefficacy. BMJ. 2005 Jul 9;331(7508):108-9; author reply 109. doi: 10.1136/bmj.331.7508.108-b. PMID: 16002891; PMCID: PMC558659.
Letters and replies that are actually published in journals typically have to be very short per a strict word limit and also have to have a very limited number of citations, which explains why the “rapid response” published on the BMJ website (below) is longer than the corresponding paper-printed publication in the journal. However, because the online version is longer and more complete, it has additional information and citations. Forcing replies and comments to be very short is one of the ways that journals create the illusion of comment and feedback while ensuring that the published research remains standing even after flaws have been noted.
Finally, when I wrote this back in 2005—before I had written my major books and before I attended medical school (2006-2010), I was still somewhat of a “young pup” in terms of my writing and grammatical style. You’ll notice in my later writings I strictly avoided passive sentences, etc. Actually, sometimes journal Editors change (ie, butcher) the original style of the authors in order to make it more consistent with the journal’s style and more palatable to an audience that is accustomed to passive sentences. The most painful example of that was in my 1996 article in Arthritis and Rheumatism, the publication of which I am eternally grateful even though the editor’s use of a very passive conclusion still causes me to cringe 30 years later.
Vasquez A. Musculoskeletal disorders and iron overload disease: comment on the American College of Rheumatology guidelines for the initial evaluation of the adult patient with acute musculoskeletal symptoms. Arthritis Rheum. 1996 Oct;39(10):1767-8. doi: 10.1002/art.1780391027. PMID: 8843875.
Subphysiologic Doses of Vitamin D are Subtherapeutic: Comment on the Study by Porthouse and colleagues
Dear Editor,
Based on recently published research, it is clear that the recent study by Porthouse and colleagues [1] on vitamin D and calcium in the prevention of fractures suffered from at least two major design flaws. First, the dose of vitamin D used in their study (800 IU/d) is subphysiologic and would therefore not be expected to produce a clinically meaningful effect. Second, their use of “self report” as a measure of compliance is unreliable compared to an objective assessment of compliance, namely measurement of serum 25-hydroxy-vitamin D.
The physiologic requirement for vitamin D was determined scientifically in a recent study by Heaney and colleagues [2], who showed that healthy men utilize 3,000 to 5,000 IU of cholecalciferol per day, and several recent clinical trials have been published documenting the safety and effectiveness of administering vitamin D in physiologic doses of at least 4,000 IU per day.[3-5] In fact, studies have shown a clear dose-response relationship with vitamin D supplementation [6], and low doses (e.g., 600 IU) are clearly less effective than higher doses in the physiologic range (e.g., 4,000 IU).[5] It is important to note that the commonly used dose of vitamin D at 800 IU per day was not determined scientifically; rather this amount was determined arbitrarily before sufficient scientific methodology was available.[2,7] Given that the commonly recommended daily intake of vitamin D is not sufficient for maintaining adequate serum levels of vitamin D [8], it is therefore incumbent upon modern researchers and clinicians to use doses of vitamin D that are consistent with the physiologic requirement as established in current research.
Relatedly, the goal of vitamin D supplementation is to increase serum levels into the optimal physiologic range, which has a lower end of 40 ng/mL (100 nmol/L).
Supplementation that does not accomplish the goal of raising serum vitamin D levels is valueless, and the failure to measure serum levels of 25-hydroxy-vitamin D in their study leaves the conclusions of Porthouse and colleagues [1] subject to question for at least three reasons.
First, it is clear that some vitamin supplements do not contain their claimed amount, as illustrated in the study by Heaney et al [2] who found that the vitamin D supplement used in their study, although produced by a well-known company, contained only 83% of its stated value. Did the supplement used by Porthouse and colleagues actually contain its claimed amount?
Second, the assessment of serum levels of vitamin D would have provided clear evidence of compliance (or lack thereof) and would have strengthened the conclusions of the study. Since dietary recall is notoriously unreliable [9], this question remains: Were patients in this study sufficiently compliant with treatment?
Third, given that vitamin D levels must be raised to a minimum of 40 ng/mL (100 nmol/L) in order to maximally reduce parathyroid hormone levels and bone resorption [10,11], the question remains: Was the dose of vitamin D used in this study effective in raising vitamin D levels into the optimal physiologic range?
It is clear that vitamin D deficiency is very common in industrialized nations, particularly those of northern latitudes [12-14], and that serum levels are not stabilized until after at least 3 months of supplementation [3].
In the vitamin D monograph published by Vasquez and colleagues in 2004 [15], we proposed that clinicians and researchers utilize the following six guidelines when conducting studies with vitamin D:
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 appears to be 3,000 – 5,000 IU per day in adult males. Full-body exposure to ultraviolet light (e.g., 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 [2], and 10,000 IU/day, which is the physiologic dose attained naturally via full-body sun exposure. [7]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 [3], 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 that vitamin D supplementation is ineffective for the condition being investigated.
Supplementation should be performed with D3 rather than D2: Although cholecalciferol (vitamin D3) and ergocalciferol (vitamin D2) are both used a sources of vitamin D, D3 is the human nutrient and is much more efficient in raising and sustaining serum 25(OH)D levels.
Supplements should be tested for potency: Some products do not contain their claimed amount. To ensure accuracy and consistency of clinical trials, actual dosages must be known, and products must be independently assayed when used in clinical trials.
Effectiveness of supplementation must include evaluation of serum vitamin D
levels: Supplementation 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 micro-emulsification facilitates absorption of fat-soluble nutrients [16, 17]. Measurement of 1,25-dihydroxyvitamin (calcitriol) is potentially misleading and is not recommended for the evaluation of vitamin D status.Serum vitamin D levels must enter the optimal physiologic range: The majority of clinical intervention studies using vitamin D have failed to use supplementation of sufficient dosage and duration to attain optimal serum levels of vitamin D. Based on our extensive review of the literature [15], our proposed optimal range for 25(OH)D is 40 - 65 ng/mL (100 - 160 nmol/L).
Since the study by Porthouse and colleagues [1] met only 2 of these 6 criteria
(#2 and #3), their data cannot be viewed as reliable for documenting the inefficacy of vitamin D supplementation. Their study is valuable, however, in documenting the inefficacy of subphysiologic doses of vitamin D. In order to produce more meaningful results in clinical trials, we suggest that future studies should ensure patient compliance and supplementation efficacy by measuring serum levels of 25(OH)D and should use physiologic doses (e.g., 4,000 IU per day). Researchers and clinicians should ensure that serum are levels raised to a minimum of 40 ng/mL (100 nmol/L), since levels below this threshold are associated with increased parathyroid hormone levels, increased bone resorption, and recalcitrance to bone-building interventions.[18, 19]
Alex Vasquez, B.S., D.C., N.D.
Biotics Research Corporation Rosenberg, Texas, USA 77471
John Cannell, M.D.
The Vitamin D Council (cholecalciferol-council.com)
References:
Porthouse J, Cockayne S, King C, Saxon L, Steele E, Aspray T, Baverstock M, Birks Y, Dumville J, Francis R, Iglesias C, Puffer S, Sutcliffe A, Watt I, Torgerson DJ. Randomised controlled trial of calcium and supplementation with cholecalciferol (vitamin D3) for prevention of fractures in primary care.
BMJ. 2005 Apr 30;330(7498):1003 http://bmj.bmjjournals.com/cgi/content/full/330/7498/1003Heaney RP, Davies KM, Chen TC, Holick MF, Barger-Lux MJ. Human serum 25-hydroxycholecalciferol response to extended oral dosing with cholecalciferol.
Am J Clin Nutr 2003;77:204-103. Vieth R, Chan PC, MacFarlane GD. Efficacy and safety of vitamin D3 intake exceeding the lowest observed adverse effect level.
Am J Clin Nutr. 2001 Feb;73(2):288-94Al Faraj S, Al Mutairi K. Vitamin D deficiency and chronic low back pain in Saudi Arabia.
Spine. 2003;28(2):177-9Vieth R, Kimball S, Hu A, Walfish PG. Randomized comparison of the effects of the vitamin D3 adequate intake versus 100 mcg (4000 IU) per day on biochemical responses and the wellbeing of patients.
Nutr J. 2004 Jul 19;3(1):8 http://www.nutritionj.com/content/pdf/1475-2891-3-8.pdfVan den Berghe G, Van Roosbroeck D, Vanhove P, Wouters PJ, De Pourcq L, Bouillon R. Bone turnover in prolonged critical illness: effect of vitamin D.
J Clin Endocrinol Metab. 2003 Oct;88(10):4623-327. Vieth R. Vitamin D supplementation, 25-hydroxyvitamin D concentrations, and safety.
Am J Clin Nutr. 1999 May;69(5):842-56 http://www.ajcn.org/cgi/reprint/69/5/842.pdfGlerup H, Mikkelsen K, Poulsen L, Hass E, Overbeck S, Thomsen J, Charles P, Eriksen EF. Commonly recommended daily intake of vitamin D is not sufficient if sunlight exposure is limited.
J Intern Med. 2000 Feb;247(2):260-8Wu ML, Whittemore AS, Jung DL. Errors in reported dietary intakes. I. Short-term recall.
Am J Epidemiol. 1986 Nov;124(5):826-35Kinyamu HK, Gallagher JC, Rafferty KA, Balhorn KE. Dietary calcium and vitamin D intake in elderly women: effect on serum parathyroid hormone and vitamin D metabolites.
Am J Clin Nutr 1998;67:342-8Dawson-Hughes B, Harris SS, Dallal GE. Plasma calcidiol, season, and serum parathyroid hormone concentrations in healthy elderly men and women.
Am J Clin Nutr 1997;65:67-7112. Thomas MK, Lloyd-Jones DM, Thadhani RI, Shaw AC, Deraska DJ, Kitch BT, Vamvakas EC, Dick IM, Prince RL, Finkelstein JS. Hypovitaminosis D in medical inpatients.
N Engl J Med 1998;338:777-83Dubbelman R, Jonxis JH, Muskiet FA, Saleh AE. Age-dependent vitamin D status and vertebral condition of white women living in Curacao (The Netherlands Antilles) as compared with their counterparts in The Netherlands.
Am J Clin Nutr 1993;58:106-9Kauppinen-Makelin R, Tahtela R, Loyttyniemi E, Karkkainen J, Valimaki MJ. A high prevalence of hypovitaminosis D in Finnish medical in- and outpatients.
J Intern Med. 2001;249(6):559-63Vasquez A, Manso G, Cannell J. The clinical importance of vitamin D (cholecalciferol): a paradigm shift with implications for all healthcare providers.
Altern Ther Health Med. 2004 Sep-Oct;10(5):28-36; quiz 37, 94.Bucci LR, Pillors M, Medlin R, Henderson R, Stiles JC, Robol HJ, Sparks WS. Enhanced uptake in humans of coenzyme Q10 from an emulsified form.
Third International Congress of Biomedical Gerontology; Acapulco, Mexico: June 1989Bucci LR, Pillors M, Medlin R, Klenda B, Robol H, Stiles JC, Sparks WS. Enhanced blood levels of coenzyme Q-10 from an emulsified oral form. In Faruqui SR and Ansari MS (editors). Second Symposium on Nutrition and Chiropractic Proceedings. April 15-16, 1989 in Davenport, Iowa
18. Stepan JJ, Burckhardt P, Hana V. The effects of three-month intravenous ibandronate on bone mineral density and bone remodeling in Klinefelter’s syndrome: the influence of vitamin D deficiency and hormonal status. Bone2003;33:589-596
Vasquez A. Health care for our bones: a practical nutritional approach to preventing osteoporosis. [letter] J Manipulative Physiol Ther. 2005 Mar-Apr;28(3):213
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