Effect of four monthly oral vitamin D3 (cholecalciferol) supplementation on fractures and mortality in men and women living in the community: randomised double blind controlled trial

100,000 IU of Vitamin D is a Lethal Dose for Many in our Community

3 March 2003

100,000 IU of Vitamin D is a Lethal Dose for Many in our Community

Trivedi et al, [1] continually extol the 'safety' of the therapy they are promoting, yet there are thousands, maybe hundreds of thousands, of folks for whom 100,000 IU of cholecalciferol would result in hospitalization or death.

There are groups in the community who are already known to be "at-risk" of adverse reactions to Vitamin D supplementation. This study recognized that such a risk existed, and excluded those individuals with "a history of renal stones, sarcoidosis, or malignancy". Yet they gave no detailed guidance as to their precise rejection criteria in their conclusion extolling the safety of their treatment "in the general community"... How "general"? How "safe"?

Nor did their report attempt to analyze any cholecalciferol-induced anaphylaxis which may have occurred in their cohort. For example, was there any Cardiac Arrhythmia reported within 7 days of taking the bolus? Any fatigue or muscle aches and pains? Such data, if it was gathered, certainly was not reported.

Life-threatening complications from a single bolus of 100,000 IU in Sarcoid patients were first documented by Guy Scadding in the BMJ over half a century ago [2]. But the potential for a massive Public Health disaster really comes from those with undiagnosed Vitamin D dysregulation, especially that resulting from a lesser immune dysfunction, such as Crohn's, Lupus or Rheumatoid Arthritis [3].

We recently detailed some of these 'at-risk' groups in a BMJ Rapid Response [4]. That communication explains why lethal concentrations of 1,25-dihydroxyvitamin D (1,25-D), the biologically potent metabolite, would potentially result from the administration of 100,000 IU cholecalciferol to those who are 'at-risk'. We have also detailed the actions of Vitamin D on the biochemistry of the immune system [5].

In 1994 the US FDA decreed [6] that not only must 'Vitamin D' (cholecalciferol) be assayed in any study of osteoporotic therapies, but also the inactive metabolite 25-hydroxyvitamin D (25-D) and the active secosteroid-hormone 1,25-D. As a result, the US now has much more detailed data available to characterize the entire Vitamin D metabolism. All these metabolites, including 1,25-D, may be assayed from blood drawn at any doctor's office. I could not find any reference to the monitoring of 1,25-D during this study, but my own analysis of the US 1,25-D assay data indicates that undiagnosed Vitamin D dysregulation is far more prevalent within the US community than previously suspected. A study such as this, advocating high-dose therapy without attempting to quantify the population at risk, would not pass muster with the FDA.

As a result of BMJ's publication of Trivedi et al, CNN, and other news outlets, have headlined that supplementation with huge doses of Vitamin D is beneficial to the population at large. No mention is being made of any potentially harmful side effects resulting from the profound actions of Vitamin D on susceptible individuals. No warning was issued to those groups excluded from this study, or to others who might be harmed by adopting the high-dose bolus treatment promoted by these authors. The Abstract of this study did not even bother to mention the possibility that any such harm might occur. I believe that the BMJ has done a terrible disservice to Public Health by allowing this paper to be published with such misleading safety data, and with such a simplistic analysis of morbidity endpoints.

1. Trivedi DP, Doll R, Khaw KT: Effect of four monthly oral vitamin D3 (cholecalciferol) supplementation on fractures and mortality in men and women living in the community: randomised double blind controlled trial. BMJ 2003 Mar 1;326(7387):469 [Full Text]

2. Scadding JG: Sarcoidosis, with special reference to lung changes. BR Med J 1950, 1: 745-753

3. Mawer EB, Hayes ME, Still PE, Davies M, Lumb GA, Palit J, Holt PJ: Evidence for nonrenal synthesis of 1,25-dihydroxyvitamin D in patients with inflammatory arthritis. J Bone Miner Res 1991; 6(7): 733-9 [ Abstract]

4. Marshall TG, Marshall FE: Vitamin D may be Harmful in Rheumatic Disease.
bmj.com/cgi/eletters/326/7379/12/b#28700, 12 Jan 2003 [Full Text]

5. Marshall TG, Marshall FE: New Treatments Emerge as Sarcoidosis Yields Up its Secrets. clinmed 2003 Jan 27;2003010001. clinmed.netprints.org/cgi/content/full/2003010001 (accessed 27 Jan 2003) [Full Text]

6. Division of Metabolic and Endocrine Drug Products, Food and Drug Administration: Guidelines for Preclinical and Clinical Evaluation of Agents Used in the Prevention or Treatment of Postmenopausal Osteoporosis. 5600 Fishers Lane, HFD-510, Rockville, Maryland 20857-1706
Available from URL http://www.fda.gov/cder/guidance/osteo.pdf, Accessed March 2, 2003

Competing interests:   None declared

Competing interests: None declared

Trevor G Marshall, PhD, Research Director

Sarcinfo, Thousand Oaks, California

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