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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; 326 doi: http://dx.doi.org/10.1136/bmj.326.7387.469 (Published 01 March 2003) Cite this as: BMJ 2003;326:469

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

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.

References

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: No competing interests
03 March 2003
Trevor G Marshall, PhD
Research Director
Sarcinfo, Thousand Oaks, California
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