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Rapid Responses: Rapid Responses published:
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Vitamin D deficiency, lack of sunlight, multiple sclerosis
- Peter K. Tun (1 March 2003)
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Level of vitamin D (3) supplementation 100,000IU
- Anne Woo (1 March 2003)
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Re: Level of vitamin D (3) supplementation 100,000IU
- Robert D Toon (2 March 2003)
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Why no funding for a community trial?
- Jim Page (2 March 2003)
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100,000 IU of Vitamin D is a Lethal Dose for Many in our Community
- Trevor G Marshall, PhD (3 March 2003)
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How can Trivedi et al, Overlook the Possibility of Hypervitaminosis-D?
- Belinda J Fenter (3 March 2003)
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Safety of Vitamin D dose in used in fracture trial
- Kay-Tee Khaw (3 March 2003)
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A Therapy is Only Safe if it "Does No Harm"
- Trevor G Marshall, PhD (4 March 2003)
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Could vitamin D be of potential benefit in epileptic patients?
- Mohammed S Rashid (BPharm MRPharmS) (5 March 2003)
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Make sure to measure the correct 'Vitamin D'- there are four of them
- Trevor G Marshall (6 March 2003)
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Potential Confounding Factors May Have Impacted on the Results
- Henry Zeimer (7 March 2003)
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Re: How can Trivedi et al, Overlook the Possibility of Hypervitaminosis-D?
- Reinhold Vieth (9 March 2003)
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Podiatrists administering vitamin D
- Peter J Elton (10 March 2003)
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Vitamin D, falls and fractures
- Jugdeep K Dhesi, Theresa J. Allain (16 March 2003)
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Vitamin D status in the population
- Haakon E. Meyer (18 March 2003)
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frail elderly patients and vitamin D
- Michael D Stone (22 March 2003)
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Annual injection
- Mark D Oliver (22 March 2003)
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Vitamin D for the over 65s
- Lisa A Dunkley, ASM Jawad (22 March 2003)
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Re: Vitamin D, falls and fractures
- Andrew Herxheimer (28 March 2003)
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Dose of vitamin D
- John J Cannell, MD (12 April 2003)
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The effect and administration of vitamin D.
- Rauno J. Heikinheimo, Pirkko Jäntti (26 April 2003)
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Vitamin D and fractures
- Montserrat Romera, Josep Maria Ramon (5 May 2003)
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Peter K. Tun, Staff Grade Physician, Neurorehabilitation Medicine Royal Berkshire & Battle Hospitals, Reading, RG30 1AG
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Four monthly oral Vitamin D3 (cholecalciferol), 100,000 IU over 5 years reduced fractures in over 65 year-olds by 20% in your study is very encouraging. There have been an epidemiological evidence that multiple sclerosis (MS) is unknown in equator regions and uncommon in the tropics; MS prevalence increases outside 40 degrees latitude. In Switzerland MS is more prevalent in the valleys and less on mountain tops. MS is rare among Eskimos and people living in coastal fishing villages, possibly due to vitamin D in fish oils. Vitamin D absoprtion is reduced by phytic acid in cereals like wheat, oat, barley, corn. The only cereal without phytic acid is rice. Vitamin D not only have effect on the bone but also has an immuno- modulatory effect. A recent study from Germany showed seasonal variation in the number of MS plaques on magnetic resonance imaging MRI scans, 2 months after change in season; i.e. an increase in late winter and a decrease in mid summer. Growing up in the tropics (first 15 years of life) gives partial protection against MS. People who migrated to northern Australia, even at a later age, have less MS than those in Southern Australia. A longterm prospective double blind controlled study of the effect of vitamin D3 supplementation on MS will be most valuable among the high risk population. Competing interests: None declared |
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Anne Woo, Sr. Market Development Officer, Agriculture and Agri-Food Canada, 930 Carling Ave, 5th floor, Ottawa, Ontario, K1S 5A5
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I am writing about the daily supplementation of 100,000IU of oral Vitamin D3 (cholecalciferol). Please comment on the potential of a toxicity problems with a 100,000 IU vitamin D3 taken on a daily basis for 4 months. Thank you. Competing interests: None declared |
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Robert D Toon, Orthopaedic Surgeon, Acting Chief Orthopaedic Service Ireland Army Hospital, 851 Ireland Avenue, Fort Knox, KY 40121
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This letter is in response to the question whether 100,000 units Vitamin D3 daily would be toxic. It would probably be lethal, resulting in hypercalcaemia and renal failure. The patient would become sluggish and constipated and if the serum calcium weren't measured, the diagnosis could be missed. However, the dose in the article was 100,000 units Vitamin D3 once every 4 months for 5 years, not daily. It has been an eternity since I've written anything on calcium metabolism but this dose interval needs to be underscored. Carelessly giving an excessive dose of Vitamin D3 could be lethal. I have never seen this personally but the late Dr. Fraser had seen it. Bob Toon 1. Lancet, Nov 20;2(7995):1105-7 1976, Response of protracted neonatal hypocalcaemia to 1 alpha,25-dihydroxyvitamin D3. Kooh SW, Fraser D, Toon R, DeLuca HF Competing interests: None declared |
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Jim Page, General dental practitioner The Blockley Partnership, Tunbridge Wells, TN4 8BH
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I am interested as to why, following the success of this important study, no funding could be obtained for a more powerful trial. Presumably there is not enough profit in the sale of oral vitamin D for any drug company to be interested However, in these days of evidence based medicine, surely this is the sort of thing that the NHS should be spending its billions on rather than expensive initiatives which so far have no evidence to support their value such as, dare I say it, the NHSU?! Competing interests: None declared |
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Trevor G Marshall, PhD, Research Director Sarcinfo, Thousand Oaks, California
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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 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. 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 Competing interests: None declared |
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Belinda J Fenter, Research Assistant Sarcinfo, Fort Worth, Texas, 76116
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How can Trivedi, et al, overlook the possibility of Hypervitaminosis D? Their study of 100,000 IU oral vitamin D every 4 months concluded the participants had "no adverse effects", yet the study mentioned no assessment of any symptoms of Hypervitaminosis D among the study participants. Hypervitaminosis D is a real and obvious danger when administering high doses of vitamin D. Blank, et al, reported 41 hospitalizations and two deaths in an incident of inadvertent Vitamin D overfortification of the milk from a single dairy [1]. As the Trivedi study selectively (and vaguely) excluded people already taking vitamin D "supplements" (which would be next to impossible in the USA, considering that all milk is supplemented with vitamin D) and people with a history of renal stones, sarcoidosis or malignancy, how can it be broadly applied to the general population? I am sure the study's generalized conclusion will be used to try to justify increased fortification of vitamin D in the diet of the general public. The fact that exposure to sunlight, not diet, provides most humans with their vitamin D requirement[2] was never even mentioned. People will inevitably be harmed because, in all the hoopla about this study, the exclusion of those at risk for supplemental doses of vitamin D was not considered. 1. Blank S, Scanlon KS, Sinks TH, Lett S, Falk H: An outbreak of hypervitaminosis D associated with the overfortification of milk from a home-delivery dairy. Am J Public Health 1995 May;85(5):656-9 [PubMed Abstract] 2. Holick, MF: Vitamin D and bone health. J Nutr 1996 Apr;126(4 Suppl):1159S-64S [Pubmed Abstract] Competing interests: None declared |
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Kay-Tee Khaw, Professor of Clinical Gerontology University of Cambridge
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We would like to emphasize again that the dose of vitamin D used was a single oral dose of 100,000 IU administered once every four months, which over the year averages at about 800 IU daily, a dose which has been used in other trials(1). A previous trial by Heikinheimo used an annual 300,000 IU injection apparently safely(2) . Prior to the current trial, there has been extensive work to indicate that the 100,000 IU single dose will produce an elevation in 25-hydroxyvitamin D concentrations without any increase in serum calcium or other adverse side effects that occur when such doses are given daily over a prolonged period (3-5); peak concentrations after this dose occur about two weeks after ingestion of vitamin D(3). In the current and previous studies, measured blood levels of 25-hydroxyvitamin D in the supplemented group were still not high in absolute terms and below those physiologic concentrations found in young adults in the tropics. There is always concern about possible adverse consequences of any preventive measure. Though sunlight exposure in moderate amounts may not appreciably increase skin cancer risk, there are still worries about adverse effects of unduly increasing exposure to ultraviolet light. The capacity of human skin to produce vitamin D3 in the presence of sunlight decreases with age (6); additionally, populations who live above a latitude of 42 degrees do not produce vitamin D from sun exposure from November to February so vitamin D concentrations are dependent upon those built up during the previous summer, and on dietary intake. In terms of food fortification, there are also concerns both over the effectiveness of vitamin D fortification of foods reaching those at high risk of vitamin D deficiency such as elderly populations, as well as the dangers of vitamin D overdosage, for example, through incorrect and excessive fortification of milk resulting, in one report(7) in measured concentrations of 0.79-6.08 mg/L (30,000-230,000 IU/quart) compared with the standard of 0.01mg/L (400 IU/quart). Vitamin D toxicity resulted from extreme errors in food fortification and excessive intake over a length of time. Because of the difficulties with both sunlight exposure and food fortification, this trial used once every four months a specific single supplemental dose that had previously well-documented effects. In the full paper on the website we show extensive data on several other major endpoints apart from fracture in all the participants, and found no significant adverse effects; in particular, though not statistically significant, the mortality risk was if anything slightly lower in the supplemented group. References 1. Chapuy MC, Arlot ME, Duboeuf F, Brun J, Crouzet B, Arnaud S, et al. Vitamin D3 and calcium to prevent hip fractures in the elderly women. N Engl J Med 1992; 327: 1637-1642 2. Heikinheimo RJ, Inkovaara JA, Harju EJ, Haavisto MV, Kaarela RH, Kataja JM, et al. Annual injection of vitamin D and fractures of aged bones. Calcif Tissue Int 1992; 51: 105-110 3. Weisman Y, Schen RJ, Eisenberg Z et al. Single oral high dose vitamin D3 prophylaxis in the elderly. J Am Geriatr Soc 1986;34:515-8. 4. Davies M, Mawer EB, Hann JT, Stephens WP, Taylor JL. Vitamin D prophylaxis in the elderly: a simple effective method suitable for large populations. Age Ageing 1985;14:349-54. 5. Khaw KT, Scragg R, Murphy S. Single dose cholecalciferol suppresses the winter increase in parathyroid hormone concentrations in healthy older men and women: a randomized trial. Am J Clin Nutrition 1994;59:1040-4. 6. MacLaughlin J, Holick MF. Aging decreases the capacity of human skin to produce vitamin D3. J Clin Invest 1985;76:1536-8. 7. Jacobus CH, Holick MF, Shao Q et al. Hypervitaminosis D associated with drinking milk. New Engl J Med 1992;326:1173-7. Competing interests: None declared |
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Trevor G Marshall, PhD, Research Director Sarcinfo, Thousand Oaks, California, 91360-1122
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re: Professor Kay-Tee Khaw: Safety of Vitamin D dose in used in fracture trial [1] In the early 90's there was a renaissance in our understanding of the way that Vitamin D is metabolized in the body. We now know that the metabolites which we had become accustomed to measure, Vitamin D (cholecalciferol) and 25-hydroxyvitamin D (25-D), are actually inactive intermediaries. They are converted to the active hormone, 1,25-dihydroxyvitamin D (1,25-D) in the kidneys and in the keratinocytes of the skin. 1,25-D is also manufactured in the placenta during pregnancy. Macrophages, activated during an immune response, also energetically convert 25-D to 1,25-D. Recent studies have identified other active metabolites, including 24R,25-dihydroxyvitamin D, and attempts to improve our understanding of the full effects of Vitamin D on body function are ongoing. The amount of the 1,25-D hormone is miniscule, about 30 picograms per milliliter. A sensitive radioimmunoassay is needed to measure it. But its effects on body systems are profound. The University of California, Riverside, (who have a Vit D website), and UCLA, have both added greatly to our knowledge of the effects of this secosteroid. Mawer, et al, (University of Manchester, UK) also performed landmark research to define the manner in which the D metabolism behaves in disease states. Figure 1 of the 1991 paper [2] from that group is a graph showing the concentration of serum 1,25-D measured on 5 consecutive days after the administration of just 250 µg of oral 25-hydroxyvitamin D3. It shows that the maximum concentration of 1,25-D in one Rheumatoid Arthritis (RA) patient surged to 80 pg/ml, while that of a control remained around normal (30 pg/ml). Further, the control subject was able to regulate the levels of 1,25-D generated in response to the bolus, while the RA patient was not. Merck [3] gives a maximum level for this hormone of 45 pg/ml, which is also the 2 sigma point of the Danish population study [4]. It is clear that this RA patient was unable to safely control their generation of 1,25-D in response to the oral bolus. In fact, a total of 8 of the 19 RA subject patients produced 1,25-D levels which "exceeded the normal upper limit" [2]. In the USA the FDA issued its "Good Guidance Practice" in 1994 [5], formally published in 1997, which effectively put an end to the measurement of 25-D without consideration of the effects of the active hormone, 1,25-D. Any study of osteoporotic therapies must measure the active hormone, or justify why it is not relevant. As a result, the assay of 1,25-D has become routine at all the major labs, and any Physician in the USA can now draw 8ml of blood and order the assay of both 25-D and 1,25-D. A full understanding of the Vitamin D metabolism, and the effects of the active hormone on the body, allow much deeper insights into potential morbidity than were explored in the Trivedi, at al, study. In particular, morbidity endpoints can be identified which cannot be anticipated merely from consideration of the prior epidemiological data cited by Khaw [1]. Again I refer to our previous Rapid Response [6] for a more in-depth explanation of the key issues. We have observed two pathways potentially resulting in the death of the patient. The first is via involuntary contraction of throat muscles, which progresses with increasing 1,25-D concentration until the patient can no longer breathe. The second is muscle spasm and cramp, ultimately manifesting itself as uncontrolled Cardiac Arrhythmia. Other serious morbidity attributable to excessive levels of this hormone include Facial Palsy [7] and a host of other problems which have collectively become known as "Hypervitaminosis D". In my opinion, it is not adequate to look at epidemiological data from a study of this limited size and draw any conclusions relating to the safety of admistering a 100,000 IU bolus of Vitamin D "in the general community". I can personally identify patients who would likely be killed by such a dose. At the other extreme it is clear that the healthy can assimilate the dose safely. The most seriously ill individuals would be protected by their physicians from being given such a potentially fatal dose (wouldn't they?), so the problem is to define the reaction of population between these extremes. What would have happened to the Manchester RA patient if he/she had been given a 100,000 IU bolus? Would they have survived? Maybe with just facial palsy? How many members of the population with undiagnosed "dysregulation of 1,25-dihydroxyvitamin D synthesis" (the terminology used by the FDA) would be harmed by such a dose? Crude, and statistically inaccurate estimation, might say that at least 1 of the 19 Manchester RA subjects was at serious risk, and, since RA affects as much as 6% of the population, maybe around 6%/19, or 0.3%, of the population is at serious risk. Clearly this is an unacceptable level, although it would only represent 8 patients in the tested cohort, of which only 4 would have been randomized to receive the bolus. The question as to how many susceptible individuals might be in the total population cannot be answered from studies which ignore the biologically active hormone of the Vitamin D metabolism, 1,25-dihydroxyvitamin D. No assertions should be made about the safety of a Vitamin D therapy unless it is reasonably certain that the population as a whole can tolerate it ("Do no harm"). In this case the reverse is actually true. We know from prior studies [eg 2] that some individuals will be harmed. Those with "a history of renal stones, sarcoidosis, or malignancy" were excluded from the cohort, presumably because they were thought to be at risk of harm. But this 100,000 IU bolus therapy is being advocated for implementation "in the general community" [8]. Surely the definition of exactly which individuals will be harmed, together with comprehensive and easily implemented screening procedures, would be a minimal prerequisite before any claims of "no significant adverse effects" "in the general community" could be made? References 2. 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] 3. The Merck Manual of Diagnosis and Therapy: Vitamin D Deficiency and Dependency. 17th Edition, Section 1, Chapter 3 [Full Text] 4. Brot C, Jorgensen NR, Sorensen OH: The influence of smoking on vitamin D status and calcium metabolism. Eur J Clin Nutr Dec 1999; 53(12): 920-6 [ Abstract] 5. 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 6. Marshall TG, Marshall FE: Vitamin D may be Harmful in Rheumatic
Disease. 7. Muler H, Paquelin F, Cotin G, Luboinski B, Henin JM: Facial paralysis in children. Ann Otolaryngol Chir Cervicofac 1975 May-Jun; 92(4-5): 229-34 [PubMed Abstract] 8. 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] Competing interests: None declared |
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Mohammed S Rashid (BPharm MRPharmS), Medical Student Univeristy of Liverpool
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Epilepsy is the commonest serious chronic disease of the nervous system affecting at least 380000 people in the United Kingdom [1]. Around 30000 people develop epilepsy every year and the condition will affect about 1 person in 20 at some time during their lives [2]. About 250000 people take antiepileptic drugs (AEDs) [3]. The aim of the treatment is to prevent seizures without causing adverse effects. Approximately 35 years ago, osteopathies occurring with long-term chronic antiepileptic treatment were first noted [4,5] and there have been numerous publications concerning the influence of AEDs on bone health ever since [6]. However, the underlying mechanisms leading to pathological bone mineral balance with these drugs remain largely unclear. Alterations in vitamin D metabolism are frequent in patients treated with anticonvulsant drugs [7-10]. Besides nutritional influences and sunlight dependent 7-dehydrocholestrol conversion in the skin, enzyme induction in the liver seems to be the major mechanism responsible for decreased vitamin D hormone levels [11]. Institutionalised patients [12], postmenopausal women [13,14], older men [14] and children [15] receiving AEDs have been identified to be more susceptible to AED-induced bone disease such as osteomalacia and osteopenia/osteoporosis. There are numerous reports documenting radiological [14-23], histological [24] and biochemical [11,25] evidence of bone disease in patients taking AEDs. Because epileptic patients are usually treated for many years with AEDs, and occasionally with more than one AED, the risk for bone complications is often enhanced [11,15,26]. Several studies have shown that there is a marked increase in the expected fracture rate in epileptic patients on long-term AED treatment [13,27,28]. With a significant number of people having epilepsy, AED-induced osteoporosis might be a major neglected health problem in this country. As many patients present with hypocalcaemia and low vitamin D levels, these parameters should be monitored in all patients under antiepileptic therapy and adequate supplementation of calcium and vitamin D should be considered. Raising awareness of this problem amongst health care professionals could significantly improve the skeletal health of AED-treated individuals. Manufacturers and investigators, irrespective of any legal obligation, should continue to study new AEDs after marketing in order to detect long-term adverse effects on bone health. References 1.Department of Health. Annual Report of the Chief Medical Officer. London: Department of Health, 2001. 2.Shorvon S. D.. Epidemiology, classification, natural history and genetics of epilepsy. Lancet 1990;336:93-96. 3.Clarke C. R. A.. Neurological diseases and diseases of voluntary muscle. In: Kumar P., Clark M., editors.. Clinical medicine. London: Saunders, 3rd ed., 1996:912-916. 4.Schmid F.. Osteopathien bei antiepileptischer Dauerbehandlung. Fortschr Med 1967;85:381-382. 5.Kruse R.. Osteopathien bei antiepileptischer Langzeittherapie (vorlaufige Mitteilung). Mschr Kinderleilkd 1968;116:378-380. 6.Pack A. M., Morrell M. J.. Adverse effects of antiepileptic drugs on bone structure. CNS Drugs 2001;15(8):633-642. 7.Hahn T. J., Hendin B. A., Scharp C. R., Haddad J. G.. Effect of chronic anticonvulsant therapy on serum 25-hydroxycalciferol levels in adults. N Engl J Med 1972;287:900-904. 8.Bell R. D., Pak C. Y. C., Zerwekh J., Barilla D. E., Vasko M.. Effect of phenytoin on bone and vitamin D metabolism. Ann Neurol 1979;5:374-378. 9.Zerwekh J., Homan R., Tindall R., Pak C.. Decreased serum 24,25- dihyroxyvitamin D concentration during long-term anticonvulsant therapy in adult epileptics. Ann Neurol 1982;12:184-186. 10.Collins N., Maher J., Cole M., Baker M., Callaghan N.. A prospective study to evaluate the dose of vitamin D required to correct low 25-hydroxyvtamin D levels, calcium, and alkaline phosphatase in patients at risk of developing antiepileptic-drug induced osteomalacia. Quart J Med 1991;78:113-122. 11.Gough H., Goggin T., Bissesar A., Baker M., Crowley M., Callaghan N.. A comparative study of the relative influence of different anticonvulsant drugs, UV exposure and diet on vitamin D and calcium metabolism in patients with epilepsy. Quart J Med 1986;59:569-577. 12.Hoikka V., Savolainen K., Esko M., et al.. Osteomalacia in institutionalised epileptic patients on long-term anticonvulsant therapy. Acta Neurol Scan 1981;64:122-131. 13.Cummings S. R., Nevitt M. C., Browner W. S., et al.. Risk factors for hip fracture in white women. Study of Osteoporotic Fracture Research Group. N Engl J Med 1995;332(12):767-773. 14.Stephen L. J., McLellan A. R., Harrison J. H., et al.. Bone density and antiepileptic drugs: a case controlled study. Seizure 1999;8(6):339-342. 15.Chung S., Ahn C.. Effects of anti-epileptic drug therapy on bone mineral density in ambulatory epileptic children. Brain Dev 1994;16:382- 385. 16.Chun-Yuan G., Ronen G. M., Atkinson S. A.. Long-term valproate and lamotrigine treatment may be a marker for reduced growth and bone mass in children with epilepsy. Epilepsia 2001;42(9):1141-1147. 17.Sato Y., Kondo I., Ishida S., et al.. Decreased bone mass and increased bone turnover with valproate therapy in adults with epilepsy. Neurology 2001;57:445-449. 18.Altay E. E., Serdaroglu A., Tumer L., et al.. Evaluation of bone mineral metabolism in children receiving carbamazepine and valproic acid. J of Ped Endocrinol Metab 2000;13:933-939. 19.Badcock L. J., Smth J. A., Price T., Mulherin D. M.. Bone mineral density in post-menopausal women on anticonvulsant therapy. J Ir Coll Phys Surg 2000;29(3):138-140. 20.Kubota F., Kifune A., Shibata N., et al.. Bone mineral density of epileptic patients on long-term antiepileptic drug therapy: a quantitative digital radiography study. Epilepsy Res 1999;33(2-3):93-97. 21.Kafali G., Erselcan T., Tanzer F.. Effect of antiepileptic drugs on bone mineral density in children between ages 6 and 12 years. Clin Pediatr 1999;38(2):93-98. 22.Akin R., Okutan V., Sarici U., et al.. Evaluation of bone mineral density in children receiving antiepileptic drugs. Pediatr Neurol 1998;19:129-131. 23.Sheth R. D., Wesolowski C. A., Jacob J. C., et al.. Effect of carbamazepine and valproate on bone mineral density. J Pediatr 1995;127:256-262. 24.Mosekilde L., Melsen F.. Anticonvulsant osteomalacia determined by quantitative analysis of bone changes. Acta Med Scand 1976;199:349-355. 25.Verrotti A., Greco R., Morgese G., et al.. Increased bone turnover in epileptic patients treated with carbamazepine. Ann Neurol 2000;47:385- 388. 26.Gough H., Bissesar A., Goggin T., et al.. Factors associated with the biochemical changes in vitamin D and calcium metabolism in institutionalised patients with epilepsy. Ir J Med Sci 1986;155(6):181- 189. 27.Nilsson O. S., Lindholm T. S., Elmsteadt E., Lindback A., Lindholm T.C.. Fracture incidence and bone disease in epileptics receiving long- term anticonvulsant drug treatment. Arch Orthop Trauma Surg 1986;105:146- 149. 28.Desai K. B., Ribbans W. J., Taylor G. J.. Incidence of five common fracture types in an institutional epileptic population. Injury 1996;27:97 -100. Competing interests: None declared |
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Trevor G Marshall, Research Director Sarcinfo, Thousand Oaks, California 91360-1122
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re: Mohammed S Rashid: Could vitamin D be of potential benefit in epileptic patients? I would suggest that Riancho et al, 1989, [1] might be a better starting point than Gough et al, 1986, the reference cited as a description of "Vitamin D" in Epilepsy. The only 'Vitamin D' measured by Gough, et al, is 25-dihydroxyvitamin D (25-D). This is an inactive metabolite and a very poor indicator of 'Vitamin D' activity within the body. The hormone that is active in the regeneration and strengthening of bone is 1,25-dihydroxyvitamin D (1,25-D), which is metabolized from the intermediate 25-D. In our BMJ Rapid response to Mudur titled "Vitamin D may be Harmful in Rheumatic Disease" [2] (Click here to read it) we explain why measurement if the inactive hormone 25-D will usually give a totally incorrect impression of the activity of Vitamin D in the body. Our two Rapid Responses in this thread, "100,000 IU of Vitamin D is a Lethal Dose for Many in our Community" and A Therapy is Only Safe if it "Does No Harm" also give many references to the literature and pharmacology which explain the Vitamin D metabolism in more detail. In my opinion, 'Vitamin D' should NEVER be supplemented unless the individual's level of the active hormone 1,25-D has been measured, and it has been verified to be less than the 'normal mean' (29 pg/ml or 75 pmol/L [3]). Too much active hormone (1,25-D) risks hyper-activation of the immune system and exacerbating Rheumatic Disease. The actions of 'Vitamin D' hold the clue to many diseases, such as Sarcoidosis [4]. But any studies which attempt to draw conclusions about Vitamin D's biological activity without first studying the active hormone are, at best, crude guesstimates of reality. References: 2. Marshall TG, Marshall FE: Vitamin D may be Harmful in Rheumatic
Disease. 3. Brot C, Jorgensen NR, Sorensen OH: The influence of smoking on vitamin D status and calcium metabolism. Eur J Clin Nutr Dec 1999; 53(12): 920-6 [ Abstract] 4. 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] Competing interests: None declared |
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Henry Zeimer, Consultant Geriatrician Austin & Repatriation Medical Centre , Aged Care Services,Heidelberg,Victoria,3084,Australia
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I read the study by Trivedi et al (1) with interest , but it appears to me that the study methodology has some serious omissions and possible flaws . People taking vitamin D supplements were excluded from the study , but it is not clear as to whether calcium supplements , or indeed antiresorptive treatment with bisphosphonate or selective estrogen receptor modulator , were allowed during the 5 years of the trial . These medications would certainly impact on fracture incidence , and their usage across the 2 patient groups would need to be controlled for in order to make conclusions about the benefit of vitamin D therapy . As we know that sunlight is the richest source of vitamin D in community dwelling adults , other potential confounding factors do not appear to have been considered in the subgroup population used to study serum vitamin D and parathyroid hormone ( PTH ) levels . Previous studies have shown differing serum vitamin D and PTH levels across different racial groups within the same population (2-4). Information regarding the relative numbers of participants from Caucasian or other racial backgrounds is not given in this study subgroup . Another theoretical confounding factor which needs to be considered in all trials involving vitamin D is the amount of time spent by the participants in sunlight . How was this controlled for across the 2 study subgroups ? Although the results of this study were encouraging , the authors need to provide additional information on the study methodology in order to add credibility to the results . 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 controled trial.BMJ 2003;326:469-474 2. Perry HM III,Miller DK,Morley JE et al. A preliminary report of vitamin D and calcium metabolism in older African Americans.J Am Geriatric Soc 1993;41:612-616. 3. Harris SS,Dawson-Hughes B.Seasonal changes in plasma 25 - hydoxyvitamin D concentration of young American black and white women.Am J Clin Nutr 1998;67:1232-1236. 4.Nesby-O'Dell S,Scanlon KS,Cogswell ME et al.Hypovitaminosis D prevalence and determinants among African American and white women of reproductive age:third National Health and Nutrition Examination Survey,1988-1994.Am J Clin Nutr 2002;76:187-192. Competing interests: None declared |
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Reinhold Vieth, Associate Professor Mount Sinai Hospital, and University of Toronto, Toronto, Canada, M5G 1X5
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The BMJ electronic responses of Marshall, and of Fenter are pressing the issue vitamin D toxicity too severely. Readers interested or concerned about the issue of vitamin D excess should refer to the recent European Commission opinion paper that reviews the field. The document is freely available at the following internet address: http://europa.eu.int/comm/food/fs/sc/scf/out157_en.pdf The equivalent to 800 IU/day used by Trivedi et al is one fifth the 4000 IU/day that is the "No observed adverse effect level". It is also far below the amount that Heaney et al showed did not cause hypercalcemia (1). The situation reported by Blank et al, and cited by Fenter, involved 10,000 households that were delivered milk for years from one dairy. That milk contained an average of 12,000 IU per quart (and which ranged to over 100,000 IU/quart). This was an industrial accident. It is nowhere near comparable to anything being considered for osteoporosis prevention. I have two concerns about the dosing strategy used by Trivedi, Doll and Khaw. First, vitamin D, through its metaboite 25(OH)D, has a biological half-life of approximately 2 months (3). It is unusual for any compound to be administered at this long an interval in relation to metabolic clearance. This creates a situation where 3/4ths of the peak circulating concentration has dissipated prior to the next dose of vitamin D. Dawson-Hughes has shown that the seasonal fluctuations in 25(OH)D contribute to loss of BMD (4), and that daily supplementation lessens the BMD losses. Second, administration of 100,000 IU of vitamin D all at once exceeds the physiological rate of acquisition by ten-fold. To assure people that this is safe, the serum and urine calcium levels should be monitored during the first 72 hours after the dose is taken, not later, when the stress of the dose has dissipated. I congratulate Trivedi, Doll and Khaw on a truly fine study that moves the field of osteoporosis prevention forward. Reinhold Vieth Literature Cited 1. Heaney 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;77:204-10. 2. Blank S, Scanlon KS, Sinks TH, Lett S, Falk H: An outbreak of hypervitaminosis D associated with the overfortification of milk from a home-delivery dairy. Am J Public Health 1995;85(5):656-9 3. Vieth R. Vitamin D supplementation, 25-hydroxyvitamin D concentrations, and safety. Am.J Clin.Nutr. 1999;69:842-56. 4. Dawson-Hughes B, Dallal GE, Krall EA, Harris S, Sokoll LJ, Falconer G. Effect of vitamin D supplementation on wintertime and overall bone loss in healthy postmenopausal women . Annals of Internal Medicine 1991;115:505-512. Competing interests: None declared |
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Peter J Elton, Director of Public health Bury Primary Care Trust, Bury BL9 0EN
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From the mid 1980s, North Manchester podiatry service offered all its patients over the age of 65, 100,000 i.u. vitamin D orally twice yearly when they were seen for their podiatry needs. This was based on the suggestive evidence that vitamin D deficiency increased the risk of hip fracture and caused osteomalacia. As there had been no intervention trial of vitamin D for the reduction of osteomalacia, we undertook such a study in Bolton in 1996-8 (1) The prevalence of osteomalacia in the elderly has been estimated at rates of 1.5% to 4%(2-4). In this double-blind study, 3,443 patients aged over 65 were randomised to either 5ml of arachis oil containing 30,000 i.u. of vitamin D or 5ml of arachis oil only. In the absence of any validated questionnaire for osteomalacia, patients were asked about non-joint pain by a series of questions (available on request) at two to three months and, for who had an improvement in bone pain at this first assessment, at twelve months after further doses of vitamin D or placebo every two to three months. Of the 3,443 patients who took part in the study, 1,246 (36%) reported non-joint bone pain at baseline. The results showed no difference between the two groups (full results available on request). For example, amongst those initially reporting non-joint bone pain, the results at three months were: Number Number Total improved(%) worse(%) number Intervention 113 (17.5) 20 (3.1) 645 Control 105 (17.5) 21 (3.5) 601 Although we failed to show any difference or get our results published, mainly due to the use of unvalidated questions, both this study and the experience in North Manchester shows the feasibility of podiatrists administering vitamin D in their everyday work. As it appears that vitamin D does reduce fractures(5), and podiatrists see a considerable proportion of people aged over 65, their possible role should be considerd. Competing interests: None declared |
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Jugdeep K Dhesi, SpR Clinical Age Research Unit, King's College Hospital,GKT School of Medicine, Bessemer Rd, London, SE, Theresa J. Allain
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Editor- Daksha P Trivedi and colleagues report that vitamin D supplementation prevents fractures in older adults, despite no difference in heel ultrasound measurements (1). Previous work has also demonstrated only modest improvements in hip and spinal bone density following vitamin D supplementation (2;3). In view of this, changes in bone mineral density are unlikely to be the sole explanation for the reduced fracture rate. A more likely explanation for the results is a decrease in the incidence of falls in the treatment group. However, the incidence of falls was not reported in this study. In older adults 90% of non vertebral fractures occur as a result of falls(4) and age related factors other than bone mineral density become dominant determinants of hip fracture risk(5). These factors include changes in neuromuscular and central nervous system function that predispose to falls and fractures. Vitamin D deficiency is common among people who fall(6;7) and there is increasing evidence to suggest vitamin D plays an important role in the maintenance of functions which protect against falls. Significant relationships have been identified between vitamin D and muscle strength, postural sway, reaction times, and functional performance(8). In prospective studies of vitamin D supplementation, improvements in neuromuscular and psychomotor function and a reduction in falls has been demonstrated(9). Further work in this important area is underway. It is likely that vitamin D supplementation reduces fracture rate via two different mechanisms; by improving the mechanical and structural integrity of the skeleton, and by maintaining or improving neuromuscular function and/or neuroprotection, thus reducing the incidence of falls. In order to understand the causes of fractures and to appropriately address the increasing prevalence and consequent morbidity in the elderly, trials assessing treatment should include information about the incidence of falls. JK Dhesi Research Fellow1 TJ Allain Consultant, Care of the Elderly2 1Clinical Age Research Unit New Medical School, King’s College Hospital Bessemer Rd, London SE5 9PJ 2Department of Care of the Elderly Southmead Hospital, North Bristol NHS Trust, Bristol, BS10 5NB UK Reference List (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;326:469-472. (2) Chapuy MC, Arlot ME, Duboeuf F, Brun J. Vitamin D3 and Calcium to prevent hip fractures in elderly females. N Eng J Med 1992; 327(23):1637-1642. (3) Dawson-Hughes B, Harris SS, Krall EA, Dallal GE. Effect of calcium and vitamin D supplementation on bone density in females and males 65 years of age and older. N Eng J Med 1997; 337(10):670-676. (4) Gaerdsell P, Jonell O, Nilsson BE, Nillson JA. The predictive value of fracture, disease and falling tendency for fragility fractures in women. Calcif Tiss Inter 1989; 45:327-330. (5) Melton LJ, Kan SH, Wahner HW, Riggs K. Lifetime fracture risk: An approach to hip fracture risk assessment based on bone mineral density and age. J Clin Epidemiol 1988; 41:985-994. (6) Stein MS, Wark JD, Scherer SC, Walton SL, Chick P, Di Carlantonio M et al. Falls relate to vitamin D and parathyroid hormone in an Australian nursing home and hostel. J Am Geriatr Soc 1999; 47(10):1195- 1201. (7) Dhesi JK, Close J, Jackson SHD, Moniz C, Allain TJ. A rationale for vitamin D prescribing in a falls clinic population. Age Ageing 2002;31: 267-271. (8) Dhesi JK, Bearne L, Moniz C, Hurley M, Swift CG, Jackson SHD et al. Neuromuscular and psychomotor function in elderly people who fall and the relationship with vitamin D status. J Bone Miner Res 2002;17:891-897. (9) Pfeifer M, Begerow B, Minne HW, Abrams C, Nachtigall D, Hansen C. Effects of a short term vitamin D and calcium supplementation on body sway and secondary hyperparathyroidism in elderly women. J Bone Miner Res 2000;15:1113-1118. Competing interests: None declared |
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Haakon E. Meyer, Senior medical officer & Epidemiologist Norwegian Institute of Public Health, P.O.Box 4404 Nydalen, 0403 Oslo, Norway
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I have with great interest read the article by Trivedi, Doll and Khaw [1]. Concerning the generalisability of their results, it would be very informative to know more about the vitamin D status in the background population in which the study was undertaken. According to the results from blood samples collected from a subsample of 235 study participants, the vitamin D status in the placebo group was surprisingly good (mean serum 25-hydroxyvitamin D 53.4 nmol/l, SD 21.1). However, the blood samples were collected in September and October, a time of the year when the vitamin D stores have been optimised by cutaneous production of vitamin D during the summer. In addition, it is not stated which method was used in the analysis of 25-hydroxyvitamin D, and large interlaboratory variation makes it difficult to compare results across studies [2]. The study participants did not take vitamin D supplements at baseline. Is there any information available concerning their dietary intake of vitamin D? 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;326:469. 2. Lips P, Chapuy MC, Dawson-Hughes B, Pols HA, Holick MF. An international comparison of serum 25-hydroxyvitamin D measurements. Osteoporos.Int. 1999;9:394-7. Competing interests: None declared |
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Michael D Stone, Director of Bone Research UWCM, Llandough Hospital, Penarth, CF64 2XX
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I read with great interest this article not least because we are conducting a very similar trial in Wales using the same dosing regimen of 100,000 units of vitamin D thrice yearly in 3,500 elderly patients. However the patients in our trial are all in institutional care or sheltered accommodation in contradistinction to the fitter and slightly younger patients in the study by Travedi et al. It does of course raise the important question (which has been partially addressed in this paper) of whether calcium or vitamin D or both is required for beneficial effects on fracture risk. Direct comparison was made with the study by Chapuy et al but of course the patients in the Chapuy trial were considerably older and frailer in that they were recruited from nursing homes and the degree of vitamin D deficiency and secondary hyperparathyroidism were greater. Although conjecture, it has been suggested that the lack of beneficial effect in the study by Lips et al with 400 units of oral vit D daily represented a failure of adequate suppression of parathyroid hormone and addition of extra calcium supplementation would be physiologically the neatest solution to this. For example the percentage reductions in excess serum PTH concentartions were far higher in studies using a combination of calcium and vit D supplements than with Vitamin D alone. The dietary calcium intake of the subjects may also be relevant. In the study by Travedi et al the average daily calcium intake was 742 mg compared with 500 mg per day in the Chapuy study. Thus the efficacy of vitamin D alone remains in question in the institutionalised or frail elderly. Competing interests: Member of Shire Pharmaceuticals Advisory Board |
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Mark D Oliver, GP Principal Stafford ST16 3AT
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An annual injection of the 300 000 units/ml dose in the BNF given to the frail elderly with their flu jab seems to me to have enormous potential to reduce fractures, without much increase in workload.A study of the safety of this is urgently needed. Competing interests: None declared |
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Lisa A Dunkley, SpR Rheumatology Royal London Hospital, Bancroft Road, London, E1 4DG, ASM Jawad
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Sir Though previous studies of isolated Vitamin D supplementation have been inconclusive [1], Trivedi et al have shown that four monthly oral Vitamin D3 supplementation may prevent fracture, without adverse effects, in men and women aged 65 years and over living in the community [2]. Because Vitamin D levels are lowest from October to March in people aged 65 years and over (not living in institutions)[3],it is reasonable to recommend that those people are given one tablet of Vitamin D3 100 000 iu when they attend for the influenza vaccine injection in the autumn. This simple and inexpensive measure may prove cost effective in fracture prevention in the over 65s. References: [1]Gillespie WJ, Henry DA, O'Connell DL, Robertson J: Vitamin D and Vitamin D analogues for preventing fracture associated with involutional and post-menopausal osteoporosis. Cochrane Database Syst Rev 2002;(3):CD 000227 [2]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;326(1 March): 469-472. [3]Finch S, Doyle W, Lowe C, Bates CJ, Prentice A, Smithers G, Clarke PC: National Diet and Nutrition Survey: people aged 65 years and over. Volume I: report of the diet and nutrition survey. London: The Stationery Office, 1998. Dr LA Dunkley SpR Rheumatology Dr ASM Jawad Consultant Rheumatologist Dept of Rheumatology Royal London NHS Trust Bancroft Road London E1 4DG Competing interests: None declared |
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Andrew Herxheimer, emeritus fellow, UK Cochrane Centre London N3 2NL
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In addition to knowing how many falls each of the participants had during the period of the trial, it would be useful to know how many of them had two or more fractures at some time in the five years. The hypothesis would be strengthened if fewer of the treated individuals had more than one fracture. Competing interests: None declared |
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John J Cannell, MD, Atascadero State Hospital Atascadero, CA 93422
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Trivedi et al, has done a service to medicine by using a dose of cholecalciferol (averaging 800 IU a day) that was slightly more than homeopathic. As the authors themselves concluded, parathormone levels were not significantly lower in the vitamin D group suggesting that the 100,000 IU dose every four months was insufficient. The most important fact anyone should know about vitamin D dose is that sunbathing for an hour in the summer gives one 10,000 units (1,2). This fact, if it is accurate, leads one to inescapable conclusions concerning man's historical "dose" of vitamin D, at least before humans went inside. In 1997 the Food and Nutirition Board increased their recommendations, suggesting elderly persons get 600 IU a day of Vitmain D. Two former members of that Board (Robert P Heaney and Michael F Holick) together with collegues(3)recently conducted the first systematic investigation of the dose-response relation of physiologically doses of vitamin D and 25-OH vitamin D levels. They concluded "healthy men seem to use 3000–5000 IU cholecalciferol/day," adding "the recommendations of the FNB with respect to oral vitamin D input fall into a curious zone between irrelevance and inadequacy. For those persons with extensive solar exposure, the recommended inputs add little to their usual daily production, and for those with no exposure (or those, such as the elderly, with reduced cutaneous synthesis), the recommended doses are insufficient to ensure desired 25(OH)D concentrations." Current fears about vitamin D toxicity are the single greatest impediment to clinical research concerning vitamin D. Vieth's comphrehensive 1999 review on the safety of vitamin D (1) should be required reading in medical school. The most intriguing aspect of the Trivedi, Doll and Khawir study was the insignificant, but suggestive, decline in all cause mortality (p value of .18), including cancer mortality. One can only wonder what they would have found if they had used physiological doses of vitamin D. 1. Vieth R. Vitamin D supplementation, 25-hydroxyvitamin D concentrations, and safety. Am J Clin Nutr 1999;69:842-856. 2. Holick MF. Sunlight "D"ilemma: risk of skin cancer or bone disease and muscle weakness. Lancet 2001;357:4–6. 3. Heaney RP, Davies KM, Chen TC, Holick MF, and Barger-Lux MJ. Human serum 25-hydroxycholecalciferol response to extended oral dosing with cholecalciferol. Am J Clin Nutr 2003;77:204-210. 4. Reinhold Vieth, Pak-Cheung R Chan, and Gordon D MacFarlane Efficacy and safety of vitamin D3 intake exceeding the lowest observed adverse effect level Am J Clin Nutr 2001 73: 288-294. Competing interests: None declared |
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Rauno J. Heikinheimo, retired, reader in geriatric medicine none, Pirkko Jäntti
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We were most delighted to read the paper by Dr. Trivedi et al.(1)because it presented a very practical way of saving the work in the vitamin D treatment and especially because their results were very similar with the ours (2) and contrary to those of some others. The first similarity was that vitamin D treatment helps significantly in diminishing the fractures of wrists and forearm (22 fractures instead of 38 in controls) but shows only a slight non significant trend in hip fractures ( 21 instead of 24 in controls). Soon after our paper of clinical results was published in August l992 (2) a paper by Dr. Chapuy et al. came out in December l992 (3) in which the writers obtained the most succesful effect precisely in hip fractures. Another point is that Trivedi et al found no difference between the groups in heel ultrasound measures. We found the same result in Bone Mineral Density (4) whereas in the paper of Dr Chapuy et al. (3) a highly significant difference in the bone is presented. The intramuscular administration of vitamin D we used really raised the 25OHD for all the year (5) - and actually for most of the second year (2) when we did our study. However, when we tried to refresh our knolidge - and that of the other's - of the most practical way of vitamin D treatment and compared the effect of Calciferol inject ampoules (Celltech) 150 000 IU and peroral vitamin D 400 IU a day and placebo we found to our astonishment that the curve of 25OHD after the injection of Calciferol hardly differed at all from that of the placebo group whereas it rose most beautifully in the peroral vitamin D group. The manufacturers of the Calciferol ampoules have probably changed the content somehow in the mid l980's and send for our studies the old type of ampoules with a brilliant and longlasting effect, but are at the present making it somehow differently. The presently available Calciferol (Celltech) ampoules have no significant effect to 25OHD - in the long run at least. The preparation Trivedi et al. used may now be the best possible form of vitamin D treatment. Only what we still wanted to see is a weekly value of 25OHD during this three monthly period after one pill of 100 000 IU of vitamin D. Yampere, Finland 25 April 2003. Rauno Heikinheimo Pirkko Jäntti Hämeenpuisto l. Tunturikatu 8.A.14. FIN - 33210 Tampere, Finland FIN - 33500 Tampere, Finland. Tel and Fax 358-3-222 7332. rauno.heikinheimo@raunomo.fi References. 1.Trivedi DP, Doll R,Khaw ET: Effect of four monthly oral vitamin D3 (cholecalciferol) supplementation on fractures and mortality in men and women living in the community: randomised double blind trial. BMJ. 2003:326:469. 2. Heikinheimo RJ, Inkovaara JA Harju EJ et al. :Annual injection of vitamin D and Fractures of Aged Bones. Calcif. Tissue Int. l992:51:l05- 110. 3. Chapuy MC,Arlot ME, Duboef et al: Vitamin D3 and Calcium to prevent hip fractures in the elderly women. N. Engl.J.Med. 1992:327:1637- l642. 4. Heikinheimo R, Sievänen H, Jäntti P et al. Vitamin D treatment and bone mineral density in the aged. Maturitas l996 Suppl 23:s 77-80. 5. Heikinheimo RJ, Haavisto MV, Harju EJ et al. Serum vitamin D level after an annual intramuscular injection of ergocalciferol. Calcif Tissue Int. l99l Suppl. 49:s87. Competing interests: None declared |
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Montserrat Romera, Rhumatologist CAP Just Oliveras. L¨Hospitalet de LL. Ciutat Sanitaria i Universitaria de Bellvitge (Barcelona), Josep Maria Ramon
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Editor: We read with interest the study by Trivedi et al concerning oral vitamin D3 supplementation on fractures and mortality in men and women living in the community (1). The authors found a 22% lower rate for first fracture at any site and 33% lower rate for a fracture occurring on the hip, wrist or forearm, or vertebrae. However the age adjusted relative risks in the vitamin D group compared with the placebo group were: 0,85 ( 95% CI: 0,47-1,53; p=0,59) for hip and 0,63 ( 95% CI: 0,35-1,14; p= 0,12) for vertebral fracture, and we don’t know the relative risk for wrist or forearm. Although they refer that the differences were consistent when stratified by sex, this difference was not significant (Table 2). With de Cox regression method, the authors adjust only for age. If the osteoporotic fractures are more frequent in women than in men and in this study there are more men than women, we think that an adjustment for sex of relative risk has to be made too. The 22% reduction in fractures in this study translates to approximately 250 people treated for one year to prevent any fracture. It is important to confirm these results because this would mean a prevention of fractures in high risked people with a minimal cost (< 2 Euros). 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.com 2003; 326:469. Competing interests: None declared |
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