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What about vitamin K
- Thomas E Radecki (1 May 2005)
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D-vitamin
- Bengt H Möller (1 May 2005)
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An analogy that may help readers understand this unique study design.
- Reinhold Vieth (1 May 2005)
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Calcium, vitamin D and Aromatase inhibitors
- Hazel Thornton (2 May 2005)
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Subphysiologic Doses of Vitamin D are Subtherapeutic: Comment on the Study by Porthouse and colleagues
- Alex Vasquez, John Cannell, The Vitamin D Council (4 May 2005)
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Zinc and magnesium supplements, not calcium supplements, are needed in osteoporosis
- Ellen C G Grant (5 May 2005)
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Calcium intake, absorption and hip fractures
- Julian RF Walters (5 May 2005)
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Calcium and vitamin D supplementation for prevention of fractures: a flawed study
- Peter J Lewis (9 May 2005)
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More on vitamin D and fracture prevention
- Peter J Lewis (11 May 2005)
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Adherence rate
- M Berends (11 May 2005)
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Calcium and vitamin D supplement in a calcium and vitamin D replete population
- Pierre J. Meunier (18 May 2005)
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supplementation with calcium and cholecalciferol
- Alan W Fowler (19 May 2005)
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Vitamin D and Calcium for fracture prevention in primary care
- Stephan H Scharla (26 May 2005)
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The value of clinical trial registry
- Daniela M Gallo, Andrew Wyllie (9 July 2005)
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Biochemists' perspective
- Anand C V, Usha Anand (4 August 2005)
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Thomas E Radecki, Psychiatrist State College, Pennsylvania 16803
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The study by Porthouse et al appears well done with an excellent review of the vitamin D and calcium research. Obviously, vitamin D and calcium are not enough. What I was disappointed with is that there is absolutely no mention of the extensive research coming out of Japan and the Netherlands showing that vitamin K supplementation has a powerful effect in decreasing osteoporosis and osteoporosis related fractures. And combining vitamin K, vitamin D, and calcium appears ideal. Researchers from Osaka Medical College showed that vitamin K and vitamin D together increased bone density much better than vitamin K alone (Maturitas. 2002 Mar 25;41(3):211-21). When comparing calcium and vitamin D alone vs. placebo, University of Maastricht researchers found little benefit on bone loss. But those randomized to take vitamin K in addition to calcium and vitamin D had significantly less femoral neck bone loss after three years (Calcif Tissue Int. 2003 Jul;73(1):21-6). The Yamaguchi Osteoporosis Prevention Study showed that vitamin K alone reduced vertebral fractures by 56% compared to placebo, comparable to the benefit found from etidronate (Am J Med. 2004 Oct 15;117(8):549- 55).šš Researchers at Hirosaki University in Japan showed that vitamin K lowered bone fractures in elderly female Parkinson's patients by 90% (Bone. 2002 Jul;31(1):114-8).šThe same research team showed an 86% decrease in fractures in elderly Alzheimer's patients treated with a combination of vitamin K, vitamin D, and calcium vs. placebo (Bone. 2005 Jan;36(1):61-8). I just can't believe how the medical establishment blocks out the vitamin K research. Trashing vitamin D and calcium helps certain international drug giants who control most academic centers in the U.S. and around the world. If the medical standard became to first use vitamins D and K with calcium before using bisphosphates and SERMs, billions of dollars per year would be saved by the public. Competing interests: None declared |
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Bengt H Möller, Chief physician Department of Internal Medicine
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Porthouse et al have performed a major study in investigating the effect of supplementation of calcium and D vitamin (D3) in order to decrease the rate of fractures in elderly people. It is well known that blood levels of D vitamin are often low in elderly people and possibly contributing to the increased risk of fractures in this population . It is too early to discard the possibility that a comparative cheap supplementation with D vitamin may have a protective effect as the recent study of Porthause and al gives no information about the blood levels of D vitamin. It has been suggested that the elderly need a higher dose D vitamin to overcome the hyperparathyroidism associated with the decreasing renal function in older adults . Using functional indicators, several studies have more accurately defined vitamin D deficiency as circulating levels of 25(OH)D < or = 80 nmol or 32 microg/L . In the study of Daksha et al in which there were a significant decrease in fracture rate after supplementation with 100 000 IU oral D vitamin every four months the mean values of D vitamin were significantly separated in the treatment group from the controls but even in the treatment group the attained mean values were below 80 nmol/L. The open design of the study may even have an effect on the intake of D vitamin in the placebo group initiated by the information given to both groups at inclusion in the study. The low incidence of fractures far below the calculated expected fracture rate at the start of the study may be an indication of a confounding factor. Bengt Hj Möller
References Porthaus J et al Randomised controlled trial of calcium and supplementation with cholecalciferol (vitamin D3) for prevention of fractures in primary care BMJ 2005;330;1003-1008 Mosekilde L Vitamin D and the elderly Clin endocrinol (Oxf). 2005 Mar;62(3):265-81 Vieth et al Age-related changes in the 25-hydroxyvitamin D versus parathyroid hormone relationship suggest a different reason why older adults require more vitamin J Clin Endocrinol Metab. 2003 Jan;88(1):185-91. Hollis BW Circulating 25-hydroxyvitamin D levels indicative of vitamin D sufficiency: implications for establishing a new effective dietary intake recommendation for vitamin D. J Nutr. 2005 Feb;135(2):317-22. Daksha P et al 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;3 Competing interests: None declared |
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Reinhold Vieth, Professor, Nutritional Sciences Mount Sinai Hospital, Toronto, Canada M5G 1L5
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Think of calcium like car maintenance, and vitamin D like an oil change for the car. A low-trauma fracture is like a roadside breakdown of the car. The study reported by Porthouse et al (BMJ 2005; 330:1003) is analogous to a situation in which you want to find out if car breakdown is less likely if you randomize car owners either to giving them free oil and maintenance, or to a control group for which you do not provide them with any free oil and maintenance, but instead, give them information on how to do this themselves. Then, you re-enforce the advice every six months with questions about whether the car has broken down yet. If you were running the garage and did this sort of research, it would come as no surprise that the free oil produced an outcome no different than good advice. Furthermore, the experimenters never even looked at the dipstick to check the oil in any car (i.e. never tested the blood vitamin D level to confirm treatment did anything at all). Porthouse et al advised all subjects to take calcium and vitamin D. The result was that all women developed fewer fractures than expected without such advice! How then can anyone read this paper and come to the conclusion that calcium and vitamin D are of no value? Porthouse et al must have been very disappointed with their negative findings. The lesson to be learned is that it is extremely difficult to do convincing research without a proper placebo. The study of Porthouse et al is unique in design. Because of this, it cannot be included in any meta-analysis of calcium, vitamin D, and osteoporosis. Competing interests: None declared |
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Hazel Thornton, Honorary Visiting Fellow, Department of Health Sciences, University of Leicester "Saionara", 31 Regent Street, Rowhedge, Colchester. CO5 7EA
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There is increasing use of aromatase inhibitors (AIs) for patients with breast cancer following wide enthusiastic promotion of evidence of their survival advantage over tamoxifen. [1] All AIs [anastrozole, letrozole, exemastane) cause bone loss of between 2.17% and 3.2% per annum. Tamoxifen has beneficial effect on bone providing 0.6% increase of bone mineral density over 2 years. Treatments recommended for patients taking AIs include vitamin D and calcium. [2] Vitamin D is produced by synthesis in the skin following sunlight exposure. Currently, there is controversy about the optimum degree of sunlight exposure and the Cancer Research UK`s recommendations with respect to exposure and melanoma risk. [3] Furthermore, recent evidence from two studies involving more than 8,000 elderly people who took vitamin D and calcium found no evidence that these supplements reduce the risk of fracture. [4][5] Aside from the need to reconsider recommendations for women taking AIs, a survey [2] has revealed other concerns about the necessary expertise and resources for managing this inevitable bone loss. These include awareness by oncologists and surgeons of the need to monitor and treat; access and waiting times for bone density scans; access to osteoporosis specialists; and provision of regular monitoring. If NICE (National Institute of Clinical Excellence) recommend discharge after 3 years, who is to do this? Emerging evidence alters the balance of benefits and harms, and the costs both to the patients and the NHS. It demonstrates that policy recommendations should only be made on the basis of robust evidence and that uncertainties and individual preferences should be carefully considered in each case according to health profile. Is it wise to state: "anastrozole should replace tamoxifen as first-line treatment after surgery in hormone-receptive breast cancer."? [1] [1] Joanna Lyall. Has tamoxifen had its day? Cancer World No. 5. March-April 2005, p.41 (photograph caption) [2] Dr. Jim Lester. Use of aromatase inhibitors in early breast cancer and an assessment of bone loss - A Questionnaire Based Survey of UK Practice. Paper presented at Yorkshire Cancer Network Breast Cancer Educational Event, Tuesday, 26th April 2005, Harrogate. [3] HealthWatch Forum; Newsletter 57 April 2005: pp 4-7. Sunscreening: can you be too careful? Oliver Gillie and Sara Hiom debate the dangers. [4] Jill Porterhouse, Sarah Cockayne, Christine King, Lucy Saxon, Elizabeth Steel et al. Randomised controlled trial of supplementation with calcium and cholecalciferol (Vitamin D3) for prevention of fractures in primary care. BMJ 2005; 330:1003-5 [5] Professor Adrian M. Grant and RECORD Trial Group. Oral Vitamin D3 and Calcium for secondary prevention of low-trauma fractures in elderly people (Randomised Evaluation of Calcium OR Vitamin D (RECORD)): a randomised placebo-controlled trial The Lancet Early Online Publication 28 April 2005. http://www.thelancet.com/journals/lancet/article/PIIS0140673605630139/abstract Accessed 30th April 2005. Competing interests: None declared |
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Alex Vasquez, Private practice, author, researcher, and consultant Biotics Research Corporation Rosenberg, Texas, USA 77471, John Cannell, The Vitamin D Council
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Dear Editor, 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: 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 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] 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 [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. 3. 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. 4. 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. 5. 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. 6. 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).
1. 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/330/7498/1003 2. 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 3. 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):288-94 4. Al Faraj S, Al Mutairi K. Vitamin D deficiency and chronic low back pain in Saudi Arabia. Spine. 2003;28(2):177-9 5. Vieth 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.pdf 6. Van 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):4623-32 7. 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.pdf 8. Glerup 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):260-8 9. Wu ML, Whittemore AS, Jung DL. Errors in reported dietary intakes. I. Short-term recall. Am J Epidemiol. 1986 Nov;124(5):826-35 10. Kinyamu 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;67:342-8 11. Dawson-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;65:67-71 12. 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;338:777-83 13. Dubbelman 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;58:106-9 14. Kauppinen-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):559-63 15. Vasquez 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. 16. 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 1989 17. Bucci 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. Bone 2003;33:589-596 19. 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 Competing interests: Dr. Vasquez is a researcher at Biotics Research Corporation, an FDA-approved drug manufacturing facility in the USA. |
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Ellen C G Grant, physician Kingston KT2 7JU, UK
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Calcium supplements would not be expected to reduce the risk of fracures because it is magnesium and not calcium which is needed to prevent the loss of intra cellular calcium. The main causes of reductions in serum bone specific alkaline phosphatase and increases in urinary losses of minerals can to demonstrated to be deficiencies of zinc and magnesium.1,2 1 McLaren-Howard J, Grant ECG, Davies S. Hormone Replacement Therapy and Osteoporosis: Bone Enzymes and Nutrient Imbalances. J Nutr Environ Med 1998; 8: 129-138. 2 Grant ECG. Osteoporosis caused by zinc and magnesium deficiencies. http://bmj.com/cgi/eletters/330/7496/859#104597, 22 Apr 2005 Competing interests: None declared |
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Julian RF Walters, Reader in Gastroenterology Hammersmith Hospital, Imperial College London W12 0NN
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In their prospective randomised trial of calcium and vitamin D supplementation, Porthouse et al. [1] found no evidence that this reduced the risk of clinical fractures in women at risk. However, a number of aspects of this study need closer examination before the therapeutic role for these supplements can be defined. Although these women all had risk factors for hip factors, they were highly self-selected. Out of 48,987 originally invited, only 3314 (7%) were eventually randomised. Median follow-up overall was only 25 months, and the design of the recruitment process means that this must have differed between the two groups. It is interesting that in the “unequally allocated group”, followed for longer, there is greater evidence of a benefit of the intervention. It is unfortunate that no attempt was made to measure vitamin D levels to see the prevalence of insufficiency, and whether this degree of supplementation was able to produce a significant improvement in levels. It would also have been informative to see if improved calcium absorption was able to reduce PTH levels. Perhaps the most important factor that must be considered is calcium intake from the diet. The self-reported estimated intake in both groups was over 1000mg/d, which is greater than in many other studies, and both groups received literature on adequate calcium and vitamin D intake. There is high-quality data from the US Study of Osteoporotic Fractures Research Group regarding dietary calcium, intestinal calcium absorption and hip fractures that the authors do not cite, and which put these findings into context. Ensrud et al. [2] studied 5452 women with a mean follow-up of 4.8 years. Approximately 33% had a dietary calcium intake less than 400mg/d. In this group, when fractional calcium absorption was below the mean, the risk of hip fractures was 2.5-fold greater than when absorption was above average. It is logical to presume that this combination of factors (low dietary calcium intake and low fractional absorption) identifies women most likely to benefit from calcium and vitamin D supplements. Many factors contribute to hip fractures and many alternative therapies are available. Hence it is important to identify those individuals who have low calcium absorption, so they can be considered for this simple, cheap, preventative intervention, and that appropriately designed trials are performed. Attention must also be given to vertebral fractures, which are usually undiagnosed, the differing effects that may be found in men and women, and the other benefits, such as those found in neoplasia, of vitamin D and calcium supplements. 1. Porthouse J, Cockayne S, King C, et al. Randomised controlled trial of calcium and supplementation with cholecalciferol (vitamin D3) for prevention of fractures in primary care. BMJ 2005;330:1003. 2. Ensrud KE, Duong T, Cauley JA, et al. Low fractional calcium absorption increases the risk for hip fracture in women with low calcium intake. Ann Intern Med 2000;132:345-53. Competing interests: None declared |
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Peter J Lewis, integrative physician 15 South Steyne, Manly, NSW 2095, Australia
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The study by Porthouse and colleagues (1) was seriously flawed, and indeed, by the authors’ own admission, was so underpowered that they ‘could not reliably exclude a reduction in all fractures of less than 30%’; one wonders whether it should have been published at all. Certainly it would be entirely inappropriate to conclude from this study that calcium and vitamin D don't prevent fractures. No reference was made to vitamin D status of the study participants (which was presumably not assessed) but it would be expected that a significant number would have been vitamin D deficient at the start of the study. Vitamin D status is most commonly assessed by measuring serum levels of 25-hydroxyvitamin D [25(OH)D], the major circulating form. Although published lower reference values for circulating 25(OH)D levels are generally in the range 30-50 nmol/L, assessing ‘normal’ levels based on a Gaussian distribution is now considered to be a grossly inaccurate method of determining the normal range. Using functional indicators of vitamin D status (such as intact parathyroid hormone, calcium absorption, and bone mineral density), several studies have more accurately defined vitamin D deficiency as circulating 25(OH)D levels </= 80 nmol/L (2); Veith argues for a lower limit of 100 nmol/L (3). Calcium absorption increases with increasing 25(OH)D concentrations up to ~80-90 nmol/L, and plateaus above that level. Heaney and colleagues found calcium absorption to be 65% higher at 25(OH)D levels averaging 86.5 nmol/L than at levels averaging 50 nmol/L (4). The (UK) National Diet & Nutrition Survey (5) found that the mean 25-hydroxyvitamin D 25(OH)D level for men was 48.3 nmol/L and for women 49.6 nmol/L; 57% of men and 54% of women had a 25(OH)D level of less than 50 nmol/L; 91% of men and 88% of women had 25(OH)D levels less than 80 nmol/L; 98% of men and 97% of women had 25(OH)D levels less than 100 nmol/L. Thus it appears that the majority of British adults have suboptimal 25OHD levels. Vitamin D deficiency is an even greater problem amongst the elderly as a result of reduced sunlight exposure, and also the age-related reduction in capacity to produce previtamin D3 even when exposed to sunlight. A vitamin D3 dose of 800 IU/day is inadequate to attain optimal serum 25(OH)D concentrations in the absence of substantial cutaneous production of vitamin D. In the RECORD trial, a secondary prevention study in hospital based fracture clinics in the UK, mean baseline concentrations of 25(OH)D for a sample of 60 participants were 15.2 ng/ml (38 nmol/L), rising to 24.9 ng/ml (62 nmol/L) after 1 year of supplementation with vitamin D3 800 IU/day (6). Thus, subjects in this trial were vitamin D deficient at the start of the trial, and the vitamin D dose of 800 IU/day failed to raise 25(OH)D levels sufficiently to maximise calcium absorption. To ensure that 25(OH)D levels exceed 100 nmol/L, a total vitamin D supply of 4,000 IU of vitamin D3 is required (3). However, in cases of established vitamin D deficiency, oral vitamin D3 doses of 8-12,000 IU daily for 3 months or more are not infrequently required to attain optimal vitamin D status. (Although vitamin D is potentially toxic, published cases of vitamin D toxicity with hypercalcaemia all involve intake of >/= 40,000 IU/day.) In addition to using an inappropriately low dose of vitamin D3, a poor choice of calcium supplement was made. Calcium carbonate may be poorly absorbed in the absence of adequate gastric acid; the elderly are especially prone to hypochlorhydria. A more appropriate choice would be calcium citrate, as absorption of this does not seem to be affected by low gastric acid. Future trails should utilise an appropriate dose of vitamin D3, in combination with calcium citrate, and, ideally, other important bone nutrients (including vitamin K, boron, manganese, zinc, silicon, and perhaps strontium). In the meantime, the continued failure to recognise and adequately treat vitamin D deficiency in patients at risk of fractures (as well as a range of other conditions related to vitamin D deficiency, such as diabetes, heart disease and many cancers) is likely to result in a great deal of unnecessary suffering, as well as substantial direct and indirect costs. References 1. Porthouse J, Cockayne S, King C, et al. Randomised controlled trial of calcium and supplementation with cholecalciferol (vitamin D3) for prevention of fractures in primary care. BMJ 2005;330:1003-1008. 2. Hollis BW. Circulating 25-hydroxyvitamin D levels indicative of vitamin D sufficiency: implications for establishing a new effective dietary intake recommendation for vitamin D. J Nutr 2005;135:317-322. 3. Veith R. Vitamin D supplementation, 25-hydroxyvitamin D concentrations, and safety. Am J Clin Nutr 1999;69:482-56. 4. Heaney RP, Dowell S, Hale CA, Bendich A. Calcium absorption varies within the reference range for serum 25-hydroxyvitamin D. J Am Coll Nutr 2003;22:142-146. 5. Rushton D, Hoare J, Henderson L, Gregory J. The National Diet & Nutrition Survey: adults aged 19 to 64 years. Volume 4: Nutritional status (anthropometry and blood analytes), blood pressure and physical activity The Stationary Office, London, 2004. 6. The RECORD Trial Group. Oral vitamin D3 and calcium for secondary prevention of low-trauma fractures in elderly people (Randomised Evaluation of calcium Or vitamin D, RECORD): a randomised placebo- controlled trial. The Lancet 2005;365:1621-1628. Competing interests: None declared |
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Peter J Lewis, integrative physician 15 South Steyne, Manly, NSW 2095, Australia
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Further to the study by Porthouse and colleagues (1), a timely meta- analysis of double-blind randomised, controlled trials of oral vitamin D supplementation (cholecalciferol) with or without calcium supplementation vs calcium supplementation or placebo in older persons ( 60 years) has just been published in the Journal of the American Medical Association (2). The authors concluded that oral vitamin D supplementation between 700 to 800 IU/day appears to reduce the risk of hip and any nonvertebral fractures (by 26% and 23% respectively), but that an oral vitamin D dose of 400 IU/d is not sufficient for fracture prevention. References 1. Porthouse J, Cockayne S, King C, et al. Randomised controlled trial of calcium and supplementation with cholecalciferol (vitamin D3) for prevention of fractures in primary care. BMJ 2005;330:1003-1008. 2. Bischoff-Ferrari HA, Willett WC, Wong JB, et al. Fracture Prevention With Vitamin D Supplementation: A Meta-analysis of Randomized Controlled Trials . JAMA 2005;293:2257-2264. Competing interests: None declared |
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M Berends, GP Little Paxton, PE28 5AB
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Compliance with offered treatment is always difficult. The reported adherence rate in the intervention group was 69% of women completing follow up at 24 months and suggested to be 55% with the inclusion of those known to be alive. In figure 1 of the article I found some data on this where at 18 months follow up the adherence rate is published to be 58.6% (514/877). This was apparently calculated by subtracting those who had died and ought to include the ones that failed to return the questionnaires. All goes well at 6 and 12 months when there appears to be a sudden unexplained death rate (from 1185 to 877). By my calculations the adherence rate at 18 months can at best be 514/1185 44.3%, assuming no deaths between 12 and 18 months follow up. I can try to conjure up the amount of patients that became adherent between 18 months and 24 months but will leave that for now... Competing interests: None declared |
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Pierre J. Meunier, Professor of medicine Laennec Faculty of Medicine, INSERM U403, 69372 Lyon cedex 08,France
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In contrast to the general view, Porthouse et al. reported that the daily supplementation with calcium and vitamin D did not result in any significant reduction of bone fracture rates in community dwelling, elderly women in the UK. As already raised in previous ‘rapid responses’ to this publication, the study suffers from a number of flaws mainly by lacking: (1) any measurement of the calcium and vitamin D status to control the effect of supplementation [1]; (2) proper control, since the control group also got advice on how to improve dietary calcium and vitamin D uptake, which even worsens point (1); (3) no information on vitamin D status of the cohort at baseline. The authors report that based on the results of a food questionnaire the mean dietary calcium intake of subjects at study entry exceeded 1000 mg/day. Previous publications, which demonstrated a reduction of hip fractures among institutionalised elderly women by supplementation with calcium and vitamin D, consistently reported initial dietary calcium intakes of about 500-600 mg/day [2,3]. This is in agreement with dietary calcium intakes reported in several other recent studies in the US [4,5], Scandinavia [6] or the SU.VI.MAX study in France. Indeed, dietary calcium uptake in the UK might be higher than in other countries, since foods such as bread and baked products, breakfast bars and cereals or juices and other beverages are commonly fortified in the UK. For example, 100 g of flour is required by law to be supplemented with 200-400 mg of calcium [The UK Expert Group on Vitamins and Minerals; www.food.gov.uk/multimedia/pdfs/evm0112p.pdf]. Thus, the high calcium intakes reported in this study may reflect a British particularity, although reports of lower calcium intakes in the UK also exist [7,8]. Taking this into account, it is most unfortunate that Porthouse and colleagues did not screen for hypercalcemia and hypercalciuria either, which can be suspected to have occurred in the supplemented subjects. Thus, putting aside the experimental flaws, Porthouse et al. may simply have confirmed what is common sense: that calcium and vitamin D supplementation is of no additional use in the prevention of fractures for subjects who already benefit from an optimal dietary calcium intake. References: 1. Vieth R. Vitamin D supplementation, 25-hydroxyvitamin D concentrations, and safety. Am J Clin Nutr 1999;69(5):842-56. 2. 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(23):1637-42. 3. Chapuy MC, Pamphile R, Paris E, Kempf C, Schlichting M, Arnaud S, et al. Combined calcium and vitamin D3 supplementation in elderly women: confirmation of reversal of secondary hyperparathyroidism and hip fracture risk: the Decalyos II study. Osteoporos Int 2002;13(3):257-64. 4. Ensrud KE, Duong T, Cauley JA, Heaney RP, Wolf RL, Harris E, et al. Low fractional calcium absorption increases the risk for hip fracture in women with low calcium intake. Study of Osteoporotic Fractures Research Group. Ann Intern Med 2000;132(5):345-53. 5. Dawson-Hughes B, Harris SS, Krall EA, Dallal GE. Effect of calcium and vitamin D supplementation on bone density in men and women 65 years of age or older. N Engl J Med 1997;337(10):670-6. 6. Meyer HE, Smedshaug GB, Kvaavik E, Falch JA, Tverdal A, Pedersen JI. Can vitamin D supplementation reduce the risk of fracture in the elderly? A randomized controlled trial. J Bone Miner Res 2002;17(4):709-15. 7. 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(7387):469. 8. Gregory J, Foster K, Tyler H, Wiseman M. The Dietary and Nutritional Survey of British Adults. London: HMSO, 1990. Competing interests: None declared |
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Alan W Fowler, Retired orthopaedic surgeon Home
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Randomised controlled trial of supplementation with calcium and vitamin D for prevention of fractures in primary care It is not surprising that the York Trials Unit found no evidence that supplementation with calcium and vitamin D reduced the risk of fractures in women over 70.1 In 1984 Aitken found that those who suffered fractures of the femoral neck had the same bone density as controls,2 thereby showing that the essential cause of these age related fractures is loss of balance and falling. A week after the publication of the York trial a similar study from Aberdeen was published which also showed no benefit from calcium and vitamin D supplementation.3 We need therefore to turn from chemical treatments for osteoporosis and direct our attention to physical treatments which will not only prevent falls but also maintain bone strength.. In 1970 Chalmers and Ho presented demographic evidence that fractures of the femoral neck were inversely related to the level of physical activity.4 Maintaining physical activity into old age not only prevents osteoporosis, more importantly it preserves muscle coordination and balance which are crucially important in preventing falls and fractures. Alan W Fowler 1. Porthouse J, Cockayne S, King C, Saxon L, Steele E, Aspray T, Baverstock M, Birks Y, Dumville J, Francis RM, Iglesias C, Puffer S, Sutcliff A, Watt I, Torgerson DJ. Randomised controlled trial of supplementation with calcium and cholecalciferol (vitamin D¬Ù) for prevention of fractures in primary care, BMJ 2005;330:1003-6. 2. Aitken JM. Relevance of osteoporosis in women with fractures of the femoral neck. BMJ 1984;288:597-601. 3. The RECORD trial group. Oral vitamin D3 and calcium for secondary prevention of low-trauma fractures in elderly people: a randomised placebo controlled trial. Lancet 2005;365:1621-28. 4. Chalmers J, Ho KC. Geographical variations in senile osteoporosis. J.Bone Jt. Surg. 1970;52B:667-675. Competing interests: None declared |
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Stephan H Scharla, Faculty member of LMU University of Munich Practice for Endocrinology, 83435 Bad Reichenhall, Germany
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Dear editor, J. Porthouse and coworkers conducted a trial in elderly women (> 70 years) with risk factors for hip fractures and found no effect of calcium and supplementation with vitamin D3 on the rate of clinical fractures compared to a control group. In addition, there was no effect on frequency of falls and quality of life. However, these results should not be interpreted in such a way, that there would be no rationale for the supplementation of calcium and vitamin D in elderly people in order to prevent fractures. Vitamin D deficiency and the resulting secondary hyperparathyroidism are important pathophysiological causes for fractures in elderly people. Therefore, the correction of vitamin D deficiency and improving the calcium supply appear as a logical consequence. In population with a high prevalence of vitamin D deficiency, several studies have demonstrated the ability of calcium and vitamin D to reduce the incidence of peripheral fractures (Chapuy et al. 1992, Dawson-Hughes et al.1997, Larsen et al 2004). Several reasons may be responsible for the missing effect of calcium and vitamin D in the present study of Porthouse and coworkers: The participating women were identified by risk factors like low body weight (> 1/3 of participants), poor or fair health (> 1/3 of participants), and genetic predisposition (maternal history of hip fracture). These criteria may have selected women, who are at risk for hip fracture resulting from other causes than vitamin D or calcium deficiency. The average nutritional calcium intake of the participating women was rather high (1075 mg daily in the intervention group and 1084 mg daily in the control group) compared to other population (for example, the average calcium intake in Germany is about 850 mg calcium daily). Data on the vitamin D status are not reported. Only 7 % of the originally identified women were recruited into the study. Therefore the sample may not be representative for the population at risk. After 6 months only 61.3 % of the women in the intervention group were adherent to the treatment. In the control group up to 6 % of the women reported to take calcium and vitamin D. This percentage may have been greater since all women had been instructed about the importance of adequate calcium and vitamin D intake. Otherwise than stated by the authors, a dilution effect could have had a greater impact on the results. The ability of calcium and vitamin D to reduce the risk for falls and fractures is underscored by a recent prospective double blind study in Germany and Austria, which was conducted in elderly women with vitamin D insufficiency (serum 25-OH-vitamin D < 78 nmol/l) (Pfeifer et al. 2005). Therefore the recommendation to provide a sufficient supply of calcium and vitamin D for elderly people should not be dismissed. This is especially true for countries with a high prevalence of vitamin D deficiency such as Germany (Scharla et al. 1996). Dawson-Hughes B, Harris SS, Krall EA, Dallal GE. N Engl J Med 337 (1997) 670-676 Chapuy MC, Arlot ME, Duboeuf F, et al. N Engl J Med 327 (1992) 1637- 1642 Larsen ER, Mosekilde L, Foldspang A. Journal of Bone and Mineral Research 2004;19:370-378 Pfeifer M, Dobnig H, Minne HW, Suppan K. Osteoporos Int 2005;16(Supplement 3):S45 Scharla SH, Scheidt-Nave C, Leidig G, Woitge H, W¸ster C, Seibel MJ, Ziegler R. Exp Clin Endocrinol Diabetes 1996; 104:289-292 Stephan Scharla, MD
Competing interests: None declared |
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Daniela M Gallo, Pharmacist Care Of: Mount Sinai Hospital, Toronto, Canada, Andrew Wyllie
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Dear Editor: We read with interest the design of the study by Porthouse and colleagues concluding that they found no evidence that calcium and vitamin D reduced clinical fractures in elderly women.(1) The treatment intervention was nurse-delivered lifestyle advice in conjunction with daily oral supplementation of calcium and vitamin D. However, the authors conclude that it was calcium and vitamin D supplementation that was ineffective at reducing the fracture rate.(1) We are concerned with discrepancy between the description and setting of the intervention and the reporting of the results. The published title compared with the ISRCTN registry title of the article (A randomized trial of nurse led clinics to promote increased use of calcium with vitamin D supplements for fracture prevention in women over 70 years) further questions whether the original intervention was meant to be pharmaceutical in nature or one of counseling, or both. This highlights the value of clinical trial registries and, given this description, the study results would be more fairly represented as nurse led clinics can promote increased use of calcium and vitamin D supplements by counseling and providing medication, but this did not lead to a reduced risk of fractures. Respectfully, Daniela Gallo, BScPhm, RPh Toronto, Canada Andrew Wyllie, BScPhm, PharmD, RPh Mount Sinai Hospital Toronto, Canada Reference 1. Porthouse J, Cockayne S, King C, Saxon L, Steele E, Aspray T et al. Randomised controlled trial of calcium and supplementation with cholecalciferol (vitamin D3) for prevention of fractures in primary care. BMJ 2005;330:1003. Competing interests: None declared |
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Anand C V, Professor M.S.Ramaiah Medical College, Bangalore, 560054, India, Usha Anand
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Calcium and vitamin D in preventing fractures Biochemists’ perspective EDITOR -We read with interest the article by Porthouse et al1 in which they report that there is no significant reduction in the risk of clinical fractures in women supplemented with vitamin D3 and calcium. There could be several reasons for the failure of an isolated supplementation of vitamin D and calcium, in protecting against clinical fractures. Firstly, vitamin D by itself is inactive in promoting the absorption of calcium in the intestines. It has to be converted to calcitriol by successive hydroxylation reactions in the liver and the kidneys2. A slowing down of one of these steps could negate the beneficial effects of vitamin D administration. In fact oestrogens and progesterone are known to stimulate the renal 1á- hydroxylase enzyme3 which means that, in post- menopausal women, formation of active vitamin D is likely to be affected. The use of calcitriol supplements instead of vitamin D3 would have probably improved the clinical outcome. Calcium absorption is favoured by an acidic environment in the intestines. Most of the dietary calcium is absorbed in the proximal parts of the intestines while the contents are still acidic. Elderly subjects in whom there is a fall in gastric acid secretion would have an impaired absorption. Calcium tends to form insoluble calcium soaps in alkaline environments, in which form, it cannot be absorbed. Vitamin K is said to have a role in the synthesis of bone proteins such as osteocalcin. It is required for the ã-carboxylation of glutamate residues of osteocalcin and bone matrix gla proteins4. Such post- translationally modified ã-carboxy glutamate residues are capable of chelating calcium ions. The idea of supplementation of populations prone to fractures, with vitamin K, therefore has a scientific basis. As Dr Radecki has pointed out, the study would have yielded valuable information if vitamin K supplementation had been included5. The functionally active form of vitamin K has the naphthoquinone structure. During the K cycle this is regenerated from its epoxide form by using NADPH. The generation of NADPH itself requires the operation of the pentose phosphate pathway. NADPH is produced by the action of glucose-6- phosphate dehydrogenase and 6-phosphogluconate dehydrogenase. In the osteoblasts, the enzyme glucose-6-phosphate dehydrogenase is regulated by the polyamine putrescine 6. The formation of putrescine is by a pyridoxal phosphate dependent ornithine decarboxylase reaction. Therefore there is an indirect role for the vitamin pyridoxine in bone metabolism. Collagen is a structural protein present in the bones. The proper formation of collagen requires vitamin C as a co-factor for the hydroxylation of proline and lysine residues7 Osteoporosis is characterized by not only loss of minerals but also the organic matrix onto which the minerals are deposited. Therefore it is important to realize that are several links in the sequence of events associated with mineralization/ demineralization of bone. To cut a long story short, there are a multitude of factors which work in concert to regulate mineral metabolism in the bones. The results of the study conducted by Porthouse et al should be viewed from a different perspective. It has served to prove the point that, for supplementation to be effective, it should be in the form of a cocktail of several other nutrients and that calcium and vitamin D alone would not suffice. C.V.Anand, Professor in Biochemistry
M.S.Ramaiah Medical College, M.S.R.I.T. Post, Bangalore -560 054, India.
1.Porthouse J, Cockayne S, King C, Saxon I, Steele E, Aspray T, et al. Randomised controlled trial of calcium and supplementation with cholecalciferol (vitamin D3) for prevention of fractures in primary care. BMJ 2005; 330:1003. 2.Garrett RH, Grisham CM. Principles of Biochemistry with a human focus. 1997, Books/Cole, Thomson Learning, USA, pp 465-7. 3.Murray RK, Granner DK, Mayes PA, Rodwell VW, eds, Harper’s Biochemistry, Prentice Hall International Inc. 24 th ed, 1996, pp. 539-46. 4.Hauschika PV, Lian JB, Cole DBC, Gundberg CM. Osteocalcin and matrix gla protein: vitamin K dependent proteins in bone. Physiol Rev 1989; 69: 990- 1047. 5.Radecki TE. Vitamin K supplementation has powerful effect. (Letter) BMJ 2005; 331:108. 6.Bachrach U. Physiological aspects of ornithine decarboxylase. Cell Biochem Funct 1984; 2: 6-10. 7.Berg JM, Tymoczko JL, Stryer L.Biochemistry, W.H.Freeman and Co. New York, 5 th ed, 2002, pp 216-225. Competing interests: None declared |
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