BMJ 2003;326:469-472 ( 1 March )

Papers

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

Daksha P Trivedi, research fellow ^a, Richard Doll, emeritus professor ^b, Kay Tee Khaw, professor of clinical gerontology ^a. 

^a Clinical Gerontology Unit, University of Cambridge School of Clinical Medicine, Addenbrooke's Hospital, Cambridge CB2 2QQ, ^b Clinical Trial Service Unit and Epidemiological Studies Unit, University of Oxford

Correspondence to: K T Khaw kk101{at}medschl.cam.ac.uk

	Abstract

Top Abstract Introduction Methods Results Discussion References

Objective: To determine the effect of four monthly vitamin D supplementation on the rate of fractures in men and women aged 65 years and over living in the community.
Design: Randomised double blind controlled trial of 100 000 IU oral vitamin D₃ (cholecalciferol) supplementation or matching placebo every four months over five years.
Setting and participants: 2686 people (2037 men and 649 women) aged 65-85 years living in the general community, recruited from the British doctors register and a general practice register in Suffolk.
Main outcome measures: Fracture incidence and total mortality by cause.
Results: After five years 268 men and women had incident fractures, of whom 147 had fractures in common osteoporotic sites (hip, wrist or forearm, or vertebrae). Relative risks in the vitamin D group compared with the placebo group were 0.78 (95% confidence interval 0.61 to 0.99, P=0.04) for any first fracture and 0.67 (0.48 to 0.93, P=0.02) for first hip, wrist or forearm, or vertebral fracture. 471 participants died. The relative risk for total mortality in the vitamin D group compared with the placebo group was 0.88 (0.74 to 1.06, P=0.18). Findings were consistent in men and women and in doctors and the general practice population.
Conclusion: Four monthly supplementation with 100 000 IU oral vitamin D may prevent fractures without adverse effects in men and women living in the general community.

What is already known in this topic Vitamin D and calcium supplements are effective in preventing fractures in elderly women Whether isolated vitamin D supplementation prevents fractures is not clear What this paper adds Four monthly oral supplementation with 100 000 IU vitamin D reduces fractures in men and women aged over 65 living in the general community Total fracture incidence was reduced by 22% and fractures in major osteoporotic sites by 33%

	Introduction

Top Abstract Introduction Methods Results Discussion References

Osteoporotic fractures are projected to increase exponentially worldwide.¹ Most fracture prevention trials have focused on clinically defined groups such as people with osteoporosis or previous fractures and have mainly been conducted in women.^2-7 Safe, effective, feasible, and cost effective primary prevention measures are needed in older men and women, in whom most osteoporotic fractures occur. We report results from a randomised double blind trial of four monthly supplementation with oral vitamin D₃ on fractures and mortality in 2686 men and women aged 65-85 years living in the community.

	Methods

Top Abstract Introduction Methods Results Discussion References

Study population This trial was a pilot to assess the feasibility of a community trial (not subsequently conducted owing to lack of funding) in 20 000 men and women. We recruited men and women aged 65-85 from the British doctors study register at the Clinical Trials Studies Unit, Oxford,⁸ and the age-sex register of a general practice in Ipswich, Suffolk. We excluded people who were already taking vitamin D supplements and people with conditions that were contraindications to vitamin D supplementationfor example, a history of renal stones, sarcoidosis, or malignancy. We sent invitations to 11 120 people, and 3504 (31.5%) of them initially agreed to participate. From June 1996 to March 1997 we randomised 2686 (77.5%) people to receive either treatment with vitamin D or a placebo. Participants and investigators were blinded to the treatment until the study ended.

Study design We conducted the study by post. Participants completed an initial questionnaire. We assessed prevalence of disease with the question "Do you have the following conditions?" followed by a checklist. We used a modified food frequency questionnaire at four years to estimate dietary calcium intake.

Intervention We sent one capsule containing 100 000 IU vitamin D₃ (cholecalciferol) or matching placebo by post every four months for five years (15 doses in total). We asked participants to take the capsule immediately on receipt, complete a form indicating that they had done so, and return the form by Freepost.

Endpoint ascertainment On receiving the capsule, participants filled in a checklist of events (fracture or major illness) and returned the form by Freepost. All participants were flagged at the Office for National Statistics for mortality and followed until 31 March 2002. A nosologist blind to the intervention coded death certificates by using ICD-9 (international classification of diseases, 9th revision). We ascertained incidences of fracture, cardiovascular disease, and cancer by using events identified from questionnaires or death certification by cause.

Serum 25-hydroxyvitamin D, parathyroid hormone, and heel sonometry After four years we invited 235 participants from general practice who had taken at least 10 capsules to a clinic for measurement of serum vitamin D and parathyroid hormone concentrations.

Statistical analyses We included all participants randomised to active vitamin D or placebo in the analyses, according to intention to treat. We compared relative risks for incidence of fracture, mortality by cause, and incidence of cardiovascular disease and cancer for active vitamin D versus placebo by using crude rates and then, after adjustment for age, with the Cox regression method.⁹

	Results

Top Abstract Introduction Methods Results Discussion References

Characteristics of participants Baseline descriptive data did not differ between the groups (see bmj.com). Mean calcium intake at four years was 742 mg/day and did not differ by treatment allocation.

Incidence of fracture The table shows five year fracture rates. Participants in the vitamin D treatment group had a 22% lower rate for first fracture at any site and a 33% lower rate for a fracture occurring in the hip, wrist or forearm, or vertebrae. The differences were consistent when stratified by sex or by doctor versus general practice population. We observed differences one year into the study (fig 1).

View this table: [in this window] [in a new window]   Incidence of fractures based on self report or mortality certification 1996-2002 and age adjusted relative risks (Cox regression), according to treatment allocation at randomisation (intention to treat) in 2686 men and women aged 65-85 years. Values are numbers (percentages) unless stated otherwise

View larger version (22K): [in this window] [in a new window]   Fig 1.   Cumulative probability of any first fracture according to treatment with vitamin D (n=1345) or placebo (n=1341), based on Cox regression; difference between two groups, P=0.04

Other health events The vitamin D group had slightly but not significantly lower mortality from all causes, cardiovascular disease, and cancer than the placebo group (fig 2). The incidence of major health events did not differ significantly between the treatment groups (see bmj.com).

View larger version (20K): [in this window] [in a new window]   Fig 2.   Cumulative survival according to treatment with vitamin D (n=1345) or placebo (n=1341), based on Cox regression; no significant difference between groups

Physiological variables and compliance The mean serum concentrations of vitamin D and parathyroid hormone and heel bone ultrasound attenuation in the subgroup are presented on bmj.com. Mean vitamin D concentrations were 40% higher in the active treatment group than in the placebo group (p<0.001). Mean parathyroid concentrations were 6% lower, but this difference was not significant. Heel ultrasound measures did not differ by treatment. Compliance did not differ between doctors and the general practice population or between the treatment groups; 76% (2050/2686) of participants had at least 80% compliance (12/15 doses).

	Discussion

Top Abstract Introduction Methods Results Discussion References

Limitations
We ascertained the incidence of fracture through self report by questionnaire. This may have led to ascertainment errors, but random errors would underestimate associations. In this randomised double blinded design, biased ascertainment between the treatment groups is unlikely. Most of the participants were doctors, which increases the likelihood of accurate ascertainment of events. Fracture rates did not differ significantly between doctors and the general practice population, indicating that people in the general community report fracture accurately, an assumption supported by several studies. ^{10 11}

Comparisons with previous studies
Several studies report that daily supplementation with vitamin D and calcium reduces fractures. ^{2 3} In our study the effect size of isolated vitamin D supplementationabout 20% reduction in total fractures and 30% reduction in fractures at major osteoporotic sitesis comparable to that reported by Chapuy for combined daily vitamin D and calcium.²

Previous studies of isolated vitamin D supplementation have been inconclusive.^12-14 The lack of significant reduction in fractures in these studies could be explained by a lack of power due to a lower dose of supplement, shorter duration, or lower number of events as well as ineffectiveness of vitamin D. Lips found no protective effect of vitamin D 400 IU daily in 1578 participants.¹³ This dose may have been too low to achieve a clinical effect. In our study the four monthly 100 000 IU dose averages a daily equivalent similar to the 800 IU vitamin D used in the trials by Chapuy and Dawson Hughes. ^{2 3} Heikinheimo, using annual injections of 150 000-300 000 IU in 899 participants, reported a reduction in fractures of the upper limb but not the lower limb.¹⁴ This study was not properly randomised or blinded, and a single annual dose may not provide adequate concentrations in the blood over a whole year.

Vitamin D may protect against fractures through concentrations of parathyroid hormone. The 40% higher mean concentrations of vitamin D seen in the active treatment group in our trial, however, were still not high in absolute terms. Parathyroid hormone concentrations were only slightly and not significantly lower. This suggests that 100 000 IU vitamin D four monthly may not have lowered parathyroid hormone concentrations adequately, and a more frequent dose might be considered in future trials.

We found no significant effects of vitamin D on total mortality or incidence of cancer or cardiovascular disease, as suggested by observational studies. ^{15 16} However, the fact that the relative risks were in a favourable direction in the active treatment group is reassuring.

Generalisability
To maximise generalisability, this was a pragmatic trial with minimal exclusion criteria. The doctors were similar to the general practice population in terms of compliance, fracture rates, and effects of vitamin D. Blood concentrations of vitamin D in participants taking placebo were comparable to those of population groups of similar ages in northern latitudes in the United States³ and higher than those in older European populations living in northern latitudes. ^{13 17}

Public health implications
This trial was a pilot for a larger trial that was not funded and was, consequently, too small for any decisive effect on fractures to be expected. The results, nevertheless, indicate that isolated vitamin D supplementation prevents fractures. The 22% reduction in fractures in our study translates to approximately 250 people treated for one year to prevent any fracture. This is particularly important for primary prevention. Several interventionssuch as bisphosphonates, oestrogen, and calcium and vitamin Dreduce fractures in high risk groups.^2-7 Their application to primary prevention is, however, problematic as the balance of risk-benefit and cost-benefit differs in primary and secondary prevention.

Risk of fracture is related to bone health across the whole population distribution, such that most fractures do not occur in the small numbers of people with severe osteoporosis at very high risk but in the large numbers at moderately increased risk. To have a substantial effect on total fractures in the population, intervention would be needed in large numbers of people; consequently, population-wide preventive interventions have been proposed for all elderly people.¹⁸

However, the dilemma for primary prevention is that whereas the population attributable risk is large, the absolute individual risk is still low.¹⁹ The risk-benefit balance for community based prevention differs from that for intervention in clinically defined groups. Safety, feasibility, and cost effectiveness are crucial. Side effects are less acceptable in a healthy group in which the risk of fracture is not high. This is a particular issue in men, in whom evidence on effective fracture prevention is lacking. Many interventions effective in high risk groups are not feasible in the general population owing to poor compliance or side effects or are not cost effective.²⁰ In contrast, the cost of four monthly oral 100 000 IU vitamin D is minimal (<£1 annually).

	Acknowledgments

We thank all the participants in the trial from the British doctors study and the general practice in Ipswich. We also thank A J Hicks and colleagues at the Norwich Road Surgery, Ipswich; G Hanson, Ipswich Hospital NHS Trust Pharmacy Manufacturing Department; Richard Dexter, Pelican Computing, for computing support; Rosemary Reader and Sandra Owen for database assistance; and Sir Richard Peto for advice and access to the British doctors. The 100 000 IU vitamin D supplement or placebo used in this trial was specially prepared by the Ipswich Hospital Pharmacy. Ergocalciferol (physiologically the same action as cholecalciferol) 50 000 IU is obtainable from chemists.

Contributors: See bmj.com

	Footnotes

Funding: Start up grant from the Medical Research Council.

Competing interests: None declared.

This is an abridged version; the full version is on bmj.com

	References

Top Abstract Introduction Methods Results Discussion References

1.	Cooper C, Campion G, Melton 3rd LJ. Hip fractures in the elderly: a world-wide projection. Osteoporos Int 1992; 2: 285-289[CrossRef][ISI][Medline].
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: 1637-1642[Abstract].
3.	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: 670-676[Abstract/Free Full Text].
4.	Black DM, Cummings SR, Karpf DB, Cauley JA, Thompson DE, Nevitt MC, et al. Randomised trial of effect of alendronate on risk of fracture in women with existing vertebral fractures. Lancet 1996; 348: 1535-1541[CrossRef][ISI][Medline].
5.	Cummings SR, Black DM, Thompson DE, Applegate WB, Barrett-Connor E, Musliner TA, et al. Effect of alendronate on risk of fracture in women with low bone density but without vertebral fractures: results from the fracture intervention trial. JAMA 1998; 280: 2077-2082[Abstract/Free Full Text].
6.	McClung MR, Geusens P, Miller PD, Zippel H, Bensen WG, et al. Effect of risedronate on the risk of hip fracture in elderly women. N Engl J Med 2001; 344: 333-340[Abstract/Free Full Text].
7.	Writing Group for the Women's Health Initiative. Risks and benefits of estrogen plus progestin in healthy postmenopausal women. JAMA 2002; 288: 321-333[Abstract/Free Full Text].
8.	Doll R, Peto R, Hall E, Wheatley K, Gray R. Mortality in relation to consumption of alcohol: 13 years' observations on male British doctors. BMJ 1994; 309: 911-918[Abstract/Free Full Text].
9.	Cox DR. Regression models and life tables. J R Stat Soc B 1972; 34: 187-220.
10.	Ismail AA, O'Neill TW, Cockerill W, Finn JD, Cannata JB, Hoszowski K, et al. Validity of self-report of fractures: results from a prospective study in men and women across Europe. Osteoporos Int 2000; 11: 248-254[CrossRef][ISI][Medline].
11.	Nevitt MC, Cummings SR, Browner WS, Seeley DG, Cauley JA, Vogt TM, et al. The accuracy of self-report of fractures in elderly women: evidence from a prospective study. Am J Epidemiol 1992; 135: 490-499[Abstract/Free Full Text].
12.	Gillespie WJ, Henry DA, O'Connell DL, Robertson J. Vitamin D and vitamin D analogues for preventing fractures associated with involutional and post-menopausal osteoporosis. Cochrane Database Syst Rev 2002;(3):CD000227.
13.	Lips P, Graafmans WC, Ooms ME, Bezemer PD, Bouter LM. Vitamin D supplementation and fracture incidence in elderly persons. A randomized, placebo-controlled clinical trial. Ann Intern Med 1996; 124: 400-406[Abstract/Free Full Text].
14.	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[CrossRef][ISI][Medline].
15.	Scragg R, Jackson R, Holdaway IM, Lim T, Beaglehole R. Myocardial infarction is inversely associated with plasma 25-hydroxyvitamin D3 levels: a community based study. Int J Epidemiol 1990; 19: 559-562[Abstract/Free Full Text].
16.	Garland CF, Garland FC, Gorham ED. Calcium and vitamin D: their potential roles in colon and breast cancer prevention. Ann N Y Acad Sci 1999; 889: 107-119[Abstract/Free Full Text].
17.	Chapuy MC, Preziosi P, Maamer M, Arnaud S, Galan P, Hercberg S, et al. Prevalence of vitamin D insufficiency in an adult normal population. Osteoporos Int 1997; 7: 439-443[CrossRef][ISI][Medline].
18.	Barrett-Connor E, Gore R, Browner WS, Cummings SR. Prevention of osteoporotic hip fracture: global versus high-risk strategies. Osteoporos Int 1998; 8: S2-S7.
19.	Rose G. Strategy of preventive medicine. Oxford: Oxford University Press, 1992.
20.	Torgerson D, Donaldson C, Reid D. Using economics to prioritize research: a case study of randomized trials for the prevention of hip fractures due to osteoporosis. J Health Serv Res Policy 1996; 1: 141-146[Medline].

(Accepted 10 December 2002)

---

© 2003 BMJ Publishing Group Ltd
CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

Related Articles

Randomised controlled trial of calcium and supplementation with cholecalciferol (vitamin D₃) for prevention of fractures in primary care

Jill Porthouse, Sarah Cockayne, Christine King, Lucy Saxon, Elizabeth Steele, Terry Aspray, Mike Baverstock, Yvonne Birks, Jo Dumville, Roger Francis, Cynthia Iglesias, Suezann Puffer, Anne Sutcliffe, Ian Watt, and David J Torgerson
BMJ 2005 330: 1003. [Abstract] [Full Text] [PDF]

Vitamin D three times a year can prevent fractures
BMJ 2003 326: 0. [Full Text] [PDF]

This article has been cited by other articles:

• Reis, J. P, von Muhlen, D., Miller, E. R III (2008). Relation of 25-hydroxyvitamin D and parathyroid hormone levels with metabolic syndrome among US adults.. Eur J Endocrinol 159: 41-48 [Abstract] [Full text]  
• Ng, K., Meyerhardt, J. A., Wu, K., Feskanich, D., Hollis, B. W., Giovannucci, E. L., Fuchs, C. S. (2008). Circulating 25-Hydroxyvitamin D Levels and Survival in Patients With Colorectal Cancer. JCO 26: 2984-2991 [Abstract] [Full text]  
• Mucci, L. A., Spiegelman, D. (2008). Vitamin D and Prostate Cancer Risk--A Less Sunny Outlook?. JNCI J Natl Cancer Inst 100: 759-761 [Full text]  
• Heaney, R. P, Armas, L. A., Shary, J. R, Bell, N. H, Binkley, N., Hollis, B. W (2008). 25-Hydroxylation of vitamin D3: relation to circulating vitamin D3 under various input conditions. Am. J. Clin. Nutr. 87: 1738-1742 [Abstract] [Full text]  
• Fleet, J. C., Gliniak, C., Zhang, Z., Xue, Y., Smith, K. B., McCreedy, R., Adedokun, S. A. (2008). Serum Metabolite Profiles and Target Tissue Gene Expression Define the Effect of Cholecalciferol Intake on Calcium Metabolism in Rats and Mice. J. Nutr. 138: 1114-1120 [Abstract] [Full text]  
• Ilahi, M., Armas, L. A., Heaney, R. P (2008). Pharmacokinetics of a single, large dose of cholecalciferol. Am. J. Clin. Nutr. 87: 688-691 [Abstract] [Full text]  
• Petridou, E. Th., Dikalioti, S. K., Dessypris, N., Skalkidis, I., Barbone, F., Fitzpatrick, P., Heloma, A., Segui-Gomez, M., Sethi, D. (2008). The Evolution of Unintentional Injury Mortality Among Elderly in Europe. J Aging Health 20: 159-182 [Abstract]  
• MacLaughlin, E. J., Raehl, C. L. (2008). ASHP Therapeutic Position Statement on the Prevention and Treatment of Osteoporosis in Adults. Am J Health Syst Pharm 65: 343-357 [Full text]  
• Smith, H., Anderson, F., Raphael, H., Maslin, P., Crozier, S., Cooper, C. (2007). Effect of annual intramuscular vitamin D on fracture risk in elderly men and women a population-based, randomized, double-blind, placebo-controlled trial. Rheumatology (Oxford) 46: 1852-1857 [Abstract] [Full text]  
• Freedman, D. M., Looker, A. C., Chang, S.-C., Graubard, B. I. (2007). Prospective Study of Serum Vitamin D and Cancer Mortality in the United States. JNCI J Natl Cancer Inst 99: 1594-1602 [Abstract] [Full text]  
• Alpert, P. T., Shaikh, U. (2007). The Effects of Vitamin D Deficiency and Insufficiency on the Endocrine and Paracrine Systems. Biol Res Nurs 9: 117-129 [Abstract]  
• Autier, P., Gandini, S. (2007). Vitamin D Supplementation and Total Mortality: A Meta-analysis of Randomized Controlled Trials. Arch Intern Med 167: 1730-1737 [Abstract] [Full text]  
• Burleigh, E., McColl, J., Potter, J. (2007). Does vitamin D stop inpatients falling? A randomised controlled trial. Age Ageing 36: 507-513 [Abstract] [Full text]  
• Holick, M. F. (2007). Vitamin D Deficiency. NEJM 357: 266-281 [Full text]  
• Weng, F. L, Shults, J., Leonard, M. B, Stallings, V. A, Zemel, B. S (2007). Risk factors for low serum 25-hydroxyvitamin D concentrations in otherwise healthy children and adolescents. Am. J. Clin. Nutr. 86: 150-158 [Abstract] [Full text]  
• Jackson, C., Gaugris, S., Sen, S.S., Hosking, D. (2007). The effect of cholecalciferol (vitamin D3) on the risk of fall and fracture: a meta-analysis. QJM 100: 185-192 [Abstract] [Full text]  
• Hathcock, J. N, Shao, A., Vieth, R., Heaney, R. (2007). Risk assessment for vitamin D. Am. J. Clin. Nutr. 85: 6-18 [Abstract] [Full text]  
• Heaney, R. P (2007). Bone health. Am. J. Clin. Nutr. 85: 300S-303S [Abstract] [Full text]  
• Albertsson, D. M., Mellstrom, D., Petersson, C., Eggertsen, R. (2007). Validation of a 4-Item Score Predicting Hip Fracture and Mortality Risk Among Elderly Women. Ann Fam Med 5: 48-56 [Abstract] [Full text]  
• Law, M., Withers, H., Morris, J., Anderson, F. (2006). Vitamin D supplementation and the prevention of fractures and falls: results of a randomised trial in elderly people in residential accommodation. Age Ageing 35: 482-486 [Abstract] [Full text]  
• Bischoff-Ferrari, H. A, Giovannucci, E., Willett, W. C, Dietrich, T., Dawson-Hughes, B. (2006). Estimation of optimal serum concentrations of 25-hydroxyvitamin D for multiple health outcomes. Am. J. Clin. Nutr. 84: 18-28 [Abstract] [Full text]  
• Cockayne, S., Adamson, J., Lanham-New, S., Shearer, M. J., Gilbody, S., Torgerson, D. J. (2006). Vitamin K and the Prevention of Fractures: Systematic Review and Meta-analysis of Randomized Controlled Trials.. Arch Intern Med 166: 1256-1261 [Abstract] [Full text]  
• Francis, R.M., Anderson, F.H., Patel, S., Sahota, O., van Staa, T.P. (2006). Calcium and vitamin D in the prevention of osteoporotic fractures. QJM 99: 355-363 [Full text]  
• Heaney, R. P. (2006). Barriers to Optimizing Vitamin D3 Intake for the Elderly. J. Nutr. 136: 1123-1125 [Abstract] [Full text]  
• Jackson, R. D., LaCroix, A. Z., Gass, M., Wallace, R. B., Robbins, J., Lewis, C. E., Bassford, T., Beresford, S. A.A., Black, H. R., Blanchette, P., Bonds, D. E., Brunner, R. L., Brzyski, R. G., Caan, B., Cauley, J. A., Chlebowski, R. T., Cummings, S. R., Granek, I., Hays, J., Heiss, G., Hendrix, S. L., Howard, B. V., Hsia, J., Hubbell, F. A., Johnson, K. C., Judd, H., Kotchen, J. M., Kuller, L. H., Langer, R. D., Lasser, N. L., Limacher, M. C., Ludlam, S., Manson, J. E., Margolis, K. L., McGowan, J., Ockene, J. K., O'Sullivan, M. J., Phillips, L., Prentice, R. L., Sarto, G. E., Stefanick, M. L., Van Horn, L., Wactawski-Wende, J., Whitlock, E., Anderson, G. L., Assaf, A. R., Barad, D., the Women's Health Initiative Investigators, (2006). Calcium plus Vitamin D Supplementation and the Risk of Fractures. NEJM 354: 669-683 [Abstract] [Full text]  
• Steingrimsdottir, L., Gunnarsson, O., Indridason, O. S., Franzson, L., Sigurdsson, G. (2005). Relationship Between Serum Parathyroid Hormone Levels, Vitamin D Sufficiency, and Calcium Intake. JAMA 294: 2336-2341 [Abstract] [Full text]  
• Allain, T. J. (2005). Vitamin D and fracture prevention--treatment still indicated but clarification needed. Age Ageing 34: 542-544 [Full text]  
• Rockell, J. E., Green, T. J., Skeaff, C. M., Whiting, S. J., Taylor, R. W., Williams, S. M., Parnell, W. R., Scragg, R., Wilson, N., Schaaf, D., Fitzgerald, E. D., Wohlers, M. W. (2005). Season and Ethnicity Are Determinants of Serum 25-Hydroxyvitamin D Concentrations in New Zealand Children Aged 5-14 y. J. Nutr. 135: 2602-2608 [Abstract] [Full text]  
• Karlsson, M. K., Gerdhem, P., Ahlborg, H. G. (2005). The prevention of osteoporotic fractures. J Bone Joint Surg Br 87-B: 1320-1327 [Full text]  
• Moore, C. E., Murphy, M. M., Holick, M. F. (2005). Vitamin D Intakes by Children and Adults in the United States Differ among Ethnic Groups. J. Nutr. 135: 2478-2485 [Abstract] [Full text]  
• Rosen, C. J. (2005). Postmenopausal Osteoporosis. NEJM 353: 595-603 [Full text]  
• Hodsman, A. B., Bauer, D. C., Dempster, D. W., Dian, L., Hanley, D. A., Harris, S. T., Kendler, D. L., McClung, M. R., Miller, P. D., Olszynski, W. P., Orwoll, E., Yuen, C. K. (2005). Parathyroid Hormone and Teriparatide for the Treatment of Osteoporosis: A Review of the Evidence and Suggested Guidelines for Its Use. Endocr. Rev. 26: 688-703 [Abstract] [Full text]  
• Aloia, J. F., Talwar, S. A., Pollack, S., Yeh, J. (2005). A Randomized Controlled Trial of Vitamin D3 Supplementation in African American Women. Arch Intern Med 165: 1618-1623 [Abstract] [Full text]  
• Heaney, R. P. (2005). To D or Not to D. IBMS BoneKEy 2: 28-31 [Full text]  
• FUSARO, R. M., RICE, E. G. (2005). The Maillard Reaction for Sunlight Protection. Ann. N. Y. Acad. Sci. 1043: 174-183 [Abstract] [Full text]  
• Holick, M. F., Siris, E. S., Binkley, N., Beard, M. K., Khan, A., Katzer, J. T., Petruschke, R. A., Chen, E., de Papp, A. E. (2005). Prevalence of Vitamin D Inadequacy among Postmenopausal North American Women Receiving Osteoporosis Therapy. J. Clin. Endocrinol. Metab. 90: 3215-3224 [Abstract] [Full text]  
• Bischoff-Ferrari, H. A., Willett, W. C., Wong, J. B., Giovannucci, E., Dietrich, T., Dawson-Hughes, B. (2005). Fracture Prevention With Vitamin D Supplementation: A Meta-analysis of Randomized Controlled Trials. JAMA 293: 2257-2264 [Abstract] [Full text]  
• 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, D. J (2005). Randomised controlled trial of calcium and supplementation with cholecalciferol (vitamin D3) for prevention of fractures in primary care. BMJ 330: 1003- [Abstract] [Full text]  
• Dawson-Hughes, B. (2005). The Role of Vitamin D in Fracture Prevention. IBMS BoneKEy 2: 6-10 [Full text]  
• Venning, G. (2005). Recent developments in vitamin D deficiency and muscle weakness among elderly people. BMJ 330: 524-526 [Full text]  
• Smith, S. M., Zwart, S. R., Block, G., Rice, B. L., Davis-Street, J. E. (2005). The Nutritional Status of Astronauts Is Altered after Long-Term Space Flight Aboard the International Space Station. J. Nutr. 135: 437-443 [Abstract] [Full text]  
• Calvo, M. S., Whiting, S. J., Barton, C. N. (2005). Vitamin D Intake: A Global Perspective of Current Status. J. Nutr. 135: 310-316 [Abstract] [Full text]  
• Hollis, B. W. (2005). Circulating 25-Hydroxyvitamin D Levels Indicative of Vitamin D Sufficiency: Implications for Establishing a New Effective Dietary Intake Recommendation for Vitamin D. J. Nutr. 135: 317-322 [Abstract] [Full text]  
• Gross, M. D. (2005). Vitamin D and Calcium in the Prevention of Prostate and Colon Cancer: New Approaches for the Identification of Needs. J. Nutr. 135: 326-331 [Abstract] [Full text]  
• Hanley, D. A., Davison, K. S. (2005). Vitamin D Insufficiency in North America. J. Nutr. 135: 332-337 [Abstract] [Full text]  
• Heaney, R. P (2004). Functional indices of vitamin D status and ramifications of vitamin D deficiency. Am. J. Clin. Nutr. 80: 1706S-1709S [Abstract] [Full text]  
• Fleet, J. C (2004). Genomic and proteomic approaches for probing the role of vitamin D in health. Am. J. Clin. Nutr. 80: 1730S-1734S [Abstract] [Full text]  
• Weaver, C. M, Fleet, J. C (2004). Vitamin D requirements: current and future. Am. J. Clin. Nutr. 80: 1735S-1739S [Abstract] [Full text]  
• Dawson-Hughes, B. (2004). Racial/ethnic considerations in making recommendations for vitamin D for adult and elderly men and women. Am. J. Clin. Nutr. 80: 1763S-1766S [Abstract] [Full text]  
• Cummings, S., Sellmeyer, D. (2004). Review: calcium supplementation has a small positive effect on bone mineral density but not fractures in postmenopausal women. Evid. Based Med. 9: 170-170 [Full text]  
• Armas, L. A. G., Hollis, B. W., Heaney, R. P. (2004). Vitamin D2 Is Much Less Effective than Vitamin D3 in Humans. J. Clin. Endocrinol. Metab. 89: 5387-5391 [Abstract] [Full text]  
• Sambrook, P. N., Chen, J. S., March, L. M., Cameron, I. D., Cumming, R. G., Lord, S. R., Schwarz, J., Seibel, M. J. (2004). Serum Parathyroid Hormone Is Associated with Increased Mortality Independent of 25-Hydroxy Vitamin D Status, Bone Mass, and Renal Function in the Frail and Very Old: A Cohort Study. J. Clin. Endocrinol. Metab. 89: 5477-5481 [Abstract] [Full text]  
• Bischoff-Ferrari, H. A, Dietrich, T., Orav, E J., Hu, F. B, Zhang, Y., Karlson, E. W, Dawson-Hughes, B. (2004). Higher 25-hydroxyvitamin D concentrations are associated with better lower-extremity function in both active and inactive persons aged >=60 y. Am. J. Clin. Nutr. 80: 752-758 [Abstract] [Full text]  
• Dietrich, T., Joshipura, K. J, Dawson-Hughes, B., Bischoff-Ferrari, H. A (2004). Association between serum concentrations of 25-hydroxyvitamin D3 and periodontal disease in the US population. Am. J. Clin. Nutr. 80: 108-113 [Abstract] [Full text]  
• Binkley, N., Krueger, D., Cowgill, C. S., Plum, L., Lake, E., Hansen, K. E., DeLuca, H. F., Drezner, M. K. (2004). Assay Variation Confounds the Diagnosis of Hypovitaminosis D: A Call for Standardization. J. Clin. Endocrinol. Metab. 89: 3152-3157 [Abstract] [Full text]  
• Bischoff-Ferrari, H. A., Dawson-Hughes, B., Willett, W. C., Staehelin, H. B., Bazemore, M. G., Zee, R. Y., Wong, J. B. (2004). Effect of Vitamin D on Falls: A Meta-analysis. JAMA 291: 1999-2006 [Abstract] [Full text]  
• Valimaki, V.-V., Alfthan, H., Lehmuskallio, E., Loyttyniemi, E., Sahi, T., Stenman, U.-H., Suominen, H., Valimaki, M. J. (2004). Vitamin D Status as a Determinant of Peak Bone Mass in Young Finnish Men. J. Clin. Endocrinol. Metab. 89: 76-80 [Abstract] [Full text]  
• Somner, J., McLellan, S., Cheung, J., Mak, Y. T., Frost, M. L., Knapp, K. M., Wierzbicki, A. S., Wheeler, M., Fogelman, I., Ralston, S. H., Hampson, G. N. (2004). Polymorphisms in the P450 c17 (17-Hydroxylase/17,20-Lyase) and P450 c19 (Aromatase) Genes: Association with Serum Sex Steroid Concentrations and Bone Mineral Density in Postmenopausal Women. J. Clin. Endocrinol. Metab. 89: 344-351 [Abstract] [Full text]  
• Gordon, J. (2003). OSTEOPOROSIS: TRANSLATING RESEARCH INTO CLINICAL PRACTICE. Gerontologist 43: 939-944 [Full text]  
• Heaney, R. P (2003). Long-latency deficiency disease: insights from calcium and vitamin D. Am. J. Clin. Nutr. 78: 912-919 [Abstract] [Full text]  
• Heaney, R. P. (2003). Vitamin D, Nutritional Deficiency, and the Medical Paradigm. J. Clin. Endocrinol. Metab. 88: 5107-5108 [Full text]  
• Forbes, D. (2003). Oral vitamin D3 supplementation reduced fractures in community dwelling elderly people. Evid. Based Nurs. 6: 113-113 [Full text]  
• Woolf, A. D, Akesson, K. (2003). Preventing fractures in elderly people. BMJ 327: 89-95 [Full text]  
• (2003). Robin Goodfellow (42-6). Rheumatology (Oxford) 42: 813-813 [Full text]  
• (2003). Vitamin D: A Simple Way to Prevent Fractures. Journal Watch Dermatology 2003: 13-13 [Full text]  
• (2003). Vitamin D: A Simple Way to Prevent Fractures. JWatch General 2003: 2-2 [Full text]  
• Heaney, R. P., Dowell, M. S., Hale, C. A., Bendich, A. (2003). Calcium Absorption Varies within the Reference Range for Serum 25-Hydroxyvitamin D. J. Am. Coll. Nutr. 22: 142-146 [Abstract] [Full text]  

Rapid Responses:

Read all Rapid Responses

Vitamin D deficiency, lack of sunlight, multiple sclerosis

Peter K. Tun
bmj.com, 1 Mar 2003 [Full text]

Level of vitamin D (3) supplementation 100,000IU

Anne Woo
bmj.com, 1 Mar 2003 [Full text]

Re: Level of vitamin D (3) supplementation 100,000IU

Robert D Toon
bmj.com, 2 Mar 2003 [Full text]

Why no funding for a community trial?

Jim Page
bmj.com, 2 Mar 2003 [Full text]

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

Trevor G Marshall, PhD
bmj.com, 3 Mar 2003 [Full text]

How can Trivedi et al, Overlook the Possibility of Hypervitaminosis-D?

Belinda J Fenter
bmj.com, 3 Mar 2003 [Full text]

Safety of Vitamin D dose in used in fracture trial

Kay-Tee Khaw
bmj.com, 3 Mar 2003 [Full text]

A Therapy is Only Safe if it "Does No Harm"

Trevor G Marshall, PhD
bmj.com, 4 Mar 2003 [Full text]

Could vitamin D be of potential benefit in epileptic patients?

Mohammed S Rashid (BPharm MRPharmS)
bmj.com, 5 Mar 2003 [Full text]

Make sure to measure the correct 'Vitamin D'- there are four of them

Trevor G Marshall
bmj.com, 6 Mar 2003 [Full text]

Potential Confounding Factors May Have Impacted on the Results

Henry Zeimer
bmj.com, 7 Mar 2003 [Full text]

Re: How can Trivedi et al, Overlook the Possibility of Hypervitaminosis-D?

Reinhold Vieth
bmj.com, 9 Mar 2003 [Full text]

Podiatrists administering vitamin D

Peter J Elton
bmj.com, 10 Mar 2003 [Full text]

Vitamin D, falls and fractures

Jugdeep K Dhesi, et al.
bmj.com, 16 Mar 2003 [Full text]

Vitamin D status in the population

Haakon E. Meyer
bmj.com, 18 Mar 2003 [Full text]

frail elderly patients and vitamin D

Michael D Stone
bmj.com, 22 Mar 2003 [Full text]

Annual injection

Mark D Oliver
bmj.com, 22 Mar 2003 [Full text]

Vitamin D for the over 65s

Lisa A Dunkley, et al.
bmj.com, 22 Mar 2003 [Full text]

Re: Vitamin D, falls and fractures

Andrew Herxheimer
bmj.com, 28 Mar 2003 [Full text]

Dose of vitamin D

John J Cannell, MD
bmj.com, 12 Apr 2003 [Full text]

The effect and administration of vitamin D.

Rauno J. Heikinheimo, et al.
bmj.com, 26 Apr 2003 [Full text]

Vitamin D and fractures

Montserrat Romera, et al.
bmj.com, 5 May 2003 [Full text]