Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
Calcified Tissue International
Published in: Calcified Tissue International 2/2013

01-02-2013 | Original Research

Is High Dose Vitamin D Harmful?

Authors: Kerrie M. Sanders, Geoffrey C. Nicholson, Peter R. Ebeling

Published in: Calcified Tissue International | Issue 2/2013

Login to get access

Abstract

With the potential to minimize the risk of many chronic diseases and the apparent biochemical safety of ingesting doses of oral vitamin D several-fold higher than the current recommended intakes, recent research has focussed on supplementing individuals with intermittent, high-dose vitamin D. However, two recent randomized controlled trials (RCTs) both using annual high-dose vitamin D reported an increase, rather than a decrease, in the primary outcome of fractures. This review summarises the results from studies that have used intermittent, high doses of vitamin D, with particular attention to those finding evidence of adverse effects. Results from observational, population-based studies with evidence of a U- or J-shaped curve are also presented as these findings suggest an increased risk in those with the highest serum 25D levels. Speculative mechanisms are discussed and biochemical results from studies using high-dose vitamin D are also presented. Emerging evidence from both observational studies and RCTs suggests there should be a degree of caution about recommending high serum 25D concentrations for the entire population. Furthermore, benefit of the higher doses commonly used in clinical practice on falls risk reduction needs to be demonstrated. The safety of loading doses of vitamin D should be demonstrated before these regimens become recommended as routine clinical practice. The current dilemma of defining vitamin D insufficiency and identifying safe and efficacious repletion regimens needs to be resolved.
Literature
1.
Mithal A, Wahl D, Bonjour J, Burckhardt P, Dawson-Hughes B, Eisman J et al (2009) Global vitamin D status and determinants of hypovitaminosis D. Osteoporos Int 20(11):1807–1820PubMedCrossRef
2.
Nowson C, McGrath J, Ebeling P, Haikerwal A, Daly R, Sanders K et al (2012) Vitamin D and health in adults in Australia and New Zealand: a position statement. Med J Aust 196(11):686–687PubMedCrossRef
3.
Dawson-Hughes B, Mithal A, Bonjour JP, Boonen S, Burckhardt P, Fuleihan GE et al (2010) IOF position statement: vitamin D recommendations for older adults. Osteoporos Int 21(7):1151–1154PubMedCrossRef
4.
Henry HL, Bouillon R, Norman AW, Gallagher JC, Lips P, Heaney RP et al (2010) 14th Vitamin D Workshop consensus on vitamin D nutritional guidelines. J Steroid Biochem Mol Biol 121(1–2):4–6PubMedCrossRef
5.
Heaney RP, Holick MF (2011) Why the IOM recommendations for vitamin D are deficient. J Bone Miner Res 26(3):455–457PubMedCrossRef
6.
Ebeling PR (2005) Megadose therapy for vitamin D deficiency. Med J Aust 183(1):4–5PubMed
7.
Tang B, Eslick G, Nowson C, Smith C, Bensoussan A (2007) Use of calcium or calcium in combination with vitamin D supplementation to prevent fractures and bone loss in people aged 50 years and older: a meta-analysis. Lancet 370(9588):657–1656PubMedCrossRef
8.
Giusti A, Barone A, Pioli G, Girasole G, Razzano M, Pizzonia M et al (2010) Heterogeneity in serum 25-hydroxyvitamin D response to cholecalciferol in elderly women with secondary hyperparathyroidism and vitamin D deficiency. J Am Geriatr Soc 58:1489–1495PubMedCrossRef
9.
Leidig-Bruckner G, Roth H, Bruckner T, Lorenz A, Raue F, Frank-Raue K (2011) Are commonly recommended dosages for vitamin D supplementation too low? Vitamin D status and effects of supplementation on serum 25-hydroxyvitamin D levels—an observational study during clinical practice conditions. Osteoporos Int 22:231–240PubMedCrossRef
10.
Chung M, Balk EM, Brendel M, Ip S, Lau J, Lee J et al (2009) Vitamin D and calcium: a systematic review of health outcomes. Evid Rep Technol Assess (Full Rep) 183:1–420
11.
12.
13.
Committee to Review Dietary Reference Intakes for Calcium and Vitamin D, Food and Nutrition Board (2010) Dietary reference intakes for calcium and vitamin D. Institute of Medicine, Washington, DC
14.
Lips P, Bouillon R, van Schoor NM, Vanderschueren D, Verschueren S, Kuchuk N et al (2010) Reducing fracture risk with calcium and vitamin D. Clin Endocrinol (Oxf) 73(3):277–285CrossRef
15.
Dawson-Hughes B, Heaney RP, Holick MF, Lips P, Meunier PJ, Vieth R (2005) Estimates of optimal vitamin D status. Osteoporos Int 16(7):713–716PubMedCrossRef
16.
17.
Vieth R, Chan P, MacFarlane G (2001) Efficacy and safety of vitamin D3 input exceeding the lowest observed adverse effect concentration. Am J Clin Nutr 73:288–294PubMed
18.
Montero-Odasso M, Duque G (2005) Vitamin D in the aging musculoskeletal system: an authentic strength preserving hormone. Mol Aspects Med 26:203–219PubMedCrossRef
19.
Anderson P, May B, Morris H (2003) Vitamin D metabolism: new concepts and clinical implications. Clin Biochem Rev 24:13–26PubMed
20.
Group DIPART (2010) Patient level pooled analysis of 68,500 patients from seven major vitamin D fracture trials in US and Europe. BMJ 340:b5463CrossRef
21.
Elders P, Lips P, Netelenbos J, Van Grinkel F, Khoe E, Van der Vijgh W et al (1994) Long-term effect of calcium supplementation on bone loss in perimenopausal women. J Bone Miner Res 9:963–970PubMedCrossRef
22.
Reid I, Mason B, Horne A, Ames R, Reid H, Bava U et al (2006) Randomized controlled trial of calcium in healthy older women. Am J Med 119(9):777–785PubMedCrossRef
23.
Cipriani C, Romagnoli E, Scillitani A, Chiodini I, Clerio R, Carnevale V et al (2010) Effect of a single oral dose of 600,000 IU of cholecalciferol on serum calciotropic hormones in young people with vitamin D deficiency: a prospective intervention study. J Clin Endocrinol Metab 95:4771–4777PubMedCrossRef
24.
Bacon C, Gamble G, Horne A, Scott M, Reid I (2009) High-dose vitamin D3 supplementation in the elderly. Osteoporos Int 20(8):1407–1415PubMedCrossRef
25.
Diamond T, Ho K, Rohl P, Meerkin M (2005) Annual intramuscular injection of a megadose of cholecalciferol for treatment of vitamin D deficiency: efficacy and safety data. Med J Aust 183(1):10–12PubMed
26.
Vieth R (2011) The pharmacology of vitamin D. In: Feldman D, Pike J, Adams J (eds) vitamin D. Academic Press, London, pp 1041–1066CrossRef
27.
Sanders K, Stuart A, Williamson E, Simpson J, Kotowicz M, Young D et al (2010) Annual high-dose oral vitamin D for falls and fractures in elderly women: a randomised, double-blind, placebo-controlled study. JAMA 303(18):1815–1822PubMedCrossRef
28.
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 46(12):1852–1857PubMedCrossRef
29.
Bischoff-Ferrari H, Willett W, Wong J, Giovannucci E, Dietrich T, Dawson-Hughes B (2005) Fracture prevention with vitamin D supplementation: a meta-analysis of randomized controlled trials. JAMA 293(18):2257–2264PubMedCrossRef
30.
Bischoff-Ferrari H, Willett W, Wong J, Stuck A, Staehelin H, Orav J et al (2009) Prevention of nonvertebral fractures with oral vitamin D and dose dependency: a meta-analysis of randomized controlled trials. Arch Intern Med 169(6):551–561PubMedCrossRef
31.
Reid I, Bolland M, Grey A (2008) Effect of calcium supplementation on hip fractures. Osteoporos Int 19(8):1119–1123PubMedCrossRef
32.
Cranney A, Weiler H, O’Donnell S, Puil L (2008) Summary of evidence-based review on vitamin D efficacy and safety in relation to bone health. Am J Clin Nutr 88(2):513S–519SPubMed
33.
Ross AC, Manson JE, Abrams SA, Aloia JF, Brannon PM, Clinton SK et al (2011) The 2011 report on dietary reference intakes for calcium and vitamin D from the Institute of Medicine: what clinicians need to know. J Clin Endocrinol Metab 96(1):53–58PubMedCrossRef
34.
Grimnes G, Joakimsen R, Figenschau Y, Torjesen PA, Almas B, Jorde R (2012) The effect of high-dose vitamin D on bone mineral density and bone turnover markers in postmenopausal women with low bone mass—a randomized controlled 1-year trial. Osteoporos Int 23(1):201–211PubMedCrossRef
35.
von Restorff C, Bischoff-Ferrari H, Theiler R (2009) High-dose oral vitamin D3 supplementation in rheumatology patients with severe vitamin D3 deficiency. Bone 45:747–749CrossRef
36.
Byrne P, Freaney R, McKenna M (1995) Vitamin D supplementation in the elderly: review of safety and effectiveness of different regimes. Calcif Tissue Int 56:518–520PubMedCrossRef
37.
Heaney R, Davies K, Chen T, Holick M, Barger-Lux M (2003) Human serum 25-hydroxycholecalciferol response to extended oral dosing with cholecalciferol. Am J Clin Nutr 77:204–210PubMed
38.
Binkley N, Gemar D, Engelke J, Gangnon R, Ramamurthy R, Krueger D et al (2011) Evaluation of ergocalciferol or cholecalciferol dosing, 1,600 IU daily or 50,000 IU monthly in older adults. J Clin Endocrinol Metab 96(4):981–988PubMedCrossRef
39.
Garland C, Garland F, Gorham E, Lipkin M, Newmark H, Mohr S et al (2006) The role of vitamin D in cancer prevention. Am J Public Health 96(2):252–261PubMedCrossRef
40.
41.
Evatt M (2010) Beyond vitamin status: is there a role for vitamin D in Parkinson disease? Arch Neurol 67(7):795–796PubMedCrossRef
42.
Grant W (2002) An estimate of premature cancer mortality in the U.S. due to inadequate doses of solar ultraviolet-B radiation. Cancer 94(6):1867–1875PubMedCrossRef
43.
Freedman DM, Looker AC, Abnet CC, Linet MS, Graubard BI (2010) Serum 25-hydroxyvitamin D and cancer mortality in the NHANES III study (1988–2006). Cancer Res 70(21):8587–8597PubMedCrossRef
44.
Vieth R (2004) Enzyme kinetics hypothesis to explain the U-shaped risk curve for prostate cancer vs. 25-hydroxyvitamin D in Nordic countries. Int J Cancer 111(3):468PubMedCrossRef
45.
Grant WB (2004) Geographic variation of prostate cancer mortality rates in the United States: implications for prostate cancer risk related to vitamin D. Int J Cancer 111(3):470–472PubMedCrossRef
46.
Trivedi D, Doll R, Khaw K (2003) Effect of four monthly oral vitamin D supplementation on fractures and mortality in men and women living in the community: randomised double blind controlled trial. BMJ 326(7387):469–475PubMedCrossRef
47.
Ilahi M, Armas L, Heaney R (2008) Pharmokinetics of a single, large dose of cholecalciferol. Am J Clin Nutr 87:688–691PubMed
48.
Rossini M, Adami S, Viapiana O, Fracassi E, Idolazzi L, Povino M et al (2012) Dose-dependent short-term effects of single high doses of oral vitamin D3 on bone turnover markers. Calcif Tissue Int 91:365–369PubMedCrossRef
49.
Sanders K, Ebeling P, Stuart A, Williamson E, Kotowicz M, Nicholson G (2011) Annual high-dose oral vitamin D3: is increased risk of fractures attributable to changes in bone turnover markers? In: ANZBMS/IOF JSBR annual scientific meeting, Gold Coast, Australia
50.
Heikinheimo R (1992) Annual injection of vitamin D and fractures of aged bones. Calcif Tissue Int 51(2):105–110PubMedCrossRef
51.
Pasco J, Henry M, Kotowicz M, Sanders K, Seeman E, Pasco J et al (2004) Seasonal periodicity of serum vitamin D and parathyroid hormone, bone resorption, and fractures: the Geelong Osteoporosis Study. J Bone Miner Res 19(5):752–758PubMedCrossRef
52.
Dawson-Hughes B, Harris S (2010) High-dose vitamin D supplementation: too much of a good thing? JAMA 303(18):1861–1862PubMedCrossRef
53.
Ensrud K, Ewing S, Fredman L, Hochberg M, Cauley J, Hillier T et al (2010) Circulating 25-hydroxyvitamin D levels and frailty status in older women. J Clin Endocrinol Metab 95:5266–5273PubMedCrossRef
54.
Michaelsson K, Baron J, Snellman G, Gedeborg R, Bysberg L, Sundstrom J et al (2010) Plasma vitamin D and mortality in older men: a community-based prospective cohort study. Am J Clin Nutr 92(4):841–848PubMedCrossRef
55.
McGrath J, Eyles D, Pedersen C, Ko P, Burne T et al (2010) Neonatal vitamin D status and risk of schizophrenia. Arch Gen Psychiatry 67(9):889–894PubMedCrossRef
56.
Lyons R, Johansen A, Brophy S, Newcombe R, Phillips C, Lervy B et al (2007) Preventing fractures among older people living in institutional care: a pragmatic randomised double blind placebo controlled trial of vitamin D supplementation. Osteoporos Int 18(6):811–818PubMedCrossRef
57.
Sanders K, Stuart A, Williamson E, Jacka F, Dodd S, Nicholson G et al (2011) A randomised controlled trial investigating an annual high dose vitamin D3 and mental well-being: vital D study. Br J Psychiatry 198:357–364PubMedCrossRef
58.
Beckman MJ, Johnson JA, Goff JP, Reinhardt TA, Beitz DC, Horst RL (1995) The role of dietary calcium in the physiology of vitamin D toxicity: excess dietary vitamin D3 blunts parathyroid hormone induction of kidney 1-hydroxylase. Arch Biochem Biophys 319(2):535–539PubMedCrossRef
59.
Vieth R (2009) Proposal A: optimal health requires high 25OHD levels >40 ng/ml (>100 nmol/L). Fourteenth Workshop on Vitamin D. Brugge, Belgium, p 72
60.
Sanders K, Ebeling P, Stuart A, Williamson E, Simpson J, Kotowicz M, et al. (2011) The efficacy of high-dose vitamin D3 administered once a year: is the increased risk of falls attributable to changes in muscle strength? American Society of Bone and Mineral Research scientific meeting. San Diego, CA, September 16–20
61.
Reid IR (2010) Vitamin D—let’s get back to the evidence base. IBMS Bonekey 7(7):249–253CrossRef
62.
Buell JS, Dawson-Hughes B (2008) Vitamin D and neurocognitive dysfunction: preventing “D”ecline? Mol Aspects Med 29(6):415–422PubMedCrossRef
63.
Glendenning P, Zhu K, Inderjeeth C, Howat P, Lewis JR, Prince RL (2012) Effects of three-monthly oral 150,000 IU cholecalciferol supplementation on falls, mobility, and muscle strength in older postmenopausal women: a randomized controlled trial. J Bone Miner Res 27(1):170–176CrossRef
64.
Stockton KA, Mengersen K, Paratz JD, Kandiah D, Bennell KL (2011) Effect of vitamin D supplementation on muscle strength: a systematic review and meta-analysis. Osteoporos Int 22(3):859–871PubMed
65.
Cummings S (2010) A single, annual, high dose of oral vitamin D increased falls and fractures in older women. ACP J Club 153(3):JC3–3
66.
67.
World Cancer Research Fund, American Institute for Cancer Research (2007) Food, nutrition, physical activity, and the prevention of cancer: a global perspective. AICR, Washington, DC
68.
69.
70.
Premaor MO, Scalco R, da Silva MJ, Froehlich PE, Furlanetto TW (2008) The effect of a single dose versus a daily dose of cholecalciferol on the serum 25-hydroxycholecalciferol and parathyroid hormone levels in the elderly with secondary hyperparathyroidism living in a low-income housing unit. J Bone Miner Metab 26(6):603–608PubMedCrossRef
71.
Pekkarinen T, Valimaki VV, Aarum S, Turpeinen U, Hamalainen E, Loyttyniemi E et al (2010) The same annual dose of 292000 IU of vitamin D (cholecalciferol) on either daily or four monthly basis for elderly women: 1-year comparative study of the effects on serum 25(OH)D concentrations and renal function. Clin Endocrinol (Oxf) 72(4):455–461CrossRef
72.
Jorde R, Sneve M, Figenschau Y, Svartberg J, Waterloo K (2008) Effects of vitamin D supplementation on symptoms of depression in overweight and obese subjects: randomized double blind trial. J Intern Med 264:599–609PubMedCrossRef
73.
Vieth R, Kimball S, Hu A, Walfish P (2004) 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 3:8PubMedCrossRef
74.
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 35:482–486PubMedCrossRef
75.
Aloia J, Bojadzievski T, Yusupov E, Shadzad G, Pollack S, Mikhail M et al (2010) The relative influence of calcium intake and vitamin D status on serum parathyroid hormone and bone turnover biomarkers in a double-blind, placebo-controlled parallel group, longitudinal factorial desigin. J Clin Endocrinol Metab 95(7):3216–3224PubMedCrossRef
76.
Chen W, Dawsey SM, Qiao YL, Mark SD, Dong ZW, Taylor PR et al (2007) Prospective study of serum 25(OH)-vitamin D concentration and risk of oesophageal and gastric cancers. Br J Cancer 97(1):123–128PubMedCrossRef
77.
Ahn J, Peters U, Albanes D, Purdue MP, Abnet CC, Chatterjee N et al (2008) Serum vitamin D concentration and prostate cancer risk: a nested case–control study. J Natl Cancer Inst 100(11):796–804PubMedCrossRef
78.
Tuohimaa P, Tenkanen L, Ahonen M, Lumme S, Jellum E, Hallmans G et al (2004) Both high and low levels of blood vitamin D are associated with a higher prostate cancer risk: a longitudinal, nested case-control study in the Nordic countries. Int J Cancer 108(1):104–108PubMedCrossRef
79.
Stolzenberg-Solomon R, Vieth R, Azad A, Pietinen P, Taylor P, Virtamo J et al (2006) A prospective nested case–control study of vitamin D status and pancreatic cancer risk in male smokers. Cancer Res 66(20):10213–10219PubMedCrossRef
80.
Stolzenberg-Solomon RZ, Hayes RB, Horst RL, Anderson KE, Hollis BW, Silverman DT (2009) Serum vitamin D and risk of pancreatic cancer in the prostate, lung, colorectal, and ovarian screening trial. Cancer Res 69(4):1439–1447PubMedCrossRef
81.
Flicker L, Mead K, MacInnis R, Nowson C, Scherer S, Stein M et al (2003) Serum vitamin D and falls in older women in residential care in Australia. J Am Geriatr Soc 51(11):1533–1538PubMedCrossRef
82.
Stein MS, Scherer SC, Ladd KS, Harrison LC (2011) A randomized controlled trial of high-dose vitamin D2 followed by intranasal insulin in Alzheimer’s disease. J Alzheimers Dis 26(3):477–484PubMed
83.
Bischoff-Ferrari HA, Dawson-Hughes B, Platz A, Orav EJ, Stahelin HB, Willett WC et al (2010) Effect of high-dosage cholecalciferol and extended physiotherapy on complications after hip fracture: a randomized controlled trial. Arch Intern Med 170(9):813–820PubMedCrossRef
Metadata
Title
Is High Dose Vitamin D Harmful?
Authors
Kerrie M. Sanders
Geoffrey C. Nicholson
Peter R. Ebeling
Publication date
01-02-2013
Publisher
Springer-Verlag
Published in
Calcified Tissue International / Issue 2/2013
Print ISSN: 0171-967X
Electronic ISSN: 1432-0827
DOI
https://doi.org/10.1007/s00223-012-9679-1

Other articles of this Issue 2/2013

Calcified Tissue International 2/2013 Go to the issue

Original Research

What is the Optimal Dietary Intake of Vitamin D for Reducing Fracture Risk?

Original Research

What Is Vitamin D Insufficiency? And Does It Matter?

Original Research

Casting New Light on the Sunshine Vitamin

Original Research

Vitamin D and Bone Health in Childhood and Adolescence

Original Research

Contributions of Sunlight and Diet to Vitamin D Status

Original Research

Prevention and Treatment of Vitamin D Deficiency
Live Webinar | 27-06-2024 | 18:00 (CEST)

Keynote webinar | Spotlight on medication adherence

Reserve your place

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

WHO estimates that half of all patients worldwide are non-adherent to their prescribed medication. The consequences of poor adherence can be catastrophic, on both the individual and population level.

Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.

Prof. Kevin Dolgin
Prof. Florian Limbourg
Prof. Anoop Chauhan
Developed by: Springer Medicine
Obesity Clinical Trial Summary

At a glance: The STEP trials

Read more

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine

Highlights from the ACC 2024 Congress

Year in Review: Pediatric cardiology

Pediatric Cardiology Video

Watch Dr. Anne Marie Valente present the last year's highlights in pediatric and congenital heart disease in the official ACC.24 Year in Review session.

Year in Review: Pulmonary vascular disease

Cardiopulmonary Comorbidity Video

The last year's highlights in pulmonary vascular disease are presented by Dr. Jane Leopold in this official video from ACC.24.

Year in Review: Valvular heart disease

Valvular Heart Disease Video

Watch Prof. William Zoghbi present the last year's highlights in valvular heart disease from the official ACC.24 Year in Review session.

Year in Review: Heart failure and cardiomyopathies

Heart Failure Video

Watch this official video from ACC.24. Dr. Biykem Bozkurt discusses last year's major advances in heart failure and cardiomyopathies.

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Heart Failure Video

Watch this official video from ACC.24. Dr. Biykem Bozkurt discusses last year's major advances in heart failure and cardiomyopathies.

Watch now

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

16-04-2024 Type 2 Diabetes News

Incentivised to exercise

11-04-2024 Lifestyle Modifications News

New intervention for STEMI-related cardiogenic shock

10-04-2024 Myocardial Infarction News

» View more highlights on the ACC 2024 congress hub page

Image Credits