Calcified Tissue International

, Volume 92, Issue 2, pp 191–206 | Cite as

Is High Dose Vitamin D Harmful?

  • Kerrie M. Sanders
  • Geoffrey C. Nicholson
  • Peter R. Ebeling
Original Research


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.


Steroid hormones Vitamin D Osteoporosis Fractures Age Aging 


  1. 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):1807–1820PubMedCrossRefGoogle Scholar
  2. 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):686–687PubMedCrossRefGoogle Scholar
  3. 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):1151–1154PubMedCrossRefGoogle Scholar
  4. 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):4–6PubMedCrossRefGoogle Scholar
  5. 5.
    Heaney RP, Holick MF (2011) Why the IOM recommendations for vitamin D are deficient. J Bone Miner Res 26(3):455–457PubMedCrossRefGoogle Scholar
  6. 6.
    Ebeling PR (2005) Megadose therapy for vitamin D deficiency. Med J Aust 183(1):4–5PubMedGoogle Scholar
  7. 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):657–1656PubMedCrossRefGoogle Scholar
  8. 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 58:1489–1495PubMedCrossRefGoogle Scholar
  9. 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 22:231–240PubMedCrossRefGoogle Scholar
  10. 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) 183:1–420Google Scholar
  11. 11.
    Hansen KE (2011) High-dose vitamin D: helpful or harmful? Curr Rheumatol Rep 13(3):257–264PubMedCrossRefGoogle Scholar
  12. 12.
    Holick M (2007) Medical progress: vitamin D deficiency. N Engl J Med 357:266–281PubMedCrossRefGoogle Scholar
  13. 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, DCGoogle Scholar
  14. 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):277–285CrossRefGoogle Scholar
  15. 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):713–716PubMedCrossRefGoogle Scholar
  16. 16.
    Heaney R (2008) Vitamin D: criteria for safety and efficacy. Nutr Rev 66(Suppl 2):s178–s181PubMedCrossRefGoogle Scholar
  17. 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 73:288–294PubMedGoogle Scholar
  18. 18.
    Montero-Odasso M, Duque G (2005) Vitamin D in the aging musculoskeletal system: an authentic strength preserving hormone. Mol Aspects Med 26:203–219PubMedCrossRefGoogle Scholar
  19. 19.
    Anderson P, May B, Morris H (2003) Vitamin D metabolism: new concepts and clinical implications. Clin Biochem Rev 24:13–26PubMedGoogle Scholar
  20. 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:b5463CrossRefGoogle Scholar
  21. 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 9:963–970PubMedCrossRefGoogle Scholar
  22. 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):777–785PubMedCrossRefGoogle Scholar
  23. 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 95:4771–4777PubMedCrossRefGoogle Scholar
  24. 24.
    Bacon C, Gamble G, Horne A, Scott M, Reid I (2009) High-dose vitamin D3 supplementation in the elderly. Osteoporos Int 20(8):1407–1415PubMedCrossRefGoogle Scholar
  25. 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):10–12PubMedGoogle Scholar
  26. 26.
    Vieth R (2011) The pharmacology of vitamin D. In: Feldman D, Pike J, Adams J (eds) vitamin D. Academic Press, London, pp 1041–1066CrossRefGoogle Scholar
  27. 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):1815–1822PubMedCrossRefGoogle Scholar
  28. 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):1852–1857PubMedCrossRefGoogle Scholar
  29. 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):2257–2264PubMedCrossRefGoogle Scholar
  30. 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):551–561PubMedCrossRefGoogle Scholar
  31. 31.
    Reid I, Bolland M, Grey A (2008) Effect of calcium supplementation on hip fractures. Osteoporos Int 19(8):1119–1123PubMedCrossRefGoogle Scholar
  32. 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–519SPubMedGoogle Scholar
  33. 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):53–58PubMedCrossRefGoogle Scholar
  34. 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):201–211PubMedCrossRefGoogle Scholar
  35. 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 45:747–749CrossRefGoogle Scholar
  36. 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 56:518–520PubMedCrossRefGoogle Scholar
  37. 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 77:204–210PubMedGoogle Scholar
  38. 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):981–988PubMedCrossRefGoogle Scholar
  39. 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):252–261PubMedCrossRefGoogle Scholar
  40. 40.
    Lin R, White J (2004) The pleiotropic actions of vitamin D. BioEssays 26(1):21–28PubMedCrossRefGoogle Scholar
  41. 41.
    Evatt M (2010) Beyond vitamin status: is there a role for vitamin D in Parkinson disease? Arch Neurol 67(7):795–796PubMedCrossRefGoogle Scholar
  42. 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):1867–1875PubMedCrossRefGoogle Scholar
  43. 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):8587–8597PubMedCrossRefGoogle Scholar
  44. 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):468PubMedCrossRefGoogle Scholar
  45. 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):470–472PubMedCrossRefGoogle Scholar
  46. 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):469–475PubMedCrossRefGoogle Scholar
  47. 47.
    Ilahi M, Armas L, Heaney R (2008) Pharmokinetics of a single, large dose of cholecalciferol. Am J Clin Nutr 87:688–691PubMedGoogle Scholar
  48. 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 91:365–369PubMedCrossRefGoogle Scholar
  49. 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, AustraliaGoogle Scholar
  50. 50.
    Heikinheimo R (1992) Annual injection of vitamin D and fractures of aged bones. Calcif Tissue Int 51(2):105–110PubMedCrossRefGoogle Scholar
  51. 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):752–758PubMedCrossRefGoogle Scholar
  52. 52.
    Dawson-Hughes B, Harris S (2010) High-dose vitamin D supplementation: too much of a good thing? JAMA 303(18):1861–1862PubMedCrossRefGoogle Scholar
  53. 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 95:5266–5273PubMedCrossRefGoogle Scholar
  54. 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):841–848PubMedCrossRefGoogle Scholar
  55. 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):889–894PubMedCrossRefGoogle Scholar
  56. 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):811–818PubMedCrossRefGoogle Scholar
  57. 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 198:357–364PubMedCrossRefGoogle Scholar
  58. 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):535–539PubMedCrossRefGoogle Scholar
  59. 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 72Google Scholar
  60. 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 16–20Google Scholar
  61. 61.
    Reid IR (2010) Vitamin D—let’s get back to the evidence base. IBMS Bonekey 7(7):249–253CrossRefGoogle Scholar
  62. 62.
    Buell JS, Dawson-Hughes B (2008) Vitamin D and neurocognitive dysfunction: preventing “D”ecline? Mol Aspects Med 29(6):415–422PubMedCrossRefGoogle Scholar
  63. 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):170–176CrossRefGoogle Scholar
  64. 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):859–871PubMedGoogle Scholar
  65. 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):JC3–3Google Scholar
  66. 66.
    Byers T (2010) Anticancer vitamins du jour—the ABCED’s so far. Am J Epidemiol 172(1):1–3PubMedCrossRefGoogle Scholar
  67. 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, DCGoogle Scholar
  68. 68.
    Francis R (2007) The vitamin D paradox. Rheumatology 46:1749–1750PubMedCrossRefGoogle Scholar
  69. 69.
    Bouillon R, Norman AW, Lips P (2007) Vitamin D deficiency. N Engl J Med 357(19):1980–1981PubMedCrossRefGoogle Scholar
  70. 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):603–608PubMedCrossRefGoogle Scholar
  71. 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):455–461CrossRefGoogle Scholar
  72. 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 264:599–609PubMedCrossRefGoogle Scholar
  73. 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 3:8PubMedCrossRefGoogle Scholar
  74. 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 35:482–486PubMedCrossRefGoogle Scholar
  75. 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):3216–3224PubMedCrossRefGoogle Scholar
  76. 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):123–128PubMedCrossRefGoogle Scholar
  77. 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):796–804PubMedCrossRefGoogle Scholar
  78. 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):104–108PubMedCrossRefGoogle Scholar
  79. 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):10213–10219PubMedCrossRefGoogle Scholar
  80. 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):1439–1447PubMedCrossRefGoogle Scholar
  81. 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):1533–1538PubMedCrossRefGoogle Scholar
  82. 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):477–484PubMedGoogle Scholar
  83. 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):813–820PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2012

Authors and Affiliations

  • Kerrie M. Sanders
    • 1
  • Geoffrey C. Nicholson
    • 1
    • 2
  • Peter R. Ebeling
    • 1
  1. 1.Department of Medicine, Western HealthNorthWest Academic Centre, University of MelbourneSt AlbansAustralia
  2. 2.Rural Clinical School, School of MedicineUniversity of QueenslandToowoombaAustralia

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