Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

A systematic review and meta-analysis of the response of serum 25-hydroxyvitamin D concentration to vitamin D supplementation from RCTs from around the globe

European Journal of Clinical Nutrition volume 73, pages 816–834 (2019)Cite this article

Subjects

Abstract

Background/Objectives

Optimal doses of vitamin D (VitD) supplement in different populations are unclear. We aim to evaluate the relationship between VitD supplementation and post-intervention serum 25-hydroxyvitamin D [25(OH)D] concentration, to provide a recommended dosage of VitD for achieving an optimal 25(OH)D concentration for different populations.

Subjects/Methods

Literature search was conducted in Embase, etc. Randomized controlled trials about VitD supplemental intakes and their effect on 25(OH)D concentration were enrolled. The effect on 25(OH)D concentration between different supplementation doses in each population group was compared by meta-analysis. Multivariate meta-regression model is utilized to establish reference intake dosage of VitD.

Results

A total of 136 articles were included about children (3–17 years), adults (18–64 years), postmenopausal women, the elderly ( >64 years), pregnant, or lactating women. Overall, intervention groups obtained higher 25(OH)D concentration than controls and there was obvious dose–response effect between intake dose and 25(OH)D concentration. Baseline 25(OH)D concentration and age were significant indicators for 25(OH)D concentration. To reach sufficient 25(OH)D concentration (75 nmol/L), the recommended VitD supplemental intakes was 1340 and 2250 IU/day for children and pregnant women, 2519 and 797 IU/day for European adults aged 18–64 and 65–85 years, 729, 2026, and 1229 IU/day for adults in North America, Asia and Middle East and Africa, respectively.

Conclusions

Regional- and age-specific recommended dosages of VitD supplements for population to achieve optimal 25(OH)D concentrations have been suggested.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Alshahrani F, Aljohani N. Vitamin D: deficiency, sufficiency and toxicity. Nutrients. 2013;5:3605–16.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  2. Holick MF. Vitamin D deficiency. New Engl J Med. 2007;357:266–81.

    Article  CAS  PubMed  Google Scholar 

  3. Malabanan A, Veronikis IE, Holick MF. Redefining vitamin D insufficiency. Lancet (Lond, Engl). 1998;351:805–6.

    Article  CAS  Google Scholar 

  4. Hansen KE, Jones AN, Lindstrom MJ, Davis LA, Engelke JA, Shafer MM. Vitamin D insufficiency: disease or no disease? J Bone Mineral Res. 2008;23:1052–60.

    Article  CAS  Google Scholar 

  5. Palacios C, Gonzalez L. Is vitamin D deficiency a major global public health problem? J Steroid Biochem Mol Biol. 2014;144:138–45. Pt A

    Article  CAS  PubMed  Google Scholar 

  6. Sharma LK, Dutta D, Sharma N, Gadpayle AK. The increasing problem of subclinical and overt hypervitaminosis D in India: an institutional experience and review. Nutr (Burbank, Los Angel Cty, Calif). 2017;34:76–81.

    Article  Google Scholar 

  7. Al-Dabhani K, Tsilidis KK, Murphy N, Ward HA, Elliott P, Riboli E, et al. Prevalence of vitamin D deficiency and association with metabolic syndrome in a Qatari population. Nutr Diabetes. 2017;7:e263–e8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Bani-Issa W, Eldeirawi K, Harfil S, Fakhry R. Vitamin D deficiency and its determinants in adults: a sample from community-based settings in the United Arab Emirates. Int J Endocrinol. 2017;2017:3906306–12.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  9. Kaddam IM, Al-Shaikh AM, Abaalkhail BA, Asseri KS, Al-Saleh YM, Al-Qarni AA, et al. Prevalence of vitamin D deficiency and its associated factors in three regions of Saudi Arabia. Saudi Med J. 2017;38:381–90.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Zhao Y, Yu Y, Li H, Chang Z, Li Y, Duan Y, et al. Vitamin D status and the prevalence of deficiency in lactating women from eight provinces and municipalities in China. PLoS ONE. 2017;12:e0174378–e89.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  11. Cashman KD, Dowling KG, Skrabakova Z, Gonzalez-Gross M, Valtuena J, De Henauw S, et al. Vitamin D deficiency in Europe: pandemic? Am J Clin Nutr. 2016;103:1033–44.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Chen Y, Zhu B, Wu X, Li S, Tao F. Association between maternal vitamin D deficiency and small for gestational age: evidence from a meta-analysis of prospective cohort studies. BMJ Open. 2017;7:e016404–e12.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Wang S, Shen G, Jiang S, Xu H, Li M, Wang Z, et al. Nutrient status of vitamin D among Chinese children. Nutrients. 2017;9:319–28.

    Article  CAS  PubMed Central  Google Scholar 

  14. Yu RQ, Zhao X, Chen DZ, Liao XP, Zhou Q. [Vitamin D level at birth and influencing factors in preterm infants]. Zhongguo dang dai er ke za zhi=Chin J Contemp Pediatr. 2017;19:800–5.

    Google Scholar 

  15. Park YW, Zhu S, Palaniappan L, Heshka S, Carnethon MR, Heymsfield SB. The metabolic syndrome: prevalence and associated risk factor findings in the US population from the Third National Health and Nutrition Examination Survey, 1988-1994. Arch Intern Med. 2003;163:427–36.

    Article  PubMed  PubMed Central  Google Scholar 

  16. Chon SJ, Yun BH, YS J. Association between vitamin D status and risk of metabolic syndrome among Korean postmenopausal women. PLoS ONE. 2014;9:e89721.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  17. Moghassemi S, Marjani A. The effect of short-term vitamin D supplementation on lipid profile and blood pressure in post-menopausal women: a randomized controlled trial. Iran J Nurs Midwifery Res. 2014;19:517–21.

    PubMed  PubMed Central  Google Scholar 

  18. Bandeira F, Griz L, Freese E, Lima DC, Diniz ET, et al. Vitamin D deficiency and its relationship with bone mineral density among postmenopausal women living in the tropics. Arq Bras Endocrinol Metabol. 2010;54:227–32. TheAC

    Article  PubMed  Google Scholar 

  19. Paul TV, Thomas N, Seshadri MS, Oommen R, Jose A, Mahendri NV. Prevalence of osteoporosis in ambulatory postmenopausal women from a semiurban region in Southern India: relationship to calcium nutrition and vitamin D status. Endocr Pract. 2008;14:665–71.

    Article  PubMed  Google Scholar 

  20. Dawson-Hughes B, Dallal GE, Krall EA, Harris S, Sokoll LJ, Falconer G. Effect of vitamin D supplementation on wintertime and overall bone loss in healthy postmenopausal women. Ann Intern Med. 1991;115:505–12.

    Article  CAS  PubMed  Google Scholar 

  21. Ooms ME, Roos JC, Bezemer PD, van der Vijgh WJ, Bouter LM, Lips P. Prevention of bone loss by vitamin D supplementation in elderly women: a randomized double-blind trial. J Clin Endocrinol Metab. 1995;80:1052–8.

    CAS  PubMed  Google Scholar 

  22. Mithal A, Wahl DA, Bonjour JP, Burckhardt P, Dawson-Hughes B, Eisman JA, et al. Global vitamin D status and determinants of hypovitaminosis D. Osteoporos Int. 2009;20:1807–20.

    Article  CAS  PubMed  Google Scholar 

  23. Carrillo-Vega MF, Garcia-Pena C, Gutierrez-Robledo LM, Perez-Zepeda MU. Vitamin D deficiency in older adults and its associated factors: a cross-sectional analysis of the Mexican Health and Aging Study. Arch Osteoporos. 2017;12:8–14.

    Article  PubMed  Google Scholar 

  24. Deplanque X, Wullens A, Norberciak L. [Prevalence and risk factors of vitamin D deficiency in healthy adults aged 18-65 years in northern France]. Rev Med Interne. 2017;38:368–73.

    Article  CAS  PubMed  Google Scholar 

  25. Rahmaniyan M, Bell N. CHAPTER 47 – Effects of race, geography, body habitus, diet, and exercise on vitamin D metabolism. Vitamin D. 2005;I:789–801.

    Article  Google Scholar 

  26. Ovesen L, Andersen R, Jakobsen J. Geographical differences in vitamin D status, with particular reference to European countries. Proc Nutr Soc. 2003;62:813–21.

    Article  CAS  PubMed  Google Scholar 

  27. La-Or C, Wichai A, Boonsong O. Regional variation and determinants of vitamin D status in sunshine-abundant Thailand. BMC Public Health. 2011;11:853.

    Article  CAS  Google Scholar 

  28. Rp V, Löwik M, Van dB, de Groot L, Haller J, Moreiras O. Serum vitamin D concentrations among elderly people in europe. Lancet (Lond, Engl). 1995;346:207–10.

    Article  Google Scholar 

  29. Zhou SS, Tao YH, Huang K, Zhu BB, Tao FB. Vitamin D and risk of preterm birth: up-to-date meta-analysis of randomized controlled trials and observational studies. J Obstet Gynaecol Res. 2017;43:247–56.

    Article  CAS  PubMed  Google Scholar 

  30. Nassar N, Halligan GH, Roberts CL, Morris JM, Ashton AW. Systematic review of first-trimester vitamin D normative levels and outcomes of pregnancy. Am J Obstet Gynecol. 2011;205:1–7.

    Article  CAS  Google Scholar 

  31. Verrusio W, Andreozzi P, Renzi A, Musumeci M, Gueli N, Cacciafesta M. Association between serum vitamin D and metabolic syndrome in middle-aged and older adults and role of supplementation therapy with vitamin D. Ann dell’Istituto Super di Sanita. 2017;53:54–9.

    CAS  Google Scholar 

  32. Stefanowski B, Antosik-Wojcinska AZ, Swiecicki L. The effect of vitamin D3 deficiency on the severity of depressive symptoms. Overview of current research. Psychiatr Pol. 2017;51:437–54.

    Article  PubMed  Google Scholar 

  33. Annweiler C. Vitamin D in dementia prevention. Ann NY Acad Sci. 2016;1367:57–63.

    Article  CAS  PubMed  Google Scholar 

  34. Kocovska E, Gaughran F, Krivoy A, Meier UC. Vitamin-D deficiency as a potential environmental risk factor in multiple sclerosis, schizophrenia, and autism. Front Psychiatry. 2017;8:47–57.

    Article  PubMed  PubMed Central  Google Scholar 

  35. Stege H, Schwarz T. [Vitamin D and UV protection]. Hautarzt. 2017;68:364–7.

    Article  CAS  PubMed  Google Scholar 

  36. Dudenkov DV, Yawn BP, Oberhelman SS, Fischer PR, Singh RJ, Cha SS, et al. Changing incidence of serum 25-hydroxyvitamin D values above 50 ng/mL: a 10-year population-based study. Mayo Clin Proc. 2015;90:577–86.

    Article  CAS  PubMed  Google Scholar 

  37. Khan AH, Majid H, Iqbal R. Shifting of vitamin D deficiency to hypervitaminosis and toxicity. J Coll Physicians Surg--Pak. 2014;24:536.

    PubMed  Google Scholar 

  38. In: Ross AC, Taylor CL, Yaktine AL, Del Valle HB, editors. Dietary reference intakes for calcium and vitamin D. Washington (DC): The National Academies Collection: Reports funded by National Institutes of Health; 2011.

  39. Holick MF, Binkley NC, Bischoff-Ferrari HA, Gordon CM, Hanley DA, Heaney RP, et al. Evaluation, treatment, and prevention of vitamin D deficiency: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2011;96:1911–30.

    Article  CAS  PubMed  Google Scholar 

  40. Seamans KM, Cashman KD. Existing and potentially novel functional markers of vitamin D status: a systematic review. Am J Clin Nutr. 2009;89:1997S–2008S.

    Article  CAS  PubMed  Google Scholar 

  41. Chakhtoura M, El Ghandour S, Shawwa K, Akl EA, Arabi A, Mahfoud Z, et al. Vitamin D replacement in children, adolescents and pregnant women in the Middle East and North Africa: a systematic review and meta-analysis of randomized controlled trials. Metab-Clin Exp. 2017;70:160–76.

    Article  CAS  PubMed  Google Scholar 

  42. Chakhtoura M, Akl EA, El Ghandour S, Shawwa K, Arabi A, Mahfoud Z, et al. Impact of vitamin D replacement in adults and elderly in the Middle East and North Africa: a systematic review and meta-analysis of randomized controlled trials. Osteoporos Int. 2017;28:35–46.

    Article  CAS  PubMed  Google Scholar 

  43. Munns CF, Shaw N, Kiely M, Specker BL, Thacher TD, Ozono K, et al. Global consensus recommendations on prevention and management of nutritional rickets. Horm Res Paediatr. 2016;85:83–106.

    Article  CAS  PubMed  Google Scholar 

  44. Bouillon R, Van Schoor NM, Gielen E, Boonen S, Mathieu C, Vanderschueren D, et al. Optimal vitamin D status: a critical analysis on the basis of evidence-based medicine. J Clin Endocr Metab. 2013;98:E1283–E304.

    Article  CAS  PubMed  Google Scholar 

  45. McGuire S. WHO guideline: vitamin A supplementation in pregnant women. Geneva: WHO, 2011; WHO Guideline: vitamin A supplementation in postpartum women. Geneva: WHO, 2011. Adv Nutr (Bethesda, Md). 2012;3:215–20.

    Article  Google Scholar 

  46. Cashman KD, Fitzgerald AP, Kiely M, Seamans KM. A systematic review and meta-regression analysis of the vitamin D intake-serum 25-hydroxyvitamin D relationship to inform European recommendations. Brit J Nutr. 2011;106:1638–48.

    Article  CAS  PubMed  Google Scholar 

  47. Wagner CL, Greer FR. American Academy of Pediatrics Section on B, American Academy of Pediatrics Committee on N. Prevention of rickets and vitamin D deficiency in infants, children, and adolescents. Pediatrics. 2008;122:1142–52.

    Article  PubMed  Google Scholar 

  48. Moher D, Liberati A, Tetzlaff J, Altman DG, Group P. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med. 2009;6:e1000097.

    Article  PubMed  PubMed Central  Google Scholar 

  49. Higgins J, Green S. Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0. The Cochrane Collaboration: Wiley-Blackwell; 2011.

    Google Scholar 

  50. Hozo SP, Djulbegovic B, Hozo I. Estimating the mean and variance from the median, range, and the size of a sample. BMC Med Res Methodol. 2005;5:13.

    Article  PubMed  PubMed Central  Google Scholar 

  51. Jadad A, Moore R, Carrol D. Assessing the quality of reports of randomized clinical trials: is blinding necessary? Control Clin Trials. 1996;17:1–12.

    Article  CAS  PubMed  Google Scholar 

  52. Jackson D, Riley R, White IR. Multivariate meta-analysis: potential and promise. Stat Med. 2011;30:2481–98.

    Article  PubMed  PubMed Central  Google Scholar 

  53. van Houwelingen HC, Arends LR, Stijnen T. Advanced methods in meta-analysis: multivariate approach and meta-regression. Stat Med. 2002;21:589–624.

    Article  PubMed  Google Scholar 

  54. Autier P, Gandini S, Mullie P. A systematic review: influence of vitamin D supplementation on serum 25-hydroxyvitamin D concentration. J Clin Endocrinol Metab. 2012;97:2606–13.

    Article  CAS  PubMed  Google Scholar 

  55. Mazahery H, von Hurst PR. Factors affecting 25-hydroxyvitamin D concentration in response to vitamin D supplementation. Nutrients. 2015;7:5111–42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Mortensen C, Damsgaard CT, Hauger H, Ritz C, Lanham-New SA, T JS, et al. Estimation of the dietary requirement for vitamin D in white children aged 4-8 y: a randomized, controlled, dose-response trial. Am J Clin Nutr. 2016;104:1310–7.

    Article  CAS  PubMed  Google Scholar 

  57. Mølgaard C, Larnkjær A, Cashman KD, Lamberg-Allardt C, Jakobsen J, Michaelsen KF. Does vitamin D supplementation of healthy Danish Caucasian girls affect bone turnover and bone mineralization? Bone. 2010;46:432–9.

    Article  PubMed  CAS  Google Scholar 

  58. Ala-Houhala M, Koskinen T, Koskinen M, Visakorpi JK. Double blind study on the need for vitamin D supplementation in prepubertal children. Acta Paediatr Scand. 1988;77:89–93.

    Article  CAS  PubMed  Google Scholar 

  59. Smith TJ, Tripkovic L, Damsgaard CT, Molgaard C, Ritz C, Wilson-Barnes SL, et al. Estimation of the dietary requirement for vitamin D in adolescents aged 14-18 y: a dose-response, double-blind, randomized placebo-controlled trial. Am J Clin Nutr. 2016;104:1301–9.

    Article  CAS  PubMed  Google Scholar 

  60. Cashman K, FitzGerald A, Viljakainen H, Jakobsen J, Michaelsen K, Lamberg-Allardt C, et al. Estimation of the dietary requirement for vitamin D in healthy adolescent white girls. Am J Clin Nutr. 2011;3:549–55.

    Article  CAS  Google Scholar 

  61. Andersen R, Mogaard C, Skovgaard L, Brot C, Cashman K, Jakobsen J, et al. Effect of vitamin D supplementation on bone and vitamin D status among Pakistani immigrants in Denmark: a randomised double-blinded placebo-controlled intervention study. Br J Nutr. 2008;1:197–207.

    Article  CAS  Google Scholar 

  62. Cosenza L, Pezzella V, Nocerino R, Costanzo M, Coruzzo A, Passariello A. et al. Calcium and vitamin D intakes in children: a randomized controlled trial. BMC Pediatr. 2013;13:62.

    Article  Google Scholar 

  63. Ohlund I, Lind T, Hernell O, Silfverdal SA, Karlsland Akeson P. Increased vitamin D intake differentiated according to skin color is needed to meet requirements in young Swedish children during winter: a double-blind randomized clinical trial. Am J Clin Nutr. 2017;106:105–12.

    Article  PubMed  Google Scholar 

  64. Rajakumar K, Moore C, Yabes J, Olabopo F, Haralam M, Comer D, et al. Estimations of dietary vitamin D requirements in black and white children. Pediatr Res. 2016;1:14–20.

    Article  CAS  Google Scholar 

  65. Abrams SA, Hawthorne KM, Chen Z. Supplementation with 1000 IU vitamin D/d leads to parathyroid hormone suppression, but not increased fractional calcium absorption, in 4-8-y-old children: a double-blind randomized controlled trial. Am J Clin Nutr. 2013;97:217–23.

    Article  CAS  PubMed  Google Scholar 

  66. Rajakumar K, Moore C, Yabes J, Olabopo F, Haralam M, Comer D, et al. Effect of vitamin D3 supplementation in Black and in White children: a randomized, placebo-controlled trial. J Clin Endocrinol Metab. 2016;8:3183–92.

    Google Scholar 

  67. Aglipay M, Birken CS, Parkin PC, Loeb MB, Thorpe K, Chen Y, et al. Effect of high-dose vs standard-dose wintertime vitamin D supplementation on viral upper respiratory tract infections in young healthy children. JAMA. 2017;318:245–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Sacheck JM, Van Rompay MI, Chomitz VR, Economos CD, Eliasziw M, Goodman E, et al. Impact of three doses of vitamin D3 on serum 25(OH)D deficiency and insufficiency in at-risk schoolchildren. J Clin Endocrinol Metab. 2017;102:4496–505.

    Article  PubMed  PubMed Central  Google Scholar 

  69. Tavakoli F, Namakin K, Zardast M. Vitamin D supplementation and high-density lipoprotein cholesterol: a study in healthy school children. Iran J Pediatr. 2016;26:e3311–e6.

    Article  PubMed  PubMed Central  Google Scholar 

  70. Ghazi AA, Hosseinpanah F, M AE, Ghazi S, Hedayati M, Azizi F. Effects of different doses of oral cholecalciferol on serum 25(OH)D, PTH, calcium and bone markers during fall and winter in schoolchildren. Eur J Clin Nutr. 2010;64:1415–22.

    Article  CAS  PubMed  Google Scholar 

  71. Saad K, Abdel-Rahman AA, Elserogy YM, Al-Atram AA, El-Houfey AA, Othman HA, et al. Randomized controlled trial of vitamin D supplementation in children with autism spectrum disorder. J Child Psychol Psychiatry. 2018;59:20–9.

    Article  PubMed  Google Scholar 

  72. Wadia U, Soon W, Chivers P, Thambiran A, Burgner D, Cherian S, et al. Randomised controlled trial comparing daily versus depot vitamin D3 therapy in 0-16-year-old newly settled refugees in Western Australia over a period of 40 weeks. Nutrients. 2018;10:3.

    Article  CAS  Google Scholar 

  73. Ganmaa D, Giovannucci E, Bloom BR, Fawzi W, Burr W, Batbaatar D, et al. Vitamin D, tuberculin skin test conversion, and latent tuberculosis in Mongolian school-age children: a randomized, double-blind, placebo-controlled feasibility trial. Am J Clin Nutr. 2012;96:391–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Ganmaa D, Stuart JJ, Sumberzul N, Ninjin B, Giovannucci E, Kleinman K, et al. Vitamin D supplementation and growth in urban Mongol school children: results from two randomized clinical trials. PLoS ONE. 2017;12:e0175237.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  75. Zhang R, Muyiduli X, Su D, Zhou B, Fang Y, Jiang S, et al. Effect of low-dose vitamin D supplementation on serum 25(OH)D in school children and white-collar workers. Nutrients. 2017;9:5.

    Google Scholar 

  76. Yao P, Lu L, Hu Y, Liu G, Chen X, Sun L, et al. A dose-response study of vitamin D3 supplementation in healthy Chinese: a 5-arm randomized, placebo-controlled trial. Eur J Nutr. 2016;55:383–92.

    Article  CAS  PubMed  Google Scholar 

  77. Ramly M, Ming M, Chinna K, Suboh S, Pendek R. Effect of vitamin D supplementation on cardiometabolic risks and health-related quality of life among urban premenopausal women in a tropical country--a randomized controlled trial. PLoS ONE. 2016;10:e110476–e86.

    Google Scholar 

  78. Malhotra N, Mithal A, Gupta S, Shukla M, Godbole M. Effect of vitamin D supplementation on bone health parameters of healthy young Indian women. Arch Osteoporos. 2009;1-2:47–53.

    Article  Google Scholar 

  79. Yao P, Sun L, Lu L, Ding H, Chen X, Tang L, et al. Effects of genetic and nongenetic factors on total and bioavailable 25(OH)D responses to vitamin D supplementation. J Clin Endocrinol Metab. 2017;102:100–10.

    Article  PubMed  Google Scholar 

  80. Goswami R, Vatsa M, Sreenivas V, Singh U, Gupta N, Lakshmy R, et al. Skeletal muscle strength in young Asian Indian females after vitamin D and calcium supplementation: a double-blind randomized controlled clinical trial. J Clin Endocrinol Metab. 2012;97:4709–16.

    Article  CAS  PubMed  Google Scholar 

  81. Chen WR, Liu ZY, Shi Y, Yin DW, Wang H, Sha Y, et al. Vitamin D and nifedipine in the treatment of Chinese patients with grades I-II essential hypertension: a randomized placebo-controlled trial. Atherosclerosis. 2014;235:102–9.

    Article  CAS  PubMed  Google Scholar 

  82. Sun X, Cao ZB, Tanisawa K, Ito T, Oshima S, Higuchi M. Vitamin D supplementation reduces insulin resistance in Japanese adults: a secondary analysis of a double-blind, randomized, placebo-controlled trial. Nutr Res. 2016;36:1121–9.

    Article  CAS  PubMed  Google Scholar 

  83. Watabe A, Yamasaki K. Efficacy of oral cholecalciferol on rhododendrol-induced vitiligo: a blinded randomized clinical trial. J Dermatol. 2018;45:456–62.

    Article  CAS  PubMed  Google Scholar 

  84. Arden NK, Cro S, Sheard S, Doré CJ, Bara A, Tebbs SA, et al. The effect of vitamin D supplementation on knee osteoarthritis, the VIDEO study: a randomised controlled trial. Osteoarthr Cartil. 2016;24:1858–66.

    Article  CAS  Google Scholar 

  85. Barnes MS, Robson PJ, Bonham MP, Strain JJ, Wallace JMW. Effect of vitamin D supplementation on vitamin D status and bone turnover markers in young adults. Eur J Clin Nutr. 2006;60:727–33.

    Article  CAS  PubMed  Google Scholar 

  86. Oosterwerff MM, Eekhoff EMW, Van Schoor NM, Boeke AJP, Nanayakkara P, Meijnen R, et al. Effect of moderate-dose vitamin D supplementation on insulin sensitivity in vitamin D-deficient non-Western immigrants in the Netherlands: a randomized placebo-controlled trial. Am J Clin Nutr. 2014;100:152–60.

    Article  CAS  PubMed  Google Scholar 

  87. Knutsen K, Madar A, Brekke M, Meyer H, Natvig B, Mdala I, et al. Effect of vitamin D on musculoskeletal pain and headache: a randomized, double-blind, placebo-controlled trial among adult ethnic minorities in Norway. Pain. 2014;12:2591–8.

    Article  CAS  Google Scholar 

  88. Nygaard B, Frandsen NE, Brandi L, Rasmussen K, Oestergaard OV, Oedum L, et al. Effects of high doses of cholecalciferol in normal subjects: a randomized double-blinded, placebo- controlled trial. PLoS One. 2014;9:e102965–e76.

    Article  PubMed  PubMed Central  Google Scholar 

  89. Brunel E, Schnitzler M, Foidart-Dessalle M, Souberbielle J, Cavalier E. A double-blind, placebo controlled, randomized trial to assess the impact of a monthly administration of 50,000 IU of vitamin D3 for 6 months on serum levels of 25-hydroxyvitamin d in healthy young adults. Int J Endocrinol. 2013;2013:652648–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Wamberg L, Pedersen SB, Richelsen B, Rejnmark L. The effect of high-dose vitamin D supplementation on calciotropic hormones and bone mineral density in obese subjects with low levels of circulating 25-hydroxyvitamin D: results from a randomized controlled study. Calcif Tissue Int. 2013;93:69–77.

    Article  CAS  PubMed  Google Scholar 

  91. Schleck ML, Souberbielle JC, Jandrain B, Da SS, De Niet S, Vanderbist F, et al. A randomized, double-blind, parallel study to evaluate the dose-response of three different vitamin D treatment schemes on the 25-hydroxyvitamin D serum concentration in patients with vitamin D deficiency. Nutrients. 2015;7:5413–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Wamberg L, Kampmann U, Stødkilde-Jørgensen H, Rejnmark L, Pedersen SB, Richelsen B. Effects of vitamin D supplementation on body fat accumulation, inflammation, and metabolic risk factors in obese adults with low vitamin D levels - Results from a randomized trial. Eur J Intern Med. 2013;24:644–9.

    Article  CAS  PubMed  Google Scholar 

  93. Close GL, Leckey J, Patterson M, Bradley W, Owens DJ, Fraser WD, et al. The effects of vitamin D(3) supplementation on serum total 25[OH]D concentration and physical performance: a randomised dose-response study. Br J Sports Med. 2013;47:692–6.

    Article  PubMed  Google Scholar 

  94. Cashman KD, Hill TR, Lucey AJ, Taylor N, Seamans KM, Muldowney S, et al. Estimation of the dietary requirement for vitamin D in healthy adults. Am J Clin Nutr. 2008;88:1535–42.

    Article  CAS  PubMed  Google Scholar 

  95. Laaksi I, Ruohola J-P, Mattila V, Auvinen A, Ylikomi T, Pihlajamäki H. Vitamin D supplementation for the prevention of acute respiratory tract infection: a randomized, double-blinded trial among young Finnish men. J Infect Dis. 2010;202:809–14.

    Article  CAS  PubMed  Google Scholar 

  96. Wicherts IS, Boeke AJP, Van Der Meer IM, Van Schoor NM, Knol DL, Lips P. Sunlight exposure or vitamin D supplementation for vitamin D-deficient non-western immigrants: a randomized clinical trial. Osteoporos Int. 2012;22:873–82.

    Article  CAS  Google Scholar 

  97. Didriksen A, Burild A, Jakobsen J, Fuskevag OM, Jorde R. Vitamin D3 increases in abdominal subcutaneous fat tissue after supplementation with vitamin D3. Eur J Endocrinol. 2015;172:235–41.

    Article  CAS  PubMed  Google Scholar 

  98. Osmancevic A, Demeke T, Gillstedt M, Angesjö E, Sinclair H, Abd El-Gawad G. et al. Vitamin D treatment in Somali women living in Sweden - two randomized, placebo-controlled studies. Clin Endocrinol. 2016;85:535–43.

    Article  CAS  Google Scholar 

  99. Jastrzebski Z, Kortas J, Kaczor K, Antosiewicz J. Vitamin D supplementation causes a decrease in blood cholesterol in professional rowers. J Nutr Sci Vitaminol (Tokyo). 2016;62:88–92.

    Article  CAS  Google Scholar 

  100. Ernst J, Tomaschitz A, Grubler M, Gaksch M, Kienreich K, Verheyen N. et al. Vitamin D supplementation and hemoglobin levels in hypertensive patients: a randomized controlled trial. Int J Endocrinol. 2016;2016:6836402–8.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  101. Holmlund-Suila E, Pekkinen M, Ivaska KK, Andersson S, Mäkitie O, Viljakainen H. Obese young adults exhibit lower total and lower free serum 25-hydroxycholecalciferol in a randomized vitamin D intervention. Clin Endocrinol (Oxf). 2016;85:378–85.

    Article  CAS  Google Scholar 

  102. Seamans KM, Hill TR, Wallace JMW, Horigan G, Lucey AJ, Barnes MS, et al. Cholecalciferol supplementation throughout winter does not affect markers of bone turnover in healthy young and elderly adults. J Nutr. 2010;140:454–60.

    Article  CAS  PubMed  Google Scholar 

  103. Kerley CP, Hutchinson K, Bramham J, McGowan A, Faul J, Cormican L. Vitamin D improves selected metabolic parameters but not neuropsychological or quality of life indices in OSA: a pilot study. J Clin Sleep Med. 2017;13:19–26.

    Article  PubMed  PubMed Central  Google Scholar 

  104. Lerchbaum E, Pilz S, Trummer C, Schwetz V, Pachernegg O, Heijboer AC, et al. Vitamin D and testosterone in healthy men: a randomized controlled trial. J Clin Endocrinol Metab. 2017;102:4292–302.

    Article  PubMed  Google Scholar 

  105. Luger M, Kruschitz R. Vitamin D3 loading is superior to conventional supplementation after weight loss surgery in vitamin D-deficient morbidly obese patients: a double-blind randomized placebo-controlled trial. Obes Surg. 2017;27:1196–207.

    Article  PubMed  Google Scholar 

  106. Pasing Y, Fenton CG, Jorde R, Paulssen RH. Changes in the human transcriptome upon vitamin D supplementation. J Steroid Biochem Mol Biol. 2017;173:93–9.

    Article  CAS  PubMed  Google Scholar 

  107. Seibert E, Lehmann U, Riedel A, Ulrich C, Hirche F, Brandsch C, et al. Vitamin D3 supplementation does not modify cardiovascular risk profile of adults with inadequate vitamin D status. Eur J Nutr. 2017;56:621–34.

    Article  CAS  PubMed  Google Scholar 

  108. Todd JJ, McSorley EM, Pourshahidi LK, Madigan SM, Laird E, Healy M, et al. Vitamin D3 supplementation using an oral spray solution resolves deficiency but has no effect on VO2 max in Gaelic footballers: results from a randomised, double-blind, placebo-controlled trial. Eur J Nutr. 2017;56:1577–87.

    Article  CAS  PubMed  Google Scholar 

  109. Blomberg Jensen M, Lawaetz JG, Petersen JH, Juul A, Jorgensen N. Effects of vitamin D supplementation on semen quality, reproductive hormones, and live birth rate: a randomized clinical trial. J Clin Endocrinol Metab. 2018;103:870–81.

    Article  PubMed  Google Scholar 

  110. Cefalo CMA, Conte C, Sorice GP, Moffa S, Sun VA, Cinti F, et al. Effect of vitamin D supplementation on obesity-induced insulin resistance: a double-blind, randomized, placebo-controlled trial. Obesity (Silver Spring, Md). 2018;26:651–7.

    Article  CAS  Google Scholar 

  111. Takacs I, Toth BE, Szekeres L, Szabo B, Bakos B, Lakatos P. Randomized clinical trial to comparing efficacy of daily, weekly and monthly administration of vitamin D3. Endocrine. 2017;55:60–5.

    Article  CAS  PubMed  Google Scholar 

  112. Salehpour A, Shidfar F, Hosseinpanah F, Vafa M, Razaghi M, Amiri F. Does vitamin D3 supplementation improve glucose homeostasis in overweight or obese women? A double-blind, randomized, placebo-controlled clinical trial. Diabet Med. 2013;30:1477–81.

    Article  CAS  PubMed  Google Scholar 

  113. Sadat-Ali M, Bubshait DA, Al-Turki HA, Al-Dakheel DA, Al-Olayani WS. Topical delivery of vitamin D3: a randomized controlled pilot study. Int J Biomed Sci. 2014;10:21–4.

    CAS  PubMed  PubMed Central  Google Scholar 

  114. Taheri M, Baheiraei A, Rahimi Foroushani A, Modarres M. Resolving vitamin D deficiency in the preconception period among high-risk reproductive women: a randomized controlled trial. Iran Red Crescent Med J. 2014;16:e11175–e9.

    PubMed  PubMed Central  Google Scholar 

  115. Saadi HF, Dawodu A, Afandi BO, Zayed R, Benedict S, Nagelkerke N. Efficacy of daily and monthly high-dose calciferol in vitamin D-deficient nulliparous and lactating women. Am J Clin Nutr. 2007;85:1565–71.

    Article  CAS  PubMed  Google Scholar 

  116. Zabihiyeganeh M, Ahmadi F, Jahed SA. Treatment of hypovitaminosis D with pharmacologic doses of cholecalciferol, oral versus intramuscular: an open labeled RCT. Clin Endocrinol (Oxf). 2013;78:210–6.

    Article  CAS  Google Scholar 

  117. Kamelian T, Saki F, Jeddi M, Dabbaghmanesh MH, Omrani GHR. Effect of cholecalciferol therapy on serum FGF23 in vitamin D deficient patients: a randomized clinical trial. J Endocrinol Invest. 2018;41:299–306.

    Article  CAS  PubMed  Google Scholar 

  118. Roosta S, Kharadmand M, Teymoori F, Birjandi M, Adine A, Falahi E. Effect of vitamin D supplementation on anthropometric indices among overweight and obese women: a double blind randomized controlled clinical trial. Diabetes Metab Syndr. 2018;12:537–41.

    Article  PubMed  Google Scholar 

  119. Pettersen JA. Does high dose vitamin D supplementation enhance cognition?: a randomized trial in healthy adults. Exp Gerontol. 2017;90:90–7.

    Article  CAS  PubMed  Google Scholar 

  120. Ng K, Scott JB, Drake BF, Chan AT, Hollis BW, Chandler PD, et al. Dose response to vitamin D supplementation in African Americans: results of a 4-arm, randomized, placebo-controlled trial. Am J Clin Nutr. 2014;99:587–98.

    Article  CAS  PubMed  Google Scholar 

  121. Zwart SR, Parsons H, Kimlin M, Innis SM, Locke JP, Smith SM. A 250 µg/week dose of vitamin D was as effective as a 50 µg/d dose in healthy adults, but a regimen of four weekly followed by monthly doses of 1250 µg raised the risk of hypercalciuria. Br J Nutr. 2013;110:1866–72.

    Article  CAS  PubMed  Google Scholar 

  122. Lewis R, Redzic M, Thomas D. The effects of season-long vitamin D supplementation on collegiate swimmers and divers. Int J Sport Nutr Exerc Metab. 2013;5:431–40.

    Article  Google Scholar 

  123. Chandler PD, Giovannucci EL, Scott JB, Bennett GG, Ng K, Chan AT, et al. Effects of vitamin D supplementation on C-peptide and 25-hydroxyvitamin D concentrations at 3 and 6 months. Sci Rep. 2015;5:10411–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Zhu H, Guo D, Li K, Pedersen-White J, Stallmann-Jorgensen IS, Huang Y, et al. Increased telomerase activity and vitamin D supplementation in overweight African Americans. Int J Obes (Lond). 2012;36:805–9.

    Article  CAS  Google Scholar 

  125. Li-Ng M, Aloia JF, Pollack S, Cunha BA, Mikhail M, Yeh J, et al. A randomized controlled trial of vitamin D3 supplementation for the prevention of symptomatic upper respiratory tract infections. Epidemiol Infect. 2009;137:1396–404.

    Article  CAS  PubMed  Google Scholar 

  126. Harris SS, Pittas AG, Palermo NJ. A randomized, placebo-controlled trial of vitamin D supplementation to improve glycaemia in overweight and obese African Americans. Diabetes Obes Metab. 2012;14:789–94.

    Article  CAS  PubMed  Google Scholar 

  127. Carrillo AE, Flynn MG, Pinkston C, Markofski MM, Jiang Y, Donkin SS, et al. Impact of vitamin D supplementation during a resistance training intervention on body composition, muscle function, and glucose tolerance in overweight and obese adults. Clin Nutr. 2013;32:375–81.

    Article  CAS  PubMed  Google Scholar 

  128. Holick MF, Biancuzzo RM, Chen TC, Klein EK, Young A, Bibuld D, et al. Vitamin D2 is as effective as vitamin D3 in maintaining circulating concentrations of 25-hydroxyvitamin D. J Clin Endocrinol Metab. 2008;93:677–81.

    Article  CAS  PubMed  Google Scholar 

  129. McCullough ML, Bostick RM, Daniel CR, Flanders WD, Shaukat A, Davison J, et al. Vitamin D status and impact of vitamin D3 and/or calcium supplementation in a randomized pilot study in the Southeastern United States. J Am Coll Nutr. 2009;28:678–86.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Biancuzzo RM, Clarke N, Reitz RE, Travison TG, Holick MF. Serum concentrations of 1,25-dihydroxyvitamin D2 and 1,25-dihydroxyvitamin D3 in response to vitamin D2 and vitamin D3 supplementation. J Clin Endocrinol Metab. 2013;98:973–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Pop LC, Sukumar D, Schneider SH, Schlussel Y, Stahl T, Gordon C, et al. Three doses of vitamin D, bone mineral density, and geometry in older women during modest weight control in a 1-year randomized controlled trial. Osteoporos Int. 2016;28:377–88.

    Article  PubMed  CAS  Google Scholar 

  132. Alzaman NS, Dawson-Hughes B, Nelson J, D’Alessio D, Pittas AG. Vitamin D status of black and white Americans and changes in vitamin D metabolites after varied doses of vitamin D supplementation. Am J Clin Nutr. 2016;104:205–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Brisson J, Berube S, Diorio C, Masse B, Lemieux J, Duchesne T, et al. A randomized double-blind placebo-controlled trial of the effect of vitamin D3 supplementation on breast density in premenopausal women. Cancer Epidemiol Biomark Prev. 2017;26:1233–41.

    Article  CAS  Google Scholar 

  134. Mazahery H, Stonehouse W, Hurst P. The effect of monthly 50,000?IU or 100,000?IU vitamin D supplements on vitamin D status in premenopausal Middle Eastern women living in Auckland. Eur J Clin Nutr. 2016;3:367–72.

    Google Scholar 

  135. Diamond T, Wong YK, Golombick T. Effect of oral cholecalciferol 2,000 versus 5,000 IU on serum vitamin D, PTH, bone and muscle strength in patients with vitamin D deficiency. Osteoporos Int. 2013;24:1101–5.

    Article  CAS  PubMed  Google Scholar 

  136. Gagnon C, Daly RM, Carpentier A, Lu ZX, Shore-Lorenti C, Sikaris K, et al. Effects of combined calcium and vitamin D supplementation on insulin secretion, insulin sensitivity and β-cell function in multi-ethnic vitamin D-deficient adults at risk for type 2 diabetes: a pilot randomized, placebo-controlled trial. PLoS ONE. 2014;9:e109607–e18.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  137. Logan VF, Gray AR, Peddie MC, Harper MJ, Houghton LA. Long-term vitamin D3 supplementation is more effective than vitamin D2 in maintaining serum 25-hydroxyvitamin D status over the winter months. Brit J Nutr. 2013;109:1082–8.

    Article  CAS  PubMed  Google Scholar 

  138. von Hurst PR, Stonehouse W, Coad J. Vitamin D supplementation reduces insulin resistance in South Asian women living in New Zealand who are insulin resistant and vitamin D deficient - a randomised, placebo-controlled trial. Br J Nutr. 2010;103:549–55.

    Article  CAS  Google Scholar 

  139. Iuliano-Burns S, Ayton J, Hillam S, Jones G, King K, Macleod S, et al. Skeletal and hormonal responses to vitamin D supplementation during sunlight deprivation in Antarctic expeditioners. Osteoporos Int. 2012;23:2461–7.

    Article  CAS  PubMed  Google Scholar 

  140. Mousa A, Naderpoor N, de Courten MP. Vitamin D supplementation has no effect on insulin sensitivity or secretion in vitamin D-deficient, overweight or obese adults: a randomized placebo-controlled trial. Am J Clin Nutr. 2017;105:1372–81.

    CAS  PubMed  Google Scholar 

  141. Silk LN, Greene DA, Baker MK, Jander CB. The effect of calcium and vitamin D supplementation on bone health of male Jockeys. J Sci Med Sport. 2017;20:225–9.

    Article  PubMed  Google Scholar 

  142. Smith SM, Gardner KK, Locke J, Zwart SR. Vitamin D supplementation during Antarctic winter. Am J Clin Nutr. 2009;89:1092–8.

    Article  CAS  PubMed  Google Scholar 

  143. Agarwal N, Mithal A, Dhingra V, Kaur P, Godbole M, Shukla M. Effect of two different doses of oral cholecalciferol supplementation on serum 25-hydroxy-vitamin D levels in healthy Indian postmenopausal women: a randomized controlled trial. Indian J Endocrinol Metab. 2013;17:883–9.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  144. Venugopal Y, Hatta S, Musa N, Rahman SA, Ratnasingam J, Paramasivam SS, et al. Maintenance vitamin D3 dosage requirements in Chinese women with post menopausal osteoporosis living in the tropics. Asia Pac J Clin Nutr. 2017;26:412–20.

    CAS  PubMed  Google Scholar 

  145. Cangussu L, Nahas-Neto J, Orsatti C, Poloni P, Schmitt E, Almeida-Filho B, et al. Effect of isolated vitamin D supplementation on the rate of falls and postural balance in postmenopausal women fallers: a randomized, double-blind, placebo-controlled trial. Menopause (New York, NY). 2017;3:267–74.

    Google Scholar 

  146. Mastaglia SR, Mautalen CA, Parisi MS, Oliveri B. Vitamin D2 dose required to rapidly increase 25OHD levels in osteoporotic women. Eur J Clin Nutr. 2006;60:681–7.

    Article  CAS  PubMed  Google Scholar 

  147. Nolasco R, Moreira LD, Bocalini DS, Fronza FC, Marin RV, Lazaretti-Castro M. Effects of vitamin D supplementation on pulmonary function in postmenopausal women following an aquatic exercise program. J Matern-Fetal Neonatal Med. 2017;61:28–35.

    Google Scholar 

  148. MacDonald HM, Wood AD, Aucott LS, Black AJ, Fraser WD, Mavroeidi A, et al. Hip bone loss is attenuated with 1000 IU but not 400 IU daily vitamin D3: a 1-year double-blind RCT in postmenopausal women. J Bone Miner Res. 2013;28:2202–13.

    Article  CAS  PubMed  Google Scholar 

  149. Schaafsma A, Muskiet FA, Storm H, Hofstede GJ, Pakan I, Van der Veer E. Vitamin D(3) and vitamin K(1) supplementation of Dutch postmenopausal women with normal and low bone mineral densities: effects on serum 25-hydroxyvitamin D and carboxylated osteocalcin. Eur J Clin Nutr. 2000;54:626–31.

    Article  CAS  PubMed  Google Scholar 

  150. Verschueren SM, Bogaerts A, Delecluse C, Claessens AL, Haentjens P, Vanderschueren D, et al. The effects of whole-body vibration training and vitamin D supplementation on muscle strength, muscle mass, and bone density in institutionalized elderly women: a 6-month randomized, controlled trial. J Bone Mineral Res. 2011;26:42–9.

    Article  CAS  Google Scholar 

  151. Grimnes G, Emaus N, Cashman KD, Jorde R. The effect of high-dose vitamin D supplementation on muscular function and quality of life in postmenopausal women-A randomized controlled trial. Clin Endocrinol. 2017;87:20–8.

    Article  CAS  Google Scholar 

  152. Oberg J, Verelst M, Jorde R, Cashman K, Grimnes G. High dose vitamin D may improve lower urinary tract symptoms in postmenopausal women. J Steroid Biochem Mol Biol. 2017;173:28–32.

    Article  CAS  PubMed  Google Scholar 

  153. Chadha C, Neff LM, Brodsky IG, Rosen C, Desouza CV, Foreyt JP, et al. The effects of single high-dose or daily low-dosage oral colecalciferol treatment on vitamin D levels and muscle strength in postmenopausal women. Diabetes Care. 2018;18:48.

    Google Scholar 

  154. Talwar SA, Aloia JF, Pollack S, Yeh JK. Dose response to vitamin D supplementation among postmenopausal African American women. Am J Clin Nutr. 2007;86:1657–762.

    Article  CAS  PubMed  Google Scholar 

  155. Lappe JM, Travers-Gustafson D, Davies KM, Recker RR, Heaney RP. Vitamin D and calcium supplementation reduces cancer risk: results of a randomized trial. Am J Clin Nutr. 2007;85:1586–91.

    Article  CAS  PubMed  Google Scholar 

  156. Mason C, Xiao L, Imayama I, Duggan C, Wang CY, Korde L, et al. Vitamin D3 supplementation during weight loss: a double-blind randomized controlled trial. Am J Clin Nutr. 2014;99:1015–25.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. Hansen KE, Johnson RE, Chambers KR, Johnson MG, Lemon CC, Vo TN, et al. Treatment of vitamin D insufficiency in postmenopausal women: a randomized clinical trial. JAMA Intern Med. 2015;175:1612–21.

    Article  PubMed  PubMed Central  Google Scholar 

  158. Lappe J, Watson P, Travers-Gustafson D, Recker R, Garland C, Gorham E, et al. Effect of vitamin D and calcium supplementation on cancer incidence in older women: a randomized clinical trial. JAMA. 2017;317:1234–43.

    Article  CAS  PubMed  Google Scholar 

  159. Pfeifer M, Begerow B, Minne HW, Suppan K, Fahrleitner-Pammer A, Dobnig H. Effects of a long-term vitamin D and calcium supplementation on falls and parameters of muscle function in community-dwelling older individuals. Osteoporos Int. 2009;20:315–22.

    Article  CAS  PubMed  Google Scholar 

  160. Patil R, Karinkanta S, Tokola K, Kannus P, Sievänen H, Uusi-Rasi K. Effects of vitamin D and exercise on the wellbeing of older community-dwelling women: a randomized controlled trial. Gerontology. 2016;62:401–8.

    Article  CAS  PubMed  Google Scholar 

  161. Toss G, Magnusson P. Is a daily supplementation with 40 microgram vitamin D3 sufficient? A randomised controlled trial. Eur J Nutr. 2012;51:939–45.

    Article  CAS  PubMed  Google Scholar 

  162. Hin H, Tomson J, Newman C, Kurien R, Lay M, Cox J, et al. Optimum dose of vitamin D for disease prevention in older people: BEST-D trial of vitamin D in primary care. Osteoporos Int. 2017;28:841–51.

    Article  CAS  PubMed  Google Scholar 

  163. Cashman KD, Wallace JMW, Horigan G, Hill TR, Barnes MS, Lucey AJ, et al. Estimation of the dietary requirement for vitamin D in free-living adults ≥ 64 y of age. Am J Clin Nutr. 2009;89:1366–74.

    Article  CAS  PubMed  Google Scholar 

  164. Viljakainen HT, Palssa A, Kärkkäinen M, Jakobsen J, Lamberg-Allardt C. How much vitamin D3 do the elderly need? J Am Coll Nutr. 2006;25:429–35.

    Article  CAS  PubMed  Google Scholar 

  165. Berlanga-Taylor AJ, Plant K, Dahl A, Lau E, Hill M, Sims D, et al. Genomic response to vitamin D supplementation in the setting of a randomized, placebo-controlled trial. EBioMedicine. 2018;31:133–42.

    Article  PubMed  PubMed Central  Google Scholar 

  166. Imaoka M, Higuchi Y, Todo E, Kitagwa T, Ueda T. Low-frequency exercise and vitamin D supplementation reduce falls among institutionalized frail elderly. Int J Gerontol. 2016;4:1–5.

    Google Scholar 

  167. Zhu K, Devine A, Dick IM, Wilson SG, Prince RL. Effects of calcium and vitamin D supplementation on hip bone mineral density and calcium-related analytes in elderly ambulatory Australian women: a five-year randomized controlled trial. J Clin Endocrinol Metab. 2008;93:743–9.

    Article  CAS  PubMed  Google Scholar 

  168. Glendenning P, Chew GT, Seymour HM, Gillett MJ, Goldswain PR, Inderjeeth CA, et al. Serum 25-hydroxyvitamin D levels in vitamin D-insufficient hip fracture patients after supplementation with ergocalciferol and cholecalciferol. Bone. 2009;45:870–5.

    Article  CAS  PubMed  Google Scholar 

  169. Bacon CJ, Gamble GD, Horne AM, Scott MA, Reid IR. High-dose oral vitamin D3 supplementation in the elderly. Osteoporos Int. 2009;20:1407–15.

    Article  CAS  PubMed  Google Scholar 

  170. Reid IR, Horne AM, Mihov B, Gamble GD, Al-Abuwsi F, Singh M, et al. Effect of monthly high-dose vitamin D on bone density in community-dwelling older adults substudy of a randomized controlled trial. J Intern Med Suppl. 2017;282:452–60.

    Article  CAS  Google Scholar 

  171. El-Hajj F, Baddoura R, Habib R, Halaby G, Arabi A, Rahme M, et al. Effect of vitamin D replacement on indexes of insulin resistance in overweight elderly individuals: a randomized controlled trial. Am J Clin Nutr. 2017;2:315–23.

    Google Scholar 

  172. Cherniack EP, Florez HJ, Hollis BW, Roos BA, Troen BR, Levis S. The response of elderly veterans to daily vitamin D3 supplementation of 2,000 IU: a pilot efficacy study. J Am Geriatr Soc. 2011;59:286–90.

    Article  PubMed  Google Scholar 

  173. Rahme M, Sharara SL, Baddoura R, Habib RH, Halaby G, Arabi A, et al. Impact of calcium and two doses of vitamin D on bone metabolism in the elderly: a randomized controlled trial. J Bone Mineral Res. 2017;32:1486–95.

    Article  CAS  Google Scholar 

  174. Bunout D, Barrera G, Leiva L, Gattas V, Maza M, Avenda M, et al. Effects of vitamin D supplementation and exercise training on physical performance in Chilean vitamin D deficient elderly subjects. Exp Gerontol. 2006;8:746–52.

    Article  CAS  Google Scholar 

  175. Dimitris MC, Perumal N, Craig-Barnes HA, Leadley M, Mahmud AA, Baqui AH, et al. Effect of weekly high-dose vitamin D3 supplementation on serum cholecalciferol concentrations in pregnant women. J Steroid Biochem Mol Biol. 2016;158:76–81.

    Article  CAS  PubMed  Google Scholar 

  176. Moon R, Harvey N, Cooper C, D’Angelo S, Crozier S, Inskip H, et al. Determinants of the maternal 25-Hydroxyvitamin D response to Vitamin D supplementation during pregnancy. J Clin Endocrinol Metab. 2017;12:5012–20.

    Google Scholar 

  177. Barker M, D’Angelo S, Ntani G, Lawrence W, Baird J, Jarman M, et al. The relationship between maternal self-efficacy, compliance and outcome in a trial of vitamin D supplementation in pregnancy. Osteoporos Int. 2017;28:77–84.

    Article  CAS  PubMed  Google Scholar 

  178. Hashemipour S, Ziaee A, Javadi A, Movahed F, Elmizadeh K, Javadi EH, et al. Effect of treatment of vitamin D deficiency and insufficiency during pregnancy on fetal growth indices and maternal weight gain: a randomized clinical trial. Eur J Obstet Gynecol Reprod Biol. 2014;172:15–9.

    Article  CAS  PubMed  Google Scholar 

  179. Asemi Z, Samimi M, Siavashani MA, Mazloomi M, Tabassi Z, Karamali M, et al. Calcium-vitamin D Co-supplementation affects metabolic profiles, but not pregnancy outcomes, in healthy pregnant women. Int J Prev Med. 2016;7:49–56.

    Article  PubMed  PubMed Central  Google Scholar 

  180. Karamali M, Beihaghi E, Mohammadi AA, Asemi Z. Effects of high-dose Vitamin D supplementation on metabolic status and pregnancy outcomes in pregnant women at risk for pre-eclampsia. Horm Metab Res. 2015;47:867–72.

    Article  CAS  PubMed  Google Scholar 

  181. Chen NN, March K, Innis SM, Shand A, Von Dadelszen P, Lyon M, et al. The effect of vitamin D supplementation during pregnancy and lactation on maternal & infant 25-hydroxyvitamin D (25OHD) concentration. FASEB J. 2013;27:1–134.

    Article  CAS  Google Scholar 

  182. Diogenes MEL, Bezerra FF, Rezende EP, Taveira MF, Pinhal I, Donangelo CM. Effect of calcium plus vitamin D supplementation during pregnancy in Brazilian adolescent mothers: a randomized, placebo-controlled trial. Am J Clin Nutr. 2013;98:82–91.

    Article  CAS  PubMed  Google Scholar 

  183. Yap C, Cheung NW, Gunton JE, Athayde N, Munns CF, Duke A, et al. Vitamin D supplementation and the effects on glucose metabolism during pregnancy: a randomized controlled trial. Diabetes Care. 2014;37:1837–44.

    Article  CAS  PubMed  Google Scholar 

  184. Yesiltepe Mutlu G, Ozsu E, Kalaca S, Yuksel A, Pehlevan Y, Cizmecioglu F, et al. Evaluation of vitamin D supplementation doses during pregnancy in a population at high risk for deficiency. Horm Res Paediatr. 2014;81:402–8.

    Article  PubMed  CAS  Google Scholar 

  185. Sahoo SK, Katam KK, Das V, Agarwal A, Bhatia V. Maternal vitamin D supplementation in pregnancy and offspring outcomes: a double-blind randomized placebo-controlled trial. J Bone Miner Metab. 2017;35:464–71.

    Article  CAS  PubMed  Google Scholar 

  186. Hollis BW, Johnson D, Hulsey TC, Ebeling M, Wagner CL. Vitamin D supplementation during pregnancy: double-blind, randomized clinical trial of safety and effectiveness. J Bone Mineral Res. 2011;26:2341–57.

    Article  CAS  Google Scholar 

  187. Chandy DD, Kare J, Singh SN, Agarwal A, Das V, Singh U, et al. Effect of Vitamin D supplementation, directly or via breast milk for term infants, on serum 25 hydroxyVitamin D and related biochemistry, and propensity to infection: a randomised placebo-controlled trial. Brit J Nutr. 2016;116:52–8.

    Article  CAS  PubMed  Google Scholar 

  188. Basile LA, Taylor SN, Wagner CL, Horst RL, Hollis BW. The effect of high-dose vitamin D supplementation on serum vitamin D levels and milk calcium concentration in lactating women and their infants. Breastfeed Med. 2006;1:27–35.

    Article  PubMed  Google Scholar 

  189. Hollis BW, Wagner CL. Vitamin D requirements during lactation: high-dose maternal supplementation as therapy to prevent hypovitaminosis D for both the mother and the nursing infant. Am J Clin Nutr. 2004;80(6 Suppl):1752S–8S.

    Article  CAS  PubMed  Google Scholar 

  190. Grant CC, Stewart AW, Scragg R, Milne T, Rowden J, Ekeroma A, et al. Vitamin D during pregnancy and infancy and infant serum 25-hydroxyvitamin D concentration. Pediatrics. 2014;133:e143–e53.

    Article  PubMed  Google Scholar 

  191. Saadi HF, Dawodu A, Afandi B, Zayed R, Benedict S, Nagelkerke N, et al. Effect of combined maternal and infant vitamin D supplementation on vitamin D status of exclusively breastfed infants. Matern Child Nutr. 2009;5:25–32.

    Article  PubMed  Google Scholar 

  192. Dawson-Hughes B, Mithal A, Bonjour JP, Boonen S, Burckhardt P, Fuleihan GE, et al. IOF position statement: vitamin D recommendations for older adults. Osteoporos Int. 2010;21:1151–4.

    Article  CAS  PubMed  Google Scholar 

  193. Heaney R, Armas L, Shary J, Bell N, Binkley N. 25-Hydroxylation of vitamin D3: relation to circulating vitamin D3 under various input conditions. Am J Clin Nutr. 2008;87:1738–42.

    Article  CAS  PubMed  Google Scholar 

  194. Bouillon R. Comparative analysis of nutritional guidelines for vitamin D. Nat Rev Endocrinol. 2017;13:466–79.

    Article  CAS  PubMed  Google Scholar 

  195. Barger-Lux MJ, Heaney RP, Dowell S, Chen TC, Holick MF. Vitamin D and its major metabolites: serum levels after graded oral dosing in healthy men. Osteoporos Int. 1998;8:222–30.

    Article  CAS  PubMed  Google Scholar 

  196. Tripkovic L, Wilson LR, Hart K, Johnsen S, de Lusignan S, Smith CP, et al. Daily supplementation with 15 mug vitamin D2 compared with vitamin D3 to increase wintertime 25-hydroxyvitamin D status in healthy South Asian and white European women: a 12-wk randomized, placebo-controlled food-fortification trial. Am J Clin Nutr. 2017;106:481–90.

    Article  CAS  PubMed  Google Scholar 

  197. Munns CF, Shaw N, Kiely M, Specker BL, Thacher TD, Ozono K, et al. Global consensus recommendations on prevention and management of nutritional rickets. J Clin Endocrinol Metab. 2016;101:394–415.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  198. Itkonen ST, Skaffari E, Saaristo P, Saarnio EM, Erkkola M, Jakobsen J, et al. Effects of vitamin D2-fortified bread v. supplementation with vitamin D2 or D3 on serum 25-hydroxyvitamin D metabolites: an 8-week randomised-controlled trial in young adult Finnish women. Br J Nutr. 2016;115:1232–9.

    Article  CAS  PubMed  Google Scholar 

  199. Bouillon R, Verlinden L, Verstuyf A. Is vitamin D2 really bioequivalent to vitamin D3? Endocrinology. 2016;157:3384–7.

    Article  CAS  PubMed  Google Scholar 

  200. Armas L, Hollis B, Heaney R. Vitamin D2 is much less effective than vitamin D3 in humans. J Clin Endocrinol Metab. 2004;89:5387–91.

    Article  CAS  PubMed  Google Scholar 

  201. Horst R, Reinhardt T, Ramberg C, Koszewski N, Napoli J. 24-Hydroxylation of 1,25dihydroxyergocalciferol—an unambiguous deactivation process. J Biol Chem. 1986;261:9250–6.

    Article  CAS  PubMed  Google Scholar 

  202. Houghton LA, Vieth R. The case against ergocalciferol (vitamin D-2) as a vitamin supplement. Am J Clin Nutr. 2006;84:694–7.

    Article  CAS  PubMed  Google Scholar 

  203. IOM (Institute of Medicine). Dietary reference intakes for calcium and vitamin D. Washington, DC: The National Academies Press; 2011.

    Google Scholar 

  204. Clemens TL, Zhou XY, Myles M, Endres D, Lindsay R. Serum vitamin D2 and vitamin D3 metabolite concentrations and absorption of vitamin D2 in elderly subjects. J Clin Endocrinol Metab. 1986;63:656–60.

    Article  CAS  PubMed  Google Scholar 

  205. MacLaughlin J, Holick MF. Aging decreases the capacity of human skin to produce vitamin D3. J Clin Invest. 1985;76:1536–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  206. Gloth FM, Tobin JD, Sherman SS, Hollis BW. Is the recommended daily allowance for vitamin-D too low for the homebound elderly. J Am Geriatr Soc. 1991;39:137–41.

    Article  PubMed  Google Scholar 

  207. Dixon T, Mitchel P, Beringer T, Gallacher S, Moniz C, Patel S, et al. An overview of the prevalence of 25-hydroxy-vitamin D inadequacy amongst elderly patients with or without fragility fracture in the United Kingdom. Curr Med Res Opin. 2006;22:405–15.

    Article  CAS  PubMed  Google Scholar 

  208. Hollis BW, Wagner CL. The role of the parent compound vitamin D with respect to metabolism and function: why clinical dose intervals can affect clinical outcomes. J Clin Endocr Metab. 2013;98:4619–28.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  209. Webb AR, Kline L, Holick MF. Influence of season and latitude on the cutaneous synthesis of vitamin-D3 - exposure to winter sunlight in Boston and Edmonton will not promote vitamin-D3 synthesis in human-skin. J Clin Endocr Metab. 1988;67:373–8.

    Article  CAS  PubMed  Google Scholar 

  210. Lips P, Duong T, Oleksik A, Black D, Cummings S, Cox D, et al. A global study of vitamin D status and parathyroid function in postmenopausal women with osteoporosis: baseline data from the multiple outcomes of raloxifene evaluation clinical trial. J Clin Endocrinol Metab. 2001;86:1212–21.

    Article  CAS  PubMed  Google Scholar 

  211. Aloia JF, Patel M, Dimaano R, Li-Ng M, Talwar SA, Mikhail M, et al. Vitamin D intake to attain a desired serum 25-hydroxyvitamin D concentration. Am J Clin Nutr. 2008;87:1952–8.

    Article  CAS  PubMed  Google Scholar 

  212. Guyatt GH, Oxman AD, Kunz R, Woodcock J, Brozek J, Helfand M, et al. GRADE guidelines: 7. Rating the quality of evidence-inconsistency. J Clin Epidemiol. 2011;64:1294–302.

    Article  PubMed  Google Scholar 

  213. Berry DJ, Dutton J, Fraser WD, Jarvelin MR, Hypponen E. Harmonization study between LC-MS/MS and Diasorin RIA for measurement of 25-hydroxyvitamin D concentrations in a large population survey. J Clin Lab Anal. 2017;31:3.

    Article  CAS  Google Scholar 

  214. Wielders JP, Carter GF, Eberl H, Morris G, Roth HJ, Vogl C. Automated competitive protein-binding assay for total 25-OH vitamin D, multicenter evaluation and practical performance. J Clin Lab Anal. 2015;29:451–61.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank for the support from experts who provided guidance on methods and authors who shared their articles with us.

Funding

This work was funded by the National Key Research and Development Program of China (2016YFC1305301), Key Research and Development Projects of Zhejiang Science and Technology Department (2018C03010), WeiJian Special Foundation, Zhejiang University School of Public Health, the Natural Science Foundation of Zhejiang Province in China (grant no.: LY14H260003 and Y20100505).

Author information

Authors and Affiliations

  1. Department of Public Health, and Department of Anesthesiology, Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China

    Minjia Mo, Shijie Wang, Zun Chen, Xiamusiye Muyiduli, Shuojia Wang, Yu Shen, Bule Shao, Minchao Li, Zexin Chen & Yunxian Yu

  2. Department of Obstetrics and Gynaecology, Woman’s Hospital, School of Medicine, Zhejiang University, Hangzhou, China

    Danqing Chen

Authors
  1. Minjia Mo
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Shijie Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Zun Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Xiamusiye Muyiduli
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Shuojia Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Yu Shen
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Bule Shao
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Minchao Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Danqing Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Zexin Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Yunxian Yu
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

YXY, ZXC, and MJM designed research and conducted research. Shijie Wang and MJM conducted research. ZC and Shuojia Wang provided essential reagents or provided essential materials. MJM, Shijie Wang, ZC, and ZXC analyzed data or performed statistical analysis. MJM and YXY wrote paper. MJM had primary responsibility for final content. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Yunxian Yu.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Appendix 1. Funnel plots

Appendix 2. Supplementary figure legends of meta-analysis

Figure S1. Funnel plot of high-dose (>3000 IU) versus placebo with baseline 25(OH)D < 50 nmol/l in adults

Figure S2. Funnel plot of low dose (<1500 IU) versus placebo with baseline 25(OH)D < 50 nmol/l in adults

Figure S3. Funnel plot of moderate dose (1500–3000 IU) versus placebo with baseline 25(OH)D < 50 nmol/l in adults

Figure S4. Funnel plot of low dose (<1500 IU) versus placebo with baseline 25(OH)D (50–75 nmol/l) in adults

Change of authorship request form 1

Change of authorship request form 2

Appendix 3. Search Strategies for Electronic Databases

Supplementary table 1. Characteristics of included studies by treatment arm.

Figure S1. High dose (>1600 IU) versus placebo in children with baseline 25(OH)D concentration < 50 nmol/L

Figure S2. Low dose (<800 IU) versus placebo in children with baseline 25(OH)D concentration < 50 nmol/L

Figure S3. Moderate dose (800–1600 IU) versus placebo in children with baseline 25(OH)D concentration < 50 nmol/L

Figure S4. Low dose (<800 IU) versus placebo in children with baseline 25(OH)D concentration reached 50–75 nmol/L

41430_2019_417_MOESM15_ESM.eps

Figure S5. Moderate dose (800–1600 IU) versus placebo in children with baseline 25(OH)D concentration reached 50–75 nmol/L

Figure S6. Low dose (<800 IU) versus placebo in children from Europe

Figure S7. Moderate dose (800–1600 IU) versus placebo in children from Europe

Figure S8. Moderate dose (800–1600 IU) versus placebo in children from North America

Figure S9. High dose (>3000 IU) versus placebo in adult subjects with baseline 25(OH)D concentration < 50 nmol/L

41430_2019_417_MOESM20_ESM.eps

Figure S10. High dose (>3000 IU) versus placebo in adult subjects with baseline 25(OH)D concentration < 50 nmol/L from different latitudes

41430_2019_417_MOESM21_ESM.eps

Figure S11. High dose (>3000 IU) versus low dose (<1500 IU) in adult subjects with baseline 25(OH)D concentration < 50 nmol/L

41430_2019_417_MOESM22_ESM.eps

Figure S12. High dose (>3000 IU) versus moderate dose (1500–3000 IU) in adult subjects with baseline 25(OH)D concentration < 50 nmol/L

41430_2019_417_MOESM23_ESM.eps

Figure S13. Moderate dose (1500–3000 IU) versus low dose (<1500 IU) in adult subjects with baseline 25(OH)D concentration < 50 nmol/L

41430_2019_417_MOESM24_ESM.eps

Figure S14. Moderate dose (1500–3000 IU) versus placebo in adult subjects with baseline 25(OH)D concentration < 50 nmol/L

41430_2019_417_MOESM25_ESM.eps

Figure S15. Moderate dose (1500–3000 IU) versus placebo in adult subjects with baseline 25(OH)D concentration < 50 nmol/L from different latitudes

41430_2019_417_MOESM26_ESM.eps

Figure S16. High dose (>3000 IU) versus moderate dose (1500–3000 IU) in adult subjects with baseline 25(OH)D concentration reached 50–75 nmol/L

41430_2019_417_MOESM27_ESM.eps

Figure S17. High dose (>3000 IU) versus placebo in adult subjects with baseline 25(OH)D concentration reached 50–75 nmol/L

41430_2019_417_MOESM28_ESM.eps

Figure S18. Moderate dose (1500–3000 IU) versus placebo in adult subjects with baseline 25(OH)D concentration reached 50–75 nmol/L

41430_2019_417_MOESM29_ESM.eps

Figure S19. Low dose (<1500 IU) versus placebo in adult subjects with baseline 25(OH)D concentration reached 50–75 nmol/L

41430_2019_417_MOESM30_ESM.eps

Figure S20. Moderate dose (1500–3000 IU) versus low dose (<1500 IU) in adult subjects with baseline 25(OH)D concentration reached 50–75 nmol/L

Figure S21. Low dose (<1500 IU) versus placebo in adult subjects with baseline 25(OH)D concentration >75 nmol/L

Figure S22. Low dose (<1500 IU) versus placebo in postmenopausal women with baseline 25(OH)D concentration < 50 nmol/L

41430_2019_417_MOESM33_ESM.eps

Figure S23. Low dose (<1500 IU) versus placebo in postmenopausal women with baseline 25(OH)D concentration reached 50–75 nmol/L

Figure S24. Low dose (<1500 IU) versus placebo in the elderly with baseline 25(OH)D concentration < 50 nmol/L

Figure S25. Low dose (<1500 IU) versus placebo in the elderly with baseline 25(OH)D concentration reached 50–75 nmol/L

41430_2019_417_MOESM36_ESM.eps

Figure S26. Low dose (<1500 IU) versus placebo in the elderly with baseline 25(OH)D concentration reached 50–75 nmol/L from Europe

Figure S27. Moderate dose (1500–3000 IU) versus low dose (<1500 IU) in pregnant women

Figure S28. Low dose (<1500 IU) versus placebo in pregnant women

Figure S29. High dose (>3000 IU) versus low dose (<1500 IU) in pregnant women

Figure S30. Moderate dose (1500–3000 IU) versus low dose (<1500 IU) in pregnant women from North America

Figure S31. Low dose (<1500 IU) versus placebo in pregnant women from UK

Figure S32. High dose (>3000 IU) versus low dose (<1500 IU) in pregnant women from Iran

Figure S33. High dose (>3000 IU) versus moderate dose (1500–3000 IU) in lactating women

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Mo, M., Wang, S., Chen, Z. et al. A systematic review and meta-analysis of the response of serum 25-hydroxyvitamin D concentration to vitamin D supplementation from RCTs from around the globe. Eur J Clin Nutr 73, 816–834 (2019). https://doi.org/10.1038/s41430-019-0417-x

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41430-019-0417-x

This article is cited by

Search

Advanced search

Quick links