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European Journal of Nutrition

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02-03-2023 | Vitamin D Deficiency | Review

Calcifediol: a review of its pharmacological characteristics and clinical use in correcting vitamin D deficiency

Authors: Esteban Jodar, Claudia Campusano, Renate T. de Jongh, Michael F. Holick

Published in: European Journal of Nutrition | Issue 4/2023

Abstract

Background

In addition to the role of vitamin D in bone mineralization, calcium and phosphate homeostasis, and skeletal health, evidence suggests an association between vitamin D deficiency and a wide range of chronic conditions. This is of clinical concern given the substantial global prevalence of vitamin D deficiency. Vitamin D deficiency has traditionally been treated with vitamin D₃ (cholecalciferol) or vitamin D₂ (ergocalciferol). Calcifediol (25-hydroxyvitamin D₃) has recently become available more widely.

Methods

By means of targeted literature searches of PubMed, this narrative review overviews the physiological functions and metabolic pathways of vitamin D, examines the differences between calcifediol and vitamin D₃, and highlights clinical trials conducted with calcifediol in patients with bone disease or other conditions.

Results

For supplemental use in the healthy population, calcifediol can be used at doses of up to 10 µg per day for children ≥ 11 years and adults and up to 5 µg/day in children 3−10 years. For therapeutic use of calcifediol under medical supervision, the dose, frequency and duration of treatment is determined according to serum 25(OH)D concentrations, condition, type of patient and comorbidities. Calcifediol differs pharmacokinetically from vitamin D₃ in several ways. It is independent of hepatic 25-hydroxylation and thus is one step closer in the metabolic pathway to active vitamin D. At comparable doses to vitamin D₃, calcifediol achieves target serum 25(OH)D concentrations more rapidly and in contrast to vitamin D₃, it has a predictable and linear dose–response curve irrespective of baseline serum 25(OH)D concentrations. The intestinal absorption of calcifediol is relatively preserved in patients with fat malabsorption and it is more hydrophilic than vitamin D₃ and thus is less prone to sequestration in adipose tissue.

Conclusion

Calcifediol is suitable for use in all patients with vitamin D deficiency and may be preferable to vitamin D₃ for patients with obesity, liver disease, malabsorption and those who require a rapid increase in 25(OH)D concentrations.

Holick MF (2007) Vitamin D deficiency. N Engl J Med 357(3):266–281. https://doi.org/10.1056/NEJMra070553CrossRefPubMed

Tsiaras WG, Weinstock MA (2011) Factors influencing vitamin D status. Acta Derm Venereol 91(2):115–124. https://doi.org/10.2340/00015555-0980CrossRefPubMed

Hilger J, Friedel A, Herr R, Rausch T, Roos F, Wahl DA, Pierroz DD, Weber P, Hoffmann K (2014) A systematic review of vitamin D status in populations worldwide. Br J Nutr 111(1):23–45. https://doi.org/10.1017/S0007114513001840CrossRefPubMed

Bouillon R, Marcocci C, Carmeliet G, Bikle D, White JH, Dawson-Hughes B, Lips P, Munns CF, Lazaretti-Castro M, Giustina A, Bilezikian J (2019) Skeletal and extraskeletal actions of vitamin D: current evidence and outstanding questions. Endocr Rev 40(4):1109–1151. https://doi.org/10.1210/er.2018-00126CrossRefPubMed

Amrein K, Scherkl M, Hoffmann M, Neuwersch-Sommeregger S, Köstenberger M, Tmava Berisha A, Martucci G, Pilz S, Malle O (2020) Vitamin D deficiency 2.0: an update on the current status worldwide. Eur J Clin Nutr 74(11):1498–1513. https://doi.org/10.1038/s41430-020-0558-yCrossRefPubMedPubMedCentral

Charoenngam N, Holick MF (2020) Immunologic effects of vitamin D on human health and disease. Nutrients 12(7):2097. https://doi.org/10.3390/nu12072097CrossRefPubMedPubMedCentral

Ahmad S, Arora S, Khan S, Mohsin M, Mohan A, Manda K, Syed MA (2021) Vitamin D and its therapeutic relevance in pulmonary diseases. J Nutr Biochem 90:108571. https://doi.org/10.1016/j.jnutbio.2020.108571CrossRefPubMed

Dawson-Hughes B (2021) Role of vitamin D in COVID-19: active or passive? J Clin Endocrinol Metab 106:e5260–e5261. https://doi.org/10.1210/clinem/dgab505CrossRefPubMed

Gil Á, Plaza-Diaz J, Mesa MD (2018) Vitamin D: classic and novel actions. Ann Nutr Metab 72(2):87–95. https://doi.org/10.1159/000486536CrossRefPubMed

10.

Tripkovic L, Lambert H, Hart K, Smith CP, Bucca G, Penson S, Chope G, Hyppönen E, Berry J, Vieth R, Lanham-New S (2012) Comparison of vitamin D2 and vitamin D3 supplementation in raising serum 25-hydroxyvitamin D status: a systematic review and meta-analysis. Am J Clin Nutr 95(6):1357–1364. https://doi.org/10.3945/ajcn.111.031070CrossRefPubMedPubMedCentral

11.

Biancuzzo RM, Clarke N, Reitz RE, Travison TG, Holick MF (2013) 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 98(3):973–979. https://doi.org/10.1210/jc.2012-2114CrossRefPubMedPubMedCentral

12.

Cardwell G, Bornman JF, James AP, Black LJ (2018) A review of mushrooms as a potential source of dietary vitamin D. Nutrients 10(10):1498. https://doi.org/10.3390/nu10101498CrossRefPubMedPubMedCentral

13.

Kennel KA, Drake MT, Hurley DL (2010) Vitamin D deficiency in adults: when to test and how to treat. Mayo Clin Proc 85(8):752–757. https://doi.org/10.4065/mcp.2010.0138. (quiz 757−758)CrossRefPubMedPubMedCentral

14.

Christakos S, Ajibade DV, Dhawan P, Fechner AJ, Mady LJ (2010) Vitamin D: metabolism. Endocrinol Metab Clin North Am 39(2):243–253. https://doi.org/10.1016/j.ecl.2010.02.002. (table of contents)CrossRefPubMedPubMedCentral

15.

Wacker M, Holick MF (2013) Sunlight and Vitamin D: A global perspective for health. Dermatoendocrinol 5(1):51–108. https://doi.org/10.4161/derm.24494CrossRefPubMedPubMedCentral

16.

EFSA Panel on Nutrition, Novel Foods and Food Allergens (NDA), Turck D, Castenmiller J, De Henauw S, Hirsch-Ernst KI, Kearney J, Maciuk A, Mangelsdorf I, McArdle HJ, Naska A, Peláez C, Pentieva K, Siani A, Thies F, Tsabouri S, Vinceti M, Cubadda F, Frenzel T, Heinonen M, Marchelli R, Neuhauser-Berthold M, Poulsen M, Maradona MP, Schlatter JR, van Loveren H, Dumas C, Roldán-Torres R, Steinkellner H, Knutsen HK (2021) Safety of calcidiol monohydrate produced by chemical synthesis as a novel food pursuant to Regulation (EU) 2015/2283. EFSA J 19(7):e06660. https://doi.org/10.2903/j.efsa.2021.6660CrossRef

17.

Bergwitz C, Jüppner H (2010) Regulation of phosphate homeostasis by PTH, vitamin D, and FGF23. Annu Rev Med 61:91–104. https://doi.org/10.1146/annurev.med.051308.111339CrossRefPubMedPubMedCentral

18.

Fukumoto S (2014) Phosphate metabolism and vitamin D. Bonekey Rep 3:497. https://doi.org/10.1038/bonekey.2013.231CrossRefPubMedPubMedCentral

19.

Erben RG (2018) Physiological actions of fibroblast growth factor-23. Front Endocrinol (Lausanne) 9:267. https://doi.org/10.3389/fendo.2018.00267CrossRefPubMed

20.

Bouillon R, Carmeliet G, Verlinden L, van Etten E, Verstuyf A, Luderer HF, Lieben L, Mathieu C, Demay M (2008) Vitamin D and human health: lessons from vitamin D receptor null mice. Endocr Rev 29(6):726–776. https://doi.org/10.1210/er.2008-0004CrossRefPubMedPubMedCentral

21.

Kongsbak M, Levring TB, Geisler C, von Essen MR (2013) The vitamin D receptor and T cell function. Front Immunol 4:148. https://doi.org/10.3389/fimmu.2013.00148CrossRefPubMedPubMedCentral

22.

Lou YR, Molnár F, Peräkylä M, Qiao S, Kalueff AV, St-Arnaud R, Carlberg C, Tuohimaa P (2010) 25-hydroxyvitamin D(3) is an agonistic vitamin D receptor ligand. J Steroid Biochem Mol Biol 118(3):162–170. https://doi.org/10.1016/j.jsbmb.2009.11.011CrossRefPubMed

23.

Donati S, Palmini G, Romagnoli C, Aurilia C, Miglietta F, Falsetti I, Marini F, Zonefrati R, Galli G, Marcucci G, Iantomasi T, Brandi ML (2021) In vitro non-genomic effects of calcifediol on human preosteoblastic cells. Nutrients 13(12):4227. https://doi.org/10.3390/nu13124227CrossRefPubMedPubMedCentral

24.

Diaz de Barboza G, Guizzardi S, Tolosa de Talamoni N (2015) Molecular aspects of intestinal calcium absorption. World J Gastroenterol 21(23):7142–7154. https://doi.org/10.3748/wjg.v21.i23.7142CrossRefPubMedPubMedCentral

25.

Holick MF, Binkley NC, Bischoff-Ferrari HA, Gordon CM, Hanley DA, Heaney RP, Murad MH, Weaver CM, Endocrine Society (2011) Evaluation, treatment, and prevention of vitamin D deficiency: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 96(7):1911–1930. https://doi.org/10.1210/jc.2011-0385. (Erratum in: J Clin Endocrinol Metab 2011;96(12):3908)CrossRefPubMed

26.

Ross AC, Manson JE, Abrams SA, Aloia JF, Brannon PM, Clinton SK, Durazo-Arvizu RA, Gallagher JC, Gallo RL, Jones G, Kovacs CS, Mayne ST, Rosen CJ, Shapses SA (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):53–58. https://doi.org/10.1210/jc.2010-2704CrossRefPubMed

27.

van Schoor NM, Lips P (2011) Worldwide vitamin D status. Best Pract Res Clin Endocrinol Metab 25(4):671–680. https://doi.org/10.1016/j.beem.2011.06.007CrossRefPubMed

28.

Cashman KD, Dowling KG, Škrabáková Z, Gonzalez-Gross M, Valtueña J, De Henauw S, Moreno L, Damsgaard CT, Michaelsen KF, Mølgaard C, Jorde R, Grimnes G, Moschonis G, Mavrogianni C, Manios Y, Thamm M, Mensink GB, Rabenberg M, Busch MA, Cox L, Meadows S, Goldberg G, Prentice A, Dekker JM, Nijpels G, Pilz S, Swart KM, van Schoor NM, Lips P, Eiriksdottir G, Gudnason V, Cotch MF, Koskinen S, Lamberg-Allardt C, Durazo-Arvizu RA, Sempos CT, Kiely M (2016) Vitamin D deficiency in Europe: pandemic? Am J Clin Nutr 103(4):1033–1044. https://doi.org/10.3945/ajcn.115.120873CrossRefPubMedPubMedCentral

29.

van Schoor N, Lips P (2017) Global overview of vitamin D status. Endocrinol Metab Clin North Am 46(4):845–870. https://doi.org/10.1016/j.ecl.2017.07.002CrossRefPubMed

30.

Herrick KA, Storandt RJ, Afful J, Pfeiffer CM, Schleicher RL, Gahche JJ, Potischman N (2019) Vitamin D status in the United States, 2011–2014. Am J Clin Nutr 110(1):150–157. https://doi.org/10.1093/ajcn/nqz037CrossRefPubMedPubMedCentral

31.

Sarafin K, Durazo-Arvizu R, Tian L, Phinney KW, Tai S, Camara JE, Merkel J, Green E, Sempos CT, Brooks SP (2015) Standardizing 25-hydroxyvitamin D values from the Canadian health measures survey. Am J Clin Nutr 102(5):1044–1050. https://doi.org/10.3945/ajcn.114.103689CrossRefPubMedPubMedCentral

32.

Asakura K, Etoh N, Imamura H, Michikawa T, Nakamura T, Takeda Y, Mori S, Nishiwaki Y (2020) Vitamin D status in Japanese adults: relationship of serum 25-hydroxyvitamin D with simultaneously measured dietary vitamin D intake and ultraviolet ray exposure. Nutrients 12(3):743. https://doi.org/10.3390/nu12030743CrossRefPubMedPubMedCentral

33.

Brito A, Cori H, Olivares M, Fernanda Mujica M, Cediel G, López de Romaña D (2013) Less than adequate vitamin D status and intake in Latin America and the Caribbean: a problem of unknown magnitude. Food Nutr Bull 34(1):52–64. https://doi.org/10.1177/156482651303400107CrossRefPubMed

34.

González G (2013) Vitamin D status among healthy postmenopausal women in South America. Dermatoendocrinol 5(1):117–120. https://doi.org/10.4161/derm.24807CrossRefPubMedPubMedCentral

35.

Palacios S, Cerdas S, Da Silva R, Paradas A, Vargas J, Mostajo D, Tserotas K, Danckers L, Moreno M, Navas M, Muñoz-Louis R, Maida T, Rosero O, Rueda C, Vasquez D, Melo L, Córdoba S, Rasec-Morales L, de Melo NR (2021) Vitamin D supplementation: position statement of the iberoamerican society of osteoporosis and mineral metabolism (SIBOMM). Gynecol Endocrinol 37(1):10–14. https://doi.org/10.1080/09513590.2020.1858781CrossRefPubMed

36.

Dawson-Hughes B, Mithal A, Bonjour JP, Boonen S, Burckhardt P, Fuleihan GE, Josse RG, Lips P, Morales-Torres J, Yoshimura N (2010) IOF position statement: vitamin D recommendations for older adults. Osteoporos Int 21(7):1151–1154. https://doi.org/10.1007/s00198-010-1285-3CrossRefPubMed

37.

Munns CF, Shaw N, Kiely M, Specker BL, Thacher TD, Ozono K, Michigami T, Tiosano D, Mughal MZ, Mäkitie O, Ramos-Abad L, Ward L, DiMeglio LA, Atapattu N, Cassinelli H, Braegger C, Pettifor JM, Seth A, Idris HW, Bhatia V, Fu J, Goldberg G, Sävendahl L, Khadgawat R, Pludowski P, Maddock J, Hyppönen E, Oduwole A, Frew E, Aguiar M, Tulchinsky T, Butler G, Högler W (2016) Global consensus recommendations on prevention and management of nutritional rickets. J Clin Endocrinol Metab 101(2):394–415. https://doi.org/10.1210/jc.2015-2175CrossRefPubMedPubMedCentral

38.

Giustina A, Adler RA, Binkley N, Bouillon R, Ebeling PR, Lazaretti-Castro M, Marcocci C, Rizzoli R, Sempos CT, Bilezikian JP (2019) Controversies in vitamin D: summary statement from an international conference. J Clin Endocrinol Metab 104(2):234–240. https://doi.org/10.1210/jc.2018-01414CrossRefPubMed

39.

Pludowski P, Holick MF, Grant WB, Konstantynowicz J, Mascarenhas MR, Haq A, Povoroznyuk V, Balatska N, Barbosa AP, Karonova T, Rudenka E, Misiorowski W, Zakharova I, Rudenka A, Łukaszkiewicz J, Marcinowska-Suchowierska E, Łaszcz N, Abramowicz P, Bhattoa HP, Wimalawansa SJ (2018) Vitamin D supplementation guidelines. J Steroid Biochem Mol Biol 175:125–135. https://doi.org/10.1016/j.jsbmb.2017.01.021CrossRefPubMed

40.

EFSA Nda Panel (EFSA Panel on Dietetic Products, Nutrition and Allergies) (2016) Scientific opinion on dietary reference values for vitamin D. EFSA J 14:4547. https://doi.org/10.2903/j.efsa.2016.4547CrossRef

41.

Lips P, Cashman KD, Lamberg-Allardt C, Bischoff-Ferrari HA, Obermayer-Pietsch B, Bianchi ML, Stepan J, El-Hajj Fuleihan G, Bouillon R (2019) Current vitamin D status in European and Middle East countries and strategies to prevent vitamin D deficiency: a position statement of the European Calcified Tissue Society. Eur J Endocrinol 180(4):P23–P54. https://doi.org/10.1530/EJE-18-0736CrossRefPubMed

42.

Sassi F, Tamone C, D’Amelio P (2018) Vitamin D: nutrient, hormone, and immunomodulator. Nutrients 10(11):1656. https://doi.org/10.3390/nu10111656CrossRefPubMedPubMedCentral

43.

Hahn J, Cook NR, Alexander EK, Friedman S, Walter J, Bubes V, Kotler G, Lee IM, Manson JE, Costenbader KH (2022) Vitamin D and marine omega 3 fatty acid supplementation and incident autoimmune disease: VITAL randomized controlled trial. BMJ 376:e066452. https://doi.org/10.1136/bmj-2021-066452CrossRefPubMedPubMedCentral

44.

Charoenngam N, Shirvani A, Holick MF (2021) Vitamin D and its potential benefit for the COVID-19 pandemic. Endocr Pract 27(5):484–493. https://doi.org/10.1016/j.eprac.2021.03.006CrossRefPubMedPubMedCentral

45.

Seal KH, Bertenthal D, Carey E, Grunfeld C, Bikle DD, Lu CM (2022) Association of vitamin D status and COVID-19-related hospitalization and mortality. J Gen Intern Med 37(4):853–861. https://doi.org/10.1007/s11606-021-07170-0CrossRefPubMedPubMedCentral

46.

Jolliffe DA, Holt H, Greenig M, Talaei M, Perdek N, Pfeffer P, Maltby S, Symons J, Barlow NL, Normandale A, Garcha R, Richter AG, Faustini SE, Orton C, Ford D, Lyons RA, Davies GA, Kee F, Griffiths CJ, Norrie J, Sheikh A, Shaheen SO, Relton C, Martineau AR (2022) Vitamin D supplements for prevention of COVID-19 or other acute respiratory infections: a phase 3 randomized controlled trial (CORONAVIT). BMJ 378:e071230. https://doi.org/10.1136/bmj-2022-071230CrossRefPubMed

47.

Dunlop E, Kiely M, James AP, Singh T, Black LJ (2020) Efficacy of vitamin D food fortification and biofortification in children and adults: a systematic review protocol. JBI Evid Synth 18(12):2694–2703. https://doi.org/10.11124/JBISRIR-D-19-00373CrossRefPubMed

48.

Jan Y, Malik M, Yaseen M, Ahmad S, Imran M, Rasool S, Haq A (2019) Vitamin D fortification of foods in India: present and past scenario. J Steroid Biochem Mol Biol 193:105417. https://doi.org/10.1016/j.jsbmb.2019.105417CrossRefPubMed

49.

Blunt JW, Tanaka Y, DeLuca HF (1968) Biological activity of 25-hydroxycholecalciferol, a metabolite of vitamin D3. Proc Natl Acad Sci USA 61(4):1503–1506. https://doi.org/10.1073/pnas.61.4.1503CrossRefPubMedPubMedCentral

50.

Cesareo R, Falchetti A, Attanasio R, Tabacco G, Naciu AM, Palermo A (2019) Hypovitaminosis D: is it time to consider the use of calcifediol? Nutrients 11(5):1016. https://doi.org/10.3390/nu11051016CrossRefPubMedPubMedCentral

51.

Quesada-Gomez JM, Bouillon R (2018) Is calcifediol better than cholecalciferol for vitamin D supplementation? Osteoporos Int 29(8):1697–1711. https://doi.org/10.1007/s00198-018-4520-yCrossRefPubMed

52.

Thompson GR, Lewis B, Booth CC (1966) Absorption of vitamin D3–3H in control subjects and patients with intestinal malabsorption. J Clin Invest 45(1):94–102. https://doi.org/10.1172/JCI105327CrossRefPubMedPubMedCentral

53.

Davies M, Mawer EB, Krawitt EL (1980) Comparative absorption of vitamin D3 and 25-hydroxyvitamin D3 in intestinal disease. Gut 21(4):287–292. https://doi.org/10.1136/gut.21.4.287CrossRefPubMedPubMedCentral

54.

Sitrin MD, Bengoa JM (1987) Intestinal absorption of cholecalciferol and 25-hydroxycholecalciferol in chronic cholestatic liver disease. Am J Clin Nutr 46(6):1011–1015. https://doi.org/10.1093/ajcn/46.6.1011CrossRefPubMed

55.

Charoenngam N, Kalajian TA, Shirvani A, Yoon GH, Desai S, McCarthy A, Apovian CM, Holick MF (2021) A pilot-randomized, double-blind crossover trial to evaluate the pharmacokinetics of orally administered 25-hydroxyvitamin D3 and vitamin D3 in healthy adults with differing BMI and in adults with intestinal malabsorption. Am J Clin Nutr 114(3):1189–1199. https://doi.org/10.1093/ajcn/nqab123CrossRefPubMedPubMedCentral

56.

Cianferotti L, Cricelli C, Kanis JA, Nuti R, Reginster JY, Ringe JD, Rizzoli R, Brandi ML (2015) The clinical use of vitamin D metabolites and their potential developments: a position statement from the European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis (ESCEO) and the International Osteoporosis Foundation (IOF). Endocrine 50(1):12–26. https://doi.org/10.1007/s12020-015-0606-xCrossRefPubMed

57.

Cesareo R, Attanasio R, Caputo M, Castello R, Chiodini I, Falchetti A, Guglielmi R, Papini E, Santonati A, Scillitani A, Toscano V, Triggiani V, Vescini F, Zini M, AME and Italian AACE Chapter (2018) Italian Association of Clinical Endocrinologists (AME) and Italian Chapter of the American Association of Clinical Endocrinologists (AACE) position statement: clinical management of vitamin D deficiency in adults. Nutrients 10(5):546. https://doi.org/10.3390/nu10050546CrossRefPubMedPubMedCentral

58.

Casado E, Quesada JM, Naves M, Peris P, Jódar E, Giner M, Neyro JL, Del Pino J, Sosa M, De Paz HD, Blanch-Rubió J (2021) SEIOMM recommendations on the prevention and treatment of vitamin D deficiency. Rev Osteoporos Metab Miner 13:84–97. https://doi.org/10.4321/S1889-836X2021000200007CrossRef

59.

Robien K, Oppeneer SJ, Kelly JA, Hamilton-Reeves JM (2013) Drug-vitamin D interactions: a systematic review of the literature. Nutr Clin Pract 28(2):194–208. https://doi.org/10.1177/0884533612467824CrossRefPubMedPubMedCentral

60.

Bischoff-Ferrari HA, Dawson-Hughes B, Stöcklin E, Sidelnikov E, Willett WC, Edel JO, Stähelin HB, Wolfram S, Jetter A, Schwager J, Henschkowski J, von Eckardstein A, Egli A (2012) Oral supplementation with 25(OH)D3 versus vitamin D3: effects on 25(OH)D levels, lower extremity function, blood pressure, and markers of innate immunity. J Bone Miner Res 27(1):160–169. https://doi.org/10.1002/jbmr.551CrossRefPubMed

61.

Cashman KD, Seamans KM, Lucey AJ, Stöcklin E, Weber P, Kiely M, Hill TR (2012) Relative effectiveness of oral 25-hydroxyvitamin D3 and vitamin D3 in raising wintertime serum 25-hydroxyvitamin D in older adults. Am J Clin Nutr 95(6):1350–1356. https://doi.org/10.3945/ajcn.111.031427CrossRefPubMed

62.

Jetter A, Egli A, Dawson-Hughes B, Staehelin HB, Stoecklin E, Goessl R, Henschkowski J, Bischoff-Ferrari HA (2014) Pharmacokinetics of oral vitamin D(3) and calcifediol. Bone 59:14–19. https://doi.org/10.1016/j.bone.2013.10.014CrossRefPubMed

63.

Catalano A, Morabito N, Basile G, Cucinotta D, Lasco A (2015) Calcifediol improves lipid profile in osteopenic atorvastatin-treated postmenopausal women. Eur J Clin Invest 45(2):144–149. https://doi.org/10.1111/eci.12390CrossRefPubMed

64.

Jakobsen J, Andersen EAW, Christensen T, Andersen R, Bügel S (2017) Vitamin D vitamers affect vitamin d status differently in young healthy males. Nutrients 10(1):12. https://doi.org/10.3390/nu10010012CrossRefPubMedPubMedCentral

65.

Vaes AMM, Tieland M, de Regt MF, Wittwer J, van Loon LJC, de Groot LCPGM (2018) Dose-response effects of supplementation with calcifediol on serum 25-hydroxyvitamin D status and its metabolites: a randomized controlled trial in older adults. Clin Nutr 37(3):808–814. https://doi.org/10.1016/j.clnu.2017.03.029CrossRefPubMed

66.

Graeff-Armas LA, Bendik I, Kunz I, Schoop R, Hull S, Beck M (2020) Supplemental 25-hydroxycholecalciferol is more effective than cholecalciferol in raising serum 25-hydroxyvitamin D concentrations in older adults. J Nutr 150(1):73–81. https://doi.org/10.1093/jn/nxz209CrossRefPubMed

67.

Pérez-Castrillón JL, Dueñas-Laita A, Brandi ML, Jódar E, Del Pino-Montes J, Quesada-Gómez JM, Cereto Castro F, Gómez-Alonso C, Gallego López L, Olmos Martínez JM, Alhambra Expósito MR, Galarraga B, González-Macías J, Bouillon R, Hernández-Herrero G, Fernández-Hernando N, Arranz-Gutiérrez P, Chinchilla SP (2021) Calcifediol is superior to cholecalciferol in improving vitamin D status in postmenopausal women: a randomized trial. J Bone Miner Res 36(10):1967–1978. https://doi.org/10.1002/jbmr.4387CrossRefPubMed

68.

Shieh A, Lee SM, Lagishetty V, Gottleib C, Jacobs JP, Adams JS (2021) Pilot trial of vitamin D₃ and calcifediol in healthy vitamin D deficient adults: does it change the fecal microbiome? J Clin Endocrinol Metab 106(12):3464–3476. https://doi.org/10.1210/clinem/dgab573CrossRefPubMedPubMedCentral

69.

Shieh A, Ma C, Chun RF, Witzel S, Rafison B, Contreras HTM, Wittwer-Schegg J, Swinkels L, Huijs T, Hewison M, Adams JS (2017) Effects of cholecalciferol vs calcifediol on total and free 25-hydroxyvitamin D and parathyroid hormone. J Clin Endocrinol Metab 102(4):1133–1140. https://doi.org/10.1210/jc.2016-3919CrossRefPubMedPubMedCentral

70.

Ruggiero C, Baroni M, Bini V, Brozzetti A, Parretti L, Zengarini E, Lapenna M, Antinolfi P, Falorni A, Mecocci P, Boccardi V (2019) Effects of weekly supplementation of cholecalciferol and calcifediol among the oldest-old people: findings from a randomized pragmatic clinical trial. Nutrients 11(11):2778. https://doi.org/10.3390/nu11112778CrossRefPubMedPubMedCentral

71.

Corrado A, Rotondo C, Cici D, Berardi S, Cantatore FP (2021) Effects of different vitamin D supplementation schemes in post-menopausal women: a monocentric open-label randomized study. Nutrients 13(2):380. https://doi.org/10.3390/nu13020380CrossRefPubMedPubMedCentral

72.

Navarro-Valverde C, Sosa-Henríquez M, Alhambra-Expósito MR, Quesada-Gómez JM (2016) Vitamin D3 and calcidiol are not equipotent. J Steroid Biochem Mol Biol 164:205–208. https://doi.org/10.1016/j.jsbmb.2016.01.014CrossRefPubMed

73.

Carmel AS, Shieh A, Bang H, Bockman RS (2012) The 25(OH)D level needed to maintain a favorable bisphosphonate response is ≥33 ng/ml. Osteoporos Int 23(10):2479–2487. https://doi.org/10.1007/s00198-011-1868-7CrossRefPubMedPubMedCentral

74.

da Rocha VM, Faria MBB, Júnior FADR, Lima COGX, Fiorelli RKA, Cassiano KM (2020) Use of bisphosphonates, calcium and vitamin D for bone demineralization in patients with human immunodeficiency virus/acquired immune deficiency syndrome: a systematic review and meta-analysis of clinical trials. J Bone Metab 27(3):175–186. https://doi.org/10.1100/jbm.2020.27.3.175CrossRefPubMedPubMedCentral

75.

Need AG, Morris HA, Horowitz M, Nordin C (1993) Effects of skin thickness, age, body fat, and sunlight on serum 25-hydroxyvitamin D. Am J Clin Nutr 58(6):882–885. https://doi.org/10.1093/ajcn/58.6.882CrossRefPubMed

76.

Carrelli A, Bucovsky M, Horst R, Cremers S, Zhang C, Bessler M, Schrope B, Evanko J, Blanco J, Silverberg SJ, Stein EM (2017) Vitamin D storage in adipose tissue of obese and normal weight women. J Bone Miner Res 32(2):237–242. https://doi.org/10.1002/jbmr.2979CrossRefPubMed

77.

Jones G (2008) Pharmacokinetics of vitamin D toxicity. Am J Clin Nutr 88:582S-586S. https://doi.org/10.1093/ajcn/88.2.582SCrossRefPubMed

78.

Migliaccio S, Di Nisio A, Mele C, Scappaticcio L, Savastano S, Colao A, Obesity Programs of nutrition, Education, Research and Assessment (OPERA) Group (2019) Obesity and hypovitaminosis D: causality or casualty? Int J Obes Suppl 9(1):20–31. https://doi.org/10.1038/s41367-019-0010-8CrossRefPubMedPubMedCentral

79.

Elkhwanky MS, Kummu O, Piltonen TT, Laru J, Morin-Papunen L, Mutikainen M, Tavi P, Hakkola J (2020) Obesity represses CYP2R1, the vitamin D 25-hydroxylase, in the liver and extrahepatic tissues. JBMR Plus 4(11):e10397. https://doi.org/10.1002/jbm4.10397CrossRefPubMedPubMedCentral

80.

Roizen JD, Long C, Casella A, O’Lear L, Caplan I, Lai M, Sasson I, Singh R, Makowski AJ, Simmons R, Levine MA (2019) Obesity decreases hepatic 25-hydroxylase activity causing low serum 25-hydroxyvitamin D. Bone Miner Res 34(6):1068–1073. https://doi.org/10.1002/jbmr.3686CrossRef

81.

Aatsinki SM, Elkhwanky MS, Kummu O, Karpale M, Buler M, Viitala P, Rinne V, Mutikainen M, Tavi P, Franko A, Wiesner RJ, Chambers KT, Finck BN, Hakkola J (2019) Fasting-induced transcription factors repress vitamin D bioactivation, a mechanism for vitamin D deficiency in diabetes. Diabetes 68(5):918–931. https://doi.org/10.2337/db18-1050CrossRefPubMedPubMedCentral

82.

EU Union Register of Medicinal Products. Calcifediol. Summary of Product Characteristics. https://mri.cts-mrp.eu/Human/Downloads/ES_H_0412_001_FinalSPC.pdf

83.

García Doladé N, Cereza García G, Madurga Sanz M, Montero Corominas D (2013) Riesgo de hipercalcemia e hipervitaminosis D por calcifediol. Revisión de casos notificados al Sistema Español de Farmacovigilancia [Risk of hypercalcemia and hipervitaminosis D induced by calcifediol. Review of cases reported to the Spanish Pharmacovigilance System]. Med Clin (Barc) 141(2):88–89. https://doi.org/10.1016/j.medcli.2013.02.021. (Spanish)CrossRefPubMed

84.

Olmos JM, Arnaiz F, Hernández JL, Olmos-Martínez JM, González-Macías J (2018) Calcifediol mensual frente a calcifediol quincenal en el tratamiento de pacientes osteoporóticos. Estudio en la vida real [Monthly versus biweekley calcifediol in the treatment of osteoporotic patients. Study in real life]. Rev Osteoporos Metab Miner 10:89–95. https://doi.org/10.4321/s1889-836x2018000200005CrossRef

85.

Andújar-Espinosa R, Salinero-González L, Illán-Gómez F, Castilla-Martínez M, Hu-Yang C, Ruiz-López FJ (2021) Effect of vitamin D supplementation on asthma control in patients with vitamin D deficiency: the ACVID randomised clinical trial. Thorax 76(2):126–133. https://doi.org/10.1136/thoraxjnl-2019-213936CrossRefPubMed

86.

Varsavsky M, Rozas Moreno P, Becerra Fernández A, Luque Fernández I, Quesada Gómez JM, Ávila Rubio V, García Martín A, Cortés Berdonces M, Naf Cortés S, Romero Muñoz M, Reyes García R, Jódar Gimeno E, Muñoz Torres M, en representación del Grupo de Trabajo de Osteoporosis y Metabolismo Mineral de la Sociedad Española de Endocrinología y Nutrición (2017) Recommended vitamin D levels in the general population. Endocrinol Diabetes Nutr 64(Suppl 1):7–14. https://doi.org/10.1016/j.endinu.2016.11.002. (English, Spanish)CrossRefPubMed

87.

AIFA (Italian Medicines Agency). Gazzetta Ufficiale Della Repubblica Italiana, Serie generale–n 252. https://www.aifa.gov.it/documents/20142/1030827/Determina_n.1533_2019_Nota96.pdf

88.

Balvers MG, Brouwer-Brolsma EM, Endenburg S, de Groot LC, Kok FJ, Gunnewiek JK (2015) Recommended intakes of vitamin D to optimise health, associated circulating 25-hydroxyvitamin D concentrations, and dosing regimens to treat deficiency: workshop report and overview of current literature. J Nutr Sci 4:e23. https://doi.org/10.1017/jns.2015.10CrossRefPubMedPubMedCentral

89.

Vaes AMM, Tieland M, Toussaint N, Nilwik R, Verdijk LB, van Loon LJC, de Groot LCPGM (2018) Cholecalciferol or 25-hydroxycholecalciferol supplementation does not affect muscle strength and physical performance in prefrail and frail older adults. J Nutr 148(5):712–720. https://doi.org/10.1093/jn/nxy024CrossRefPubMed

90.

Gonnelli S, Tomai Pitinca MD, Camarri S, Lucani B, Franci B, Nuti R, Caffarelli C (2021) Pharmacokinetic profile and effect on bone markers and muscle strength of two daily dosage regimens of calcifediol in osteopenic/osteoporotic postmenopausal women. Aging Clin Exp Res 33(9):2539–2547. https://doi.org/10.1007/s40520-020-01779-7CrossRefPubMedPubMedCentral

91.

Iolascon G, Moretti A, de Sire A, Calafiore D, Gimigliano F (2017) Effectiveness of calcifediol in improving muscle function in post-menopausal women: a prospective cohort study. Adv Ther 34(3):744–752. https://doi.org/10.1007/s12325-017-0492-0CrossRefPubMed

92.

Andújar-Espinosa R, Aparicio-Vicente M, Ruiz-López FJ, Salinero-González L (2021) Influence of vitamin D supplementation on the quality of life of asthma patients: findings from ACVID randomised clinical trial. Respir Med 185:106484. https://doi.org/10.1016/j.rmed.2021.106484CrossRefPubMed

93.

Entrenas Castillo M, Entrenas Costa LM, Vaquero Barrios JM, Alcalá Díaz JF, López Miranda J, Bouillon R, Quesada Gomez JM (2020) Effect of calcifediol treatment and best available therapy versus best available therapy on intensive care unit admission and mortality among patients hospitalized for COVID-19: a pilot randomized clinical study. J Steroid Biochem Mol Biol 203:105751. https://doi.org/10.1016/j.jsbmb.2020.105751CrossRefPubMedPubMedCentral

94.

Maghbooli Z, Sahraian MA, Jamalimoghadamsiahkali S, Asadi A, Zarei A, Zendehdel A, Varzandi T, Mohammadnabi S, Alijani N, Karimi M, Shirvani A, Holick MF (2021) Treatment with 25-hydroxyvitamin D3 (calcifediol) is associated with a reduction in the blood neutrophil-to-lymphocyte ratio marker of disease severity in hospitalized patients with COVID-19: a pilot multicenter, randomized, placebo-controlled, double-blinded clinical trial. Endocr Pract 27(12):1242–1251. https://doi.org/10.1016/j.eprac.2021.09.016CrossRefPubMedPubMedCentral

95.

Alcala-Diaz JF, Limia-Perez L, Gomez-Huelgas R, Martin-Escalante MD, Cortes-Rodriguez B, Zambrana-Garcia JL, Entrenas-Castillo M, Perez-Caballero AI, López-Carmona MD, Garcia-Alegria J, Lozano Rodríguez-Mancheño A, Arenas-de Larriva MDS, Pérez-Belmonte LM, Jungreis I, Bouillon R, Quesada-Gomez JM, Lopez-Miranda J (2021) Calcifediol treatment and hospital mortality due to COVID-19: a cohort study. Nutrients 13(6):1760. https://doi.org/10.3390/nu13061760CrossRefPubMedPubMedCentral

96.

Nogues X, Ovejero D, Pineda-Moncusí M, Bouillon R, Arenas D, Pascual J, Ribes A, Guerri-Fernandez R, Villar-Garcia J, Rial A, Gimenez-Argente C, Cos ML, Rodriguez-Morera J, Campodarve I, Quesada-Gomez JM, Garcia-Giralt N (2021) Calcifediol treatment and COVID-19-related outcomes. J Clin Endocrinol Metab 106(10):e4017–e4027. https://doi.org/10.1210/clinem/dgab405CrossRefPubMed

97.

Loucera C, Peña-Chilet M, Esteban-Medina M, Muñoyerro-Muñiz D, Villegas R, Lopez-Miranda J, Rodriguez-Baño J, Túnez I, Bouillon R, Dopazo J, Quesada Gomez JM (2021) Real world evidence of calcifediol or vitamin D prescription and mortality rate of COVID-19 in a retrospective cohort of hospitalized Andalusian patients. Sci Rep 11(1):23380. https://doi.org/10.1038/s41598-021-02701-5CrossRefPubMedPubMedCentral

98.

Oristrell J, Oliva JC, Casado E, Subirana I, Domínguez D, Toloba A, Balado A, Grau M (2022) Vitamin D supplementation and COVID-19 risk: a population-based, cohort study. J Endocrinol Invest 45(1):167–179. https://doi.org/10.1007/s40618-021-01639-9CrossRefPubMed

99.

Sprague SM, Silva AL, Al-Saghir F, Damle R, Tabash SP, Petkovich M, Messner EJ, White JA, Melnick JZ, Bishop CW (2014) Modified-release calcifediol effectively controls secondary hyperparathyroidism associated with vitamin D insufficiency in chronic kidney disease. Am J Nephrol 40(6):535–545. https://doi.org/10.1159/000369939CrossRefPubMed

100.

Sprague SM, Crawford PW, Melnick JZ, Strugnell SA, Ali S, Mangoo-Karim R, Lee S, Petkovich PM, Bishop CW (2016) Use of extended-release calcifediol to treat secondary hyperparathyroidism in stages 3 and 4 chronic kidney disease. Am J Nephrol 44(4):316–325. https://doi.org/10.1159/000450766CrossRefPubMed

101.

Barbagallo M, Veronese N, Di Prazza A, Pollicino F, Carruba L, La Carrubba A, Dominguez LJ (2022) Effect of calcifediol on physical performance and muscle strength parameters: a systematic review and meta-analysis. Nutrients 14(9):1860. https://doi.org/10.3390/nu14091860CrossRefPubMedPubMedCentral

102.

Quesada-Gomez JM, Lopez-Miranda J, Entrenas-Castillo M, Casado-Díaz A, Nogues Y, Solans X, Mansur JL, Bouillon R (2022) Vitamin D endocrine system and COVID-19: treatment with calcifediol. Nutrients 14(13):2716. https://doi.org/10.3390/nu14132716CrossRefPubMedPubMedCentral

103.

Cozzolino M, Ketteler M (2019) Evaluating extended-release calcifediol as a treatment option for chronic kidney disease-mineral and bone disorder (CKD-MBD). Expert Opin Pharmacother 20(17):2081–2093. https://doi.org/10.1080/14656566.2019.1663826CrossRefPubMed

Title: Calcifediol: a review of its pharmacological characteristics and clinical use in correcting vitamin D deficiency
Authors: Esteban Jodar
Claudia Campusano
Renate T. de Jongh
Michael F. Holick
Publication date: 02-03-2023
Publisher: Springer Berlin Heidelberg
Keyword: Vitamin D Deficiency
Published in: European Journal of Nutrition / Issue 4/2023
Print ISSN: 1436-6207
Electronic ISSN: 1436-6215
DOI: https://doi.org/10.1007/s00394-023-03103-1

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