, Volume 50, Issue 1, pp 12–26 | Cite as

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)

  • Luisella Cianferotti
  • Claudio Cricelli
  • John A. Kanis
  • Ranuccio Nuti
  • Jean-Y. Reginster
  • Johann D. Ringe
  • Rene Rizzoli
  • Maria Luisa BrandiEmail author
Position statement/Guideline


Several compounds are produced along the complex pathways of vitamin D3 metabolism, and synthetic analogs have been generated to improve kinetics and/or vitamin D receptor activation. These metabolites display different chemical properties with respect to the parental or native vitamin D3, i.e., cholecalciferol, which has been, so far, the supplement most employed in the treatment of vitamin D inadequacy. Hydrophilic properties of vitamin D3 derivatives facilitate their intestinal absorption and their manageability in the case of intoxication because of the shorter half-life. Calcidiol is a more hydrophilic compound than parental vitamin D3. Active vitamin D analogs, capable of binding the vitamin D receptor evoking vitamin D-related biological effects, are mandatorily employed in hypoparathyroidism and kidney failure with impaired 1α-hydroxylation. They have been shown to increase BMD, supposedly ameliorating calcium absorption and/or directly affecting bone cells, although their use in these conditions is jeopardized by the development of hypercalciuria and mild hypercalcemia. Further studies are needed to assess their overall safety and effectiveness in the long-term and new intermittent regimens, especially when combined with the most effective antifracture agents.


Calcidiol Calcifediol Cholecalciferol Calcitriol Alfacalcidol Eldecalcitol 



This paper was derived from a Working Group meeting supported by the European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis (ESCEO).


  1. 1.
    G. Jones, D.E. Prosser, M. Kaufmann, Cytochrome P450-mediated metabolism of vitamin D. J. Lipid Res. 55, 13 (2014)PubMedCentralPubMedGoogle Scholar
  2. 2.
    M. Imawari, Y. Akanuma, H. Itakura, Y. Muto, K. Kosaka, D.S. Goodman, The effects of diseases of the liver on serum 25-hydroxyvitamin D and on the serum binding protein for vitamin D and its metabolites. J. Lab. Clin. Med. 93, 171 (1979)PubMedGoogle Scholar
  3. 3.
    J.E. Zerwekh, Blood biomarkers of vitamin D status. Am. J. Clin. Nutr. 87, 1087S–1091S (2008)PubMedGoogle Scholar
  4. 4.
    L. Cianferotti, C. Marcocci, Subclinical vitamin D deficiency. Best Pract. Res. Clin. Endocrinol. Metab. 26, 523 (2012)PubMedGoogle Scholar
  5. 5.
    N. Binkley, D. Wiebe, Clinical controversies in vitamin D: 25(OH)D measurement, target concentration, and supplementation. J. Clin. Densitom. 16, 402 (2013)PubMedGoogle Scholar
  6. 6.
    M. Abboud, D.A. Puglisi, B.N. Davies, M. Rybchyn, N.P. Whitehead, K.E. Brock, L. Cole, C. Gordon-Thomson, D.R. Fraser, R.S. Mason, Evidence for a specific uptake and retention mechanism for 25-hydroxyvitamin D (25OHD) in skeletal muscle cells. Endocrinology 154, 3022 (2013)PubMedGoogle Scholar
  7. 7.
    F. Molnár, R. Sigüeiro, Y. Sato, C. Araujo, I. Schuster, P. Antony, J. Peluso, C. Muller, A. Mouriño, D. Moras, N. Rochel, 1α,25(OH)2-3-epi-vitamin D3, a natural physiological metabolite of vitamin D3: its synthesis, biological activity and crystal structure with its receptor. Plos One 6, e18124 (2011)PubMedCentralPubMedGoogle Scholar
  8. 8.
    M.F. Holick, Vitamin D deficiency. N. Engl. J. Med. 357, 266 (2007)PubMedGoogle Scholar
  9. 9.
    C.M. Girgis, R.J. Clifton-Bligh, M.W. Hamrick, M.F. Holick, J.E. Gunton, The roles of vitamin D in skeletal muscle: form, function, and metabolism. Endocr. Rev. 34, 33 (2013)PubMedGoogle Scholar
  10. 10.
    P. Gerdhem, K.A. Ringsberg, K.J. Obrant, K. Akesson, Association between 25-hydroxy vitamin D levels, physical activity, muscle strength and fractures in the prospective population-based OPRA Study of Elderly Women. Osteoporos. Int. 16, 1425 (2005)PubMedGoogle Scholar
  11. 11.
    J.K. Lai, R.M. Lucas, M.S. Clements, A.W. Roddam, E. Banks, Hip fracture risk in relation to vitamin D supplementation and serum 25-hydroxyvitamin D levels: a systematic review and meta-analysis of randomised controlled trials and observational studies. BMC Public Health. 10, 331 (2010)PubMedCentralPubMedGoogle Scholar
  12. 12.
    P. Pludowski, M.F. Holick, S. Pilz, C.L. Wagner, B.W. Hollis, W.B. Grant, Y. Shoenfeld, E. Lerchbaum, D.J. Llewellyn, K. Kienreich, M. Soni, Vitamin D effects on musculoskeletal health, immunity, autoimmunity, cardiovascular disease, cancer, fertility, pregnancy, dementia and mortality-a review of recent evidence. Autoimmun. Rev. 12, 976 (2013)PubMedGoogle Scholar
  13. 13.
    H.A. Bischoff-Ferrari, E. Giovannucci, W.C. Willett, T. Dietrich, B. Dawson-Hughes, Estimation of optimal serum concentrations of 25-hydroxyvitamin D for multiple health outcomes. Am. J. Clin. Nutr. 84, 18 (2006)PubMedGoogle Scholar
  14. 14.
    M. Wacker, M.F. Holick, Vitamin D—effects on skeletal and extraskeletal health and the need for supplementation. Nutrients. 5, 111 (2013)PubMedCentralPubMedGoogle Scholar
  15. 15.
    B.W. Hollis, C.L. Wagner, Clinical review: the role of the parent compound vitamin D with respect to metabolism and function: Why clinical dose intervals can affect clinical outcomes. J. Clin. Endocrinol. Metab. 98, 4619 (2013)PubMedCentralPubMedGoogle Scholar
  16. 16.
    R.F. Chun, B.E. Peercy, E.S. Orwoll, C.M. Nielson, J.S. Adams, M. Hewison, Vitamin D and DBP: the free hormone hypothesis revisited. J Steroid Biochem Mol Biol. 144, 132 (2014)PubMedGoogle Scholar
  17. 17.
    J.C. Gallagher, A. Sai, T. Templin 2nd, L. Smith, Dose response to vitamin D supplementation in postmenopausal women: a randomized trial. Ann. Intern. Med. 156, 425 (2012)PubMedGoogle Scholar
  18. 18.
    B. Dawson-Hughes, A. Mithal, J.P. Bonjour, S. Boonen, P. Burckhardt, G.E. Fuleihan, R.G. Josse, P. Lips, J. Morales-Torres, N. Yoshimura, IOF position statement: vitamin D recommendations for older adults. Osteoporos. Int. 21, 1151 (2010)PubMedGoogle Scholar
  19. 19.
    M.F. Holick, N.C. Binkley, H.A. Bischoff-Ferrari, C.M. Gordon, D.A. Hanley, R.P. Heaney, M.H. Murad, C.M. Weaver, Guidelines for preventing and treating vitamin D deficiency and insufficiency revisited. J. Clin. Endocrinol. Metab. 97, 1153 (2012)PubMedGoogle Scholar
  20. 20.
    R. Rizzoli, S. Boonen, M.L. Brandi, O. Bruyère, C. Cooper, J.A. Kanis, J.M. Kaufman, J.D. Ringe, G. Weryha, J.Y. Reginster, Vitamin D supplementation in elderly or postmenopausal women: a 2013 update of the 2008 recommendations from the European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis (ESCEO). Curr. Med. Res. Opin. 29, 305 (2013)PubMedGoogle Scholar
  21. 21.
    H.A. Bischoff-Ferrari, W.C. Willett, E.J. Orav, P. Lips, P.J. Meunier, R.A. Lyons, L. Flicker, J. Wark, R.D. Jackson, J.A. Cauley, H.E. Meyer, M. Pfeifer, K.M. Sanders, H.B. Stähelin, R. Theiler, B. Dawson-Hughes, A pooled analysis of vitamin D dose requirements for fracture prevention. N. Engl. J. Med. 367, 40 (2012)PubMedGoogle Scholar
  22. 22.
    K.M. Sanders, A.L. Stuart, E.J. Williamson, J.A. Simpson, M.A. Kotowicz, D. Young, G.C. Nicholson, Annual high-dose oral vitamin D and falls and fractures in older women: a randomized controlled trial. JAMA 303, 1815 (2010)PubMedGoogle Scholar
  23. 23.
    M. Rossini, S. Adami, O. Viapiana, E. Fracassi, L. Idolazzi, M.R. Povino, D. Gatti, Dose-dependent short-term effects of single high doses of oral vitamin D(3) on bone turnover markers. Calcif. Tissue Int. 91, 365 (2012)PubMedGoogle Scholar
  24. 24.
    M.R. Haussler, P.W. Jurutka, M. Mizwicki, A.W. Norman, Vitamin D receptor (VDR)-mediated actions of 1α,25(OH)2vitamin D3: genomic and non-genomic mechanisms. Best Pract. Res. Clin. Endocrinol. Metab. 25, 543 (2011)PubMedGoogle Scholar
  25. 25.
    H.F. Deluca, History of the discovery of vitamin D and its active metabolites. Bonekey Rep. 3, 479 (2014)PubMedCentralPubMedGoogle Scholar
  26. 26.
    J. Lund, H.F. DeLuca, Biologically active metabolite of vitamin D3 from bone, liver, and blood serum. J. Lipid Res. 7, 739 (1966)PubMedGoogle Scholar
  27. 27.
    L.V. Avioli, S.W. Lee, J.E. McDonald, J. Lund, H.F. DeLuca, Metabolism of vitamin D3-3H in human subjects: distribution in blood, bile, feces, and urine. J. Clin. Invest. 46, 983 (1967)PubMedCentralPubMedGoogle Scholar
  28. 28.
    J.W. Blunt, H.F. DeLuca, H.K. Schnoes, 25-hydroxycholecalciferol. A biologically active metabolite of vitamin D3. Biochemistry 7, 3317 (1968)PubMedGoogle Scholar
  29. 29.
    J.W. Blunt, Y. Tanaka, H.F. DeLuca, Biological activity of 25-hydroxycholecalciferol, a metabolite of vitamin D3. Proc. Natl. Acad. Sci. USA 61, 1503 (1968)PubMedCentralPubMedGoogle Scholar
  30. 30.
    J.W. Blunt, H.F. DeLuca, The synthesis of 25-hydroxycholecalciferol. A biologically active metabolite of vitamin D3. Biochemistry 8, 671 (1969)PubMedGoogle Scholar
  31. 31.
    G. Ponchon, A.L. Kennan, H.F. DeLuca, “Activation” of vitamin D by the liver. J. Clin. Invest. 48, 2032 (1969)PubMedCentralPubMedGoogle Scholar
  32. 32.
    D.R. Fraser, E. Kodicek, Unique biosynthesis by kidney of a biological active vitamin D metabolite. Nature 228, 764 (1970)PubMedGoogle Scholar
  33. 33.
    D.E. Lawson, D.R. Fraser, E. Kodicek, H.R. Morris, D.H. Williams, Identification of 1,25-dihydroxycholecalciferol, a new kidney hormone controlling calcium metabolism. Nature 230, 228 (1971)PubMedGoogle Scholar
  34. 34.
    I.T. Boyle, L. Miravet, R.W. Gray, M.F. Holick, H.F. Deluca, The response of intestinal calcium transport to 25-hydroxy and 1,25-dihydroxy vitamin D in nephrectomized rats. Endocrinology 90, 605 (1972)PubMedGoogle Scholar
  35. 35.
    M.F. Holick, M. Garabedian, H.F. DeLuca, 1,25-dihydroxycholecalciferol: metabolite of vitamin D3 active on bone in anephric rats. Science 176, 1146 (1972)PubMedGoogle Scholar
  36. 36.
    J.G. Haddad, K.J. Chyu, Competitive protein-binding radioassay for 25-hydroxycholecalciferol. J. Clin. Endocrinol. Metab. 33, 992 (1971)PubMedGoogle Scholar
  37. 37.
    R. Belsey, H.F. Deluca, J.T. Potts Jr, Competitive binding assay for vitamin D and 25-OH vitamin D. J. Clin. Endocrinol. Metab. 33, 554 (1971)PubMedGoogle Scholar
  38. 38.
    M.F. Holick, H.K. Schnoes, H.F. DeLuca, Identification of 1,25-dihydroxycholecalciferol, a form of vitamin D3 metabolically active in the intestine. Proc. Natl. Acad. Sci. USA 68, 803 (1971)PubMedCentralPubMedGoogle Scholar
  39. 39.
    A.W. Norman, J.F. Myrtle, R.J. Midgett, H.G. Nowicki, V. Williams, G. Popják, 1,25-dihydroxycholecalciferol: identification of the proposed active form of vitamin D3 in the intestine. Science 173, 51 (1971)PubMedGoogle Scholar
  40. 40.
    Y. Tanaka, H.F. DeLuca, J. Omdahl, M.F. Holick, Mechanism of action of 1,25-dihydroxycholecalciferol on intestinal calcium transport. Proc. Natl. Acad. Sci USA 68, 1286 (1971)PubMedCentralPubMedGoogle Scholar
  41. 41.
    C.A. Frolik, H.F. Deluca, 1,25-dihydroxycholecalciferol: the metabolite of vitamin D responsible for increased intestinal calcium transport. Arch. Biochem. Biophys. 147, 143 (1971)PubMedGoogle Scholar
  42. 42.
    M. Garabedian, M.F. Holick, H.F. Deluca, I.T. Boyle, Control of 25-hydroxycholecalciferol metabolism by parathyroid glands. Proc. Natl. Acad. Sci. USA 69, 1673 (1972)PubMedCentralPubMedGoogle Scholar
  43. 43.
    E.B. Mawer, C.M. Taylor, J. Backhouse, G.A. Lumb, S.W. Stanbury, Failure of formation of 1,25-dihydroxycholecalciferol in chronic renal insufficiency. Lancet 1, 626 (1973)PubMedGoogle Scholar
  44. 44.
    B.S. Chertow, D.J. Baylink, J.E. Wergedal, M.H. Su, A.W. Norman, Decrease in serum immunoreactive parathyroid hormone in rats and in parathyroid hormone secretion in vitro by 1,25-dihydroxycholecalciferol. J. Clin. Invest. 56, 668 (1975)PubMedCentralPubMedGoogle Scholar
  45. 45.
    C.A. Frolik, H.F. DeLuca, The stimulation of 1,25-dihydroxycholecalciferol metabolism in vitamin D-deficient rats by 1,25-dihydroxycholecalciferol treatment. J. Clin. Invest. 52, 543 (1973)PubMedCentralPubMedGoogle Scholar
  46. 46.
    Y. Tanaka, H.F. Deluca, Bone mineral mobilization activity of 1,25-dihydroxycholecalciferol, a metabolite of vitamin D. Arch. Biochem. Biophys. 146, 574 (1971)PubMedGoogle Scholar
  47. 47.
    L.G. Raisz, C.L. Trummel, M.F. Holick, H.F. DeLuca, 1,25-dihydroxycholecalciferol: a potent stimulator of bone resorption in tissue culture. Science 175, 768 (1972)PubMedGoogle Scholar
  48. 48.
    M. Garabedian, Y. Tanaka, M.F. Holick, H.F. Deluca, Response of intestinal calcium transport and bone calcium mobilization to 1,25-dihydroxyvitamin D3 in thyroparathyroidectomized rats. Endocrinology 94, 1022 (1974)PubMedGoogle Scholar
  49. 49.
    R.W. Gray, A.E. Caldas, D.R. Wilz, J. Lemann Jr, G.A. Smith, H.F. DeLuca, Metabolism and excretion of 3H-1,25-(OH)2-vitamin D3 in healthy adults. J. Clin. Endocrinol. Metab. 46, 756 (1978)PubMedGoogle Scholar
  50. 50.
    T.L. Clemens, G.N. Hendy, R.F. Graham, E.G. Baggiolini, M.R. Uskokovic, J.L. O’Riordan, A radioimmunoassay for 1,25-dihydroxycholecalciferol. Clin. Sci. Mol. Med. 54, 329 (1978)PubMedGoogle Scholar
  51. 51.
    Consensus Development Conference, Diagnosis, prophylaxis and treatment of osteoporosis. Am. J. Med. 94, 646 (1993)Google Scholar
  52. 52.
    M.F. Holick, E.J. Semmler, H.K. Schnoes, H.F. DeLuca, 1 -Hydroxy derivative of vitamin D 3: a highly potent analog of 1,25-dihydroxyvitamin D 3. Science 180, 190 (1973)PubMedGoogle Scholar
  53. 53.
    K. Ueno, Y. Okamiya, T. Makita, S. Kurozumi, H. Kawashima, Y. Hashimoto, Studies on biopharmacological activity of active vitamin D3 analogues (VII) Effect of 1 alpha-hydroxycholecalciferol on renal function in rats and Beagle dogs (Japanese). Nihon. Yakurigaku Zasshi. 75, 617 (1979)PubMedGoogle Scholar
  54. 54.
    S. Morimoto, S. Imanaka, E. Koh, T. Shiraishi, T. Nabata, S. Kitano, Y. Miyashita, Y. Nishii, T. Ogihara, Comparison of the inhibitions of proliferation of normal and psoriatic fibroblasts by 1 alpha,25-dihydroxyvitamin D3 and synthetic analogues of vitamin D3 with an oxygen atom in their side chain. Biochem. Int. 19, 1143 (1989)PubMedGoogle Scholar
  55. 55.
    H. Tsurukami, T. Nakamura, K. Suzuki, K. Sato, Y. Higuchi, Y. Nishii, A novel synthetic vitamin D analogue, 2 beta-(3-hydroxypropoxy)1 alpha, 25-dihydroxyvitamin D3 (ED-71), increases bone mass by stimulating the bone formation in normal and ovariectomized rats. Calcif. Tissue Int. 54, 142 (1994)PubMedGoogle Scholar
  56. 56.
    Y. Tanaka, T. Nakamura, S. Nishida, K. Suzuki, S. Takeda, K. Sato, Y. Nishii, Effects of a synthetic vitamin D analog, ED-71, on bone dynamics and strength in cancellous and cortical bone in prednisolone-treated rats. J. Bone Miner. Res. 11, 325 (1996)PubMedGoogle Scholar
  57. 57.
    Y. Uchiyama, Y. Higuchi, S. Takeda, T. Masaki, A. Shira-Ishi, K. Sato, N. Kubodera, K. Ikeda, E. Ogata, ED-71, a vitamin D analog, is a more potent inhibitor of bone resorption than alfacalcidol in an estrogen-deficient rat model of osteoporosis. Bone 30, 582 (2002)PubMedGoogle Scholar
  58. 58.
    P.H. de Freitas, T. Hasegawa, S. Takeda, M. Sasaki, C. Tabata, K. Oda, M. Li, H. Saito, N. Amizuka, Eldecalcitol, a second-generation vitamin D analog, drives bone minimodeling and reduces osteoclastic number in trabecular bone of ovariectomized rats. Bone 49, 335 (2011)PubMedGoogle Scholar
  59. 59.
    S. Harada, T. Mizoguchi, Y. Kobayashi, Y. Nakamichi, S. Takeda, S. Sakai, F. Takahashi, H. Saito, H. Yasuda, N. Udagawa, T. Suda, N. Takahashi, Daily administration of eldecalcitol (ED-71), an active vitamin D analog, increases bone mineral density by suppressing RANKL expression in mouse trabecular bone. J. Bone Miner. Res. 27, 461 (2012)PubMedGoogle Scholar
  60. 60.
    K.H. Lau, D.J. Baylink, Vitamin D therapy of osteoporosis: plain vitamin D therapy versus active vitamin D analog (D-hormone) therapy. Calcif. Tissue Int. 65, 295 (1999)PubMedGoogle Scholar
  61. 61.
    S. O’Donnell, D. Moher, K. Thomas, D.A. Hanley, A. Cranney, Systematic review of the benefits and harms of calcitriol and alfacalcidol for fractures and falls. J. Bone Miner. Metab. 26, 531 (2008)PubMedGoogle Scholar
  62. 62.
    M.L. Brandi, S. Minisola, Calcidiol [25(OH)D3]: from diagnostic marker to therapeutical agent. Curr. Med. Res. Opin. 29, 1565 (2013)PubMedGoogle Scholar
  63. 63.
    L.J. Peppone, S. Hebl, J.Q. Purnell, M.E. Reid, R.N. Rosier, K.M. Mustian, O.G. Palesh, A.J. Huston, M.N. Ling, G.R. Morrow, The efficacy of calcitriol therapy in the management of bone loss and fractures: a qualitative review. Osteoporos. Int. 21, 1133 (2010)PubMedCentralPubMedGoogle Scholar
  64. 64.
    J.A. Eisman, R. Bouillon, Vitamin D: direct effects of vitamin D metabolites on bone: lessons from genetically modified mice. Bonekey Rep. 3, 499 (2014)PubMedCentralPubMedGoogle Scholar
  65. 65.
    L. Ovesen, C. Brot, J. Jakobsen, Food contents and biological activity of 25-hydroxyvitamin D: a vitamin D metabolite to be reckoned with? Ann. Nutr. Metab. 47, 107 (2003)PubMedGoogle Scholar
  66. 66.
    J.E. Smith, D.S. Goodman, The turnover and transport of vitamin D and of a polar metabolite with the properties of 25-hydroxycholecalciferol in human plasma. J. Clin. Invest. 50, 2159 (1971)PubMedCentralPubMedGoogle Scholar
  67. 67.
    T.C. Stamp, J.M. Round, J.G. Haddad, Effect of oral vitamin D, 25-hydroxycholecalciferol (25-HCC) and whole-body ultra-violet irradiation on plasma 25-HCC levels in man. Clin. Sci. 44, 3P (1973)PubMedGoogle Scholar
  68. 68.
    T.C. Stamp, Intestinal absorption of 25-hydroxycholecalciferol. Lancet 2, 121 (1974)PubMedGoogle Scholar
  69. 69.
    J.G. Haddad, T.C. Stamp, Circulating 25-hydroxyvitamin D in man. Am. J. Med. 57, 57 (1974)PubMedGoogle Scholar
  70. 70.
    J.G. Haddad Jr, S. Rojanasathit, Acute administration of 25-hydroxycholecalciferol in man. J. Clin. Endocrinol. Metab. 42, 284 (1976)PubMedGoogle Scholar
  71. 71.
    K.S. Jones, I. Schoenmakers, L.J. Bluck, S. Ding, A. Prentice, Plasma appearance and disappearance of an oral dose of 25-hydroxyvitamin D2 in healthy adults. Br. J. Nutr. 107, 1128 (2012)PubMedCentralPubMedGoogle Scholar
  72. 72.
    T.C. Stamp, J.G. Haddad, C.A. Twigg, Comparison of oral 25-hydroxycholecalciferol, vitamin D, and ultraviolet light as determinants of circulating 25-hydroxyvitamin D. Lancet 1, 1341 (1977)PubMedGoogle Scholar
  73. 73.
    B.W. Hollis, H.R. Conrad, J.W. Hibbs, Changes in plasma 25-hydroxycholecalciferol and selected blood parameters after injection of massive doses of cholecalciferol or 25-hydroxycholecalciferol in non-lactating dairy cows. J. Nutr. 107, 606 (1977)PubMedGoogle Scholar
  74. 74.
    M.J. Barger-Lux, R.P. Heaney, S. Dowell, T.C. Chen, M.F. Holick, Vitamin D and its major metabolites: serum levels after graded oral dosing in healthy men. Osteoporos. Int. 8, 222 (1998)PubMedGoogle Scholar
  75. 75.
    A. Jetter, A. Egli, B. Dawson-Hughes, H.B. Staehelin, E. Stoecklin, R. Goessl, J. Henschkowski, H.A. Bischoff-Ferrari, Pharmacokinetics of oral vitamin D(3) and calcifediol. Bone 59, 14 (2014)PubMedGoogle Scholar
  76. 76.
    K.D. Cashman, K.M. Seamans, A.J. Lucey, E. Stöcklin, P. Weber, M. Kiely, T.R. Hill, 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, 1350 (2012)PubMedGoogle Scholar
  77. 77.
    S.H. Chou, T.K. Chung, B. Yu, Effects of supplemental 25-hydroxycholecalciferol on growth performance, small intestinal morphology, and immune response of broiler chickens. Poult. Sci. 88, 2333 (2009)PubMedGoogle Scholar
  78. 78.
    C. Lauridsen, U. Halekoh, T. Larsen, S.K. Jensen, Reproductive performance and bone status markers of gilts and lactating sows supplemented with two different forms of vitamin D. J. Anim. Sci. 88, 202 (2010)PubMedGoogle Scholar
  79. 79.
    N. Sahin, T.A. Balci, O. Kucuk, M.O. Smith, K. Sahin, Effects of 25-hydroxycholecalciferol and soy isoflavones supplementation on bone mineralisation of quail. Br. Poult. Sci. 50, 709 (2009)PubMedGoogle Scholar
  80. 80.
    E.A. Hines, J.D. Coffey, C.W. Starkey, T.K. Chung, J.D. Starkey, Improvement of maternal vitamin D status with 25-hydroxycholecalciferol positively impacts porcine fetal skeletal muscle development and myoblast activity. J. Anim. Sci. 91, 4116 (2013)PubMedGoogle Scholar
  81. 81.
    T.J. Hahn, L.R. Halstead, S.L. Teitelbaum, B.H. Hahn, Altered mineral metabolism in glucocorticoid-induced osteopenia. Effect of 25-hydroxyvitamin D administration. J. Clin. Invest. 64, 655 (1979)PubMedCentralPubMedGoogle Scholar
  82. 82.
    R.M. Francis, M. Peacock, J.H. Storer, A.E. Davies, W.B. Brown, B.E. Nordin, Calcium malabsorption in the elderly: the effect of treatment with oral 25-hydroxyvitamin D3. Eur. J. Clin. Invest. 13, 391 (1983)PubMedGoogle Scholar
  83. 83.
    S. Russo, L. Carlucci, C. Cipriani, A. Ragno, S. Piemonte, R.D. Fiacco, J. Pepe, V. Fassino, S. Arima, E. Romagnoli, S. Minisola, Metabolic changes following 500 μg monthly administration of calcidiol: a study in normal females. Calcif. Tissue Int. 89, 252 (2011)PubMedGoogle Scholar
  84. 84.
    M. Peacock, G. Liu, M. Carey, R. McClintock, W. Ambrosius, S. Hui, C.C. Johnston, Effect of calcium or 25OH vitamin D3 dietary supplementation on bone loss at the hip in men and women over the age of 60. J. Clin. Endocrinol. Metab. 85, 3011 (2000)PubMedGoogle Scholar
  85. 85.
    M. Sosa, P. Láinez, A. Arbelo, M.C. Navarro, The effect of 25-dihydroxyvitamin D on the bone mineral metabolism of elderly women with hip fracture. Rheumatology (Oxford) 39, 1263 (2000)Google Scholar
  86. 86.
    H.A. Bischoff-Ferrari, B. Dawson-Hughes, E. Stöcklin, E. Sidelnikov, W.C. Willett, J.O. Edel, H.B. Stähelin, S. Wolfram, A. Jetter, J. Schwager, J. Henschkowski, A. von Eckardstein, A. Egli, 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, 160 (2012)PubMedGoogle Scholar
  87. 87.
    M.L. Bianchi, C. Colombo, B.M. Assael, A. Dubini, M. Lombardo, S. Quattrucci, S. Bella, M. Collura, B. Messore, V. Raia, F. Poli, R. Bini, C.V. Albanese, V. De Rose, D. Costantini, G. Romano, E. Pustorino, G. Magazzù, S. Bertasi, V. Lucidi, G. Traverso, A. Coruzzo, A.D. Grzejdziak, Treatment of low bone density in young people with cystic fibrosis: a multicentre, prospective, open-label observational study of calcium and calcifediol followed by a randomised placebo-controlled trial of alendronate. Lancet Respir. Med. 1, 377 (2013)PubMedGoogle Scholar
  88. 88.
    A. Drincic, E. Fuller, R.P. Heaney, L.A. Armas, 25-Hydroxyvitamin D response to graded vitamin D3 supplementation among obese adults. J. Clin. Endocrinol. Metab. 98, 4845 (2013)PubMedGoogle Scholar
  89. 89.
    S. Petta, C. Cammà, C. Scazzone, C. Tripodo, V. Di Marco, A. Bono, D. Cabibi, G. Licata, R. Porcasi, G. Marchesini, A. Craxí, Low vitamin D serum level is related to severe fibrosis and low responsiveness to interferon-based therapy in genotype 1 chronic hepatitis C. Hepatology 51, 1158 (2010)PubMedGoogle Scholar
  90. 90.
    L.V. Avioli, S.J. Birge, S.W. Lee, Effects of prednisone on vitamin D metabolism in man. J. Clin. Endocrinol. Metab. 28, 1341 (1968)PubMedGoogle Scholar
  91. 91.
    M. Carré, O. Ayigbedé, L. Miravet, H. Rasmussen, The effect of Prednisolone upon the metabolism and action of 25-hydroxy-and 1,25-dihydroxyvitamin D3. Proc. Natl. Acad. Sci. USA 71, 2996 (1974)PubMedCentralPubMedGoogle Scholar
  92. 92.
    S.A. Hamed, Influences of bone and mineral metabolism in epilepsy. Expert Opin. Drug Saf. 10, 265 (2011)PubMedGoogle Scholar
  93. 93.
    Al Mutair, A.N., Nasrat, G.H., Russell, D.W.: mutation of the CYP2R1 vitamin D 25-hydroxylase in a Saudi Arabian family with severe vitamin D deficiency. J. Clin. Endocrinol. Metab. 97, E2022 (2012)PubMedCentralPubMedGoogle Scholar
  94. 94.
    I. Garcia-Delgado, S. Prieto, L. Gil-Fraguas, E. Robles, J.J. Rufilanchas, F. Hawkins, Calcitonin, etidronate, and calcidiol treatment in bone loss after cardiac transplantation. Calcif. Tissue Int. 60, 155 (1997)PubMedGoogle Scholar
  95. 95.
    M. Talalaj, L. Gradowska, E. Marcinowska-Suchowierska, M. Durlik, Z. Gaciong, M. Lao, Efficiency of preventive treatment of glucocorticoid-induced osteoporosis with 25-hydroxyvitamin D3 and calcium in kidney transplant patients. Transplant. Proc. 28, 3485 (1996)PubMedGoogle Scholar
  96. 96.
    J.E. Compston, B. Creamer, Plasma levels and intestinal absorption of 25-hydroxyvitamin D in patients with small bowel resection. Gut 18, 171 (1977)PubMedCentralPubMedGoogle Scholar
  97. 97.
    A.J. Batchelor, G. Watson, J.E. Compston, Changes in plasma half-life and clearance of 3H-25-hydroxyvitamin D3 in patients with intestinal malabsorption. Gut 23, 1068 (1982)PubMedCentralPubMedGoogle Scholar
  98. 98.
    M. Davies, E.B. Mawer, E.L. Krawitt, Comparative absorption of vitamin D3 and 25-hydroxyvitamin D3 in intestinal disease. Gut 21, 287 (1980)PubMedCentralPubMedGoogle Scholar
  99. 99.
    J. Michaud, J. Naud, D. Ouimet, C. Demers, J.L. Petit, F.A. Leblond, A. Bonnardeaux, M. Gascon-Barré, V. Pichette, Reduced hepatic synthesis of calcidiol in uremia. J. Am. Soc. Nephrol. 21, 1488 (2010)PubMedCentralPubMedGoogle Scholar
  100. 100.
    G. Jean, J.C. Terrat, T. Vanel, J.M. Hurot, C. Lorriaux, B. Mayor, C. Chazot, Daily oral 25-hydroxycholecalciferol supplementation for vitamin D deficiency in haemodialysis patients: effects on mineral metabolism and bone markers. Nephrol. Dial. Transplant. 23, 3670 (2008)PubMedGoogle Scholar
  101. 101.
    H. Schmidt-Gayk, C. Grawunder, W. Tschöpe, W. Schmitt, E. Ritz, V. Pietsch, K. Andrassay, R. Bouillon, 25-hydroxy-vitamin-D in nephrotic syndrome. Lancet 2, 105 (1977)PubMedGoogle Scholar
  102. 102.
    I.H. de Boer, M.C. Sachs, P.A. Cleary, A.N. Hoofnagle, J.M. Lachin, M.E. Molitch, M.W. Steffes, W. Sun, B. Zinman, J.D. Brunzell, Diabetes Control and Complication Trial/Epidemiology of Diabetes Interventions and Complications Study Research Group. Circulating vitamin D metabolites and kidney disease in type 1 diabetes. J. Clin. Endocrinol. Metab. 97, 4780 (2012)PubMedCentralPubMedGoogle Scholar
  103. 103.
    C. Foresta, G. Strapazzon, L. De Toni, L. Perilli, A. Di Mambro, B. Muciaccia, L. Sartori, R. Selice, Bone mineral density and testicular failure: evidence for a role of vitamin D 25-hydroxylase in human testis. J. Clin. Endocrinol. Metab. 96, E646 (2011)PubMedGoogle Scholar
  104. 104.
    A. Caniggia, R. Nuti, F. Lore, G. Martini, V. Turchetti, G. Righi, Long-term treatment with calcitriol in postmenopausal osteoporosis. Metabolism. 39, 43 (1990)PubMedGoogle Scholar
  105. 105.
    A. Caniggia, R. Nuti, F. Loré, G. Martini, B. Frediani, S. Giovani, Total body absorptiometry in postmenopausal osteoporosis patients treated with 1 alpha-hydroxylated vitamin D metabolites. Osteoporos. Int. 3, 181 (1993)PubMedGoogle Scholar
  106. 106.
    M.W. Tilyard, G.F. Spears, J. Thomson, S. Dovey, Treatment of postmenopausal osteoporosis with calcitriol or calcium. N. Engl. J. Med. 326, 357 (1992)PubMedGoogle Scholar
  107. 107.
    P. Sambrook, N.K. Henderson, A. Keogh, P. MacDonald, A. Glanville, P. Spratt, P. Bergin, P. Ebeling, J. Eisman, Effect of calcitriol on bone loss after cardiac or lung transplantation. J. Bone Miner. Res. 15, 1818 (2000)PubMedGoogle Scholar
  108. 108.
    J.C. Gallagher, S.E. Fowler, J.R. Detter, S.S. Sherman, Combination treatment with estrogen and calcitriol in the prevention of age-related bone loss. J. Clin. Endocrinol. Metab. 86, 3618 (2001)PubMedGoogle Scholar
  109. 109.
    J.C. Gallagher, P.B. Rapuri, L.M. Smith, An age-related decrease in creatinine clearance is associated with an increase in number of falls in untreated women but not in women receiving calcitriol treatment. J. Clin. Endocrinol. Metab. 92, 51 (2007)PubMedCentralPubMedGoogle Scholar
  110. 110.
    Y. Rhee, M. Kang, Y. Min, D. Byun, Y. Chung, C. Ahn, K. Baek, J. Mok, D. Kim, D. Kim, H. Kim, Y. Kim, S. Myoung, D. Kim, S.K. Lim, Effects of a combined alendronate and calcitriol agent (Maxmarvil) on bone metabolism in Korean postmenopausal women: a multicenter, double-blind, randomized, placebo-controlled study. Osteoporos. Int. 17, 1801 (2006)PubMedGoogle Scholar
  111. 111.
    H.W. Suh, H.O. Kim, Y.S. Kim, S. Sunwoo, J.A. Lee, H.R. Lee, B. Kim, D.H. Kim, Y.S. Choi, Y.S. Cheong, K. Yum, Y.J. Yang, B.Y. Yu, C.H. Cho, S.B. Park, D.H. Shin, Korea Post-Marketing Surveillance Research Group. The efficacy and safety of a combined alendronate and calcitriol agent (maxmarvil): a postmarketing surveillance study in korean postmenopausal women with osteoporosis. Korean. J Fam. Med. 33, 346 (2012)Google Scholar
  112. 112.
    D.L. Trump, D.M. Potter, J. Muindi, A. Brufsky, C.S. Johnson, Phase II trial of high-dose, intermittent calcitriol (1,25 dihydroxyvitamin D3) and dexamethasone in androgen-independent prostate cancer. Cancer 106, 2136 (2006)PubMedGoogle Scholar
  113. 113.
    H. Orimo, E. Schacht, The D-hormone analog alfacalcidol: the pioneer beyond the horizon of osteoporosis treatment. J. Rheumatol. Suppl. 76, 4 (2005)PubMedGoogle Scholar
  114. 114.
    R.M. Francis, I.T. Boyle, C. Moniz, A.M. Sutcliffe, B.S. Davis, G.H. Beastall, R.A. Cowan, N. Downes, A comparison of the effects of alfacalcidol treatment and vitamin D2 supplementation on calcium absorption in elderly women with vertebral fractures. Osteoporos. Int. 6, 284 (1996)PubMedGoogle Scholar
  115. 115.
    R. Nuti, G. Bianchi, M.L. Brandi, R. Caudarella, E. D’Erasmo, C. Fiore, G.C. Isaia, G. Luisetto, M. Muratore, P. Oriente, S. Ortolani, Superiority of alfacalcidol compared to vitamin D plus calcium in lumbar bone mineral density in postmenopausal osteoporosis. Rheumatol. Int. 26, 445 (2006)PubMedGoogle Scholar
  116. 116.
    J.Y. Reginster, D. Kuntz, W. Verdickt, M. Wouters, L. Guillevin, C.J. Menkès, K. Nielsen, Prophylactic use of alfacalcidol in corticosteroid-induced osteoporosis. Osteoporos. Int. 9, 75 (1999)PubMedGoogle Scholar
  117. 117.
    J.D. Ringe, A. Dorst, H. Faber, E. Schacht, V.W. Rahlfs, Superiority of alfacalcidol over plain vitamin D in the treatment of glucocorticoid-induced osteoporosis. Rheumatol. Int. 24, 63 (2004)PubMedGoogle Scholar
  118. 118.
    L. Dukas, H.A. Bischoff, L.S. Lindpaintner, E. Schacht, D. Birkner-Binder, T.N. Damm, B. Thalmann, H.B. Stähelin, Alfacalcidol reduces the number of fallers in a community-dwelling elderly population with a minimum calcium intake of more than 500 mg daily. J. Am. Geriatr. Soc. 52, 230 (2004)PubMedGoogle Scholar
  119. 119.
    L. Dukas, E. Schacht, Z. Mazor, H.B. Stähelin, Treatment with alfacalcidol in elderly people significantly decreases the high risk of falls associated with a low creatinine clearance of <65 ml/min. Osteoporos. Int. 16, 198 (2005)PubMedGoogle Scholar
  120. 120.
    J.D. Ringe, P. Farahmand, E. Schacht, Alfacalcidol in men with osteoporosis: a prospective, observational, 2-year trial on 214 patients. Rheumatol. Int. 33, 637 (2013)PubMedGoogle Scholar
  121. 121.
    J.C. Gallagher, The effects of calcitriol on falls and fractures and physical performance tests. J. Steroid Biochem. Mol. Biol. 89–90, 497 (2004)PubMedGoogle Scholar
  122. 122.
    J.D. Ringe, P. Farahmand, E. Schacht, A. Rozehnal, Superiority of a combined treatment of Alendronate and Alfacalcidol compared to the combination of Alendronate and plain vitamin D or Alfacalcidol alone in established postmenopausal or male osteoporosis (AAC-Trial). Rheumatol. Int. 27, 425 (2007)PubMedGoogle Scholar
  123. 123.
    T. Matsumoto, T. Miki, H. Hagino, T. Sugimoto, S. Okamoto, T. Hirota, Y. Tanigawara, Y. Hayashi, M. Fukunaga, M. Shiraki, T. Nakamura, A new active vitamin D, ED-71, increases bone mass in osteoporotic patients under vitamin D supplementation: a randomized, double-blind, placebo-controlled clinical trial. J. Clin. Endocrinol. Metab. 90, 5031 (2005)PubMedGoogle Scholar
  124. 124.
    T. Matsumoto, N. Kubodera, ED-71, a new active vitamin D3, increases bone mineral density regardless of serum 25(OH)D levels in osteoporotic subjects. J. Steroid Biochem. Mol. Biol. 103, 584 (2007)PubMedGoogle Scholar
  125. 125.
    T. Matsumoto, M. Ito, Y. Hayashi, T. Hirota, Y. Tanigawara, T. Sone, M. Fukunaga, M. Shiraki, T. Nakamura, A new active vitamin D3 analog, eldecalcitol, prevents the risk of osteoporotic fractures–a randomized, active comparator, double-blind study. Bone 49, 605 (2011)PubMedGoogle Scholar
  126. 126.
    H. Hagino, T. Takano, M. Fukunaga, M. Shiraki, T. Nakamura, T. Matsumoto, Eldecalcitol reduces the risk of severe vertebral fractures and improves the health-related quality of life in patients with osteoporosis. J. Bone Miner. Metab. 31, 183 (2013)PubMedCentralPubMedGoogle Scholar
  127. 127.
    M.P. Caraceni, G.C. Gandolini, F. Campanini, M.A. Iannetta, S. Ortolani, Vitamin D metabolites in spasmophilia. Biomed. Pharmacother. 44, 479 (1990)PubMedGoogle Scholar
  128. 128.
    A. Avenell, J.C. Mak, D. O’Connell, Vitamin D and vitamin D analogues for preventing fractures in post-menopausal women and older men. Cochrane Database Syst. Rev. 4, CD000227 (2014)PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  • Luisella Cianferotti
    • 1
  • Claudio Cricelli
    • 2
  • John A. Kanis
    • 3
  • Ranuccio Nuti
    • 4
  • Jean-Y. Reginster
    • 5
  • Johann D. Ringe
    • 6
  • Rene Rizzoli
    • 7
  • Maria Luisa Brandi
    • 1
    Email author
  1. 1.Bone Metabolic Diseases Unit, Department of Surgery and Translational MedicineUniversity of FlorenceFlorenceItaly
  2. 2.Italian College of General PractitionersFlorenceItaly
  3. 3.Centre for Metabolic Bone DiseasesUniversity of Sheffield Medical SchoolSheffieldUK
  4. 4.Department of Medicine, Surgery and NeuroscienceUniversity of SienaSienaItaly
  5. 5.Department of Public Health, Epidemiology and Health EconomicsUniversity of LiègeLiègeBelgium
  6. 6.Department of General Internal MedicineKlinikum Leverkusen University of CologneCologneGermany
  7. 7.Service of Bone DiseasesGeneva University Hospitals and Faculty of MedicineGenevaSwitzerland

Personalised recommendations