Download PDF
Horm Metab Res 2020; 52(03): 168-178
DOI: 10.1055/a-1114-6072
Endocrine Care
© Georg Thieme Verlag KG Stuttgart · New York

Effect of Intravenous 25OHD Supplementation on Bone Turnover and Inflammation in Prolonged Critically Ill Patients

Catherine Ingels 
1   Clinical Division and Laboratory of Intensive Care Medicine, KU Leuven, Leuven, Belgium
,
Ilse Vanhorebeek
1   Clinical Division and Laboratory of Intensive Care Medicine, KU Leuven, Leuven, Belgium
,
Sophie Van Cromphaut
1   Clinical Division and Laboratory of Intensive Care Medicine, KU Leuven, Leuven, Belgium
,
Pieter J. Wouters
1   Clinical Division and Laboratory of Intensive Care Medicine, KU Leuven, Leuven, Belgium
,
Inge Derese
1   Clinical Division and Laboratory of Intensive Care Medicine, KU Leuven, Leuven, Belgium
,
Alexander Dehouwer
1   Clinical Division and Laboratory of Intensive Care Medicine, KU Leuven, Leuven, Belgium
,
Holger Jon Møller
2   Department of Clinical Medicine and Clinical Biochemistry, Aarhus University, Aarhus, Denmark
,
Troels K. Hansen
3   Department of Clinical Medicine - Steno Diabetes Center Aarhus, Aarhus University, Aarhus, Denmark
,
Jaak Billen
4   Laboratory of Clinical and Experimental Endocrinology, Department of Chronic Diseases, KU Leuven, Belgium
,
Chantal Mathieu
4   Laboratory of Clinical and Experimental Endocrinology, Department of Chronic Diseases, KU Leuven, Belgium
,
Roger Bouillon
4   Laboratory of Clinical and Experimental Endocrinology, Department of Chronic Diseases, KU Leuven, Belgium
,
Greet Van den Berghe
1   Clinical Division and Laboratory of Intensive Care Medicine, KU Leuven, Leuven, Belgium
› Author AffiliationsSupported by: Methusalem Program (METH/14/06)
Supported by: Flemish Government through KU Leuven
Supported by: Greet Van den Berghe (ERC AdvG-2017–78580)
Further Information

Publication History

received 29 April 2019

accepted 28 January 2020

Publication Date:
25 March 2020 (online)

Also available at
    Permissions and Reprints

Abstract

Critically ill patients have low circulating 25-hydroxyvitamin D (25OHD), vitamin D binding protein (DBP), and 1,25-dihydroxyvitamin D [1,25(OH)2D]. Low 25OHD is associated with poor outcomes, possibly explained by its effect on bone and immunity. In this prospective, randomized double-blind, placebo-controlled study, we investigated the feasibility of normalizing 25OHD in prolonged (>10 days) critically ill patients and the effects thereof on 1,25(OH)2D, bone metabolism, and innate immunity. Twenty-four patients were included and compared with 24 matched healthy subjects. Patients were randomized to either intravenous bolus of 200 μg 25OHD followed by daily infusion of 15 μg 25OHD for 10 days, or to placebo. Parameters of vitamin D, bone and mineral metabolism, and innate immune function were measured. As safety endpoints, ICU length of stay and mortality were registered. Infusion of 25OHD resulted in a sustained increase of serum 25OHD (from median baseline 9.2 –16.1 ng/ml at day 10), which, however, remained below normal levels. There was no increase in serum 1,25(OH)2D but a slight increase in serum 24,25(OH)2D. Mineral homeostasis, innate immunity and clinical safety endpoints were unaffected. Thus, intravenous 25OHD administration during critical illness increased serum 25OHD concentrations, though less than expected from data in healthy subjects, which suggests illness-induced alterations in 25OHD metabolism and/or increased 25OHD distribution volume. The increased serum 25OHD concentrations were not followed by a rise in 1,25(OH)2D nor were bone metabolism or innate immunity affected, which suggests that low 25OHD and 1,25OHD levels are part of the adaptive response to critical illness.

Key words

vitamin D - critical illness - innate immunity - bone metabolism
 

  • References

  • 1 Amrein K, Venkatesh B. Vitamin D and the critically ill patient. Curr Opin Clin Nutr Metab Care 2012; 15: 188-193
    CrossrefPubMedGoogle Scholar
  • 2 Bouillon R. Why modest but widespread improvement of the vitamin status is the best strategy ?. Best Pract Res Clin Endocrinol Metab 2011; 25: 693-702
    CrossrefPubMedGoogle Scholar
  • 3 Bouillon R. Comparative analysis of nutritional guidelines for vitamin D. Nat Rev Endocrinol 2017; 13: 466-479
    CrossrefPubMedGoogle Scholar
  • 4 Holick MF. Vitamin D deficiency. N Engl J Med 2007; 19: 266-281
    PubMedGoogle Scholar
  • 5 Holick MF, Binkley NC, Bischoff-Ferrari HA. et al. Endocrine Society. Evaluation, treatment, and prevention of vitamin D deficiency: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 2011; 96: 1911-1930
    CrossrefPubMedGoogle Scholar
  • 6 Christopher KB. Vitamin D supplementation in the ICU patient. Curr Opin Clin Nutr Metab Care 2015; 18: 187-192
    CrossrefPubMedGoogle Scholar
  • 7 Lee P, Nair P, Eisman JA. et al. Vitamin D deficiency in the intensive care unit: An invisible accomplice to morbidity and mortality?. Intensive Care Med 2009; 35: 2028-2032
    CrossrefPubMedGoogle Scholar
  • 8 Gentile LF, Cuenca AG, Efron PA. et al. Persistent inflammation and immunosuppression : A common syndrome and new horizon for surgical intensive care. J Trauma Acute Care Surg 2012; 72: 1491-1501
    CrossrefPubMedGoogle Scholar
  • 9 Martín-Loeches I, Diaz E, Vallés J. Risks for multidrug-resistant pathogens in the ICU. Curr Opin Crit Care 2014; 20: 516-524
    CrossrefPubMedGoogle Scholar
  • 10 Cox CE. Persistent systemic inflammation in chronic critical illness. Resp Care 2012; 57: 859-864
    PubMedGoogle Scholar
  • 11 Van den Berghe G, Van Roosbroeck D, Vanhove P. et al. Bone turnover in prolonged critical illness: Effect of vitamin D. J Clin Endocrinol Metab 2003; 88: 4623-4632
    CrossrefPubMedGoogle Scholar
  • 12 Nierman DM, Mechanick JI. Bone hyperresorption is prevalent in chronically critically ill patients. Chest 1998; 114: 1122-1128
    CrossrefPubMedGoogle Scholar
  • 13 Nierman DM, Mechanick JI. Biochemical response to treatment of bone hyperresorption in chronically critically ill patients. Chest 2000; 118: 761-766
    CrossrefPubMedGoogle Scholar
  • 14 Van den Berghe G, Wilmer A, Hermans G. et al. Intensive insulin therapy in the medical ICU. N Engl J Med 2006; 354: 449-461
    CrossrefPubMedGoogle Scholar
  • 15 Van den Berghe G, Wouters P, Weekers F. et al. Intensive insulin therapy in critically ill patients. N Engl J Med 2001; 345: 1359-1367
    CrossrefPubMedGoogle Scholar
  • 16 Lee P, Eisman JA, Center JR. Vitamin D deficiency in critically ill patients. N Engl J Med 2009; 360: 1912-1914
    CrossrefPubMedGoogle Scholar
  • 17 Lerchbaum E, Schwetz V, Pilz S. et al. Association of bone turnover markers with mortality in men referred to coronary angiography. Osteoporos Int 2013; 24: 1321-1332
    CrossrefPubMedGoogle Scholar
  • 18 Atkinson SA. Vitamin D status and bone biomarkers in childhood cancer. Pediatr Blood Cancer 2008; 50 (2 Suppl) 479-482 discussion 486
    CrossrefPubMedGoogle Scholar
  • 19 Batra J, Buttar RS, Kaur P. et al. FGF-23 and cardiovascular disease: review of literature. Curr Opin Endocrinol Diabetes Obes 2016; 23: 423-429
    CrossrefPubMedGoogle Scholar
  • 20 Jung SM, Kim KW, Yang CW. et al. Cytokine-mediated bone destruction in rheumatoid arthritis. J Immunol Res 2014; 263625
    PubMedGoogle Scholar
  • 21 Lee P, Nair P, Eisman JA. et al. Bone Failure in Critical Illness. Crit Care Med 2016; 44: 2270-2274
    CrossrefPubMedGoogle Scholar
  • 22 Marshall JC, Charbonney E, Gonzalez PD. The immune system in critical illness. Clin Chest Med 2008; 29: 605-616 vii
    CrossrefPubMedGoogle Scholar
  • 23 Castellheim A, Brekke OL, Espevik T. et al. Innate immune responses to danger signals in systemic inflammatory response syndrome and sepsis. Scand J Immunol 2009; 69: 479-491
    PubMedGoogle Scholar
  • 24 Veldman CM, Cantorna MT, DeLuca HF. Expression of 1,25-dihydroxyvitamin D(3) receptor in the immune system. Arch Biochem Biophys 2000; 374: 334-338
    CrossrefPubMedGoogle Scholar
  • 25 Mata-Granados JM, Vargas-Vasserot J, Ferreiro-Vera C. et al. Evaluation of vitamin D endocrine system (VDES) status and response to treatment of patients in intensive care units (ICUs) using an on-line SPE-LC-MS/MS method. J Steroid Biochem Mol Biol 2010; 121: 452-455
    CrossrefPubMedGoogle Scholar
  • 26 Christopher KB. Vitamin D and critical illness outcomes. Curr Opin Crit Care 2016; 22: 332-338
    CrossrefPubMedGoogle Scholar
  • 27 Han JE, Jones JL, Tangpricha V. et al. High Dose Vitamin D Administration in Ventilated Intensive Care Unit Patients: A Pilot Double Blind Randomized Controlled Trial​. J Clin Transl Endocrinol 2016; 4: 59-65
    PubMedGoogle Scholar
  • 28 McNally JD, Ginde AA, Amrein K. Clarification needed for the systematic review of vitamin D trials in the ICU. Intensive Care Med 2017; 43: 595-596
    CrossrefPubMedGoogle Scholar
  • 29 Weng H, Li JG, Mao Z. et al. Randomised trials of vitamin D3 for critically ill patients in adults: Systematic review and meta-analysis with trial sequential analysis. Intensive Care Med 2017; 43: 277-278
    CrossrefPubMedGoogle Scholar
  • 30 Amrein K, Schnedl C, Holl A. et al. Effect of high-dose vitamin D3 on hospital length of stay in critically ill patients with vitamin D deficiency: The VITdAL-ICU randomized clinical trial. JAMA 2014; 312: 1520-1530
    CrossrefPubMedGoogle Scholar
  • 31 Bouillon R, Van Assche FA, Van Baelen H. et al. Influence of the vitamin D-binding protein on the serum concentration of 1,25-dihydroxyvitamin D3. Significance of the free 1,25-dihydroxyvitamin D3 concentration. J Clin Invest 1981; 67: 589-596
    CrossrefPubMedGoogle Scholar
  • 32 Sempos CT, Betz JM, Camara JE. et al. General Steps to Standardize the Laboratory Measurement of Serum Total 25-Hydroxyvitamin D. J AOAC Int 2017; 100: 1230-1233
    CrossrefPubMedGoogle Scholar
  • 33 Cools M, Goemaere S, Baetens D. et al. Calcium and bone homeostasis in heterozygous carriers of CYP24A1 mutations: A cross-sectional study. Bone 2015; 81: 89-96
    CrossrefPubMedGoogle Scholar
  • 34 Bouillon R, Coopmans W, Degroote DE. et al. Immunoradiometric assay of parathyrin with polyclonal and monoclonal region-specific antibodies. Clin Chem 1990; 36: 271-276
    CrossrefPubMedGoogle Scholar
  • 35 Fournier A, Cohen Solal ME, Oprisiu R. et al. 7-84 PTH or aluminum antagonism in the resistance of uremic bone to the remodeling effect of endogenous PTH?. Kidney Int 2001; 59: 2375-2376
    PubMedGoogle Scholar
  • 36 Møller HJ, Hald K, Moestrup SK. Characterization of an enzyme-linked immunosorbent assay for soluble CD163. Scand J Clin Lab Invest 2002; 62: 293-299
    CrossrefPubMedGoogle Scholar
  • 37 Bouillon R, Vanderschueren D, Van Herck E. et al. Homologous radioimmunoassay of human osteocalcin. Clin Chem 1992; 38: 2055-2060
    CrossrefPubMedGoogle Scholar
  • 38 Langouche L, Meersseman W, Vander Perre S. et al. Effect of insulin therapy on coagulation and fibrinolysis in medical intensive care patients. Crit Care Med 2008; 36: 1475-1480
    CrossrefPubMedGoogle Scholar
  • 39 Mathieu C, Van Etten E, Gysemans C. et al. In vitro and in vivo analysis of the immune system of vitamin D receptor knockout mice. J Bone Miner Res 2001; 16: 2057-2065
    CrossrefPubMedGoogle Scholar
  • 40 Knaus WA, Draper EA, Wagner DP. et al. APACHE II: A severity of disease classification system. Crit Care Med 1985; 13: 818-829
    CrossrefPubMedGoogle Scholar
  • 41 Tang JCY, Nicholls H, Piec I. et al. Reference intervals for serum 24,25-dihydroxyvitamin D and the ratio with 25-hydroxyvitamin D established using a newly developed LC–MS/MS method. J Nutr Biochem 2017; 46: 21-29
    CrossrefPubMedGoogle Scholar
  • 42 de Haan K, Groeneveld AB, de Geus HR. et al. Vitamin D deficiency as a risk factor for infection, sepsis and mortality in the critically ill: systematic review and meta-analysis. Crit Care 2014; 18: 660
    CrossrefPubMedGoogle Scholar
  • 43 Quraishi SA, Camargo CA. Vitamin D in acute stress and critical illness. Curr Opin Clin Nutr Metab Care 2012; 15: 625-634
    CrossrefPubMedGoogle Scholar
  • 44 Amrein K, Christopher KB, McNally JD. Understanding vitamin D deficiency in intensive care patients. Intensive Care Med 2015; 41: 1961-1964
    CrossrefPubMedGoogle Scholar
  • 45 Quesada-Gomez JM, Bouillon R. Is calcifediol better than cholecalciferol for vitamin D supplementation?. Osteoporos Int 2018; 29: 1697-1711
    CrossrefPubMedGoogle Scholar
  • 46 Bouillon R, Okamura WH, Norman AW. Structure-function relationships in the vitamin D endocrine system. Endocr Rev 1995; 16: 200-257
    PubMedGoogle Scholar
  • 47 Christakos S, Dhawan P, Verstuyf A. et al. Vitamin D: Metabolism, molecular mechanism of action, and pleiotropic effects. Physiol Rev 2016; 96: 365-408
    CrossrefPubMedGoogle Scholar
  • 48 Viaene L, Evenepoel P, Meijers B. et al. Uremia suppresses immune signal-induced CYP27B1 expression in human monocytes. Am J Nephrol 2012; 36: 497-508
    CrossrefPubMedGoogle Scholar
  • 49 Bikle DD. Vitamin D and Bone. Curr Osteoporos Rep 2012; 10: 151-159
    CrossrefPubMedGoogle Scholar
  • 50 Deluca HF, Cantorna MT. Vitamin D: Its role and uses in immunology. FASEB J 2001; 15: 2579-2585
    CrossrefPubMedGoogle Scholar
  • 51 Svensson D, Nebel D, Nilsson BO. Vitamin D3 modulates the innate immune response through regulation of the hCAP-18/LL-37 gene expression and cytokine production. Inflamm Res 2016; 65: 25-32
    CrossrefPubMedGoogle Scholar
  • 52 Kankova M, Luini W, Pedrazzoni M. et al. Impairment of cytokine production in mice fed a vitamin D3-deficient diet. Immunology 1991; 73: 466-471
    PubMedGoogle Scholar
  • 53 Ingels C, Gunst J, Van den Berghe G. Endocrine and metabolic alterations in sepsis and implications for treatment. Crit Care Clin 2018; 34: 81-96
    CrossrefPubMedGoogle Scholar
  • 54 Van den Berghe G. On the neuroendocrinopathy of critical illness. Perspectives for feeding and novel treatments. Am J Respir Crit Care Med 2016; 194: 1337-1348
    CrossrefPubMedGoogle Scholar