Bone metabolism and intensive care

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Bone metabolism and intensive care, Presentatie van Dr. A. Struijs op 18 november 2011 voor de Stichting IWO.

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Bone metabolism and intensive care

  1. 1. Bone  metabolism  on  the  ICU       htWat  doet  een  intensivist  als  voorzi=er  van   de  Iig   WO   ijs r u p y   tr c o .S A   r.Ard  Struijs   D Internist  intensivist   Erasmus  Medisch  Centrum      
  2. 2. Waarom  doe?e  het  nou   t h s•  PromoAe  onderzoek  naar  GIOP  in  de   ig ij r u dagelijkse  prakAjk  2000   y tr p•  Keuze  endocrinologie.  Intensive  care,  beide?   o .S c•  Voorbeelden  opleiders  H.Mulder,  A.  Fischer   r. A•  Thoraxcentrum,  hartchirurgie,  longchirurgie   D•  Beademing,  ARDS,  Hart-­‐longmachine,  long  als   motor  inlammatoire  response  •  ASBMR  NO  in  bo=en  vs  NO  op  de  IC  
  3. 3. HibernaAon   t•  Disuse  causes  imbalance  in  bone  formaAon   h s ig ij and  bone  resorpAon.   r u y tr p•  In  bears  hibernate  the  bone  volume  fracAon   o .S c and  Assue  mineral  density  do  not  differ  from   acAve  bears,     r. A•  Indices  of  cellular  level  like  mineral  apposiAon   D rate  and  ostoid  thickness  decreased.  •  Bears  maintain  coupling  between  in  bone   turnover   McGEE  Bone  21  Aug  Epub                              J  Biomech  2009:42;1378  
  4. 4. Wat  is  de  relaAe  IC  en  bo=en  ??   t h s ig ij r u y tr p o .S c r. A D
  5. 5. t h s ig ij r u y tr p o .S c r. A DBone  loss  during  cri.cal  illness:  A  skeleton  in  the  closet  for  the  intensive  care  unit  survivor?  *.  Griffith,  David;    MBChB,  FRCA;  Walsh,  Tim;    FRCP,  FRCA;    MD,  MRes    CriAcal  Care  Medicine.  39(6):1554-­‐1556,  June  2011.  DOI:  10.1097/CCM.0b013e318215beb4   ©  2011  by  the  Society  of  CriAcal  Care  Medicine  and  Lippinco=  Williams  &  Wilkins.    Published  by  Lippinco=  Williams   2   &  Wilkins,  Inc.  
  6. 6. Examples  of  Causes  of  Immobilisa.on  Bone  Loss     t h s ig ij▶  Damage  to  the  vertebral  bone  marrow  with   r udeleterious  effects  on  the  bone   y tr p▶  Hemiplegia  aker  cerebrovascular  incidents   o .S c▶  Paraplegia  of  the  lower  half  of  the  body   A▶  ImmobilisaAon  aker  fracture  of  the  lower  extremiAes   r.(rapid  bone  loss  especially  in  children)   D▶  ImmobilisaAon  aker  operaAons  on  the  legs  or  feet  with  subsequent  reduced  mobility  for  prolonged  periods  ▶  ImmobilisaAon  due  to  muscular  diseases  or  neurological  disorders,  e.g.  mulAple  sclerosis  
  7. 7. Bone  loss  due  to  immobilisaAon  •  osteoporosis.   t Insufficient  physical  ac0vity  is  one  of  the  most  important  overall  risk  factors  for   h s•  ig ij r u y tr This  is  especially  true  for  young  bed-­‐ridden  pa0ents  who  can  loose  up   p  to  30%  of  their  bone  density  within  a  few  months  while  years  are  required  for  its   o .S  replacement  –  that  is  for  restora0on  of  density  as  it  was  before,  i.e.  “res0tu0o  ad   c  integrum”  (see  also  Bartl  and  Frisch:  Atlas  of  Bone  Biopsy  in  Internal  Medicine).  •  r. A For  example,  when  an  arm  is  enclosed  in  plaster  for  3  weeks  aker  a  fracture,  the   D  immobilised  bones  may  loose  up  to  6%  of  their  bone  mass  during  this  short  period.    •  A  study  of  paAents  confined  to  bed  has  shown  that,  on  average,  trabecular    bone  decreases  by  about  1%  a  week.  When  physical  acAvity  is  resumed,  bone  density    increases  by  1%  a  month  –  considerably  slower  than  its  loss.    
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  23. 23. Bone  HyperresorpAon  •  CCI  pts  are  at  risk  for  accelerated  bone  loss  due  to:  –  Vitamin  D  deficiency  –  Prolonged  immobility   t h s ig ij•  IdenAficaAon  and  treatment  of  bone  loss  may  prevent  debilitaAng  fractures   r uaker  recovery   y trNierman  DM,  Mechanick  JI.  Chest.  1998;114:1122-­‐8   p o .S c Bone  hyperresorpAon:   Laboratory  evaluaAon   r. A •  24-­‐hr  urine  within  48  hours  of  RCU  admission,  •  Urine  N-­‐telopepAde  (NTx)   measured,  Osteomark®  assay   D •  Serum  Intact  PTH,  25-­‐vitamin  D,  1,25-­‐vitamin  D   •  Elevated  serum  intactPTH  level  diagnosAc  of  physiologically  significant   vitamin  D  deficiency   •  Elevated  Urine  NTx  =  Abnormal  Bone  ResorpAon   •  If  NTx  elevated,  then:   –  Low  PTH  =  ImmobilizaAon   –  High  PTH  =  Vitamin  D  deficiency   –  Normal  PTH  =  Both  
  24. 24. Diagram of proposed metabolic pathways that lead to bone hyperresorption with elevated urine NTx levels. t h s ig ij r u y tr p o .S c r. A D Nierman D M, Mechanick J I Chest 2000;118:761-766©2000 by American College of Chest Physicians
  25. 25. t h s ig ij r u y tr p Figure  1  .  ExcreAon  of  urinary  pyridinoline  (PYD/ CreaAnine,  top)  and  deoxypyridinoline  (DPD/CreaAnine,   o .S bo=om)  in  healthy  age-­‐matched  subjects  and  in  criAcally   ill  paAents  during  their  first  2  days  in  the  intensive  care  c unit  (ICU).  Solid  bars,  healthy  subjects  (n  =  17);  shaded   bars,  paAents  who  stayed  in  the  ICU  5  days  (n  =  5).   *Differs  from  healthy  subjects,  p  t  differs  from  paAents   A with  a  <or=to5-­‐day  stay  in  the  ICU,  p  <  .02.  D r. Urinary  pyridinium  cross-­‐link  excre.on  is  increased  in  cri.cally  ill  surgical   pa.ents.   Shapses,  Sue;    Weissman,  Charles;    Seibel,  Markus;    Chowdhury,  Hasina     CriAcal  Care  Medicine.  25(1):85-­‐90,  January  1997.    ©  Williams  &  Wilkins  1997.    All  Rights  Reserved.    Published  by  Lippinco=  Williams  &  Wilkins,  Inc.   4  
  26. 26. Kenmerken  metabole  botziekten  op  IC    •  ImmobilisaAe   t h s ig ij r u•  Ontkoppeling  aanmaak  awraak  gekenmerkt   y tr p door  hyperresorpAe   o .S c•  Secundaire  hyper  parathyreoidie   r. A•  Vitamine  D  deficienAe  •  SIRS   D•  GlucocorAcoiden  
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  39. 39. paAents,  19  months,  retrospecAve  review   t•  131  (83%)  pts  had  ↑  urine  NTx   h s ig ij•  55  pts:   r u–  ↑  NTx  levels  at  RCU  admission   y tr–  Treated  with  either  calcitriol  alone  (n  =  44)  or  calcitriol  +  pamidronate  (n  =  11)   p–  NTxs  remeasured  aker  treatment   co .S•  All  pts  received  calcitriol  (1,25-­‐dihydroxyvitamin  D3)  0.25  mcg/day  enterally  (Rocaltrol®)  or  IV  (Calcijex®)   A•  At  endocrinologist’s  discreAon,  pamidronate,  30  mg  IVSS  qD  x  3  consecuAve   r.days  given  (~  $532)   D•  IndicaAons  for  pamidronate:  –  Elevated  PTH  +  hypercalciuria  –  Very  elevated  urine  NTx  suggesAng  severe  bone  hyperresorpAon  Nierman  DM,  Mechanick  JI.  Chest  2000;  118:761-­‐6  
  40. 40. Changes  of  basic  bone  turnover  parameters  in  short-­‐term  and  long-­‐term  paAents  with   spinal  cord  injury  Autor(es)  Reiter  Andreas  Ludwig,  Volk  Andreas,  Vollmar  Jens, Fromm  Bernd,  Gerner,  Hans  Juergen  The  bone  mineral  density  (BMD),  the  cross-­‐  links  (PYD,  DPD  and  NTx)  and  the  bone  specific  alcaline  phosphatase  (BAP)  was   tinvesAgated  in  a  cross-­‐sec.onal  study  in  62  male  pa.ents  with  spinal  cord  injury  (SCI),  n  =  28  short-­‐term  (0–1  year  aQer   h s ig ijSCI)  and  n  =  34  long-­‐term  SCI  pa.ents  (>  5  years  aQer  SCI).     r uLiVle  is  known  regarding  the  extend  of  the  osteoporosis  as  well  as  the  causaAve  factors.   p y trMeasurements  of  the  BMD  in  the  proximal  femur  and  the  lumbar  spine  (DEXA),  of  the  osteoblast  marker  BAP  from   o .Sserum,  the  osteoclast  markers  PYD  (pyridinoline),  DPD  (desoxy-­‐pyridinoline)  and  NTx  (N-­‐telopepAde  of  collagen  type  I)  from  urine.   c Aa  significant  decrease  of  BMD  in  the  proximal  femur  and  no  relevant  change  in  the  lumbar  spine    (Z-­‐score)  in  short-­‐term   r.and  long-­‐term  SCI  paAents.  a  significant  bone  loss  at  the  proximal  femur,  whereas  at  the  lumbar  spine  the  BMD  even   Dslightly  increases.    Bone  resorpAon  (cross-­‐links)  was  increased  in  both  groups,  though  in  long-­‐term  SCI  paAents  it  is  significantly  decreased  compared  to  short-­‐term  SCI  paAents  (DPD  from  211.7  u/g  creaAnine  to  118.1  u/g  creaAnine;  NTx  from  215.1  nmol/mmol  creaAnine  to  83,6  nmol/mmol  creaAnine).  The  bone  formaAon  marker  BAP  is  slightly  below  normal  range  in  both  groups  (12.3  U/l  in  short-­‐term,  9.7  U/l  in  long-­‐  term  SCI  paAents).  Only  the  proximal  femur  is  affected  by  the  immobilisa.on  osteoporosis  of  SCI  pa.ents,  therefore  the  BMD  measurements  in  these  pa.ents  should  be  performed  at  the  lower  limb.  The  problem  of  the  immobilisaAon  osteoporosis  in  SCI  paAents  is  the  striking  increase  of  bone  resorpAon  and  the  missing  reacAon  of  the  bone  formaAon.  
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  43. 43. Table  1   Urinary  pyridinium  cross-­‐link  excre.on  is  increased  in   cri.cally  ill  surgical  pa.ents.   Shapses,  Sue;    Weissman,  Charles;    Seibel,  Markus;     Chowdhury,  Hasina     CriAcal  Care  Medicine.  25(1):85-­‐90,  January  1997.   t   h s ig ij r u y tr Table  1  .  PaAent  characterisAcs  (mean  +/-­‐  SD)   p o .Sc r. AD©  Williams  &  Wilkins  1997.    All  Rights  Reserved.    Published  by  Lippinco=  Williams  &  Wilkins,  Inc.   2  
  44. 44. Table  2   Urinary  pyridinium  cross-­‐link  excre.on  is  increased  in   cri.cally  ill  surgical  pa.ents.   Shapses,  Sue;    Weissman,  Charles;    Seibel,  Markus;     Chowdhury,  Hasina     CriAcal  Care  Medicine.  25(1):85-­‐90,  January  1997.   t   h s ig ij r u y tr Table  2  .  Serum  biochemical  values  (mean  +/-­‐  SD)   p o .Sc r. AD©  Williams  &  Wilkins  1997.    All  Rights  Reserved.    Published  by  Lippinco=  Williams  &  Wilkins,  Inc.   3  
  45. 45. Figure  2   Urinary  pyridinium  cross-­‐link  excre.on  is  increased  in   cri.cally  ill  surgical  pa.ents.   Shapses,  Sue;    Weissman,  Charles;    Seibel,  Markus;     Chowdhury,  Hasina     CriAcal  Care  Medicine.  25(1):85-­‐90,  January  1997.   t   h s ig ij r u y tr p Figure  2  .  Daily  urinary  excreAon  of  pyridinoline  (PYD/ CreaAnine,  top)  and  deoxypyridinoline  (DPD/CreaAnine,   o .S bo=om)  in  criAcally  ill  paAents  (n  =  9).  Solid  lines,   paAents  who  stayed  in  the  intensive  care  unit  5  days.  c r. AD©  Williams  &  Wilkins  1997.    All  Rights  Reserved.    Published  by  Lippinco=  Williams  &  Wilkins,  Inc.   5  
  46. 46. Table  1.   Skeletal  morbidity  among  survivors  of  cri.cal  illness  *.   Orford,  Neil;    MBBS,  FCICM;  Saunders,  Kym;  MBBS,   FCICM;  Merriman,  Elizabeth;  Henry,  Margaret;  Pasco,   Julie;  Stow,  Peter;  MBBS,  FCICM;  Kotowicz,  Mark;  MBBS,   FRACP   t   CriAcal  Care  Medicine.  39(6):1295-­‐1300,  June  2011.   h s DOI:  10.1097/CCM.0b013e318211ff3d   ig ij r u y tr p Table  1.    DescripAve  characterisAcs  of  all  ICU  admissions   and  admissions  venAlated  for  >=48  hrs  during  8-­‐yr  study   o .S period  (data  are  shown  as  median  [IQR]  or  no.  [%])  c r. AD©  2011  by  the  Society  of  CriAcal  Care  Medicine  and  Lippinco=  Williams  &  Wilkins.    Published  by  Lippinco=  Williams   2  &  Wilkins,  Inc.  
  47. 47. Table  2.   Skeletal  morbidity  among  survivors  of  cri.cal  illness  *.   Orford,  Neil;    MBBS,  FCICM;  Saunders,  Kym;  MBBS,   FCICM;  Merriman,  Elizabeth;  Henry,  Margaret;  Pasco,   Julie;  Stow,  Peter;  MBBS,  FCICM;  Kotowicz,  Mark;  MBBS,   FRACP   t   CriAcal  Care  Medicine.  39(6):1295-­‐1300,  June  2011.   h s DOI:  10.1097/CCM.0b013e318211ff3d   ig ij r u y tr p Table  2.    DescripAve  data  of  ICU  survivors  with  >=48  hrs   venAlaAon  by  gender  (as  above  median  [IQR]  or  no.  [%])  co .S r. AD©  2011  by  the  Society  of  CriAcal  Care  Medicine  and  Lippinco=  Williams  &  Wilkins.    Published  by  Lippinco=  Williams   3  &  Wilkins,  Inc.  
  48. 48. Table  3.   Skeletal  morbidity  among  survivors  of  cri.cal  illness  *.   Orford,  Neil;    MBBS,  FCICM;  Saunders,  Kym;  MBBS,   FCICM;  Merriman,  Elizabeth;  Henry,  Margaret;  Pasco,   Julie;  Stow,  Peter;  MBBS,  FCICM;  Kotowicz,  Mark;  MBBS,   FRACP   t   CriAcal  Care  Medicine.  39(6):1295-­‐1300,  June  2011.   h s DOI:  10.1097/CCM.0b013e318211ff3d   ig ij r u y tr Table  3.    Number  of  fractures  post-­‐ICU  by  age  in  adult   p males  co .S r. AD©  2011  by  the  Society  of  CriAcal  Care  Medicine  and  Lippinco=  Williams  &  Wilkins.    Published  by  Lippinco=  Williams   4  &  Wilkins,  Inc.  
  49. 49. Table  4.   Skeletal  morbidity  among  survivors  of  cri.cal  illness  *.   Orford,  Neil;    MBBS,  FCICM;  Saunders,  Kym;  MBBS,   FCICM;  Merriman,  Elizabeth;  Henry,  Margaret;  Pasco,   Julie;  Stow,  Peter;  MBBS,  FCICM;  Kotowicz,  Mark;  MBBS,   FRACP   t   CriAcal  Care  Medicine.  39(6):1295-­‐1300,  June  2011.   h s DOI:  10.1097/CCM.0b013e318211ff3d   ig ij r u y tr Table  4.    Number  of  fractures  in  adult  females  by  age  in   p post-­‐ICU  and  GOS  samples  co .S r. AD©  2011  by  the  Society  of  CriAcal  Care  Medicine  and  Lippinco=  Williams  &  Wilkins.    Published  by  Lippinco=  Williams   5  &  Wilkins,  Inc.  
  50. 50. Table  5.   Skeletal  morbidity  among  survivors  of  cri.cal  illness  *.   Orford,  Neil;    MBBS,  FCICM;  Saunders,  Kym;  MBBS,   FCICM;  Merriman,  Elizabeth;  Henry,  Margaret;  Pasco,   Julie;  Stow,  Peter;  MBBS,  FCICM;  Kotowicz,  Mark;  MBBS,   FRACP   t   CriAcal  Care  Medicine.  39(6):1295-­‐1300,  June  2011.   h s DOI:  10.1097/CCM.0b013e318211ff3d   ig ij r u y tr Table  5.    Comparison  of  female  ICU  survivors  by  post-­‐ICU   p fracture  status  (data  are  shown  as  median  [IQR]  or  no.   [%])  co .S r. AD©  2011  by  the  Society  of  CriAcal  Care  Medicine  and  Lippinco=  Williams  &  Wilkins.    Published  by  Lippinco=  Williams   6  &  Wilkins,  Inc.  
  51. 51. Table  6.   Skeletal  morbidity  among  survivors  of  cri.cal  illness  *.   Orford,  Neil;    MBBS,  FCICM;  Saunders,  Kym;  MBBS,   FCICM;  Merriman,  Elizabeth;  Henry,  Margaret;  Pasco,   Julie;  Stow,  Peter;  MBBS,  FCICM;  Kotowicz,  Mark;  MBBS,   FRACP   t   CriAcal  Care  Medicine.  39(6):1295-­‐1300,  June  2011.   h s DOI:  10.1097/CCM.0b013e318211ff3d   ig ij r u y tr Table  6.    Comparison  of  male  ICU  survivors  by  post-­‐ICU   p fracture  status  (data  are  shown  as  median  [IQR]  or  no.   [%])  co .S r. AD©  2011  by  the  Society  of  CriAcal  Care  Medicine  and  Lippinco=  Williams  &  Wilkins.    Published  by  Lippinco=  Williams   7  &  Wilkins,  Inc.  
  52. 52. Table  7.   Skeletal  morbidity  among  survivors  of  cri.cal  illness  *.   Orford,  Neil;    MBBS,  FCICM;  Saunders,  Kym;  MBBS,   FCICM;  Merriman,  Elizabeth;  Henry,  Margaret;  Pasco,   Julie;  Stow,  Peter;  MBBS,  FCICM;  Kotowicz,  Mark;  MBBS,   FRACP   t   CriAcal  Care  Medicine.  39(6):1295-­‐1300,  June  2011.   h s DOI:  10.1097/CCM.0b013e318211ff3d   ig ij r u y tr Table  7.    Unadjusted  and  adjusted  fracture  rates  and   p hazard  raAos  for  females  (20-­‐94  yrs  of  age)  post-­‐ICU   compared  with  populaAon-­‐based  females  (GOS)  co .S r. AD©  2011  by  the  Society  of  CriAcal  Care  Medicine  and  Lippinco=  Williams  &  Wilkins.    Published  by  Lippinco=  Williams   8  &  Wilkins,  Inc.  
  53. 53. Figure  1.   Skeletal  morbidity  among  survivors  of  cri.cal  illness  *.   Orford,  Neil;    MBBS,  FCICM;  Saunders,  Kym;  MBBS,   FCICM;  Merriman,  Elizabeth;  Henry,  Margaret;  Pasco,   Julie;  Stow,  Peter;  MBBS,  FCICM;  Kotowicz,  Mark;  MBBS,   FRACP   t   CriAcal  Care  Medicine.  39(6):1295-­‐1300,  June  2011.   h s DOI:  10.1097/CCM.0b013e318211ff3d   ig ij r u y tr p Figure  1.    Time  to  fracture  of  the  wrist,  hip,  humerus,  or   vertebral  fracture  aker  intensive  care  unit  (ICU)   o .S compared  with  the  random  populaAon-­‐based  sample  in   older  age  group  (>=  60  yrs)  females.  HR,  hazard  raAo;  CI,  c confidence  interval;  GOS,  Geelong  Osteoporosis  Study.   r. AD©  2011  by  the  Society  of  CriAcal  Care  Medicine  and  Lippinco=  Williams  &  Wilkins.    Published  by  Lippinco=  Williams   9  &  Wilkins,  Inc.  
  54. 54. 1. J Clin Endocrinol Metab. 2008 Oct;93(10):3927-35. Epub 2008 Aug 5. t Association of vitamin D deficiency with h s heart failure and sudden cardiac death in a ig ij large cross-sectional study of patients referred for coronary angiography. r u Pilz S, März W, Wellnitz B, Seelhorst U, Fahrleitner-Pammer A, Dimai HP, Boehm BO, y tr Dobnig H. Source p Department of Internal Medicine, Medical University of Graz, Auenbruggerplatz 15, 8036 Graz, Austria. stefan.pilz@chello.at o .S Comment inc • J Clin Endocrinol Metab. 2009 Feb;94(2):418-20. Abstract A CONTEXT: Vitamin D has been shown to influence cardiac contractility and myocardial calcium r. homeostasis. OBJECTIVES: We aimed to elucidate whether insufficient vitamin D status is associated with heart failureD and sudden cardiac death (SCD). DESIGN, SETTING, AND PARTICIPANTS: We measured 25-hydroxyvitamin D [25(OH)D] levels in 3299 Caucasian patients who were routinely referred to coronary angiography at baseline (1997-2000). MAIN OUTCOME MEASURES: The main outcome was cross-sectional associations of 25(OH)D levels with measures of heart failure and Cox proportional hazard ratios for deaths due to heart failure and for SCD according to vitamin D status. RESULTS: 25(OH)D was negatively correlated with N-terminal pro-B-type natriuretic peptide and was
  55. 55. 1. Am J Med. 2009 Sep;122(9):793-802. Vitamin D: bone and beyond, rationale and recommendations for supplementation. t h s ig ij r u Stechschulte SA, Kirsner RS, Federman DG. y tr Source p o .S Department of Dermatology and Cutaneous Surgery, University of Miami Miller School of c Medicine, Miami, Fla, USA. Comment in • r. A Am J Med. 2010 Feb;123(2):e17; author reply e19. D Abstract Adequate vitamin D status is necessary and beneficial for health, although deficiency plagues much of the worlds population. In addition to reducing the risk for bone disease, vitamin D plays a role in reduction of falls, as well as decreases in pain, autoimmune diseases, cancer, heart disease, mortality, and cognitive function. On the basis of this emerging understanding, improving patients vitamin D status has become an essential aspect of primary care. Although some have suggested increased sun exposure to increase serum vitamin D levels, this has the potential to induce photoaging and skin cancer, especially in patients at risk for these conditions. Vitamin D deficiency and insufficiency can be both corrected and prevented safely through supplementation.
  56. 56. 1. Mol Nutr Food Res. 2010 Aug;54(8):1103-13. Vitamin D deficiency and myocardial diseases. t h s Pilz S, Tomaschitz A, Drechsler C, Dekker JM, März W. ig ij r u Source y tr Department of Internal Medicine, Division of Endocrinology and Nuclear Medicine, p Medical University of Graz, Graz, Austria. stefan.pilz@chello.at Abstract co .S Vitamin D deficiency is common among patients with myocardial diseases because sun- A induced vitamin D production in the skin and dietary intake of vitamin D is often r. insufficient. Knockout mice for the vitamin D receptor develop myocardial hypertrophy and dysfunction. It has also been shown that children with rickets who suffered from severe D heart failure could be successfully treated with supplementation of vitamin D plus calcium. In adults, almost all patients with heart failure exhibit reduced 25-hydroxyvitamin D levels, which are used to classify the vitamin D status. In prospective studies, vitamin D deficiency was an independent risk factor for mortality, deaths due to heart failure and sudden cardiac death. Several vitamin D effects on the electrophysiology, contractility, and structure of the heart suggest that vitamin D deficiency might be a causal factor for myocardial diseases. Data from interventional trials, however, are rare and urgently needed to elucidate whether vitamin D supplementation is useful for the treatment of myocardial diseases. In our opinion, the current knowledge of the beneficial effects of vitamin D on myocardial and overall health strongly argue for vitamin D supplementation in all vitamin D-deficient patients with or at high risk for myocardial diseases.
  57. 57. 1. Curr Drug Targets. 2011 Jan;12(1):88-96. Vitamin D supplementation: a promising approach for the prevention and treatment of strokes. t h s Pilz S, Tomaschitz A, Drechsler C, Zittermann A, Dekker JM, März W. ig ij r u Source y tr Department of Internal Medicine, Division of Endocrinology and Nuclear Medicine, p Medical University of Graz, Austria. stefan.pilz@chello.at Abstract co .S Vitamin D deficiency is highly prevalent due to lifestyle and environmental factors which A limit sunlight induced vitamin D production in the skin. This "pandemic" of vitamin D r. deficiency is of concern because low levels of 25-hydroxyvitamin D (25[OH]D) have been associated with cardiovascular, musculoskeletal, infectious, autoimmune and malignant D diseases. Epidemiological studies have largely but not consistently shown that vitamin D deficiency is a risk factor for strokes. This is supported by associations of low 25(OH)D levels with cerebrovascular risk factors, in particular with arterial hypertension. Vitamin D has also been shown to exert neuroprotective, neuromuscular and osteoprotective effects which may reduce cognitive and functional impairments in poststroke patients. Hence, the current literature favours the notion that vitamin D supplementation is a promising approach for the prevention and treatment of strokes but accurate data from interventional studies are missing. Randomized controlled trials are therefore urgently needed to evaluate whether vitamin D supplementation reduces the incidence of strokes and improves the outcome of poststroke patients. We do, however, believe that currently published data on the multiple health benefits of vitamin D and the easy safe and inexpensive way by which it can be supplemented already argue for the prevention and treatment of vitamin D deficiency in order to reduce stroke associated morbidity and mortality.
  58. 58. 1. Kidney Int. 2009 Nov;76(9):931-3. Chronic kidney disease and vitamin D: how much is adequate? t h s Ruggiero M, Pacini S. ig ij r u y tr p Source o .S Department of Experimental Pathology and Oncology, University of Firenze, Firenze, Italy. c marco.ruggiero@unifi .it A Comment on r. • Kidney Int. 2009 Nov;76(9):977-83. D Abstract Mehrotra et al. demonstrate that there still is hypovitaminosis D in adults with chronic kidney disease (CKD) in the United States, and this defect is associated with increased risk for death. Definition of the adequate amount of vitamin D, however, is still uncertain; polymorphisms of the gene encoding the vitamin D receptor might be responsible for this uncertainty. People carrying less efficient variants of the receptor might need higher amounts of vitamin D.
  59. 59. 1. Mol Nutr Food Res. 2010 Aug;54(8):1103-13. Vitamin D deficiency and myocardial diseases. t h s Pilz S, Tomaschitz A, Drechsler C, Dekker JM, März W. ig ij r u Source y tr Department of Internal Medicine, Division of Endocrinology and Nuclear Medicine, p Medical University of Graz, Graz, Austria. stefan.pilz@chello.at Abstract co .S Vitamin D deficiency is common among patients with myocardial diseases because sun- A induced vitamin D production in the skin and dietary intake of vitamin D is often r. insufficient. Knockout mice for the vitamin D receptor develop myocardial hypertrophy and dysfunction. It has also been shown that children with rickets who suffered from severe D heart failure could be successfully treated with supplementation of vitamin D plus calcium. In adults, almost all patients with heart failure exhibit reduced 25-hydroxyvitamin D levels, which are used to classify the vitamin D status. In prospective studies, vitamin D deficiency was an independent risk factor for mortality, deaths due to heart failure and sudden cardiac death. Several vitamin D effects on the electrophysiology, contractility, and structure of the heart suggest that vitamin D deficiency might be a causal factor for myocardial diseases. Data from interventional trials, however, are rare and urgently needed to elucidate whether vitamin D supplementation is useful for the treatment of myocardial diseases. In our opinion, the current knowledge of the beneficial effects of vitamin D on myocardial and overall health strongly argue for vitamin D supplementation in all vitamin D-deficient patients with or at high risk for myocardial diseases.
  60. 60. 1. Eur Heart J. 2010 Sep;31(18):2253-61. Epub 2010 Aug 5. t Vitamin D deficiency is associated with h s sudden cardiac death, combined ig ij cardiovascular events, and mortality in haemodialysis patients. r u Drechsler C, Pilz S, Obermayer-Pietsch B, Verduijn M, Tomaschitz A, Krane V, Espe K, y tr Dekker F, Brandenburg V, März W, Ritz E, Wanner C. Source p Department of Internal Medicine 1, Division of Nephrology, University of Würzburg, Oberdürrbacher Str. 6, D-97080 Würzburg, Germany. c.drechsler@gmx.net o .S Abstractc AIMS: Dialysis patients experience an excess mortality, predominantly of sudden cardiac death (SCD). Accumulating evidence suggests a role of vitamin D for myocardial and overall A health. This study investigated the impact of vitamin D status on cardiovascular outcomes and fatal infections in haemodialysis patients. r. METHODS AND RESULTS: 25-hydroxyvitamin D [25(OH)D] was measured in 1108 diabetic haemodialysis patients who participated in the German Diabetes and Dialysis Study and were followed up for a median of 4 years. By Cox regression analyses, we determined hazard ratios (HR) for pre-D specified, adjudicated endpoints according to baseline 25(OH)D levels: SCD (n = 146), myocardial infarction (MI, n = 174), stroke (n = 89), cardiovascular events (CVE, n = 414), death due to heart failure (n = 37), fatal infection (n = 111), and all-cause mortality (n = 545). Patients had a mean age of 66 ± 8 years (54% male) and median 25(OH)D of 39 nmol/L (interquartile range: 28-55). Patients with severe vitamin D deficiency [25(OH)D of ≤ 25 nmol/L] had a 3-fold higher risk of SCD compared with those with sufficient 25(OH)D levels >75 nmol/L [HR: 2.99, 95% confidence interval (CI): 1.39-6.40]. Furthermore, CVE and all-cause mortality were strongly increased (HR: 1.78, 95% CI: 1.18-2.69, and HR: 1.74, 95% CI: 1.22-2.47, respectively), all persisting in multivariate models. There were borderline non-significant associations with stroke and fatal infection while MI and deaths due to heart failure were not meaningfully affected. CONCLUSION: Severe vitamin D deficiency was strongly associated with SCD, CVE, and mortality, and there were borderline associations with stroke and fatal infection. Whether vitamin D
  61. 61. 1. Curr Opin Clin Nutr Metab Care. 2009 Nov;12(6):634-9. t Vitamin D deficiency and mortality. h s ig ij Zittermann A, Gummert JF, Börgermann J. Source r u Clinic for Thoracic and Cardiovascular Surgery, Heart Center North Rhine-Westfalia, Ruhr y tr University Bochum, Georgstrsse 11, D-32545 Bad Oeynhausen, Germany. azittermann@hdz- nrw.de p Abstract o .S PURPOSE OF REVIEW:c To summarize recent findings on vitamin D deficiency and mortality. The serum concentration of 25-hydroxyvitamin D [25(OH)D], the metabolic precursor of the vitamin D hormone calcitriol, is the standard for assessing vitamin D status. Deficient 25(OH)D concentrations (<25 nmol/l) are prevalent in Europe and North America. A RECENT FINDINGS: r. Several large nonrandomized studies indicate that different from adequate 25(OH)D concentrations (>75 nmol/l), deficient 25(OH)D concentrations are associated with excess mortality in the general population and in patients with increased cardiovascular disease risk. Results support an earlier meta-analysis of controlled trials that were not primarilyD designed to assess mortality showing a survival benefit of vitamin D supplementation over no supplementation in middle-aged and elderly persons. In patients with advanced chronic diseases such as end-stage heart failure, however, circulating calcitriol predicts mid-term mortality better than 25(OH)D does. Available data indicate that these patients may enter a vicious cycle of low calcitriol, increased inflammation markers, and renal impairment, which may be difficult to escape by simple vitamin D supplementation. SUMMARY: Accumulating evidence suggests that vitamin D deficiency is linked to excess mortality. However, future studies should clarify to which extent vitamin D supplementation can improve survival in the aging population and in specific patient groups.
  62. 62. 1. Kidney Int. 2009 Nov;76(9):977-83. Epub 2009 Aug 5. t Chronic kidney disease, hypovitaminosis h s D, and mortality in the United States. ig ij Mehrotra R, Kermah DA, Salusky IB, Wolf MS, Thadhani RI, Chiu YW, Martins D, Adler r u SG, Norris KC. y tr Source p Division of Nephrology and Hypertension, Department of Medicine, Los Angeles Biomedical Research Institute, Torrance, California 90502, USA. rmehrotra@labiomed.org o .S Comment inc • Kidney Int. 2009 Nov;76(9):931-3. Abstract A Low serum 25-hydroxy vitamin D (25OHD) predicts a higher cardiovascular risk in the r. general population. Because patients with chronic kidney disease are more likely to have low serum 25OHD, we determined the relationship between hypovitaminosis D and death in this group. Analysis was done using a cohort composed of 3011 patients from the Third National Health and Nutrition Examination Survey who had chronic kidney disease butD were not on dialysis and who had a mean follow-up of 9 years. In analyses adjusted for demographics, cardiovascular risk factors, serum phosphorus, albumin, hemoglobin, stage of chronic kidney disease, albuminuria, and socioeconomic status, individuals with serum 25OHD levels less than 15 ng/ml had an increased risk for all-cause mortality when compared to those with levels over 30 ng/ml. This significantly higher risk for death with low serum 25OHD was evident in 15 of the 23 subgroups. The higher risk for cardiovascular and non-cardiovascular mortality became statistically nonsignificant on multivariable adjustment. The trend for higher mortality in patients with 25OHD levels 15- 30 ng/ml was not statistically significant. Our results indicate there is a graded relationship between serum 25OHD and the risk for death among subjects with chronic kidney disease who are not undergoing dialysis. Randomized, controlled trials are needed to conclusively determine whether vitamin D supplementation reduces mortality.
  63. 63. 1. Clin J Am Soc Nephrol. 2009 Sep;4(9):1515-22. Epub 2009 Aug 20. Vitamin D and the cardiovascular system. Artaza JN, Mehrotra R, Norris KC. Source t h s Charles Drew University of Medicine & Science, Los Angeles, CA 90059, USA. ig ij Abstract r u y tr Several epidemiologic and clinical studies have suggested that there is a strong association p between hypovitaminosis D and cardiovascular disease (CVD). Hypovitaminosis D was o .S reported as a risk factor for increased cardiovascular events among 1739 adult participants in the Framingham Offspring Study. Analysis of more than 13,000 adults in the Third c National Health and Nutrition Examination Survey (NHANES III) showed that even though hypovitaminosis D is associated with an increased prevalence of CVD risk factors, its A association with all-cause mortality is independent of these risk factors. Importantly, r. epidemiologic studies suggested that patients who had chronic kidney disease and were treated with activated vitamin D had a survival advantage when compared with those who did not receive treatment with these agents. Mechanistically, emerging data have linked D vitamin D administration with improved cardiac function and reduced proteinuria, and hypovitaminosis D is associated with obesity, insulin resistance, and systemic inflammation. Preliminary studies suggested that activated vitamin D inhibits the proliferation of cardiomyoblasts by promoting cell-cycle arrest and enhances the formation of cardiomyotubes without inducing apoptosis. Activated vitamin D has also been shown to attenuate left ventricular dysfunction in animal models and humans. In summary, emerging studies suggest that hypovitaminosis D has emerged as an independent risk factor for all- cause and cardiovascular mortality, reinforcing its importance as a public health problem. There is a need to advance our understanding of the biologic pathways through which vitamin D affects cardiovascular health and to conduct prospective clinical interventions to define precisely the cardioprotective effects of nutritional vitamin D repletion. Free Article
  64. 64. 1. Intensive Care Med. 2009 Dec;35(12):2028-32. Epub 2009 Sep 15. t Vitamin D deficiency in the intensive care h s ig ij unit: an invisible accomplice to morbidity and mortality? r u y tr p Lee P, Nair P, Eisman JA, Center JR. Source co .S A Department of Endocrinology, St Vincents Hospital, Sydney, NSW 2010, Australia. r. p.lee@garvan.org.au Abstract D The association between vitamin D deficiency and chronic illness is well-known. Vitamin D deficiency has been associated with increased mortality in the general population. Despite this knowledge, vitamin D insufficiency is seldom considered and rarely replaced adequately, if at all, in critically ill patients in intensive care. We present a hypothetic model demonstrating how vitamin D deficiency may be an unrecognized contributor to adverse outcome in intensive care patients.
  65. 65. 1. Crit Care. 2011;15(2):154. Epub 2011 Apr 19. How deficient are vitamin D deficient critically ill patients? t h s ig ij Lee P. r u y tr Source p Department of Diabetes and Endocrinology, Princess Alexandra Hospital, School of o .S Medicine, University of Queensland, 199 Ipswich Road, Woolloongabba, Brisbane, c Queensland, Australia 4102. p.lee@garvan.org.au A Comment on r. • Crit Care. 2011;15(2):R104. Abstract D Vitamin D deficiency is highly prevalent among critically ill patients and may be associated with adverse outcomes. Failure of conventional vitamin D supplementation in correcting deficiency has called for studies to evaluate the efficacy and safety of a high-dose regime in critically ill patients. High-dose vitamin D supplementation that corrects a deficient state effectively and safely allows for intervention studies to be undertaken to determine the impact of vitamin D on morbidity and mortality in critically ill patients.
  66. 66. 1. Crit Care. 2011;15(2):R104. Epub 2011 Mar 28. Short-term effects of high-dose oral vitamin D3 in critically ill vitamin D deficient patients: a randomized, double- blind, placebo-controlled pilot study. t h s Amrein K, Sourij H, Wagner G, Holl A, Pieber TR, Smolle KH, Stojakovic T, Schnedl C, Dobnig H. ig ij Source r u Medical University of Graz, Department of Internal Medicine, Division of Endocrinology y tr and Metabolism, Auenbruggerplatz 15, 8036 Graz, Austria. p Comment in o .S Crit Care. 2011;15(2):154. c • Abstract A INTRODUCTION: r. Vitamin D deficiency is encountered frequently in critically ill patients and might be harmful. Current nutrition guidelines recommend very low vitamin D doses. The objective of this trial was to evaluate the safety and efficacy of a single oral high-dose vitamin D3 D supplementation in an intensive care setting over a one-week observation period. METHODS: This was a randomized, double-blind, placebo-controlled pilot study in a medical ICU at a tertiary care university center in Graz, Austria. Twenty-five patients (mean age 62 ± 16 yrs) with vitamin D deficiency [25-hydroxyvitamin D (25(OH)D) ≤ 20 ng/ml] and an expected stay in the ICU >48 hours were included and randomly received either 540,000 IU (corresponding to 13.5 mg) of cholecalciferol (VITD) dissolved in 45 ml herbal oil or matched placebo (PBO) orally or via feeding tube. RESULTS: The mean serum 25(OH)D increase in the intervention group was 25 ng/ml (range 1-47 ng/ml). The highest 25(OH)D level reached was 64 ng/ml, while two patients showed a small (7 ng/ml) or no response (1 ng/ml). Hypercalcemia or hypercalciuria did not occur in any patient. From day 0 to day 7, total serum calcium levels increased by 0.10 (PBO) and 0.15 mmol/L (VITD; P < 0.05 for both), while ionized calcium levels increased by 0.11 (PBO) and 0.05 mmol/L (VITD; P < 0.05 for both). Parathyroid hormone levels decreased
  67. 67. Vitamin D intake in the two study groups. t h s ig ij r u y tr p o .S c r. A D Van den Berghe G et al. JCEM 2003;88:4623-4632©2003 by Endocrine Society
  68. 68. Effect of 200 IU and 500 IU of vitamin D supplement on vitamin D metabolism. t h s ig ij r u y tr p o .S c r. A D Van den Berghe G et al. JCEM 2003;88:4623-4632©2003 by Endocrine Society
  69. 69. Effect of 200 IU and 500 IU of vitamin D supplement on markers of bone formation. t h s ig ij r u y tr p o .S c r. A D Van den Berghe G et al. JCEM 2003;88:4623-4632©2003 by Endocrine Society
  70. 70. Aggravation of bone hyperresorption with time in ICU. A time-dependent increase in serum βCTX (all patients) and urine DPD (normalized for urine creatinine in those patients who did not require dialysis or hemofiltration) levels, both already elevated on IC... t h s ig ij r u y tr p o .S c r. A D Van den Berghe G et al. JCEM 2003;88:4623-4632©2003 by Endocrine Society
  71. 71. Antiinflammatory effects of vitamin D in the critically ill. t h s ig ij r u y tr p o .S c r. A D Van den Berghe G et al. JCEM 2003;88:4623-4632©2003 by Endocrine Society
  72. 72. Circulating cytokine levels with time in ICU. Elevated serum IL-6 levels, observed on ICU admission, decreased significantly with time in ICU, whereas elevated levels of TNFα and low IL-1 remained unaltered. t h s ig ij r u y tr p o .S c r. A D Van den Berghe G et al. JCEM 2003;88:4623-4632©2003 by Endocrine Society
  73. 73. t h s ig ij r u y tr p o .Sc r. AD
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  76. 76. Figure  3   Urinary  pyridinium  cross-­‐link  excre.on  is  increased  in   cri.cally  ill  surgical  pa.ents.   Shapses,  Sue;    Weissman,  Charles;    Seibel,  Markus;     Chowdhury,  Hasina     CriAcal  Care  Medicine.  25(1):85-­‐90,  January  1997.   t   h s ig ij r u y tr Figure  3  .  Nitrogen  (N)  balance  in  two  groups  of  criAcally   p ill  paAents.  Solid  circles,  paAents  who  stayed  in  the   intensive  care  unit  5  days  (n  =  5).  *Differs  from  zero   o .S nitrogen  balance,  p  <  .05.  c r. AD©  Williams  &  Wilkins  1997.    All  Rights  Reserved.    Published  by  Lippinco=  Williams  &  Wilkins,  Inc.   6  
  77. 77. t h s ig ij r u y tr p o .Sc r. AD
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  81. 81. t h s ig ij r u y tr p o .Sc r. AD
  82. 82. t h s ig ij r u y tr p o .Sc r. AD
  83. 83. Prevalence  of  bone  hyperresorpAon  in  CCI  •  49  CCI  paAents  •  Median  age  73  yrs,  M/F  =  28/21  •  22  Medical,  27  Surgical  •  Median  ICU  LOS  =  20  days   t•  Post-­‐tracheotomy  All  RCU  transfer  =  7  days   h s ig ij•  92%  of  popula0on  found  to  have  Abnormal  Bone  Resorp0on   r u   y trDistribuAon  of  PTH  levels  among  Subjects  with  high  urine  NTX   pNl  PTH  49%   o .SLow  PTH  9%  High  PTH    42%   c r. A D
  84. 84. t h s ig ijResponse  to  Treatment   r up  value  0.02  NS   y tr pPTH  Post  Rx  40  ±  28  53  ±  51   o .SPTH  Pre  Rx  93  ±  145  36  ±  29   cp  value  NS  <  0.01  Urine  NTX  Post  Rx  178  ±  123  100  ±  85   r. AUrine  NTX  Pre  Rx  187  ±  146  329  ±  238  Calcitriol  +   DCalcitriol  Pamidronate  NTX  Units  =  BCE/mmol  Cr;  PTH  Units  =  pg/mL  

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