Bone metabolism and intensive care

Bone
metabolism
on
the
ICU

ht
Wat
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

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

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

Wat
is
de
relaAe
IC
en
bo=en
??

t
h s
ig ij
r u
y tr
p
o .S
c
r. A
D

t
h s
ig ij
r u
y tr
p
o .S
c
r. A
D
Bone
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.

Examples
of
Causes
of
Immobilisa.on
Bone
Loss

t
h s
ig ij
▶
Damage
to
the
vertebral
bone
marrow
with

r u
deleterious
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

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.

t
h s
ig ij
r u
y tr
p
o .S
c
r. A
D

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 u
aker
recovery

y tr
Nierman
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

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

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

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

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

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

t
invesAgated
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 ij
SCI)
and
n
=
34
long-‐term
SCI
pa.ents
(>
5
years
aQer
SCI).

r u
LiVle
is
known
regarding
the
extend
of
the
osteoporosis
as
well
as
the
causaAve
factors.

p y tr
Measurements
of
the
BMD
in
the
proximal
femur
and
the
lumbar
spine
(DEXA),
of
the
osteoblast
marker
BAP
from

o .S
serum,
the
osteoclast
markers
PYD
(pyridinoline),
DPD
(desoxy-‐pyridinoline)
and
NTx
(N-‐telopepAde
of
collagen
type
I)

from
urine.

c
A
a
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

D
slightly
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.

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 .S
c
r. A
D

©
Williams
&
Wilkins
1997.

All
Rights
Reserved.

Published
by
Lippinco=
Williams
&
Wilkins,
Inc.
2

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 .S
c
r. A
D

©
Williams
&
Wilkins
1997.

All
Rights
Reserved.

Published
by
Lippinco=
Williams
&
Wilkins,
Inc.
3

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. A
D

©
Williams
&
Wilkins
1997.

All
Rights
Reserved.

Published
by
Lippinco=
Williams
&
Wilkins,
Inc.
5

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. A
D

©
2011
by
the
Society
of
CriAcal
Care
Medicine
and
Lippinco=
Williams
&
Wilkins.

Published
by
Lippinco=
Williams
2

&
Wilkins,
Inc.

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. A
D

©
2011
by
the
Society
of
CriAcal
Care
Medicine
and
Lippinco=
Williams
&
Wilkins.

Published
by
Lippinco=
Williams
3

&
Wilkins,
Inc.

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. A
D

©
2011
by
the
Society
of
CriAcal
Care
Medicine
and
Lippinco=
Williams
&
Wilkins.

Published
by
Lippinco=
Williams
4

&
Wilkins,
Inc.

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. A
D

©
2011
by
the
Society
of
CriAcal
Care
Medicine
and
Lippinco=
Williams
&
Wilkins.

Published
by
Lippinco=
Williams
5

&
Wilkins,
Inc.

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. A
D

©
2011
by
the
Society
of
CriAcal
Care
Medicine
and
Lippinco=
Williams
&
Wilkins.

Published
by
Lippinco=
Williams
6

&
Wilkins,
Inc.

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. A
D

©
2011
by
the
Society
of
CriAcal
Care
Medicine
and
Lippinco=
Williams
&
Wilkins.

Published
by
Lippinco=
Williams
7

&
Wilkins,
Inc.

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. A
D

©
2011
by
the
Society
of
CriAcal
Care
Medicine
and
Lippinco=
Williams
&
Wilkins.

Published
by
Lippinco=
Williams
8

&
Wilkins,
Inc.

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. A
D

©
2011
by
the
Society
of
CriAcal
Care
Medicine
and
Lippinco=
Williams
&
Wilkins.

Published
by
Lippinco=
Williams
9

&
Wilkins,
Inc.

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 in

c
• 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 failure

D
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

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 world's 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.

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.

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.

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.

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
Abstract

c
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

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 primarily

D
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.

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 in

c
• 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 but

D
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.

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

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 Vincent's 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.

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.

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

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

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


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


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


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


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


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. A
D

©
Williams
&
Wilkins
1997.

All
Rights
Reserved.

Published
by
Lippinco=
Williams
&
Wilkins,
Inc.
6

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 tr
DistribuAon
of
PTH
levels
among
Subjects
with
high
urine
NTX

p
Nl
PTH
49%

o .S
Low
PTH
9%

High
PTH

42%

c
r. A
D

t
h s
ig ij
Response
to
Treatment

r u
p
value
0.02
NS

y tr
p
PTH
Post
Rx
40
±
28
53
±
51

o .S
PTH
Pre
Rx
93
±
145
36
±
29

c
p
value
NS
<
0.01

Urine
NTX
Post
Rx
178
±
123
100
±
85

r. A
Urine
NTX
Pre
Rx
187
±
146
329
±
238

Calcitriol
+

D
Calcitriol
Pamidronate

NTX
Units
=
BCE/mmol
Cr;
PTH
Units
=
pg/mL

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