Determining Skeletal Maturity using IGF-1 test.

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Original
article
Determining
skeletal
maturation
using
insulin-like
growth
factor
I
(IGF-I)
test
Shreya
Guptaa,∗,
Sandhya
Jaina,
Puneet
Guptab,
Anuradha
Deoskara
aDepartment
of
Orthodontics,
Government
College
of
Dentistry,
Indore
(M.P.),
India
bDepartment
of
Community
Dentistry,
Government
College
of
Dentistry,
Indore
(M.P.),
India
a
r
t
i
c
l
e
i
n
f
o
Article
history:
Received
29
March
2011
Accepted
1
September
2011
Keywords:
CVM
stages
IGF-1
MP3
stages
Orthodontic
therapy
Skeletal
maturity
a
b
s
t
r
a
c
t
Objective:
To
investigate
the
validity
of
Insulin
like
Growth
Factor
-1(IGF-1)
as
a
skeletal
maturity
indicator
by
comparing
serum
IGF-1
levels
with
the
stages
in
cervical
vertebral
maturation
(CVM)
and
in
the
middle
phalanx
of
the
third
finger
(MP3).
Materials
and
methods:
The
study
population
was
selected
by
using
simple
random
sampling
technique
and
consisted
of
30
female
subjects
in
the
age
range
of
8-23
years
who
had
blood
sample,
cephalometric
and
MP3
radiographs
taken
on
the
same
day.
Serum
IGF-I
estima-
tion
was
carried
out
on
the
blood
samples
using
chemiluminescence
immunoassay
(CLIA)
method.
CVM
was
evaluated
using
method
by
Baccetti
et
al
and
MP3
staging
was
done
using
Rajagopal
&
Kansal
method.
Mean
IGF-1
level
between
the
stages
was
compared
by
Kruskal-Wallis
and
Mann
Whitney
test.
Results:
Serum
IGF-1
levels
in
females
correlate
well
with
skeletal
maturity
determined
by
CVM
and
MP3
stages
and
increase
sharply
during
early
pubertal
stages
followed
by
a
decrease
in
late
puberty.
In
addition
we
hypothesis
that
serum
IGF-1
testing
can
be
under-
taken
as
a
preliminary
screening
test
in
patients
in
whom
the
orthodontist
predicts
the
possibility
of
using
myofunctional
appliance
but
in
whom
the
chronologic
age
is
not
sug-
gestive
for
a
growth
modification
therapy.
Conclusions:
The
finding
of
the
study
highlights
the
fact
that
the
serum
IGF-1
estimation
can
be
a
valuable
tool
in
assessing
skeletal
maturation.
©
2012
Società
Italiana
di
Ortodonzia
SIDO.
Published
by
Elsevier
Srl.
All
rights
reserved.
1. Introduction
Assessment
of
maturational
status
has
a
considerable
influ-
ence
on
diagnosis,
treatment
planning
and
the
eventual
outcome
of
orthodontic
treatment.
Clinical
decisions
regard-
ing
use
of
extra-oral
traction
forces,
functional
appliances,
extraction
versus
non-extraction
treatment
or
orthognathic
surgery
are
at
least
partially
based
on
growth
considerations.1
∗Corresponding
author.
Department
of
Orthodontics,
Government
College
of
Dentistry,
Indore
(M.P.),
India.
E-mail
address:
drshreyagupta@gmail.com
(S.
Gupta).
Timing
of
craniofacial
orthopedic
growth
modification
is
typically
linked
to
the
period
of
maximum
pubertal
growth
potential.2Because
of
the
wide
individual
variation
in
the
timing
of
the
pubertal
growth
spurt,
chronological
age
is
an
unreliable
guide
for
assessment
of
children
development
status.3A
study
by
Baccetti
et
al4concluded
that
the
diagnos-
tic
performance
of
chronologic
age
for
detection
of
the
onset
of
the
adolescent
peak
in
skeletal
maturation
was
very
low
both
in
males
and
females.
Various
other
parameters
for
the
1723-7785/$
–
see
front
matter
©
2012
Società
Italiana
di
Ortodonzia
SIDO.
Published
by
Elsevier
Srl.
All
rights
reserved.
doi:10.1016/j.pio.2011.09.006

Author's personal copy
progress
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orthodontics
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(
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289
detection
of
pubertal
growth
spurt
such
as
body
height5–8,
weight6,
menarche9,
voice
and
breast
changes9and
dental
development10,11 have
also
been
shown
to
be
unreliable
and
impractical
for
estimating
the
pubertal
growth
spurt.8,12–14
According
to
a
study
by
Krailassiri
et
al10 radiographic
dental
maturation
method
of
staging
canine
and
premolar
develop-
ment
was
also
not
a
meaningful
method
because
they
found
a
large
number
of
canines
and
first
premolars
attain
the
apical
closure
since
MP3
cap
stage
(middle
phalanx
of
the
third
fin-
ger,
the
epiphysis
caps
its
diaphysis
stage)
for
males
and
DP3u
stage
(distal
phalanx
of
the
third
finger,
complete
epiphyseal
union
stage)
onwards
for
females.10
Since
there
are
individual
variations
in
timing,
duration
and
velocity
of
growth,
skeletal
maturity
assessment
is
essen-
tial
in
designing
orthodontic
treatment
plans.15 Also,
the
assessment
of
skeletal
maturity
is
an
important
method
in
the
evaluation,
follow
up,
and
timing
of
therapy
in
children
with
growth
disorders,
such
as
constitutional
growth
retardation
and
growth
hormone
deficiency
as
well
as
endocrinal
diseases,
such
as
hypothyroidism,
congenital
adrenal
hyperplasia,
and
precocious
puberty.16
Skeletal
maturation
assessed
on
hand
wrist
radiographs
is
classically
considered
as
the
best
indicator
of
maturity.17–19 Its
main
drawback
is
that
an
additional
radiograph
is
required.
In
an
attempt
to
reduce
the
radiographic
exposure,
cervical
vertebral
maturation
can
be
assessed
on
lateral
cephalomet-
ric
radiographs.2Another
simple
and
practical
alternative
is
observation
of
progressive
ossification
of
the
MP3
(middle
pha-
lanx
of
the
third
finger)
on
intraoral
periapical
x-ray
film.20,21
However,
assessment
of
cervical
vertebral
stages,
MP3
stages
and
hand
wrist
radiographs
which
are
currently
used
to
identify
peak
mandibular
bone
growth
and
skeletal
maturity
not
only
involve
radiation
exposure
but
are
highly
subjective
techniques
consisting
of
a
qualitative
comparison
between
the
patient
radiographs
and
the
images
contained
in
the
atlas.
Recently
Gabriel
et
al22 evaluated
the
reproducibility
of
cervical
vertebral
maturation
(CVM)
stage
using
a
stringent
methodology.
Ten
practicing
orthodontists,
trained
in
CVM
method,
evaluated
30
individual
and
30
pair
of
cephalometric
radiographs
in
2
sessions
to
determine
the
CVM
stage.
Inter-
observer
and
intra-observer
agreement
levels
for
CVM
staging
were
determined.
Results
showed
that
inter-observer
agree-
ment
at
both
times
were
below
50%
whereas
intra-observer
agreement
was
62%.
Thus,
they
concluded
that
the
CVM
method
cannot
be
recommended
as
a
strict
clinical
guideline
for
evaluating
the
timing
of
orthodontic
treatment.
Similarly,
Chatzgianni
et
al23 also
recently
performed
a
study
to
measure
vertebral
shape
by
using
the
tools
of
geometric
morphomet-
rics
and
to
evaluate
the
correlation
and
predictive
power
of
vertebral
shape
on
skeletal
maturation.
They
concluded
that
evaluation
of
vertebral
shape
is
mainly
based
on
qualitative
criteria,
although
vertebral
shape
is
strongly
correlated
to
skeletal
maturity
but
does
not
offer
better
predictive
value
than
chronologic
age.
In
addition
an
inherent
disadvantage
of
cervical
vertebral
staging
and
other
radiographic
method
is
that
the
final
stage
of
development
does
not
necessar-
ily
indicate
the
completion
of
growth,
especially
mandibular
growth,
several
studies
have
shown
that
mandibular
growth
continues
even
after
radiographic
skeletal
maturity
in
certain
individuals.24,25
More
recently,
a
study
by
Ball
et
al26 has
proposed
that
cervical
vertebral
maturation
stages
cannot
accurately
iden-
tify
the
onset
of
the
peak
in
mandibular
growth
and
the
therefore,
CVM
stages
should
be
used
with
other
methods
of
biologic
maturity
assessment
when
considering
both
dento-
facial
orthopedic
treatment
and
orthognathic
surgery.
Thus,
due
to
the
inherent
shortcomings
of
the
radiography-
based
skeletal
maturation
methods,
correct
identification
of
different
phases
of
skeletal
maturation
represents
a
cru-
cial
issue
in
orthodontic
diagnosis
and
treatment
planning.27
However,
new
possibilities
may
be
offered
by
biochemical
markers.
Biomarkers
avoid
radiation
exposure,
and
they
rep-
resent
agents
that
are
involved
directly
in
bone
growth
and
remodeling.27 A
recent
study
by
Perinetti
et
al27 has
shown
that
gingival
crevicular
fluid
alkaline
phosphatase
(GCF
ALP)
level
relates
well
with
CVM
stages.
They
found,
a
twofold
peak
in
the
enzyme
activity
at
cervical
stage
3
(CS3)
and
cervical
stage
4
(CS4)
pubertal
stages,
compared
to
pre-pubertal
(CS1
and
CS2)
and
post-pubertal
stages
(CS5
and
CS6),
at
both
max-
illary
and
mandibular
sites.
Hence,
they
concluded
that
GCF
ALP
may
be
used
as
a
non-invasive
clinical
biomarker
for
iden-
tification
of
pubertal
growth
spurt
in
periodontally
healthy
subjects
scheduled
for
orthodontic
treatment.
Insulin-like
growth
factor
I
(IGF-I)
is
also
an
important
fac-
tor
which
has
been
reported
to
play
important
roles
in
the
growth
of
long
bone
as
well
as
the
growth
of
mandibular
condyle.28,29 IGF-I
is
synthesized
and
secreted
in
the
liver
fol-
lowing
stimulation
by
growth
hormone.
It
accelerates
growth,
differentiation
and
substrate
synthesis
activity
in
osteoblasts
and
chondroblasts.30–32 The
purpose
of
this
investigation
was
to
provide
the
orthodontist
with
an
additional
tool
to
help
determine
growth
potential
in
the
orthodontic
patient.
Present
study
basically
is
a
cross
sectional
investigation
to
check
the
validity
of
serum
IGF-1
levels
as
an
indicator
for
evaluation
of
skeletal
maturity
by
correlating
IGF-1
levels
to
cervical
ver-
tebral
stages
and
modified
MP3
stages
and
comparing
mean
IGF-1
levels
at
each
of
those
stages.
The
present
study
may
be
of
great
importance
because
it
allows
skeletal
maturity
to
be
estimated
in
an
objective
manner.
2. Materials
and
methods
The
sample
used
in
the
study
consisted
of
30
female
sub-
jects
selected
from
the
patients
coming
to
the
Department
of
Orthodontics
and
Dentofacial
Orthopedics
and
Depart-
ment
of
Pedodontics,
Government
College
of
Dentistry,
Indore,
India
by
using
simple
random
sampling
technique,
where
patients
meeting
the
set
inclusion
criteria
were
selected
from
the
daily
patient
register
to
eliminate
both
deliberate
and
unconscious
bias.
Inclusion
criteria
were
female
subjects
between
8
to
23
years
of
age,
information
about
birth
date
and
healthy
subjects.
Exclusion
criteria
were
subjects
suffering
from
any
serious
illness,
growth
abnormality
e.g.
craniofa-
cial
syndromes,
rickets,
medical
syndromes,
bone
disease,
bone
deformities,
bleeding
disorders
or
history
of
any
serious
trauma
or
injury
to
the
face
and
the
hand
and
wrist
region.
The
research
protocol
was
approved
by
Ethical
committee.
Parental/patient’s
informed
consent
was
taken
for
enrollment
of
each
subject
in
the
study.

Author's personal copy
290
progress
in
orthodontics
1
3
(
2
0
1
2
)
288–295
Lateral
cephalogram,
MP3
radiographs
on
intraoral
peri-
apical
films
were
obtained
of
each
subject
and
on
the
same
day
blood
samples
were
collected.
Serum
was
separated
from
the
blood
samples
and
was
labeled
with
a
patient
code
(without
any
mention
of
patient
details
such
as
name,
age,
sex)
and
was
properly
sealed
and
stored
in
thermocol
box
with
ice
pack
(kept
between
2
degrees
Celsius
–
8
degrees
Celsius)
and
sent
to
the
laboratory
for
chemiluminescence
immunoassay
for
determination
of
IGF-1
levels
by
a
fully
auto-
mated,
two-site
chemiluminescent
immunoassay
(Siemens
Immunolite
2000
immnoassay
machine
at
Metropolis
laboratories).
2.1. Principles
of
Operation*
The
instrument
uses
assay-specific
antibody
or
antigen-
coated
polystyrene
beads
as
the
solid
phase.
A
bead
is
dispensed
into
a
specially
designed
reaction
tube,
which
serves
as
the
vessel
for
the
incubation,
wash,
and
signal
devel-
opment
processes.
After
the
sample
is
incubated
with
an
alkaline
phosphatase-labeled
reagent,
the
reaction
mixture
is
separated
from
the
bead
by
spinning
the
reaction
tube
at
high
speed
along
its
vertical
axis.
The
fluid
is
transferred
to
a
coax-
ial
sump
chamber,
which
is
integral
to
the
bead/tube
wash
station.
Four
discrete
washes
occur
within
seconds,
allowing
the
reaction
tubes
to
be
processed
sequentially
with
uniform
timing.
The
bead
remains
in
the
reaction
tube
with
no
residual
unbound
label.
The
bound
label
is
then
quantified
using
the
dioxetane
substrate
to
produce
light.
Light
is
emitted
when
the
chemiluminescent
substrate
reacts
with
the
alkaline
phos-
phatase
label
bound
to
the
bead.
The
amount
of
light
emitted
is
proportional
to
the
amount
of
analyte
originally
present
in
the
sample.
This
light
emission
is
detected
by
the
pho-
tomultiplier
tube
(PMT)
and
results
are
calculated
for
each
sample.
2.2.
Chemiluminescent
Reaction*
During
the
initial
immune
reaction
between
the
reagent
anti-
bodies
and
the
analyte
in
the
sample,
that
component
of
the
reagent
labeled
with
alkaline
phosphatase
(known
as
the
con-
jugate)
is
bound
to
the
bead
within
the
reaction
tube.
The
amount
of
alkaline
phosphatase
bound
is
directly
propor-
tional
(for
a
sandwich
assay),
or
inversely
proportional
(for
a
competitive
assay)
to
the
concentration
of
the
analyte
in
the
patient
sample.
After
the
reaction
tube
is
washed,
a
lumino-
genic
substrate
is
added
to
the
reaction
tube.
Five
minutes
later,
the
reaction
tube
arrives
in
front
of
the
photomulti-
plier
tube
(PMT),
where
the
light
generated
by
the
luminogenic
reaction
is
measured.
The
enzyme-amplified
reaction
in
the
system
produces
a
prolonged
output
of
light
causing
the
tube
to
glow.
In
the
luminogenic
reaction
(illustrated
in
the
next
figure),
the
substrate
(an
adamantyl
dioxetane
phosphate)
is
dephosphorylated
into
an
unstable
intermediate
by
the
alkaline
phosphatase
bound
on
the
bead.
The
unstable
inter-
mediate
rapidly
and
spontaneously
breaks
down,
emitting
a
photon
of
light.
The
amount
of
light
emitted
is
directly
propor-
tional
to
the
amount
of
bound
alkaline
phosphatase.
A
single
serum
IGF-I
analysis
result
was
obtained
from
each
subject
and
computerized
report
(in
the
form
of
a
paper
print
out)
mentioning
the
IGF-1
levels
of
the
subject
was
generated.*
Lateral
cephalograms
were
taken
in
natural
head
posi-
tion.
All
the
radiographs
were
exposed
at
80
KVP,
9
mA
for
1.25
seconds.
The
cervical
staging
technique
as
described
by
Baccetti
et
al33 was
used
to
stage
the
cervical
vertebrae.
The
intra
oral
periapical
film
was
used
for
radiograph
of
the
middle
phalanx
of
the
third
finger
(MP3)
of
the
right
hand.
This
was
done
by
placing
the
hand
palm
downward
on
a
flat
non
metallic
surface.
The
middle
phalanx
of
the
right
middle
finger
was
placed
such
that
it
lied
at
the
center
of
the
x-ray
film.
The
cone
of
the
standard
dental
x-ray
machine
(60
KVP
and
7
mA)
was
positioned
in
light
contact
with
the
middle
pha-
lanx
perpendicular
to
the
dental
x-ray
film.
The
exposure
time
was
set
to
0.25
seconds.
For
interpretation
of
MP3
radiograph
method
introduced
by
Rajagopal
and
Kansal34 was
used.
For
all
the
samples
the
chief
investigator
evaluated
CVM
and
MP3
stages
twice
at
an
interval
of
15
days.
The
intra-
observer
reliability
was
100%
for
both
CVM
and
MP3
stages
(kappa
=
1.0).
Another
senior
investigator
of
the
study
eval-
uated
the
radiographs
independently.
The
inter-observer
reliability
was
high
(kappa
=
0.918
for
CVM
staging
and
kappa
=
0.877
for
MP3
staging).
The
data
was
checked
for
assumptions
of
normality
by
Shapiro-Wilk
test.
Since
the
data
did
not
follow
normality,
non-parametric
tests
were
used.
The
IGF-1
levels
between
the
groups
were
compared
using
Kruskal-Wallis
ANOVA
(Table
1a,
2a).
The
individual
group
differences
were
tested
using
Mann-Whitney
test.
Bonferroni
correction
was
used
for
pair-wise
analysis,
alpha
value
was
divided
by
15
(num-
ber
of
comparisons)
and
the
level
of
significance
was
set
at
0.05/15
=
0.0033.Data
was
analyzed
using
SPSS
for
Windows
(ver
18.0).
3.
Results
The
IGF-1
level
of
the
subjects
ranged
from
208
to
420
ng/ml
(total
median
IGF-1
=
257
ng/ml
and
total
mean
IGF-1
=
290.43
+
71.18
ng/ml).
Table
1a
and
Table
2a
give
descriptive
IGF-1
statistics
for
different
CVM
and
MP3
stages
respectively.
Kruskal
Wallis
ANOVA
showed
significant
differences
in
IGF-1
levels
between
different
CVM
and
MP3
stages.
The
mean
IGF-1
level
in
cervical
stage
1
(CS1)
was
216
+
7.53
ng/ml
which
rose
to
its
peak
in
CS3
with
397
+
20.76
and
then
started
to
decline
to
a
mean
value
of
249.25
+
9.98
ng/ml
for
CS6.
Similarly,
the
mean
IGF-1
level
in
MP3F
stage
was
218
+
8.73
ng/ml
which
rose
to
its
peak
in
MP3G
stage
with
397
+
20.76
and
then
started
to
decline
to
a
mean
value
of
263.14
+
23.57
ng/ml
for
MP3I
stage.
The
mean
IGF-1
levels
at
CS3
is
significantly
differing
from
CS2
and
CS4
(Table
1b)
and
mean
IGF-1
levels
at
MP3G
stage
is
signifi-
cantly
differing
from
MP3F,
MP3FG
and
MP3I
stages
(Table
2b)
as
assessed
by
pair-wise
comparisons
using
Mann-Whitney
test.
∗[-
from
Immulite
2000
operator’s
manual;
available
at:
http://sky2.ch/Doc/I2500.pdf].

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Table
1a
–
IGF-1
levels
of
subjects
in
different
CVM
stages
(N
=
30).
CVM
Staging
N
Mean
IGF-1
(ng/ml)
Std.
Deviation
95%
Confidence
Interval
Median
IGF-1
(ng/ml)
Min-Max
CVM
Stage
1
4
216.00
7.53
208.62
-
223.38
215.50
208
-
225
CVM
Stage
2
6
244.33
8.41
237.61
-
251.06
248.50
229
-
250
CVM
Stage
3
8
397.00
20.76
382.61
-
411.39
401.50
364
-
420
CVM
Stage
4
5
278.80
43.27
240.87
-
316.73
289.00
209
-320
CVM
Stage
5
3
272.00
26.15
242.40
-
301.60
260.00
254
-
302
CVM
Stage
6
4
249.25
9.98
239.47
-
259.03
248.00
240
-
261
Total
30
290.43
71.18
264.96
-
315.91
257.00
208
-
420
Kruskal
Wallis
ANOVA;
p
<
0.05;
Significant.
Table
1b
–
Inter-group
comparison
of
various
CVM
stages.
CVM
Stage
Compared
to
Stage
p
value
12p
=
0.010
NS
3p
=
0.006
NS
4p
=
0.086
NS
5
p
=
0.034
NS
6
p
=
0.021
NS
2
3
p
=
0.002
Sig
4
p
=
0.100
NS
5
p
=
0.020
NS
6
p
=
0.453
NS
3
4
p
=
0.003
Sig
5
p
=
0.014
NS
6
p
=
0.006
NS
4
5
p
=
0.456
NS
6
p
=
0.142
NS
5
6
p
=
0.212
NS
Bonferroni’s
correction
for
15
comparisons,
alpha
value
was
set
to
0.05/15
=
0.0033.
(p
<
0.0033).
Sig
-
Significant,
NS
-
Non
significant.
4.
Discussion
The
results
of
the
study
reveal
that
in
all
subjects
the
highest
mean
value
of
IGF-1
levels
were
observed
at
cervical
stage
3
followed
by
cervical
stage
4
and
cervical
stage
5,
whereas
the
minimum
IGF-1
levels
were
found
in
cervical
stage
1
(Table
1a).
Based
on
the
mean
values
of
IGF-1
it
was
found
that
IGF-1
levels
at
cervical
stage
3
is
differing
significantly
from
cervical
stage
2
and
cervical
stage
4
(p
<
0.0033)
(Table
1b).
Correlating
IGF-1
with
MP3
stages
in
all
subjects
it
was
found
that
the
highest
mean
value
of
IGF-1
levels
were
observed
at
MP3G
followed
by
MP3HI
and
MP3I,
whereas
the
lowest
IGF-1
levels
were
observed
at
MP3F
stage
(Table
2a).
Table
2b
–
Inter-group
comparison
of
various
MP3
stages.
MP3
Stage
Compared
to
Stage
p
value
MP3
F MP3
FG p
=
0.009
NS
MP3
Gp
=
0.003
Sig
MP3
Hp
=
0.699
NS
MP3
HI
p
=
0.025
NS
MP3
I
p
=
0.004
NS
MP3
FG
MP3
G
p
=
0.003
Sig
MP3
H
p
=
0.100
NS
MP3
HI
p
=
0.024
NS
MP3
I
p
=
0.142
NS
MP3
G
MP3
H
p
=
0.036
NS
MP3
HI
p
=
0.014
NS
MP3
I
p
=
0.001
Sig
MP3
H
MP3
HI
p
=
0.248
NS
MP3
I
p
=
0.557
NS
MP3
HI
MP3
I
p
=
0.086
NS
Bonferroni’s
correction
for
15
comparisons,
alpha
value
was
set
to
0.05/15
=
0.0033.
(p
<
0.0033).
Sig-
Significant,
NS
-
Non
significant.
It
was
observed
that
IGF-1
levels
were
highest
in
MP3G
stage
which
showed
significant
difference
from
MP3F,
MP3FG
and
MP3I
stages
(p
<
0.0033)
(Table
2b).
Findings
of
this
study
are
consistent
with
previous
studies
that
show
that
serum
IGF-1
peak
in
early
puberty
followed
by
a
decrease
in
late
puberty.35–39 Our
study
is
correlating
well
with
the
study
by
Brabant
et
al39 in
which
they
established
refer-
ence
ranges
of
serum
IGF-I
levels
in
male
and
female
subjects
separately
between
age
group
of
1
month
to
88
yrs.
In
their
study
there
was
an
age
related
increase
in
serum
IGF-
I
lev-
els
during
the
early
pubertal
stages
followed
by
a
decrease
in
late
puberty.
Furthermore,
we
found
that
the
highest
mean
Table
2a
–
IGF-1
levels
of
subjects
in
different
MP3
stages
(N
=
30).
MP3
Staging
N
Mean
IGF-1
(ng/ml)
Std.
Deviation
95%
Confidence
Interval
Median
IGF-1
(ng/ml)
Min-Max
MP3
F
5
218.60
8.73
210.94
-
226.26
219.00
208
-
229
MP3
FG
5
247.40
4.22
243.70
-
251.10
249.00
240
-
250
MP3
G
8
397.00
20.76
382.61
-
411.39
401.50
364
-
420
MP3
H
2
239.50
43.13
179.72
-
299.28
239.50
209
-
270
MP3
HI 3
295.33
31.39
259.81
-
330.85
306.00
260
-
320
MP3
I7
263.14
23.57
245.68
-
280.60
254.00
240
-
302
Total 30
290.43
71.18
264.96
-
315.91
257.00
208
-
420
Kruskal
Wallis
ANOVA;
p
<
0.05;
Significant.

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IGF-1
levels
was
397
ng/ml
which
is
near
to
highest
mean
IGF-
I
levels
as
mentioned
in
the
study
by
Brabant
et
al.39
4.1.
Rationale
for
using
IGF-
1
for
assessment
of
skeletal
maturity
over
Radiographic
methods
1. Radiographic
techniques
for
skeletal
maturation
in
addi-
tion
to
radiation
exposure
are
subjective
methods
that
lack
the
ability
to
determine
the
intensity
of
the
growth
spurt
and
the
end
of
growth.24
2.
Several
studies
have
shown
that
mandibular
growth
con-
tinues
even
after
radiographic
skeletal
maturity.25 Study
by
Masoud
et
al24 has
shown
that
IGF
–
1
levels
were
relatively
high
in
many
subjects
who
were
at
cervical
stage
6
and
had
supposedly
completed
their
growth.
3. According
to
the
most
recent
study26,
when
treatment
tim-
ing
is
crucial
for
a
successful
orthodontic
outcome,
the
CVM
assessment
should
be
used
with
other
maturity
indicators.
Skeletal
maturity
should
not
be
assessed
by
the
cervical
vertebrae
alone.
4.2.
Rationale
for
using
IGF-1
over
other
biochemical
indicators
1 There
have
been
various
studies
on
local
and
systemic
factors
regulating
bone
growth
like
Ihh40,
PTHrP41,
FGF42,
BMP43,
VEGF43 etc.
However
these
were
immunohistological
studies
carried
out
on
experimental
animals.
Their
defi-
nite
blood
levels
during
growth,
feasibility
and
reliability
to
be
used
for
assessment
of
skeletal
maturity
are
not
well
documented.
2
IGF-1
has
been
extensively
studied
and
shown
to
play
a
prin-
ciple
role
in
systemic
and
local
regulation
of
both
prenatal
and
postnatal
longitudinal
bone
growth44 and
is
mediator
of
growth
hormone
function.45 Unlike
GH,
IGF-1
levels
do
not
fluctuate
throughout
the
day.24
4.3.
Rationale
for
using
blood
samples
(serum)
for
estimation
of
IGF-1
levels
IGF-1
is
measurable
in
serum
(in
which
it
was
first
detected)
as
well
as
urine
and
saliva.46
1.
Salivary
IGF-1
levels
reflect
its
levels
in
the
plasma.
How-
ever,
salivary
IGF-1
levels
are
extremely
low:
less
than
1%
of
serum
levels.
This
makes
accurate
measurements
difficult.
In
addition,
contamination
with
gingival
fluid
or
blood
can
result
in
inaccurate
measurement.46
2. Urine
IGF-1
levels
demand
for
greater
patient
cooperation.
In
addition
it
would
be
embarrassing
and
cumbersome
for
the
patient
as
well
as
there
are
chances
of
contamination
of
the
sample
by
the
patient.
4.4.
Limitation
of
the
study
The
finding
underlines
the
fact
that
selection
of
a
representa-
tive
reference
population
is
a
delicate
task
and
a
big
sample
size,
collected
from
different
sources;
reduce
the
risk
of
a
non
desirable
impact
from
a
single
or
few
subpopulations.
4.5. Scope
for
further
studies
A
longitudinal
study
should
be
undertaken
to
confirm
the
use-
fulness
of
this
technique
to
accurately
determine
the
timing
and
possibly
the
intensity
of
a
patient’s
growth
spurt
and
to
determine
whether
IGF-1
levels
are
good
predictor
of
residual
facial
growth.
4.6.
Clinical
Applications
This
study
has
helped
to
obtain
an
additional
valid
tool
for
orthodontic
diagnosis
and
treatment
planning.
IGF-1
estima-
tion
by
immunoassay
technique
can
be
advantageous
over
the
conventional
technique
like
cervical
vertebral
staging
and
MP3
staging
which
entails
subjective
errors.
Serum
IGF-1
testing
can
be
undertaken
as
a
preliminary
screening
test
in
patients
in
whom
the
orthodontist
predicts
the
possibility
of
using
myofunctional
appliance
but
in
whom
the
chronologic
age
is
not
suggestive
for
a
growth
modification
therapy.
If
the
patient’s
IGF-1
level
falls
in
the
peak
reference
range,
patient
is
likely
to
be
in
the
pubertal
growth
spurt.
Hence
routine
use
of
this
test
may
broaden
the
treatment
plan-
ning
options
for
utilizing
myofunctional
appliances.In
cases
with
condylar
hyperplasia
and
active
growing
bone
disorders
in
adults
S-IGF-1
estimation
might
be
used
in
diagnosing/
assessing
presence
or
absence
of
active
growth.
Several
stud-
ies
have
shown
the
correlation
between
IGF-I
and
growth
at
condylar
cartilage.47–49
5.
Conclusions
1
Serum
IGF-1
levels
in
females
correlate
well
with
skeletal
maturity
as
determined
by
CVM
stages
and
MP3
stages
and
increase
sharply
during
early
pubertal
stages
followed
by
a
decrease
in
late
puberty.
2
The
findings
of
the
present
study
suggest
that
serum
IGF-1
levels
can
be
a
valuable
tool
in
assessment
of
skeletal
matu-
rity.
However,
longitudinal
data
are
needed
to
confirm
the
usefulness
of
this
technique.
Conflict
of
interest
The
authors
have
reported
no
conflicts
of
interest.
Riassunto
Obiettivo:
Esaminare
la
validità
del
fattore
di
crescita
insulinosimile
1
(IGF-1)
come
indicatore
della
maturazione
scheletrica
confrontando
i
livelli
sierici
di
IGF-1
con
gli
stadi
di
maturazione
delle
vertebre
cervicali
(CVM)
e
della
falange
media
del
dito
medio
della
mano
(MP3).
Materiali
e
metodi:
La
popolazione
dello
studio
è
stata
selezion-
ata
utilizzando
la
tecnica
del
campionamento
per
randomizzazione
semplice
ed
è
composta
da
30
soggetti
di
sesso
femminile
di
età
com-
presa
tra
gli
8
e
i
23
anni
a
cui
sono
stati
effettuati
un
prelievo
del
sangue,
una
radiografia
cefalometrica
e
la
radiografia
della
falange
media
del
dito
medio
nella
stessa
giornata.
I
campioni
di
sangue
sono
stati
utilizzati
per
la
valutazione
dell’IGF-1
nel
siero
con
la
tec-
nica
del
dosaggio
immunologico
in
chemiluminescenza
(CLIA).
La

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maturazione
delle
vertebre
cervicali
(CVM)
è
stata
valutata
utiliz-
zando
il
metodo
di
Baccetti
et
al.
mentre
lo
stadio
di
maturazione
della
falange
media
del
dito
medio
è
stato
determinato
utilizzando
il
metodo
Rajagopal
e
Kansal.
Il
confronto
del
livello
medio
di
IGF-1
tra
i
vari
stadi
è
stato
condotto
utilizzando
i
test
di
Kruskal-Wallis
e
di
Mann
Whitney.
Risultati:
Il
livelli
sierici
di
IGF-1
riscontrati
nel
campione
composto
da
soggetti
di
sesso
femminile
mostrano
una
buona
correlazione
con
la
maturità
scheletrica
determinata
usando
la
valutazione
degli
stadi
delle
vertebre
cervicali
e
della
falange
media
del
dito
medio,
ed
aumentano
marcatamente
durante
le
prime
fasi
puberali,
per
poi
diminuire
a
fine
pubertà.
Inoltre
si
delinea
l’ipotesi
che
l’analisi
dei
livelli
sierici
dell’IGF-1
possa
essere
utilizzata
come
test
preliminare
di
screening
in
quei
pazienti
per
i
quali
l’ortodontista
prevede
la
pos-
sibilità
di
usare
un
apparecchio
miofunzionale
ma
per
i
quali
l’età
cronologica
rende
sconsigliabile
un
trattamento
basato
sulle
modi-
fiche
della
crescita.
Résumé
Objectif:
Prendre
en
examen
la
validité
du
facteur
de
croissance
analogue
à
l’insuline
-1
(IGF-1)
comme
indicateur
de
la
matura-
tion
squelettique
en
comparant
les
niveaux
d’IGF-1
dans
le
sérum
avec
les
stades
de
maturation
des
vertèbres
cervicales
(CVM)
et
de
la
phalange
moyenne
du
doigt
moyen
de
la
main
(MP3).
Matériels
et
méthodes:
La
population
de
l’étude
a
été
sélec-
tionnée
au
moyen
de
la
technique
de
l’échantillonnage
fondé
sur
l’aléatorisation
simple.
Elle
est
composée
de
30
sujets
de
sexe
féminin,
âge
8
à
23
ans,
soumis
à
une
prise
de
sang,
une
radiographie
céphalométrique
et
une
radiographie
de
la
phalange
moyenne
du
doigt
moyen
pendant
le
même
jour.
Les
échantillons
de
sang
ont
été
utilisés
pour
évaluer
l’IGF-1
dans
le
sérum
au
moyen
de
la
tech-
nique
du
dosage
immunologique
par
chimioluminescence
(CLIA).
La
maturation
des
vertèbres
cervicales
(CVM)
a
été
évaluée
en
utilisant
la
méthode
de
Baccetti
et
al.
Par
contre,
le
stade
de
maturation
de
la
phalange
moyenne
du
doigt
moyen
a
été
établi
par
la
méthode
Rajagopal
et
Kansal.
La
comparaison
du
niveau
moyen
d’IGF-1
entre
les
différents
stades
a
été
menée
par
le
biais
des
tests
Kruskal-Wallis
et
MannWhitney.
Résultats:
Les
niveaux
sériques
d’IGF-1
enregistrés
dans
l’échantillon
composé
de
sujets
de
sexe
féminin
fait
état
d’une
bonne
corrélation
avec
la
maturation
squelettique,
déterminée
en
utilisant
l’évaluation
des
stades
des
vertèbres
cervicales
et
de
la
phalange
moyenne
du
doigt
moyen.
Une
forte
hausse
du
niveau
sérique
d’IGF-1
a
été
enregistrée
pendant
les
premières
phases
pubérales,
et
ensuite
une
baisse
à
la
fin
de
la
puberté.
Par
surcroît,
l’hypothèse
est
envisagée
que
l’analyse
de
l’IGF-1
du
sérum
peut
être
utilize
comme
test
préalable
de
dépistage
chez
ces
patients
pour
lesquels
l’orthodontiste
prévoit
la
possibilité
d’utiliser
un
appareillage
myofonctionnel,
mais
pour
lesquels
l’âge
chronologique
ne
suggère
pas
un
traitement
fondé
sur
les
modifications
de
la
croissance.
Conclusions:
Les
résultats
de
l’étude
mettent
en
relief
que
l’évaluation
de
l’IGF-1
du
sérum
peut
bien
représenter
un
instrument
valable
en
vue
de
déterminer
la
maturation
squelettique.
Resumen
Objetivo:
Examinar
la
validez
del
factor
de
crecimiento
insuli-
nosimilar
-1
(IGF-1),
como
indicador
de
la
maduración
esquelética
comparando
los
niveles
de
IGF-1
en
el
suero
con
los
estadios
de
maduración
de
las
vértebras
cervicales
(CVM)
y
de
la
falange
media
del
dedo
medio
de
la
mano
(MP3).
Materiales
y
métodos:
La
población
del
estudio
fue
elegida
uti-
lizando
la
técnica
del
muestreo
por
aleatorización
simple,
integrada
por
30
sujetos
de
sexo
femenino,
cuya
edad
varía
de
8
a
23
a˜
nos,
sometidos
a
una
toma
de
sangre,
una
radiografía
cefalométrica
y
una
radiografía
de
la
falange
media
del
dedo
medio
en
el
mismo
día.
Las
muestras
de
sangre
fueron
utilizadas
para
valorar
el
IGF-1
en
el
suero
por
medio
de
la
técnica
de
la
dosificación
inmunológica
en
quimioluminiscencia
(CLIA).
La
maduración
de
las
vértebras
cervi-
cales
(CVM)
fue
valorada
aplicando
el
método
de
Baccetti
et
al.
En
cambio,
el
estadio
de
maduración
de
la
falange
media
del
dedo
medio
fue
determinado
gracias
al
método
Rajagopal
y
Kansal.
La
compara-
ción
del
nivel
medio
de
IGF-1
entre
los
diferentes
estadios
fue
llevada
a
cabo
utilizando
las
pruebas
de
Kruskal-Wallis
y
de
Mann-Whitney.
Resultados:
Los
niveles
séricos
de
IGF-1
en
la
muestra
integrada
por
sujetos
de
sexo
femenino
destacan
una
buena
correlación
con
la
maduración
esquelética
determinada
utilizando
la
valoración
de
los
estadios
de
las
vértebras
cervicales
y
de
la
falange
media
del
dedo
medio.
Se
incrementan
marcadamente
en
las
primeras
fases
puberales,
y
luego
disminuyen
al
final
de
la
pubertad.
Además,
se
baraja
la
hipótesis
de
que
el
análisis
de
los
niveles
séricos
de
IGF-1
pueda
ser
utilizado
como
ensayo
previo
de
cribado
en
aquel-
los
pacientes
para
quienes
el
ortodoncista
contempla
la
posibilidad
de
utilizar
un
aparato
miofuncional,
pero
para
los
mismos
la
edad
cronológica
hace
desaconsejable
un
tratamiento
fundamentado
en
las
modificaciones
del
crecimiento.
Conclusión:
Los
resultados
del
estudio
ponen
de
relieve
que
la
valoración
del
IGF-1
del
suero
puede
suponer
una
herramienta
valiosa
para
determinar
la
maduración
del
esqueleto.
r
e
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