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Bone mineral density is associated with carotid atherosclerosis in healthy postmenopausal women: a longitudinal analysis of randomized clinical trial data
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Bone mineral density is associated with carotid atherosclerosis in healthy postmenopausal women: a longitudinal analysis of randomized clinical trial data
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Content
Bone
Mineral
Density
is
Associated
with
Carotid
Atherosclerosis
in
Healthy
Postmenopausal
Women :A
Longitudinal
Analysis
of
Randomized
Clinical
Trial
Data
By
Jiaonan
Li
Thesis
Submitted
in
Partial
Fulfillment
of
the
Requirements
for
the
Degree
of
Master
of
Science
in
Biostatistics
University
of
Southern
California
December
2015
I
ABSTRACT
Background
and
purpose:
Atherosclerosis
and
osteoporosis
are
major
causes
of
morbidity
and
mortality
in
postmenopausal
women.
Our
study
aimed
to
analyze
the
association
between
progression
of
carotid
artery
intima-‐media
thickness
(CIMT)
and
bone
mineral
density
(BMD),
providing
more
evidence
for
the
relation
between
osteoporosis
and
subclinical
atherosclerosis
in
postmenopausal
women.
Methods:
In
this
longitudinal
analysis,
349
postmenopausal
women
were
followed
for
3
years,
and
had
an
average
6
CIMT
measurements.
BMD
had
an
average
3
measurements
using
DEXA;
we
used
the
baseline
BMD
measurements
from
the
total
hip
and
lumbar
spine.
We
used
a
linear
mixed-‐effects
model
to
analyze
the
association
between
CIMT
progression
and
baseline
BMD
and
other
clinical
variables.
Results:
Longitudinally,
both
total
hip
and
lumbar
spine
BMD
were
significantly
inversely
associated
with
CIMT
progression
(P=0.01,
P=0.03).
The
mean
CIMT
rate
was
0.002
mm/year
(95%
CI:
-‐0.020,
-‐0.003)
lower
per
0.137g/cm
2
total
hip
BMD.
The
mean
CIMT
rate
was
0.001
mm/year
(95%
CI:
-‐0.016,
-‐0.001)
lower
per
0.122g/cm
2
mean
lumbar
spine
BMD.
After
adjusting
for
age,
the
longitudinal
association
between
total
hip
BMD
and
CIMT
did
not
change.
Conclusions:
Low
BMD
in
the
total
hip
and
lumbar
spine
may
represent
a
marker
of
both
osteoporosis
and
atherosclerosis
progression
for
healthy
postmenopausal
II
women.
Postmenopausal
women
at
higher
risk
for
osteoporosis
should
also
have
concern
about
the
risk
of
atherosclerosis.
These
results
have
clinical
and
public
health
implications
with
regard
to
co-‐occurrence
of
osteoporosis
and
atherosclerosis
for
postmenopausal
women
in
the
United
States.
III
DEDICATION
I
dedicate
my
thesis
to
my
big
family.
A
special
feeling
of
gratitude
to
my
loving
parents,
Weiguo
Li
and
Yan
Wen,
who
support
me
to
finish
my
graduate
school
and
encourage
me
to
pursue
the
things
I
love.
I
also
dedicate
my
thesis
to
my
friends
who
have
supported
me
throughout
the
process,
especially
Wendy
Cai
for
being
very
patient
to
answer
my
questions.
IV
ACKNOWLEDGEMENT
I
wish
to
thank
all
my
committee
members
who
were
generous
with
their
expertise
and
precious
time.
I
wish
to
thank
my
committee
chair
Wendy
Mack,
who
helps
me
revise
my
thesis
many
times
with
great
patient.
Without
her
help,
I
could
not
finish
my
thesis
timely.
I
wish
to
thank
my
committee
member
Dr.
Roksana
Karim,
who
helping
me
through
this
program.
Without
her
guidance
and
design,
the
results
of
this
research
could
not
have
been
found.
I
wish
to
thank
Dr.
Howard
N
Hodis,
who
provide
the
clinical
trial
dataset.
Finally,
I
wish
to
thank
all
the
staffs
in
preventive
medicine
department
for
their
excitement
to
provide
feedback
made
the
completion
of
thesis
an
enjoyable
experience.
V
TABLE
OF
CONTENTS
ABSTRACT
......................................................................................................................................................
I
DEDICATION
...............................................................................................................................................
III
ACKNOWLEDGEMENT
...........................................................................................................................
IV
TABLE
OF
CONTENT
................................................................................................................................
V
LIST
OF
TABLES
......................................................................................................................................
VII
INTRODUCTION
..........................................................................................................................................
1
METHODS
......................................................................................................................................................
4
Study
Population
........................................................................................................................
4
Assessment
of
Bone
Mineral
Density
................................................................................
4
Assessment
of
Atherosclerosis
Progression
..................................................................
5
Assessment
of
Clinical
Variables
.........................................................................................
6
Statistical
Analysis
....................................................................................................................
6
RESULTS
......................................................................................................................................................
10
Clinical
Variables,
CIMT
and
BMD
in
Postmenopausal
Women
.........................
10
Cross-‐sectional
Association
between
BMD
and
Clinical
Variables
...................
12
Univariate
Association
between
CIMT
and
Clinical
Variables
and
BMD
........
15
Multivariable
Association
between
Total
Hip
BMD
and
CIMT
............................
17
Effect
Modification
by
BMI
and
Smoking
.....................................................................
19
DISCUSSION
...............................................................................................................................................
20
Associations
of
BMD
with
Clinical
Variables
..............................................................
20
VI
Association
of
CIMT
with
Clinival
Variables
...............................................................
21
Association
of
CIMT
Rate
and
Total
Hip
BMD
............................................................
21
Biological
Link
and
Possible
Pathophysiological
Mechanisms
...........................
22
REFERENCES
.............................................................................................................................................
25
VII
LIST
OF
TABLES
Table
1.
Baseline
Characteristics
of
Study
Population
.............................................................
11
Table
2.
Baseline
Cross-‐sectional
Association
between
BMD
and
Clinical
Variables
............................................................................
14
Table
3.
Univeriate
Mixed
Effects
Associations
between
CIMT
and
Clinical
Variables
and
BMD
...........................................................................
16
Table
4.
Mixed
Effects
Model
of
CIMT
and
Total
Hip
BMD
with
Age
Adjustment
.............................................................................
18
1
INTRODUCTION
Atherosclerosis
is
the
primary
cause
of
heart
disease
and
stroke.
In
Westernized
societies,
it
is
the
underlying
cause
of
about
half
of
all
deaths
for
postmenopausal
women
[1].
Atherosclerosis
is
an
inevitable
degenerative
consequence
of
aging
[2].
Epidemiological
studies
have
revealed
several
additional
important
environmental
and
genetic
risk
factors
associated
with
atherosclerosis,
such
as
obesity,
smoking
and
metabolic
syndrome
[1].
Osteoporosis
is
a
metabolic
process
that
weakens
bone,
increasing
the
risk
for
fractures
[3].
In
the
United
States,
30%
of
postmenopausal
women
have
osteoporosis
[4].
Women
are
at
greater
risk
for
osteoporosis
than
men,
and
there
is
a
direct
relationship
between
the
reduction
of
endogenous
estrogen
levels
at
menopause
and
the
development
of
osteoporosis
[3].
Epidemiological
studies
have
revealed
important
risk
factors
for
osteoporosis,
including
older
age,
ethnicity
(in
particular
non-‐Hispanic
Whites
and
Asians
are
at
higher
risk),
lower
body
weight,
current
smoking
and
hypertension.
More
than
40
million
American
women
are
currently
postmenopausal
and
as
the
United
States
population
ages,
the
number
of
women
entering
menopause
steadily
increases
by
>1
million
American
women
per
year
[5].
Atherosclerosis
and
osteoporosis
are
major
causes
of
morbidity
and
mortality
in
postmenopausal
women.
Both
osteoporosis
and
atherosclerosis,
including
vascular
calcification
have
largely
been
attributed
to
the
aging
process
[6].
In
addition
to
menopause
and
2
advanced
age,
other
risk
factors
for
vascular
disease
such
as
dyslipidemia,
oxidative
stress,
inflammation,
hypertension
and
diabetes
have
also
been
related
to
lower
bone
mineral
density
[7].
Therefore,
the
interrelation
between
the
two
age-‐related
processes
of
atherosclerosis
and
osteoporosis
requires
inquiry.
Carotid
artery
intima-‐media
thickness
(CIMT),
measured
by
high-‐resolution
B-‐
mode
ultrasound,
is
a
commonly
accepted
measure
of
subclinical
atherosclerosis
and
is
a
biomarker
of
cardiovascular
disease
risk.
CIMT
is
a
suitable
measure
for
community-‐
and
population-‐based
studies
conducted
among
persons
without
clinically-‐defined
cardiovascular
disease.
Increased
CIMT
is
significantly
associated
with
atherosclerosis
[8].
Bone
mineral
density
(BMD),
which
is
measured
by
dual-‐
energy
X-‐ray
absorptiometry
(DEXA),
is
widely
used
for
diagnosing
osteoporosis
[9].
Several
cross-‐sectional
studies
have
evaluated
carotid
artery
atherosclerosis
and
demonstrated
a
positive
association
with
osteoporosis
among
elderly
women
[8.10].
One
study
reported
that
the
progression
of
vascular
calcification
(in
the
abdominal
aorta)
was
associated
with
increased
bone
loss
(metacarpal)
among
women
aged
45
to
57
years
[1].
However,
currently
there
is
no
longitudinal
research
with
sufficient
sample
size,
investigating
the
association
of
BMD
with
atherosclerosis
progression
in
postmenopausal
women.
In
the
present
community-‐based
longitudinal
study,
we
examined
the
association
between
progression
of
CIMT,
a
measure
of
sub-‐clinical
atherosclerosis,
and
total
hip
and
lumbar
spine
BMD
among
349
postmenopausal
women.
We
also
3
considered
the
effect
of
several
potential
confounding
factors
on
this
association.
4
METHODS
Study
Population
The
Women’s
Isoflavone
Soy
Health
(WISH)
trial
was
conducted
from
April
12,
2004
to
March
19,
2009.
WISH
was
a
randomized,
double-‐blinded,
placebo-‐
controlled
trial.
Participants
were
postmenopausal
women
without
vaginal
bleeding
>1
year
and
serum
estradiol
<20
pg/mL
[5].
Detailed
inclusion
and
exclusion
criteria
and
other
aspects
of
this
trial
have
been
previously
published
[5].
The
primary
WISH
trial
outcome
was
carotid
artery
ultrasonographic
measurement
of
CIMT
to
assess
progression
of
sub-‐clinical
atherosclerosis.
Clinic
visits
to
assess
CIMT
occurred
every
6
months
and
lasted
for
2.5
years.
BMD
was
a
secondary
trial
outcome.
Clinic
visits
to
assess
BMD
occurred
every
year
for
2.5
years.
Sample
size
based
on
CIMT
progression
required
350
participants
to
detect
a
difference
in
the
rate
of
CIMT
progression
of
12.4μm/year
at
a
0.05
significance
(2-‐
sided)
with
90%
power
[5].
The
350
women
were
recruited
from
the
general
population
of
the
Greater
Los
Angeles
area
predominantly
through
media
advertisement.
A
total
of
269
(77%)
postmenopausal
women
had
at
least
6
CIMT
measures;
25(7%)
participants
had
baseline
CIMT
only.
Assessment
of
Bone
Mineral
Density
Total
hip
and
lumbar
spine
BMD
were
measured
by
DXA
[5].
DXA
is
a
fast
and
low
dose
radiation
method
that
uses
two
different
X-‐ray
beams
to
estimate
bone
density;
higher
bone
density
allows
less
of
the
X-‐ray
beam
to
pass
through
the
bone.
5
The
amount
of
each
X-‐ray
beam
that
is
blocked
by
bone
and
soft
tissue
are
compared
with
each
other.
DXA
can
measure
as
little
as
2%
of
bone
loss
per
year
[3].
The
unit
of
BMD
is
expressed
as
g/cm
2
.
348
participants
had
baseline
total
hip
BMD
measurements
and
346
participants
had
baseline
lumbar
spine
BMD
measurements.
The
number
of
BMD
measurements
for
each
subject
ranged
from
1
to
3
and
the
median
number
of
BMD
measurements
was
3(80%).
The
scheduled
times
for
BMD
measurement
is
baseline,
12
months
and
30
months.
In
this
study,
we
only
used
the
baseline
BMD
measurement.
Assessment
of
Atherosclerosis
Progression
Carotid
artery
ultrasound
is
noninvasive
and
is
therefore
suitable
for
studies
in
subjects
who
are
free
from
symptomatic
cardiovascular
disease
[11].
In
WISH,
ultrasound
imaging
of
far
wall
CIMT
was
conducted
using
standardized
procedures
and
technology
specifically
developed
for
longitudinal
measurements
(24-‐27).
The
jugular
vein
and
carotid
artery
were
imaged
longitudinally
with
the
former
stacked
above
the
latter.
All
images
contained
internal
anatomical
landmarks
for
reproducing
probe
angulation.
The
baseline
image
for
each
individual
was
used
as
an
online
guide
for
follow-‐up
examinations
on
a
split-‐screen
system
designed
for
repeat
image
acquisition
for
longitudinal
studies
[5].
CIMT
was
the
average
of
approximately
70
to
100
individual
measurements
between
the
intima-‐lumen
and
media-‐adventitia
interfaces
along
a
1-‐cm
length
just
proximal
to
the
carotid
artery
6
bulb
at
the
same
point
of
the
cardiac
cycle
[12].
This
method
standardizes
the
location
and
the
distance
over
which
CIMT
is
measured,
ensuring
comparability
within
and
across
participants
(26,27).
The
coefficient
of
variation
of
the
350
repeated
baseline
CIMT
measurement
was
<1%
[5].
A
total
of
269
(77%)
postmenopausal
women
had
at
least
6
CIMT
measures;
25(7%)
participants
had
baseline
CIMT
only.
Assessment
of
Clinical
Variables
Height
and
weight
were
measured
at
the
clinic
screening.
Body
mass
index
(BMI)
was
calculated
as
weight
(kg)
/height
2
(m
2
)
formula.
Smoking
history
and
hormone
treatment
(HT)
history,
which
are
both
associated
with
BMD,
were
assessed
by
a
structured
questionnaire
at
baseline.
Statistical
Analysis
The
current
analysis
included
349
participants
who
had
at
least
one
CIMT
measurement,
and
total
hip
BMD
and
lumbar
spine
BMD
measurement
at
baseline.
We
only
used
baseline
BMD
measurement
data
in
the
analysis.
The
baseline
CIMT
measurement
contributed
to
estimation
and
testing
of
the
cross-‐sectional
association
of
baseline
CIMT
and
BMD.
The
follow-‐up
measurements
contributed
to
estimation
and
testing
of
the
association
between
BMD
and
CIMT
change
rate
(CIMT
progression).
Age
was
categorized
into
5
groups:
≤55
years
old,
55-‐59
years
old,
60-‐64
years
old,
65-‐69
years
old
and
70+
years
old.
Smoking
was
categorized
as
current,
former
7
and
never
smokers.
BMI
was
categorized
by
the
Center
for
Disease
Control
(CDC)
classification
scheme:
<18.5
kg/m
2
=underweight,
18.5-‐24.9
kg/m
2
=
ideal
weight,
25.0-‐29.9
kg/m
2
=
overweight,
≥30
kg/m
2
=obese.
Ethnicity
was
categorized
into
five
groups:
White
(non-‐Hispanic),
Black
(non-‐Hispanic),
Hispanic,
Asian
and
other.
Education
was
categorized
into
high
school
or
below,
college
and
bachelor’s
degree
or
above.
BMI,
age
and
race
are
commonly
considered
risk
factors
for
both
atherosclerosis
and
osteoporosis
of
postmenopausal
women
[3,4].
To
identify
possible
confounders
of
the
association
between
CIMT
and
BMD,
we
analyzed
the
univariate
associations
between
baseline
BMD
and
age,
race,
BMI,
past
use
of
hormone
therapy
and
smoking
status
by
use
of
linear
regression,
with
BMD
(total
hip
and
lumbar
spine)
as
the
dependent
variable.
We
centered
total
hip
BMD
on
the
baseline
mean
(0.937)
and
centered
lumbar
spine
BMD
on
the
baseline
mean
(0.898)
to
change
the
value
of
the
intercept.
After
setting
up
linear
regression
models,
we
examined
four
assumptions
for
linear
regression
by
checking
the
residual
of
the
model:
1)
The
linearity
assumption
is
satisfied
since
the
residuals
plotted
against
BMD
showed
a
flat
scatter
around
the
zero
line;
2)
The
independence
assumption
is
satisfied
since
subjects
in
Wish
were
not
correlated.
3)
Normality
assumption
is
satisfied
since
the
sample
size
is
large
and
both
mean
and
skewness
of
residuals
are
near
to
0
and
the
distribution
of
the
residuals
is
bell
shaped;
and
4)
Equal
variance
is
satisfied
since
the
residuals
have
common
variance
across
the
range
of
X-‐values.
8
The
associations
between
CIMT
rate
and
clinical
variables
(including
age,
ethnicity,
BMI,
education,
smoking
and
hormone
therapy)
were
analyzed
by
univariate
linear
mixed-‐effect
models,
with
random
intercept
and
time.
A
linear
mixed-‐effects
model
with
random
time
and
intercept
was
also
used
to
assess
the
correlation
between
CIMT
change
rates
and
baseline
BMD
(total
hip
and
lumber
spine
separately),
using
an
unstructured
correlation
matrix
to
model
the
repeatedly
measured
CIMT
dependent
variable.
CIMT
measured
over
the
trial
was
treated
as
the
dependent
variable.
In
the
mixed-‐effects
model,
the
primary
independent
variable
of
interest
was
baseline
BMD;
additional
variables
included
follow-‐up
time
(measured
as
years
since
randomization,
or
first
CIMT
measurement)
to
model
the
longitudinal
change
in
CIMT,
and
age
as
an
adjusting
variable.
Since
age
was
correlated
with
both
CIMT
and
BMD,
we
determined
whether
BMD
and
CIMT
progression
rate
were
associated
with
and
without
age
in
the
model.
Other
clinical
variables,
such
as
BMI,
smoking
status
and
hormone
therapy,
were
not
correlated
with
both
CIMT
and
BMD;
these
variables
were
therefore
not
considered
confounders.
The
regression
coefficient
for
BMD
evaluated
the
cross-‐sectional
effect
between
BMD
and
CIMT.
The
BMD
and
follow-‐up
time
interaction
coefficient
estimated
the
effect
of
BMD
on
the
annual
CIMT
progression
rate.
In
subsequent
models,
we
added
an
interaction
term
between
BMD
and
BMI
categories,
and
between
BMD
and
smoking
status
in
the
mixed-‐effect
model
to
test
whether
the
association
between
CIMT
and
BMD
differed
by
smoking
status
or
by
BMI
9
categories.
25
participants
had
baseline
CIMT
measurements
only.
These
participants
were
included
in
the
analyses,
contributing
information
on
cross-‐
sectional
but
not
longitudinal
associations
of
BMD
with
CIMT.
Statistical
analysis
used
SAS
9.3
software
(SAS,
Inc,
Cary,
NC);
statistical
significance
testing
was
conducted
at
a
2-‐tailed
0.05
significance
level.
10
RESULTS
Clinical
Variables,
CIMT
and
BMD
in
Postmenopausal
Women
Table
1
shows
the
characteristics
of
349
postmenopausal
women
randomized
into
the
WISH
trial
who
were
included
in
the
present
analysis.
The
mean
(SD)
age
of
participants
was
61(7)
years.
The
majority
(64%)
of
the
study
population
was
White
(non-‐Hispanic).
Of
the
349
participants,
60%
had
a
bachelor’s
degree
or
above
education
level,
59%
were
never
smokers
and
70%
had
hormone
therapy
before
the
trial.
The
mean
(SD)
BMI
was
26.6
(5.2)
kg/m
2
.
The
majority
(57%)
of
the
study
population
were
overweight
or
obese.
The
mean
baseline
CIMT
was
0.811
(0.100)
mm.
The
mean
baseline
total
hip
BMD
was
0.937
(0.137)
g/cm
2
and
the
mean
baseline
lumbar
spine
BMD
was
0.898
(0.122)
g/cm
2
.
11
Table1.
Baseline
Characteristics
of
Study
Population
(n=349)
Variables
Age,
years
61
(7)
1
Age
group
≤ 55
67
(19)
1
55-‐59
88
(25)
1
60-‐64
88
(25)
1
65-‐69
67
(19)
1
70+
39
(12)
1
Ethnicity
White
(non-‐Hispanic)
223
(64)
2
Black
(non-‐Hispanic)
20
(6)
2
Hispanic
55
(15)
2
Asian
38
(11)
2
Other
13
(4)
2
Education
High
school
or
below
19
(5)
2
College
122
(35)
2
Bachelor’s
degree
or
above
208
(60)
2
Smoking
history
Current
8
(2)
2
Former
135
(39)
2
Never
smoked
206
(59)
2
Body
mass
index,
kg/m
2
26.6
(5.2)
1
BMI
group
<
18.5
(underweight)
5
(2)
1
18.5-‐-‐24.9
(ideal
weight)
143
(41)
1
25.0-‐-‐29.9
(overweight)
116
(33)
1
30.0
and
above
(obese)
85
(24)
1
Past
use
of
hormone
therapy
Yes
245
(70)
2
No
104
(30)
2
CIMT,
mm
0.811(0.100)
1
Total
hip
BMD,
g/cm
2
0.937
(0.137)
1,3
Lumbar
Spine
BMD,
g/cm
2
0.898
(0.122)
1,3
1. Mean
(SD)
for
continuous
variables
2. Number
(%)
for
categorical
variables.
3. Total
hip
BMD
measurement
(n=348);
Lumber
spine
BMD
measurement
(n=346).
12
Cross-‐sectional
Association
Between
BMD
and
Clinical
Variables
Table
2
shows
the
cross-‐sectional
associations
between
baseline
BMD
(total
hip
and
lumbar
spine)
with
clinical
variables.
There
was
a
significantly
negative
linear
trend
between
mean
total
hip
BMD
and
age
(P<0.0001).
Mean
total
hip
BMD
in
women
≥
70
years
old
was
lower
than
women
<
age
55
(P<0.0001).
Mean
total
hip
BMD
significantly
differed
among
racial
groups
(P<0.0001).
Black
(non-‐Hispanic)
participants
had
higher
mean
total
hip
BMD
than
the
White
participants
(P<0.0001).
Hispanic
participants
had
a
marginally
significantly
higher
mean
total
hip
BMD
than
White
participants
(P=0.054).
Mean
total
hip
BMD
in
Asian
participants
was
significantly
lower
than
White
participants
(P<0.0001).
Mean
total
hip
BMD
was
significantly
positively
associated
with
BMI
(P<0.0001).
Mean
total
hip
BMD
significantly
differed
among
the
three
education
groups
(P<0.0001).
Mean
total
hip
BMD
in
the
bachelor’s
degree
or
above
education
group
was
significantly
lower
than
in
women
who
had
high
school
or
below
education
(P=0.02).
Mean
total
hip
BMD
significantly
differed
among
the
three
smoking
status
groups
(P<0.05).
Mean
total
hip
BMD
in
current
smokers
was
higher
than
in
never
smoker
(P=0.01).
In
contrast
to
total
hip
BMD,
age
was
not
significantly
associated
with
lumbar
spine
BMD
(P>0.05).
Mean
lumbar
spine
BMD
differed
among
racial
groups
(P<0.0001).
Compared
with
White
participants,
Black
(non-‐Hispanic)
participants
had
a
significantly
higher
mean
lumbar
spine
BMD
(P<0.0001);
Hispanic
participants
had
a
significantly
lower
mean
lumber
spine
BMD
(P<0.01)
and
Asian
13
participants
had
a
significantly
lower
mean
lumbar
spine
BMD
(P<0.0001)
than
White
participants.
Lumbar
spine
BMD
was
significantly
positively
associated
with
BMI
(P<0.0001).
Mean
lumbar
spine
BMD
significantly
differed
among
the
three
smoking
groups
(P<0.0001).
Mean
lumbar
spine
BMD
in
former
smokers
was
significantly
higher
than
never
smokers
(P<0.0001).
Postmenopausal
women
who
had
used
hormone
therapy
had
a
higher
mean
lumbar
spine
BMD
than
women
who
did
not
use
hormone
therapy
(P<0.01).
14
Table
2.
Baseline
Cross-‐sectional
Association
between
BMD
1
and
Clinical
Variables
Total
Hip
BMD
(n=348)
2
Lumbar
Spine
BMD
(n=346)
3
Variable
Coefficient
95%CI
P
Coefficient
95%CI
P
Age
group,
years
<0.0001
0.11
<55
Reference
Reference
55-‐59
-‐0.009
(-‐0.025,
0.007)
0.014
(-‐0.004,
0.032)
60-‐64
-‐0.001
(-‐0.016,
0.016)
0.009
(-‐0.010,
0.027)
65-‐69
-‐0.009
(-‐0.027,
0.008)
-‐0.001
(-‐0.020,
0.018)
70+
-‐0.057
(-‐0.077,
-‐0.036)
0.026
(0.002,
0.049)
Trend
<0.0001
0.48
Ethnicity
<0.0001
<0.0001
White
(non-‐Hispanic)
Reference
Reference
Black
(non-‐Hispanic)
0.101
(0.078,
0.124)
0.077
(0.052,
0.103)
Hispanic
0.014
(-‐0.001,
0.029)
-‐0.027
(-‐0.044,
-‐0.010)
Asian
-‐0.044
(-‐0.061,
-‐0.028)
-‐0.050
(-‐0.068,
-‐0.031)
Other
0.001
(-‐0.027,
0.028)
-‐0.030
(-‐0.061,
0.002)
BMI
1
0.011
(0.010,
0.012)
<0.0001
0.009
(0.008,
0.010)
<0.0001
BMI
group
<0.0001
<0.0001
Below
18.5
Reference
Reference
18.5-‐-‐24.9
0.090
(0.052,0.127)
0.087
(0.043,
0.132)
25.0-‐-‐29.9
0.137
(0.099,0.175)
0.111
(0.066,
0.156)
30.0
and
above
0.220
(0.182,0.259)
0.193
(0.148,
0.238)
Education
<0.01
0.72
≤
High
school
Reference
Reference
Some
college
-‐0.004
(-‐0.029,
0.020)
-‐0.013
(-‐0.041,
0.014)
≥
Bachelor’s
degree
-‐0.029
(-‐0.052,
-‐0.006)
-‐0.016
(-‐0.042,
0.010)
Smoking
history
0.01
<0.0001
Never
smoked
Reference
Reference
Former
0.053
(-‐0.003,
0.019)
0.025
(0.013,
0.037)
Current
0.008
(0.015,
0.090)
0.040
(-‐0.002,
0.082)
Past
hormone
therapy
-‐0.008
(-‐0.020,
0.003)
0.17
0.019
(0.006,
0.032)
<0.01
1. BMD,
bone
mineral
density;
BMI,
body
mass
index.
2. Total
hip
BMD
was
centered
on
the
mean
(0.937);
n=348.
3. Lumbar
spine
BMD
was
centered
on
the
mean
(0.898);
n=346.
15
Univariate
Association
between
CIMT
and
Clinical
Variables
and
BMD
Table
3
shows
the
CIMT
associations
with
clinical
variables
and
BMD
from
a
linear
mixed
effects
models.
BMD
of
the
total
hip
and
spine
were
divided
by
their
respective
SDs;
the
regression
coefficients
associated
with
BMD
are
therefore
expressed
per
SD.
Cross-‐sectionally,
the
mean
baseline
CIMT
significantly
increased
with
age
(P<0.0001).
The
mean
baseline
CIMT
marginally
significantly
differed
among
ethnic
groups
(P=0.06).
Asian
participants
had
a
significantly
lower
mean
baseline
CIMT
than
White
participants
(P=0.01).
Mean
lumbar
spine
BMD
was
positively
significantly
associated
with
CIMT
(P<0.01);
total
hip
BMD
was
not
associated
with
baseline
CIMT.
Longitudinally,
total
hip
BMD
was
significantly
inversely
associated
with
CIMT
progression
(P=0.01).
The
mean
CIMT
rate
was
0.002
mm/year
(95%
CI:
-‐0.020,
-‐
0.003)
lower
per
0.137g/cm
2
(1
SD)
total
hip
BMD.
Lumbar
spine
BMD
was
also
significantly
inversely
associated
with
CIMT
progression
(P=0.03).
The
mean
CIMT
rate
was
0.001
mm/year
(95%
CI:
-‐0.016,
-‐0.001)
lower
per
0.122g/cm
2
(1
SD)
mean
lumbar
spine
BMD.
16
Table
3.
Univariate
Mixed
Effects
Associations
between
CIMT
and
Clinical
Variables
and
BMD
1
Cross-‐sectional
effect
on
CIMT
baseline
Longitudinal
effect
on
CIMT
rate
Variable
Coefficient
95%CI
P
Coefficient
95%CI
P
Age
group,
years
<0.01
less
than
55
Reference
Reference
0.21
55-‐59
0.024
(-‐0.005,
0.053 )
0.001
(-‐0.003,
0.003)
60-‐64
0.059
(0.030,
0.087)
0.001
(-‐0.002,
0.004)
65-‐69
0.076
(0.045,
0.107)
0.003
(-‐0.001,
0.006)
70+
0.148
(0.113,
0.184)
-‐0.002
(-‐0.006,
0.002)
Trend
<0.01
2
0.66
2
Ethnicity
0.06
0.70
White
(non-‐Hispanic)
Reference
Reference
Black
(non-‐Hispanic)
0.021
(-‐0.023,
0.066)
0.001
(-‐0.003,
0.006)
Hispanic
-‐0.006
(-‐0.035,
0.024)
-‐0.001
(-‐0.004,
0.002)
Asian
-‐0.044
(-‐0.078,
-‐0.009)
-‐0.001
(-‐0.005,
0.002)
Other
-‐0.036
(-‐0.092,
0.020)
-‐0.003
(-‐0.008,
0.003)
BMI
0.001
(-‐0.001,
0.003)
0.17
<0.001
(-‐0.001,
0.001)
0.77
BMI
categories
0.17
0.77
Below
18.5
Reference
18.5-‐-‐24.9
0.062
(-‐0.027,
0.151)
0.001
(-‐0.008,
0.009)
25.0-‐-‐29.9
0.081
(-‐0.009,
0.171)
-‐0.001
(-‐0.009,
0.008)
30.0
and
above
0.076
(-‐0.015,
0.166)
-‐0.001
(-‐0.009,
0.008)
Education
0.28
0.72
High
school
or
below
Reference
Reference
Some
college
0.010
(-‐0.039,
0.058)
-‐0.002
(-‐0.007,
0.003)
Bachelor’s
degree
or
above
-‐0.009
(-‐0.056,
0.038)
-‐0.002
(-‐0.007,
0.003)
Smoking
history
0.62
0.68
Never
smoked
Reference
Reference
Former
0.009
(-‐0.013,
0.031)
0.001
(-‐0.006,
0.008)
Current
-‐0.016
(-‐0.087,
0.055)
0.001
(-‐0.001,
0.003)
Past
use
of
hormone
therapy
0.014
(-‐0.009,
0.037)
0.24
0.001
(-‐0.001,
0.003)
0.36
Total
hip
BMD
3
0.070
(-‐0.017,0.157)
0.11
-‐0.012
(-‐0.020,
-‐0.003)
0.01
Lumbar
Spine
BMD
3
0.130
(0.054,
0.206)
<0.01
-‐0.008
(-‐0.016,
-‐0.001)
0.03
1. BMD,
bone
mineral
density;
BMI,
body
mass
index.
2. Trend
test
for
association
between
age
groups
and
CIMT.
3. The
range
of
total
hip
BMD
is
(0.720,
1.639),
mean
(SD)
is
0.937
(0.137).
The
range
of
lumbar
spine
BMD
is
(0.603,
1.399),
mean
(SD)
is
0.898
(0.122).
17
Multivariable
Associations
between
Total
Hip
BMD
and
CIMT
Table
4
shows
the
multivariable
mixed-‐effects
model
of
CIMT
and
total
hip
BMD,
adjusting
for
age.
Age
was
significantly
associated
with
baseline
CIMT
and
total
hip
BMD
(P<0.0001).
Cross-‐sectionally,
after
adjusting
for
age,
the
regression
parameter
of
adjusted
total
hip
BMD
changed
36%
from
the
unadjusted
total
hip
BMD
parameter
(age
treated
as
a
continuous
variable).
Age
therefore
confounded
the
cross-‐sectional
association
between
baseline
total
hip
BMD
and
CIMT.
Total
hip
BMD
was
significantly
positively
associated
with
CIMT,
adjusting
for
age
group
(P<0.01).
Mean
baseline
CIMT
increased
0.015
mm
(95%
CI:
0.031,
0.188)
per
0.137
g/cm
2
of
total
hip
BMD.
The
mean
total
hip
BMD
was
significantly
inversely
associated
with
CIMT
progression
(P<0.01).
The
mean
CIMT
rate
decreased
0.002
mm/year
(95%
CI:
-‐
0.021,
-‐0.003)
with
per
0.137g/cm
2
(1SD)
of
total
hip
BMD.
18
Table
4.
Mixed
Effects
Model
of
CIMT
and
Total
Hip
BMD
with
Age
Adjustment
Total
hip
BMD
model
Coefficient
95%CI
P
Intercept
0.749
(0.732,
0.765)
<0.01
Total
hip
BMD
1
0.109
(0.031,
0.188)
<0.01
Year
2,4
0.006
(0.004,
0.007)
<0.01
Total
hip
BMD
*
Year
1
-‐0.012
(-‐0.021,
-‐0.003)
<0.01
Age
3
0.034
(0.027,
0.042)
<0.01
Age
group
*Year
<0.001
(-‐0.001,
0.001)
0.97
1. Total
hip
BMD
coefficient
represent
cross-‐sectional
(baseline)
association
with
CIMT;
Total
hip
BMD*
Year
represents
longitudinal
association
with
CIMT
rate.
2. Unit
of
year
was
per
year.
3. Age
modeled
as
a
continuous
variable.
4. Year
variable
equal
year
since
randomization.
19
Effect
Modification
by
BMI
and
Smoking
Additional
interaction
term
of
BMD*BMI
and
BMD*smoking
evaluated
to
test
whether
the
cross-‐sectional
association
of
BMD
with
baseline
CIMT
differed
by
BMI
and
smoking.
Similarly,
interaction
terms
of
BMD*BMI*Year
and
BMD*Smoking*Year
tested
if
the
associations
of
BMD
with
CIMT
rate
differed
by
BMI
and
smoking.
None
of
these
interaction
terms
were
statistically
significant
(all
P>0.05).
Therefore,
the
association
between
BMD
(total
hip
BMD
and
lumbar
spine
BMD)
and
CIMT
did
not
significantly
differ
among
BMI
categories
(data
not
shown).
Similarly,
the
association
between
BMD
(total
hip
and
lumbar
spine
BMD)
and
CIMT
did
not
significantly
differ
among
smoking
categories
(data
not
shown).
20
DISCUSSION
In
the
randomized,
double-‐blinded,
placebo-‐controlled
WISH
trial,
our
analyses
showed
that
CIMT
progression
was
significantly
negatively
associated
with
BMD
of
the
total
hip
and
lumbar
spine
in
postmenopausal
women.
Epidemiology
and
clinical
trial
evidence
support
the
use
of
CIMT
as
a
validated
and
accepted
marker
for
generalized
atherosclerosis
burden
and
vascular
disease
risk
[14].
Thus,
postmenopausal
women
with
greater
BMD
loss
measured
at
the
hip
and
lumbar
spine
were
at
increased
risk
related
to
not
only
osteoporosis
but
also
atherosclerosis.
Estrogen-‐deficient
postmenopausal
women
are
at
greater
risk
for
atherosclerosis
and
osteoporosis.
These
are
not
merely
age-‐related
processes,
but
are
linked
by
many
common
factors.
Age,
ethnicity,
BMI,
education,
smoking
history
and
past
use
of
hormone
therapy
are
considered
as
common
risk
factors
for
osteoporosis
and
subclinical
atherosclerosis
in
postmenopausal
women
[5,13].
Osteoporosis
and
atherosclerosis
are
associated
with
significant
morbidity
and
mortality;
thus
analyzing
the
association
between
these
two
pathological
entities
has
important
public
health
impact.
Associations
of
BMD
with
Clinical
Variables
WISH
data
confirmed
many
of
the
known
BMD
associations.
BMD
decreased
with
age
and
significantly
differed
among
racial
groups,
with
Asian
participants
having
significantly
lower
BMD
than
White
participants.
Black
participants
had
21
significantly
higher
total
hip
and
lumbar
spine
BMD
than
White
participants
consistent
with
other
data
reporting
such
a
difference
[16].
While
smoking
is
considered
an
established
risk
factor
for
osteoporosis
[17],
BMD
was
significantly
higher
among
the
few
current
smokers
compared
to
non-‐smokers
in
the
WISH
trial.
This
finding
is
contrary
to
previous
studies
and
may
be
due
to
the
very
sample
size
of
current
smokers
(n=8).
A
positive
association
between
past
use
of
hormone
therapy
with
lumbar
spine
BMD
suggests
a
protective
effect
of
HT
on
lumbar
spine
osteoporosis,
which
is
consistent
with
previous
research
[13].
Association
of
CIMT
with
Clinical
Variables
After
analyzing
univariate
associations
between
CIMT
and
clinical
variables,
we
found
that
baseline
CIMT
was
significantly
associated
with
age,
which
is
consistent
with
other
study
[22].
Baseline
CIMT
significantly
differed
across
ethnic
groups;
the
average
baseline
CIMT
in
Asians
was
less
than
half
that
of
other
racial
groups.
While
we
did
not
find
a
difference
in
CIMT
progression
rates
across
racial
groups,
the
directions
of
race/ethnic
group
differences
in
CIMT
progression
rates
were
in
the
same
direction
as
seen
in
the
cross-‐sectional
analysis.
Association
of
CIMT
Rate
and
Total
Hip
BMD
Although
the
cross-‐sectional
association
between
CIMT
and
BMD
was
opposite
to
that
reported
in
previous
studies
[18],
the
longitudinally-‐analyzed
CIMT
rate
was
negatively
associated
with
BMD
(in
both
total
hip
and
lumbar
spine)
consistent
with
the
known
positive
association
between
osteoporosis
and
atherosclerosis.
The
mean
22
CIMT
rate
was
0.002
mm/year
(95%
CI:
-‐0.020,
-‐0.003)
lower
per
0.137g/cm
2
total
hip
BMD.
The
mean
CIMT
rate
was
0.001
mm/year
(95%
CI:
-‐0.016,
-‐0.001)
lower
per
0.122g/cm
2
mean
lumbar
spine
BMD.
This
result
is
consistent
with
and
importantly
extends
just
one
other
longitudinal
study
that
demonstrated
that
vascular
calcification
was
associated
with
increased
bone
loss
in
women
during
menopause
[1].
Our
model
ultimately
adjusted
for
age
as
age
confounded
the
cross-‐sectional
association
between
baseline
CIMT
and
total
hip
BMD.
However,
the
longitudinal
association
did
not
change
with
age
adjustment.
This
indicated
that
osteoporosis
and
atherosclerosis
are
not
associated
simply
due
to
a
common
age-‐related
process,
but
that
some
similar
pathophysiological
mechanisms
affect
both
processes.
Biological
Link
and
Possible
Pathophysiological
Mechanisms
Vascular
calcification
and
bone
mineralization
show
similarities
[1].
Calcifying
vascular
cells
appear
in
many
ways
similar
to
osteoblasts
[20]
and
specific
factors
and
proteins
crucial
to
bone
formation
are
also
associated
with
atherosclerosis
[1].
It
is
now
recognized
that
calcification
of
arterial
tissue
is
not
merely
a
passive
process
of
calcium
phosphate
precipitation
or
adsorption
in
end-‐stage
atherosclerosis,
but
instead
is
a
highly
organized
process
that
is
regulated
by
mechanisms
similar
to
those
involved
in
bone
mineralization
[23,24].
Epidemiological
data
suggest
that
estrogen
deficiency
is
a
risk
factor
for
both
cardiovascular
disease
and
osteoporosis
[19].
Arteries
and
bone
are
major
tissue
23
targets
for
estrogen.
Postmenopausal
women
who
are
estrogen
deficient
may
develop
aortic
artery
calcification
and
bone
loss
[1].
Aortic
calcification
influences
blood
flow
to
distal
regions
[21].
Impaired
blood
flow
to
the
lower
extremity
due
to
or
reflected
by
severe
atherosclerosis
in
the
lumbar
aorta
may,
at
least
to
some
extent,
contribute
to
the
complex
multi-‐factorial
pathogenesis
of
osteoporosis
in
the
hip
[21].
There
were
several
strengths
and
unique
features
of
our
study.
Most
importantly,
this
is
the
first
longitudinal
study
to
demonstrate
the
inverse
association
between
higher
BMD
and
lower
progression
of
atherosclerosis
in
healthy
postmenopausal
women.
The
WISH
participants
were
in
a
randomized
controlled
trial
of
postmenopausal
women
aged
45-‐92
years.
The
prevalence
of
prior
hormone
therapy
was
very
high
(70%).
Both
carotid
artery
ultrasound
and
bone
DXA
were
performed
under
strict
quality
control
standards
for
uniform
image
acquisition
and
minimization
of
measurement
error.
We
evaluated
and
found
consistent
associations
of
risk
factors
in
both
the
total
hip
and
lumbar
spine
BMD.
The
sample
size
that
contributed
to
estimation
and
testing
of
the
longitudinal
effect
was
large
(n=325)
and
77%
of
all
the
participants
contributed
more
than
6
measurements
of
CIMT;
this
provides
sample
size
and
power
to
detect
significant
associations
without
selection
bias.
We
used
mixed
effects
models
to
analyze
these
data;
this
method
allowed
us
to
flexibly
deal
with
the
longitudinal
data
involving
repeated
measures,
missing
measures
and
unequally
spaced
measures.
We
also
24
analyzed
the
association
between
CIMT
rate
and
BMD
stratified
by
BMI
and
smoking
categories;
we
failed
to
find
any
significant
effect
modification.
In
conclusion,
our
results
indicated
that
the
CIMT
progression
rate
is
negatively
associated
with
total
hip
and
lumbar
spine
BMD.
Low
BMD
in
the
total
hip
and
lumbar
spine
may
be
treated
as
a
marker
of
both
osteoporosis
and
atherosclerosis
progression
for
healthy
postmenopausal
women.
Postmenopausal
women
who
are
at
risk
for
osteoporosis
should
also
be
concerned
about
the
risk
for
atherosclerosis.
25
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Abstract (if available)
Abstract
Background and purpose: Atherosclerosis and osteoporosis are major causes of morbidity and mortality in postmenopausal women. Our study aimed to analyze the association between progression of carotid artery intima-media thickness (CIMT) and bone mineral density (BMD), providing more evidence for the relation between osteoporosis and subclinical atherosclerosis in postmenopausal women. ❧ Methods: In this longitudinal analysis, 349 postmenopausal women were followed for 3 years, and had an average 6 CIMT measurements. BMD had an average 3 measurements using DEXA
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Asset Metadata
Creator
Li, Jiaonan
(author)
Core Title
Bone mineral density is associated with carotid atherosclerosis in healthy postmenopausal women: a longitudinal analysis of randomized clinical trial data
School
Keck School of Medicine
Degree
Master of Science
Degree Program
Biostatistics
Publication Date
08/27/2015
Defense Date
08/26/2015
Publisher
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Tag
carotid atherosclerosis,lumbar spine BMD,OAI-PMH Harvest,postmenopausal,total hip BMD
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Electronically uploaded by the author
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Mack, Wendy (
committee chair
), Hodis, Howard (
committee member
), Karim, Roksana (
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Tags
carotid atherosclerosis
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postmenopausal
total hip BMD