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The Journal of Clinical Endocrinology & Metabolism 88(6):2573–2578
Copyright © 2003 by The Endocrine Society
doi: 10.1210/jc.2002-021511
Increased Pulse Wave Velocity Associated with Reduced
Calcaneal Quantitative Osteo-sono Index: Possible
Relationship Between Atherosclerosis and Osteopenia
KEN-ICHI HIROSE, HIROFUMI TOMIYAMA, RYO OKAZAKI, TOMIO ARAI, YUTAKA KOJI,
GULNISA ZAYDUN, SABURO HORI, AND AKIRA YAMASHINA
Second Department of Internal Medicine (K.-i.H., H.T., T.A., Y.K., G.Z.), Tokyo Medical University, Third Department of
Medicine (R.O.), Tokyo 160-0023, Japan; and Teikyo University Ichihara Hospital, Preventive Medical Center (S.H.),
St. Luke’s International Hospital, Tokyo, Japan
Although the associations between arterial calcification or
advanced atherosclerosis and osteopenia have been well documented, it is not clear whether the one is the result of the
other or they coprogress from the early stages through common mechanisms. Thus, we measured pulse wave velocity
(PWV), which reflects earlier phase atherosclerosis, and osteosono assessment index (OSI), which correlates with bone mineral density, in 7865 Japanese subjects (4183 males and 3682
females, aged 50 ⴞ 12 yr) and analyzed their association. PWV
was determined by the volume rendering method; OSI was
measured by the calcaneal quantitative ultrasound method.
We evaluated the influence of age, gender, menopausal state,
and established atherosclerotic risk factors on this associa-
I
T IS WELL ESTABLISHED that aging is associated with
both osteoporosis and atherosclerosis (1– 4). Although
both processes advance with age, osteoporosis is more
common in women, whereas men are more susceptible to
atherosclerosis. Chronological differences are also noted.
In both sexes, bone mineral density (BMD) reaches its peak
around age 30, remains constant until around age 40, and
then starts to decrease (1, 2). On the other hand, the atherosclerotic process starts earlier; it has been recognized
even in young adults (3, 4). In women, these pathophysiological abnormalities are prominent after menopause.
Recently, several clinical studies have indicated the association between the two age-related processes (5–12). In
postmenopausal Caucasian women and elderly Caucasian
men, lower bone mass and rapid bone loss is associated
with higher mortality due to atherosclerotic cardiovascular diseases (8, 10). Caucasian women with low hip BMD
are at an increased risk of developing peripheral arterial
disease (12). Conversely, aortic calcification has been
shown to be associated with a lower BMD (6, 9). However,
atherosclerotic diseases and aortic calcification occur only
at advanced stages of atherosclerosis, which by themselves
could affect bone metabolism. It is not clear whether or not
there are common mechanisms that regulate both processes from the early stages. Furthermore, most of these
Abbreviations: baPWV, Brachial-ankle pulse wave velocity; BMD,
bone mineral density; OPG, osteoprotegerin; OSI, osteo-sono assessment
index; PWV, pulse wave velocity; ABI, ankle/brachial pressure index;
RANK, receptor activator of nuclear factor-␬〉; SOS, speed of sound.
tion. In a linear regression analysis, OSI negatively correlated
with PWV in both genders, and this association was more
prominent in females (r ⴝ ⴚ0.38, P < 0.01) than in males (r ⴝ
ⴚ0.17, P < 0.01). In females, this relationship was stronger
after the menopause. In a multivariate analysis, PWV was
significantly associated with OSI independent of age and conventional atherosclerotic risk factors. In females, this association was independent from menopause. These results suggest that common or related mechanisms, which may be
accelerated after menopause, control both atherosclerosis
and osteoporosis from the early stages. (J Clin Endocrinol
Metab 88: 2573–2578, 2003)
studies examined aged Caucasian women. It is unknown
whether the relationship is also present in other races, in
men, or in younger women.
The evaluation of the association between earlier markers for atherosclerosis and osteopenia in a large general
population may provide some information for these uncertain issues. To apply general population, the methods
should preferably be simple, noninvasive, cost effective,
and radiation free. Thus, to assess osteopenia, we used
osteo-sono assessment index (OSI) determined by calcaneal quantitative ultrasound measurements which correlates with BMD and predicts fractures (13). To assess atherosclerosis, we used brachial-ankle pulse wave velocity
(baPWV). Pulse wave velocity (PWV) is the speed of the
pulse to travel between the two points and is related to
square root of elastic modulus according to the MoensKorteweg equation (14). Hence, the stiffer the artery is the
faster the PWV (14). PWV is higher in patients with atherosclerotic cardiovascular disease than that in control
subjects (15) and correlates with intima-media thickness of
carotid artery (16). In addition, PWV is a predictor for
future cardiovascular events in patients with hypertension
(17). Therefore, PWV is thought as a marker of early stage
of atherosclerosis (18).
This study was conducted to measure baPWV and OSI in
the general Japanese population and to analyze the correlation between the two. The influence of age, gender, menopausal state, and other conventional atherosclerotic risk factors on this association was analyzed.
2573
2574
J Clin Endocrinol Metab, June 2003, 88(6):2573–2578
Hirose et al. • Arterial Stiffness Predicts Osteopenia
Subjects and Methods
Subjects
We recruited 7865 Japanese men and women (4183 males and 3682
females) from among subjects who underwent annual physical checkups, including the measurement of PWV, at Tokyo Medical University
Hospital and affiliated clinics. Their ages ranged from 21– 81 yr. Smoking, menopause, and medical history of atherogenic diseases or other
diseases requiring medical treatment was obtained by a questionnaire
answered by each subject at the time of the health examination. Subjects
with a plasma creatinine concentration of more than 176.8 ␮mol/liter,
a history of implantation of an aortic graft, or atrial fibrillation, were
excluded from the present study. None of the subjects had a history of
or symptoms related to bone disorders or peripheral artery diseases. All
subjects had a normal ankle/brachial pressure index (ABI), as determined by Form/ABI (ABI ⬎0.9; Colin Co. Ltd., Komaki, Japan). Anthropometrics of participants are given in Table 1. Informed consent was
obtained from all the subjects. The study protocol was approved by the
ethical committee of Tokyo Medical University.
Measurement of pulse wave velocity
baPWV was measured using a volume-plethymographic apparatus
(Form/ABI, Colin Co. Ltd.). Details of the methodology were as described elsewhere (15, 19). The subject was examined while resting in the
supine position. Electrocardiographic electrodes were placed on both
wrists, and cuffs were wrapped on both brachia and ankles. Pulse
volume waveform at the brachium and ankle were recorded using a
semiconductor pressure sensor. PWV was measured after at least 5 min
rest. The validation of this method has been reported previously, and the
interobserver coefficient of variation of was 8.4% and the intraobserver
coefficient of variation was 10.0% (15).
sound (SOS) and broadband ultrasound attenuation has been previously
established (20, 21). Using an Achilles bone densitometer (AOS-100,
ALOKA Co. Ltd., Tokyo, Japan), SOS and the transmission index (TI) of
the right heel were measured. OSI was calculated using the following
formula:
OSI ⫽ TI ⫻ SOS2.
The coefficient of variation of intraobserver of OSI was 2.2% (20).
The Z-score of OSI was calculated by comparing our data with OSI
of healthy Japanese subjects matched for age.
Laboratory measurements
Plasma total cholesterol, high-density lipoprotein cholesterol, lowdensity lipoprotein cholesterol, triglycerides, electrolytes, blood sugar,
and glycohemoglobin A1C levels were measured enzymatically. All
blood samples were obtained in a fasting state in the morning.
Statistics
Data are expressed as the mean ⫾ sd. Statistical analysis was performed using the software package from SPSS, Inc. (Chicago, IL). Relevant parameters were tested for normality using the Kolmogrov-Smirnov’s test. Univariate linear regression analysis was performed to
determine the correlation between BMD and other clinical variables.
Step-wise multiple regression analysis was performed to determine the
interaction and independent variables for BMD. One-way ANOVA with
Scheffé’s adjustment was used for group comparison. A value of P ⬍ 0.05
was considered statistically significant. In addition, a regression coefficient of greater than 0.10 was considered to indicate a clinically significant association.
Results
Calcaneal quantitative ultrasound measurements
Calcaneal quantitative ultrasound measurements were performed,
and expressed as OSI. The validation of this method and its high reproducibility compared with the parameter obtained from speed of
TABLE 1. Anthropometrics of the subjects distributed by gender
No. of subjects
Age
Height (cm)
BMI (kg/m2)
SBP (mmHg)
DBP (mmHg)
MBP (mmHg)
PWV (cm/sec)
FBS (␮mol/liter)
HbA1C (%)
TC (␮mol/liter)
LDL (␮mol/liter)
HDL (␮mol/liter)
TG (␮mol/liter)
Ca (␮mol/liter)
P (␮mol/liter)
OSI (⫻ 106)
No. of subjects with:
Smoking habit
Hypertension
Diabetes mellitus
Dyslipidemia
Menopause
Age at menopause (y.o.)
Male
Female
1309
51 ⫾ 12
170 ⫾ 6
23.8 ⫾ 2.8
127 ⫾ 16
82 ⫾ 10
99 ⫾ 13
1367 ⫾ 284
5.7 ⫾ 1.3
5.3 ⫾ 0.7
5.3 ⫾ 0.9
3.1 ⫾ 0.8
1.5 ⫾ 0.4
1.4 ⫾ 0.4
2.3 ⫾ 0.1
1.2 ⫾ 0.1
2.85 ⫾ 0.32
383
49 ⫾ 12
157 ⫾ 6
21.3 ⫾ 3.0
120 ⫾ 18
74 ⫾ 11
92 ⫾ 14
1230 ⫾ 267
5.2 ⫾ 0.8
5.1 ⫾ 0.5
5.4 ⫾ 0.9
3.1 ⫾ 0.8
1.4 ⫾ 1.0
0.9 ⫾ 0.5
2.3 ⫾ 0.1
1.1 ⫾ 0.1
2.54 ⫾ 0.28
1163
1070
264
430
98
608
77
304
1783
47 ⫾ 3
P value
P
P
⬍ 0.01
⬍ 0.01
⬍ 0.01
⬍ 0.01
⬍ 0.01
⬍ 0.01
⬍ 0.01
⬍ 0.01
⬍ 0.01
⬍ 0.01
ns
⬍ 0.01
⬍ 0.01
ns
⬍ 0.01
⬍ 0.01
P
P
P
P
⬍
⬍
⬍
⬍
P
P
P
P
P
P
P
P
P
P
P
P
0.01
0.01
0.01
0.01
BMI, Body mass index; SBP, systolic blood pressure; DBP, diastolic
blood pressure; MBP, mean blood pressure; FBS, fasting blood sugar;
HbA1C, glycohemoglobin A1C; TC, total cholesterol; LDL, low-density lipoprotein cholesterol; HDL, high-density lipoprotein cholesterol; TG, triglycerides; Ca, plasma level of calcium; P, plasma level
of phosphate.
Table 1 summarizes the anthropometrics of participants.
Among females, 1783 women had passed the menopause.
Table 2 shows the regression coefficients of the univariate
linear regression analysis between OSI and clinical variables.
In both genders, baPWV significantly correlated with OSI
(Fig. 1), and age also showed a significant correlation with
OSI. For an age-adjusted analysis, the Z-score of OSI was
obtained. baPWV significantly correlated with the Z-score of
OSI in males (r ⫽ ⫺0.07, P ⬍ 0.01) and females (r ⫽ ⫺0.09,
P ⬍ 0.01). Figure 2 shows the mean value of baPWV by
quartiles of OSI in both genders. In both genders, baPWV
was higher in subjects with lower OSI. Table 3 shows the
regression coefficients of the univariate linear regression
TABLE 2. Regression coefficients of univariate linear regression
analysis between BMD and clinical variables
Variable
PWV
Age
Height
BMI
MBP
FBS
HbA1C
TC
HDL
TG
Age at menopause
Regression coefficient
Male
Female
⫺0.17a
⫺0.21a
0.04b
0.09a
⫺0.12a
⫺0.04b
⫺0.07a
⫺0.02
⫺0.04b
⫺0.03
⫺0.38a
⫺0.50a
0.28a
0.07a
⫺0.27a
⫺0.10a
⫺0.18a
⫺0.21a
⫺0.01
⫺0.13a
⫺0.12a
BMI, Body mass index; MBP, mean blood pressure; FBS, fasting
blood sugar; HbA1C, glycohemoglobin A1C; TC, total cholesterol;
HDL, high-density lipoprotein cholesterol; TG, triglycerides. a P ⬍
0.01; b P ⬍ 0.05.
Hirose et al. • Arterial Stiffness Predicts Osteopenia
J Clin Endocrinol Metab, June 2003, 88(6):2573–2578 2575
FIG. 1. Correlation between OSI and PWV in both genders.
FIG. 2. The mean value of baPWV by quartiles of OSI in
both genders. Lowest, Subjects with lowest osteo sonoassessment index in quartiles; Lower, subjects with lower
OSI in quartiles; Higher, subjects with higher OSI in quartile; Highest, subjects with highest OSI in quartile. **, P ⬍
0.01 vs. subjects with highest OSI in quartiles; ††, P ⬍ 0.01
vs. subjects with higher OSI in quartiles; ‡‡, P ⬍ 0.01 vs.
subjects with highest OSI in quartiles.
analysis between OSI and clinical variables in females before
and after the menopause. Whereas baPWV showed a significant correlation with baPWV both before and after the
menopause, the correlation between OSI and baPWV was
stronger after the menopause compared with that before
menopause. Table 4 shows the results of step-wise multiple
regression analysis between OSI and clinical variables (including smoking and menopausal status); baPWV was found
to be an independent variable for OSI in both genders.
baPWV showed a stronger correlation with OSI in females
than in males. The relationship was independent from the
menopausal status in females.
Discussion
In the present study, we demonstrated a significant negative correlation between baPWV and OSI. This relationship
was significant even when the values of parameters were
adjusted for age. Although the correlation was significant in
both genders, it was weaker in men. In women, the correlation was stronger after menopause, which was in line with
the results of previous studies (6, 8, 11). Multiple regression
analysis demonstrated that this relationship was independent from other confounding atherosclerotic risk factors in-
cluding height. These results suggest that common or related
mechanisms, which may be accelerated after menopause,
control the development of both atherosclerosis and osteoporosis from the early stages.
Recent studies have demonstrated that vascular calcification and bone mineralization are similar processes, which are
controlled by the same hormones (e.g. vitamin D) and cytokines (e.g. bone morphogenetic protein-2; Ref. 22). It is tempting to speculate that there are mechanisms that balance the
calcification of the two tissues. However, advanced atherosclerosis, including vascular calcification itself, could affect
bone metabolism by several mechanisms. First, arterial stenosis would decrease peripheral blood supply, which could
directly suppress bone cell functions. Second, atherosclerotic
diseases such as coronary heart diseases and stroke would
limit physical activity, which would lead to bone loss (23).
Therefore, it would be difficult to speculate whether common
factors affect both vascular and bone tissues or one is the
result of the other.
To avoid these issues, earlier markers for atherosclerosis
and osteoporosis should be employed. Because carotid-femoral PWV correlates with intimal media thickness of carotid
artery or left ventricular hypertrophy (16, 24), it is generally
2576
J Clin Endocrinol Metab, June 2003, 88(6):2573–2578
TABLE 3. Regression coefficients of univariate linear regression
analysis between BMD and clinical variables in females before and
after the menopause
Variable
PWV
Height
Age
BMI
MBP
FBS
HbA1C
TC
HDL
TG
Hirose et al. • Arterial Stiffness Predicts Osteopenia
TABLE 4. Results of multiple regression analysis between bone
mineral density and clinical variables that showed a clinically
significant correlation with bone mineral density in linear
regression analysis in both genders
Regression coefficient
Before (n ⫽ 1899)
After (n ⫽ 1783)
⫺0.05a
0.07b
⫺0.06b
0.21b
⫺0.01
0.02
0.01
⫺0.02
⫺0.05a
0.03
⫺0.23b
0.23b
⫺0.41b
0.21b
⫺0.11b
0.01
⫺0.01
⫺0.03
⫺0.05a
0.01
PWV, Pulse wave velocity; BMI, body mass index; MBP, mean
blood pressure; FBS, fasting blood sugar; HbA1C, glycohemoglobin
A1C; TC, total cholesterol; HDL, high-density lipoprotein cholesterol;
TG, triglycerides. a P ⬍ 0.05; b P ⬍ 0.01.
considered as a marker for early-stage atherosclerosis (25,
26). Although carotid-femoral PWV is an established traditional method for measuring PWV (25–27), baPWV is more
applicable to screen the general population because of its
simplicity (the examiner has only to wrap cuffs on the brachium and ankle). Several studies reported its applicability
as a marker of atherosclerosis (15, 19, 27). We have demonstrated the validity (comparing with aortic PWV obtained by
catheter method) and reproducibility of baPWV (15). baPWV
has a potential for screening vascular damage because
baPWV in patients with coronary heart disease was higher
than that in age-matched patients having atherosclerotic risk
factors without coronary heart disease (15). A high baPWV
may reflect the increase of arterial stiffness in central site
(aorta) and/or peripheral sites in the lower extremities (both
sites are known as prominent sites in the evolution of atherosclerosis), rather than in upper extremities (27). Thus, in
the present study, we used baPWV as an earlier marker of
atherosclerosis and excluded subjects with a history of atherosclerotic diseases and those with decreased ABI.
BMD assessed by dual x-ray absorptiometry is an established marker for osteoporosis (28). Although OSI does not
directly reflect BMD, it reflects elastic properties of bone
tissues (29). OSI predicts the risk of future fractures and
correlates with BMD (13). Therefore, in the present study,
OSI was used as an earlier marker of abnormal bone strength,
which predicts osteopenia. Although we did not assess the
presence or absence of arterial calcification in our study
population, the significant correlation between baPWV and
OSI, even in the younger generation, suggests that the
atherogenic evolutional processes that take place before vascular calcification also play some roles in the pathogenesis of
osteopenia.
Just as vascular and bone calcification share common
mechanisms, matrix proteins play important roles both in the
formation of bone and the development of atherosclerosis
(30). Several matrix proteins, such as type 1 collagen, proteoglycans, osteopontin, and otsteonectin, are found in both
bone and vascular matrix components (30, 31). Interestingly,
type 1 collagen genotypes associated with a lower BMD (32)
have been found to be associated with an increase in PWV
Males: R2 ⫽ 0.26
Variable
PWV
Age
Height
BMI
MBP
FBS
HbA1C
HDL
Smoking
Females: R2 ⫽ 0.57
Variables
PWV
Age
Height
BMI
MBP
FBS
HbA1C
TC
TG
Smoking
Menopause
Age at menopause
␤
P value
⫺0.07
⫺0.18
0.07
0.09
0.01
0.01
0.01
⫺0.02
⫺0.09
P
P
P
P
⬍ 0.01
⬍ 0.01
⬍ 0.01
⬍ 0.01
ns
ns
ns
ns
P ⬍ 0.01
␤
P value
⫺0.11
⫺0.35
0.09
0.23
⫺0.01
0.01
0.02
0.01
⫺0.01
⫺0.03
⫺0.17
⫺0.01
⬍ 0.01
⬍ 0.01
⬍ 0.01
⬍ 0.01
ns
ns
ns
ns
ns
P ⬍ 0.01
P ⬍ 0.01
ns
P
P
P
P
MBP, Mean blood pressure; BMI, body mass index; FBS, fasting
blood sugar; HbA1C, glycohemoglobin A1C; TC, total cholesterol;
HDL, high-density lipoprotein; TG, triglycerides.
in young men and women (33), suggesting the possibility of
common mechanisms for the development of osteopenia and
atherosclerosis.
Another important player in the development of atherosclerosis is smooth muscle cells. Smooth muscle cells proliferation is the key component of fatty streak formation. Bone
marrow stromal cells differentiate into vascular smooth muscle cells as well as into osteoblasts (34, 35). Recently, Sata et
al. (36) reported that smooth muscle cells present in atherosclerotic lesions derive from the bone marrow. These results
suggest that preferential differentiation of bone marrow cells
into smooth muscle cells over osteoblasts may be one of the
mechanisms for the coexistence of osteopenia and atherosclerosis. Indeed, aberrant differentiation of bone marrow
cells has been implicated in osteoporosis. Beside osteoblasts
and smooth muscle cells, bone marrow stromal cells are
precursors of adipocytes, whose differentiation is stimulated
in patients with osteoporosis (37, 38). Furthermore, bone
marrow stromal cells differentiation into muscle cells and
osteoblasts is reciprocally regulated in vitro (39). Therefore,
similar reciprocal regulation may work in vivo and atherogenic stimuli would promote preferential differentiation of
smooth muscle cells, which may lead to decreased osteoblastogenesis, resulting in osteopenia.
Estrogen deficiency is an important factor that causes osteoclast activation in both genders (2). Estrogen inhibits cytokines that recruit and activate osteoclasts, such as IL-1, IL-6,
and TNF␣ whereas, it stimulates osteoprotegerin (OPG) that
suppresses osteoclasts (40). All these cytokines have also
been implicated in atherogenesis (41, 42). The changes in the
Hirose et al. • Arterial Stiffness Predicts Osteopenia
action of these cytokines most likely cause both accelerated
bone loss and atherogenesis in postmenopausal women,
which would make the relationship more conspicuous, resulting in a stronger correlation between baPWV and OSI in
postmenopausal women. However, the present study
showed that baPWV significantly correlated with OSI in
males, while in females, baPWV was a determinant of OSI
independent from menopause, suggesting contribution of
other mechanisms except estrogen such as oxidized lowdensity lipoprotein or parathormone, both known to be increased with age (43, 44).
Recently, much interests are focused on the possible role
of OPG in the development of atherosclerosis (45). OPG is
originally identified as an endogenous antagonist for receptor activator of nuclear factor-␬〉 (RANK) ligand (RANKL)
that stimulates osteoclast formation by binding to its receptor
RANK expressed in osteoclast precursors (46). OPG secreted
by various cells including osteoblasts and vascular cells acts
as decoy receptor for RANK ligand, blocking its interaction
with RANK, thus inhibits osteoclast formation. Unexpectedly, OPG knockout mice have severe vascular calcification
besides severe osteoporosis (42). In these mice, both osteoporosis and aortic calcification is reversed by restoration of
OPG gene, suggesting its protective role for the development
of osteopenia and vascular diseases (47). However, recent
human clinical studies revealed that higher serum OPG levels are correlated with the severity of radiographically determined coronary heart disease and cardiovascular mortality (48, 49). Similarly, serum OPG levels tend to be higher in
subjects with lower BMD (50). These results suggest that
serum OPG level increase as a compensatory mechanism
limiting progressive athesclerosis and bone loss. Although
OPG production in vitro is stimulated by estrogen (51), the
relationship between serum OPG level and estrogen status is
obscure (50). It would be interesting to evaluate serum OPG
level in subjects stratified with both athereslcerosis and
osteopenia.
In conclusion, we have demonstrated that, in a large Japanese population, increased PWV is associated with a low
OSI, a surrogate marker for BMD, independent of conventional atherosclerotic risk factors. This association is more
prominent in females than in males, and in females it is
stronger after the menopause. Our results suggest that common or related mechanisms, to which estrogen deficiency
contributes in part, regulate the development of atherosclerosis and osteopenia from the early stages. Because our study
is limited by its cross-sectional design, prospective studies
should provide further insights into the possible relationship
between the atherosclerosis and osteopenia.
Acknowledgments
Received September 26, 2002. Accepted January 21, 2003.
Address all correspondence and requests for reprints to: Hirofumi
Tomiyama, M.D., Second Department of Internal Medicine, Tokyo Medical University, 6-7-1 Nishi-Shinjuku, Shinjuku-ku, Tokyo 160-0023,
Japan. E-mail: [email protected].
This study was partially supported by a grant in aid from the Japanese
Atherosclerosis Prevention Fund.
J Clin Endocrinol Metab, June 2003, 88(6):2573–2578 2577
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