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The Journal of Clinical Endocrinology & Metabolism Vol. 88, No. 6 2573-2578
Copyright © 2003 by The Endocrine Society

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

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: tomiyama{at}tokyo-med.ac.jp.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
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 osteo-sono assessment index (OSI), which correlates with bone mineral density, in 7865 Japanese subjects (4183 males and 3682 females, aged 50 ± 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 association. In a linear regression analysis, OSI negatively correlated with PWV in both genders, and this association was more prominent in females (r = -0.38, P < 0.01) than in males (r = -0.17, 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.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
IT IS WELL ESTABLISHED that aging is associated with both osteoporosis and atherosclerosis (1, 2, 3, 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, 6, 7, 8, 9, 10, 11, 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 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 Moens-Korteweg 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.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Subjects

We recruited 7865 Japanese men and women (4183 males and 3682 females) from among subjects who underwent annual physical check-ups, 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 µmol/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 1Go. Informed consent was obtained from all the subjects. The study protocol was approved by the ethical committee of Tokyo Medical University.


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  		Table 1. Anthropometrics of the subjects distributed by gender

 
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).

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 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:

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, low-density 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
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Table 1Go summarizes the anthropometrics of participants. Among females, 1783 women had passed the menopause. Table 2Go shows the regression coefficients of the univariate linear regression analysis between OSI and clinical variables. In both genders, baPWV significantly correlated with OSI (Fig. 1Go), 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 2Go 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 3Go shows the regression coefficients of the univariate linear regression 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 4Go 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.


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  		Table 2. Regression coefficients of univariate linear regression analysis between BMD and clinical variables

 


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  		Figure 1. Correlation between OSI and PWV in both genders.

 


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  		Figure 2. The mean value of baPWV by quartiles of OSI in both genders. Lowest, Subjects with lowest osteo sono-assessment 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; {dagger}{dagger}, P < 0.01 vs. subjects with higher OSI in quartiles; {ddagger}{ddagger}, P < 0.01 vs. subjects with highest OSI in quartiles.

 

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  		Table 3. Regression coefficients of univariate linear regression analysis between BMD and clinical variables in females before and after the menopause

 

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  		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

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
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 including 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 considered as a marker for early-stage atherosclerosis (25, 26). Although carotid-femoral PWV is an established traditional method for measuring PWV (25, 26, 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 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{alpha} whereas, it stimulates osteoprotegerin (OPG) that suppresses osteoclasts (40). All these cytokines have also been implicated in atherogenesis (41, 42). The changes in the 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 low-density 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-{kappa}B (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.


   Footnotes
 
This study was partially supported by a grant in aid from the Japanese Atherosclerosis Prevention Fund.

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-{kappa}B; SOS, speed of sound.

Received September 26, 2002.

Accepted January 21, 2003.


   References
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 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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