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Keywords:

  • atherosclerosis;
  • osteoporosis;
  • postmenopausal women;
  • prospective study

Abstract.

  1. Top of page
  2. Abstract.
  3. Introduction
  4. Subjects and methods
  5. Results
  6. Discussion
  7. Conflict of interest statement
  8. References

Objective.  To investigate whether aorta calcification (AC) – a surrogate marker of atherosclerosis – is an independent indicator of low bone mass density (BMD), accelerated bone loss, and risk of future fractures in postmenopausal women.

Design.  A prospective epidemiological study. Follow-up period was 7.5 years.

Setting.  Community-based sample followed by a research institute.

Subjects.  A total of 2662 generally healthy postmenopausal women with a mean age of 65.0 ± 7.1 years at baseline.

Main outcome measures.  Annual rate of changes in BMD (DEXA) and AC (X-rays), vertebral fractures (X-rays), hip fractures (questionnaire).

Results.  Advanced AC at baseline was significantly associated with lower BMD and accelerated bone loss from the proximal femur. In a multivariate logistic regression model, age (OR 1.1, 95% CI 1.0–1.2, P = 0.02), body mass index (BMI; OR 0.9, 95% CI 0.8–1.0, P = 0.03) and the severity of AC (OR 2.3, 95% CI 1.1–4.8, P = 0.03) were independent predictors of hip fractures. Adjusted OR for vertebral fracture was 1.2 (95% CI 1.0–1.5, P = 0.12).

Conclusions.  Aorta calcification seems to independently contribute to the development of osteoporosis in the proximal femur. Further studies are needed to clarify whether effective atherosclerosis prevention lowers hip fracture risk.


Introduction

  1. Top of page
  2. Abstract.
  3. Introduction
  4. Subjects and methods
  5. Results
  6. Discussion
  7. Conflict of interest statement
  8. References

Atherosclerosis and osteoporosis are common diseases and remain major causes of morbidity and mortality in elderly population. Cumulating evidence suggest that links between vascular and bone disease are not merely because of aging. In a recent report, we showed that bone mass density (BMD) at the hip is inversely correlated with the severity of atherosclerosis in the lumbar aorta, independently of age, body mass index (BMI) and major cardiovascular risk factors [1, 2]. Others reported similar inverse associations between the progression of atherosclerosis or decreases in blood flow to the extremities and the rate of bone loss [3, 4]. On the contrary, individuals with low BMD at the hip or calcaneus as well as those with accelerated bone loss from the hip were shown to be at increased risk for cardiovascular mortality in both genders [5, 6]. Based on these observations it seems reasonable to hypothesize that atherosclerotic vascular disease may directly impact on bone metabolism and contribute to the development of osteoporosis.

To date very few studies have addressed the implications of atherosclerosis for osteoporotic fracture risk in postmenopausal women. Very recently, a retrospective study including 2348 postmenopausal women has confirmed the inverse relationship between aortic calcification and BMD, both measured by computed tomography (CT) [7]. Moreover, in a subpopulation analysis of 238 women, AC predicted a 4.8-fold increased risk for vertebral and 2.9-fold increased risk for hip fracture [7], independently of age. However, as also emphasized in an accompanying editorial by Rubin and Silverberg, the prevalence of AC in this population was unusually high (76% of women) compared with previous reports using conventional radiography and 70% of women were classified as osteoporotic. Thus, these remarks draw attention to the need for long-term prospective observations establishing the predictive value of AC for osteoporotic fracture in the general population of postmenopausal women.

The aim of the present study was to investigate longitudinal associations of AC – as visualized and graded on lateral radiographs – with annual rate of bone loss and the risk of future fractures in a population-based cohort of 2662 postmenopausal women followed for an average period of 7.5 years.

Subjects and methods

  1. Top of page
  2. Abstract.
  3. Introduction
  4. Subjects and methods
  5. Results
  6. Discussion
  7. Conflict of interest statement
  8. References

Study population

Participants were 4779 generally healthy postmenopausal women representing a subpopulation of the Prospective Epidemiological Risk Factors study (The PERF study) [8]. This subpopulation was selected based on the availability of lateral radiograph at baseline (1988–1997) for evaluation of calcified deposits in the lumbar aorta. Women had a mean age of 65 years and were followed on average for 7.5 ± 1.7 years. From this subpopulation 395 women died (8.2%) during the follow-up period. Of all death, 125 were because of cardiovascular event. Of the remaining 4384 survivals, 3565 women returned for the follow-up examination (81.3%).

Those who had received any established anti-resorptive treatment for osteoporosis including hormone replacement therapy (HRT), bisphosphonates, selective oestrogen receptor modulators (SERMs), tibolone and calcitonin more than 1-year after baseline or those who reported current use at follow-up were excluded, whereas those (273 women) who used such treatment for <1 year were remained part of the per-protocol analysis. Thus, the per-protocol analysis is based on 2662 women.

All women gave written their informed consent to participation and the study was carried out in compliance with the Helsinki Declaration II and the European Standards for Good Clinical Practice. The study protocol was approved by the local Ethical Committee.

Demographic characteristics, risk factors and clinical events

At both baseline and follow-up, data on body weight and height, BMI, age at menarche and menopause, number of births, education (primary/secondary/university), smoking habits (never/previous/current), regular alcohol, coffee, milk consumption, weekly exercise (0: never, 1: one or more time), presence of treated hypertension, treated hyperlipidemia, treated diabetes mellitus or history of cardiovascular event (myocardial infarct and stroke), and current or previous long-term use of drugs (e.g. HRT, bisphosphonates, SERMs, tibolone and calcitonin) were gathered during personal interviews using a preformed questionnaire. The reported history of cardiovascular events [acute myocardial infarct (AMI) and stroke] was confirmed by hospital discharge summaries.

Bone mass measurements

The BMD of the lumbar spine and hip was measured by dual-energy X-ray absorptiometry (DXA) using a QDR-2000 scanner or a QDR-4500 (Hologic Inc, Waltham, MA, USA). Daily phantom scans were performed each morning for proper quality control. At follow-up, BMD of the lumbar spine and hip were measured again by DXA using either a Hologic scanner, or a Lunar Prodigy scanner. As previously described elsewhere [8], the lumbar spine and hip BMD values measured by the different scanners at follow-up were then corrected by the respective correction factors as appropriate [corrected BMD (g/cm2) = scan BMD × 1.000333/mean BMD scanner], where 1.000333 indicates BMD of the phantom.

Grading of aorta calcification

Aorta calcification at baseline and the end of the follow-up period was assessed on lateral radiographs as earlier described by Kauppila et al. [9]. Briefly, calcified deposits in the lumbar aorta adjacent to each lumbar vertebra (L1–L4) were assessed separately for the anterior and posterior wall of the aorta using the midpoint of the inter-vertebral space as the boundaries. Each wall of each segment was graded for the presence of calcified deposits with a score from 0 to 3 (0: no deposits, 1: <1/3 of the aortic wall, 2: 1/3 to 2/3 of the aortic wall, 3: more than 2/3 of the aortic wall covered with calcified deposits). The sum of the scores of individual aortic segments both for the anterior and posterior walls, termed as anterior-posterior severity score and was used to describe the overall severity of AC in the lumbar aorta. Maximum score possibly given was 4 × 2 × 3 = 24. The same investigator, who was blinded for all other results of the individual participants, carried out the evaluations. Intra-rater correlations between repeated measurements were in the range of r = 0.92–98 (n = 50), similarly to published results [9].

Fracture diagnosis

Lateral X-rays of the thoracic and lumbar spine were obtained at baseline and at the follow-up visit using standard X-ray equipment. Vertebral deformities from T4 to L4 were assessed by digital measurements of morphologic changes using the Image Pro Image Analyzer software (version 4.5 for Windows, Media Cybernetics Inc., Silver Spring, MD, USA). The ratio of the anterior and posterior heights of each vertebral body was determined digitally and a difference of more than 20% between the anterior and posterior edges was considered as a radiographic vertebral fracture. A new incidence or progression of previously existing vertebral fractures was determined by comparison of current status with previous X-rays. At baseline and at the follow-up examination, information on prevalent nonvertebral fractures (wrist, hip, humeral fracture, rib, ankle and foot) was collected and later verified by X-rays or hospital discharge summaries. None of fractures was caused by traffic accident.

Statistical analysis

The statistical analysis was carried out using the SPSS data analysis software (version 12.0, SPSS Inc., Chicago, IL, USA). Demographic characteristics and distribution of risk factors in women with or without aorta calcification were compared using student's t-test for continuous variables or chi-square tests for categorical variables. Longitudinal association between atherogenesis and bone loss was assessed by calculating the annual rate of changes in BMD in tertiles of the annual rate of changes in AC (ACfollow-up−ACbaseline years). General linear models were used to provide age- and BMI-adjusted values. The relative risk of future fractures associated with aorta calcification was analysed by logistic regression model. The risk posed by AC, independent of age, BMI, and cardiovascular risk factors were estimated by multivariate logistic regression models. Associations and differences were considered significant if the P-value was below 0.05.

Results

  1. Top of page
  2. Abstract.
  3. Introduction
  4. Subjects and methods
  5. Results
  6. Discussion
  7. Conflict of interest statement
  8. References

In this population, the mean AC score at baseline was 2.1 ± 3.3 (range 0–18). To estimate menopause-related AC, we calculated the mean plus 1 SD of AC scores obtained in a subpopulation of 694 women (26.0%), who were within 10 years since their menopause (mean age: 57.1 ± 4.8 years). The obtained value, 1.1 ± 2.0 was arbitrarily chosen as a cut-off value for separating advanced AC from ‘postmenopausal’ AC. This cut-off value pointed out 29.5% of women for having an AC score ≥3.

Table 1 summarizes the basic demographic characteristics and cardiovascular risk profile of the two groups of women. Women with advanced AC were older, had slightly lower BMI, and spent longer time in their menopause compared with controls. Furthermore, there were differences in the level of education, smoking habits, weekly exercise and daily walking activities, treated hypertension, hyperlipidemia and diabetes type 2, and the frequency of acute cardiovascular events (AMI and stroke). However, there were no differences in terms of alcohol, coffee and milk intake. Subjects with AC scores ≥3 had not only more advanced AC, but also a higher annual rate of changes in AC compared with controls.

Table 1.   Demographic characteristics between women with aorta calcification (AC) score ≥3 or AC < 3 at baseline
 AC score <3 (n = 1877)AC score ≥3 (n = 785)P-value
  1. Values are mean ± SD.

  2. *Adjustment for age and BMI. There were no significant differences in terms of alcohol, coffee and milk consumption. Manifest CVD refers to clinically verified AMI or stroke.

Mean score of AC at baseline0.4 ± 0.76.5 ± 3.2 
Age at baseline (years)63.8 ± 7.167.8 ± 6.1<0.001
Year since menopause14.6 ± 8.718.8 ± 8.6<0.001
BMI at baseline (kg/m2)25.3 ± 4.724.7 ± 3.5<0.001
Total hip BMD at baseline (g/cm2)*0.82 ± 0.010.80 ± 0.01<0.001
Spine BMD at baseline (g/cm2)*0.87 ± 0.010.84 ± 0.01<0.001
Current smoking (%)17.332.0<0.001
High education (%)31.224.1<0.001
Weekly fitness (%)72.363.6<0.001
Daily walking (%)93.191.00.059
Treated hypertension (%)23.029.6<0.001
Treated hyperlipidemia (%)2.94.50.047
Diabetes (%)4.66.60.035
Manifest CVD (%)2.97.5<0.001
Change in AC score per year0.17 ± 0.320.43 ± 0.46<0.001

At baseline, women with more advanced AC had significantly lower BMD at both the total hip (0.80 ± 0.01 g/cm2 vs. 82 ± 0.01, P < 0.001) and the lumbar spine (0.84 ± 0.01 g/cm2 and 0.87 ± 0.01 g/cm2, P < 0.001), independently of age and BMI (Table 1). Moreover, advanced AC predicted a modest but statistically significant acceleration of bone loss from the hip (mean −0.38 ± 0.05% vs. −0.25 ± 0.03%, P = 0.026). Figure 1 illustrates the linear association between the annual rate of changes in AC versus rate of annual rate of changes in hip BMD. Women with the most progressive AC revealed the highest annual rate of bone loss from the total hip. In contrast to the demineralization seen at the hip, BMD of the vertebrae tended to increase rather than decrease during the observation period without differences in the annual rate of changes in BMD (0.26 ± 0.04% vs. 0.18 ± 0.03%).

image

Figure 1.  Annual rate of change (%) in total hip BMD in tertiles of annual rate of change (%) in AC score. The cut-off values between tertiles were 0.7 and 0.22. Bars show mean ± SEM. The annual rate of demineralization at the total hip was adjusted for differences in age and baseline measure of bone mineral density (P-value for trends = 0.019).

Download figure to PowerPoint

In this population, 31.8% of women (n = 847) had a BMD T-score less than −2.5 at the spine or total hip BMD (osteoporosis) at baseline. Only 171 (6.4%) women had radiographic presence of vertebral fracture and 21 (0.8%) women reported previous hip fracture at baseline (manifest osteoporosis). At the end of the follow-up, re-examination of subjects shed light to 431 incident vertebral fractures (16.2%) and 37 incident hip fractures (1.4%). Women with advanced AC at baseline had significantly higher incidence of both hip fractures (2.5% vs. 0.9%, OR 2.9, 95% CI: 1.5–5.5, P < 0.001) and vertebral fracture (20.8% vs. 14.3%, OR 1.6, 95% CI: 1.3–2.0, P < 0.001) compared with controls.

To obtain insights into the independent predictors of hip fracture risk, we established multivariate logistic regression models including age, BMI, and all major cardiovascular risk factors that indicated differences between women with or without AC score ≥3 (Table 1). The independent variables included in the model are outlined in Table 2 in detail. Under these conditions, the independent risk factors for hip fracture were AC, age and BMI (P < 0.05). When constructing the same model for vertebral fracture as the dependent variable, AC did not emerge as an independent contributor (OR 1.2, 95% CI 1.0–1.5, P = 0.12).

Table 2.   Multivariate logistic regression analysis of risk factors of hip fracture
Risk factorRR (95% CI)P-value
  1. Other independent variables included in the model were baseline BMD, previous osteoporotic fractures, current smoking, education level, daily walking, weekly exercise, years since menopause, treated hypertension, treated hyperlipidemia, type 2 diabetes and treatment for osteoporosis.

Advanced AC at baseline2.3 (1.1–4.8)0.03
Age1.1 (1.0–1.2)0.02
BMI0.9 (0.8–1.0)0.03

In addition to the relative risk of osteoporotic fractures, we also estimated the relative risk of an incident cardiovascular event posed by the presence of AC ≥ 3. In doing so, we established multivariate logistic regression models including the same set of independent variables as in the fracture models. Under these conditions, women with AC ≥ 3 at baseline had a 2.5-fold (95% CI 1.6–3.8, P < 0.001) increased risk for a fatal or nonfatal cardiovascular event compared with the risk of controls.

Discussion

  1. Top of page
  2. Abstract.
  3. Introduction
  4. Subjects and methods
  5. Results
  6. Discussion
  7. Conflict of interest statement
  8. References

To our knowledge, this is the first long-term prospective study undertaken in a population-based cohort of generally healthy postmenopausal women that addresses the direct implications of atherosclerosis (as estimated by radiographic measures of AC) for the risk for future osteoporotic fractures. The main finding was a consistent association of advanced AC with lower BMD, accelerated bone loss and a 2.3-fold increased risk for fracture at the proximal femur. These associations were generally not applicable to the lumbar spine suggesting site-specificity for the impact of atherosclerotic vascular disease on bone metabolism. It is tempting to speculate that the structure and compensatory options of arterial supply to specific skeletal regions may have important implications for the overall impact on local bone homeostasis, in which regard it seems reasonable to hypothesize that the unilateral blood supply of the proximal femur is more vulnerable for deteriorating occlusion than the bilateral blood supply of the vertebrae.

Prospective studies indicate that AC is a valid measure of the atherosclerosis burden and an independent predictor of cardiovascular mortality in postmenopausal women [10, 11]. Atherosclerosis frequently begins at sites subject to increased blood turbulence (e.g. bifurcations of the lumbar aorta) [12]. However, presence of atherosclerosis at this aforementioned site may also be a marker of the disease in the more peripheral arterial branches. In support, studies demonstrated that presence of atherosclerotic plaques is frequently associated with plaques at other anatomical sites such as the carotid and femoral arteries [13, 14].

At baseline age-adjusted BMD at the lumbar spine was significantly lower in subjects with advanced AC. However, the prospective associations did not indicate acceleration of bone loss from the vertebrae in women with advanced atherosclerosis. Instead, BMD tended to undergo increases during the follow up period, similar to the pattern of changes in AC. These findings are in accordance with in vitro studies by Hoshino et al. [15], who elegantly demonstrated that although AC may have little influence on spine BMD measurement, its changes over time may falsely elevate BMD values in patients. In vivo studies further support this perception, indicating that AC has moderate influence on spine BMD measurements [16, 17], except for cases of severe vascular calcification [18]. There is another disease entity influencing BMD at the lumbar spine when measured with DEXA, namely osteoarthritic vertebral deformities, which were repeatedly shown to artificially increase BMD [17]. The study by Banks and colleagues using DEXA and another methodological approach, quantitative computer tomography showed that the latter method could bypass bias linked to the antero-posterior scanning of DEXA and was able to demonstrate the significant inverse association between AC and spine BMD, similar to that seen with hip BMD [19]. Collectively, these methodological limitations of the DEXA technique make it difficult to draw definite conclusions regarding the potential contribution of atherosclerotic disease to demineralization of the vertebrae.

When focusing on the hip, more advanced AC was consistently associated with both lower BMD and accelerated bone loss. The possibility of a direct contribution of vascular disease to bone metabolism at this anatomical site is corroborated by several earlier observations: (i) in cases of asymmetric vascular disease, the side more severely affected by vascular disease shows more severe demineralization [20], (ii) in the prospective analysis, the rate of bone loss at the hip and calcaneus was significantly greater among women whose annual decrease in ankle/arm index – a measure of blood flow in the extremities – was more than 1 SD greater than the mean decrease, independently of oestrogen use, smoking, BMI, pattern of fat distribution, history of diabetes, exercise and ability to walk [21], (iii) histological investigations indicate that both the larger (a. iliaca ext and a. femoris profunda) and the small vessels in the ligamentum teres supplying the proximal femur are frequently affected by atheromatous lesions in elderly patients with femoral neck fractures [20, 22], (iv) diabetic women, who are prone to macro- and microvascular complications, were recently shown to be subjects of accelerated bone loss from the hip [23] and (v) patients with serious atherosclerotic the femoral arteries show negative bone remodelling balance because of decreased bone formation [24]. Thus, these findings collectively argue for an important contribution of atherosclerotic vascular disease to the development of hip osteoporosis.

Despite the plausibility of pathogenic links between atherosclerosis and osteoporosis at the hip, limited information is available regarding the predictive value of AC for fracture risk. This question is particularly important given the fact that assessment of fracture risk is not subject to the methodological limitations of DEXA and so it is more suitable to address the regional aspects. In a recent cross-sectional analysis, presence of AC on CT scans was associated with a 4.8-fold increase in risk for vertebral and 2.9-fold increase in risk for hip fractures compared with those without vascular calcification [7]. Our prospective analysis revealed a comparable increase in risk for hip fracture (2.3-fold) in women with advanced AC, but we found no indication of a considerable increase in risk for vertebral fractures (in the latter context age was the most important independent risk factor). Major differences in study design, methodology, and statistical approach limit the valid comparison of the two conclusions. The study by Schulz et al was a cross-sectional assessment, the indicator was a CT-measure of AC, and the study population was more representative for the osteoporotic rather than the general population (70% osteoporotic, 30% having vertebral, and 9% having hip fracture). In contrast, the present study was a prospective setting, AC was graded on lateral radiographs, and only 31.8% of women had BMD T score below −2.5 and 7.1% had osteoporotic fractures at baseline. The large number of participants (n = 2662) and incident vertebral fractures (n = 431) makes it unlikely that the lack of association between AC and vertebral fracture risk is because of insufficient statistical power. Thus, our findings suggest that atherosclerotic vascular disease is an independent contributor to the development of osteoporotic fractures at the proximal femur but less so in the vertebral column.

The underlying mechanism by which osteoporosis and vascular disease may be linked are not fully understood, but can be ascribed to the contribution of common risk factors, common pathophysiological mechanisms, or both [25–27]. In our previous report, we demonstrated an inverse association between AC and hip BMD, which persisted even after adjustment for a broad range of risk factors with common implications for both entities. Accordingly, it seems reasonable to presume that the independent association reflects either a direct contribution of ischaemic vascular disease for bone turnover or common pathomechanisms acting simultaneously on both bone and vascular cells. As for the latter option, proinflammatory cytokines such as IL-6 and TNF-α are known to exert proatherogenic effects [28], but they may also enhance osteoclastogenesis and consequently increased bone resorption [29]. Oxidized lipids have also been shown to promote atherogenesis and activate calcifying vascular cells, while inhibiting osteoblastic differentiation [30]. Interestingly, several regulators of bone turnover, such as matrix GLA protein, osteoprotegerin and osteocalcin were detected in calcified atherosclerotic plaques in humans [27]. Finally, the lack (or insufficient function) of endothelial nitric oxide synthase (NOS) has been associated with both accelerated atherosclerosis [31] and decreased osteoblast function leading to low BMD [32]. The diversity of the herein listed factors provides insightful illustration of the complexity of this important issue of women's health. Targeted intervention studies modulating these factors might bring us closer to a better understanding of the underlying mechanisms and ultimately to a simultaneous prevention of these two major causes of morbidity and mortality in the elderly women.

In conclusion, the present study revealed consistent associations between advanced AC in the lumbar aorta and low BMD, accelerated bone loss, and increased risk of incident fractures at the proximal femur. These findings thus provide reasons to believe that atheromatous involvement of larger and small arteries supplying the proximal femur have important implications for local bone remodelling and thereby the development of osteoporosis at this anatomical site. Further studies are needed to clarify whether supplementation of osteoporosis treatment with adequate cardiovascular measures (i) could reduce simultaneously the increased risk of cardiovascular events and hip fractures; (ii) could provide additional benefits in terms of anti-fracture efficacy further reducing the incidence of hip fracture in the elderly women.

References

  1. Top of page
  2. Abstract.
  3. Introduction
  4. Subjects and methods
  5. Results
  6. Discussion
  7. Conflict of interest statement
  8. References
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