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Carotid intima-media thickness and calcification in relation to bone mineral density in postmenopausal women—The OSTPRE-BBA study
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Carotid intima-media thickness and calcification in relation to bone mineral density in postmenopausal women—The OSTPRE-BBA study
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Miika Värri a,∗ , Tomi-Pekka Tuomainen b , Risto Honkanen a,c , Toni Rikkonen a , Leo Niskanen d , Heikki Kröger a,e , Marjo T. Tuppurainen a,f a Bone and Cartilage Research Unit (BCRU), Surgery, Institute of Clinical Medicine, University of Eastern Finland, Mediteknia Building, P.O. Box 1627, FI-70211 Kuopio, Finland b Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Canthia Building, P.O.Box 1627, FI-70211 Kuopio, Finland c Lapland Hospital District, P.O. Box 8041, FI-96101 Rovaniemi, Finland d Institute of Clinical Medicine, University of Eastern Finland and Finnish Medicines Agency Fimea, Mannerheimintie 103b, FI-00280 Helsinki, Finland e Department of Orthopaedics, Traumatology and Hand Surgery, Kuopio University Hospital, Building 3, P.O. Box 100, FI-70029 Kuopio, Finland f Department of Obstetrics and Gynaecology, Kuopio University Hospital, Building 6, P.O. Box 100, FI-70029 Kuopio, Finland
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Article history: Received 23 February 2014 Received in revised form 17 May 2014 Accepted 21 May 2014 Available online xxx
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Keywords: DXA Osteoporosis Carotid calcification Intima-media thickness Postmenopausal hormone therapy
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1. Introduction
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Objectives: Atherosclerosis (AS) and osteoporosis are common diseases in elderly people and may be metabolically related. The aim of this cross-sectional population-based study was to explore the association between common carotid artery intima-media thickness (cIMT), carotid artery calcification (CAC), and BMD in postmenopausal women. In addition, the association of postmenopausal hormone therapy (HT) and selected diseases with cIMT and carotid calcification was studied. Study design: The 290 women (mean age 73.6 years) included in this Bone Brain Atherosclerosis study (OSTPRE-BBA) were randomly selected from the population-based Kuopio Osteoporosis Risk Factor and Prevention (OSTPRE) study cohort, Finland. Main outcome measures: For this cross-sectional study, cIMT was measured with B-mode ultrasound; femoral neck and total body BMD were measured with dual-energy X-ray absorptiometry. Results: There were no statistically significant associations between mean cIMT and femoral neck Tscore (p > 0.05). However, an increased maximum cIMT was significantly associated with low femoral neck T-score. In the osteoporotic group (T-score <−2.5, n = 20), the maximum cIMT was 2.51 ± 0.88 mm (mean ± SD); in the normal BMD group (T-score >−1, n = 122), it was 1.93 ± 0.64 mm (p = 0.001). The odds of having CAC were approximately four-fold higher in the osteoporotic group compared with the group with a normal femoral neck T-score (odds ratio [OR] = 4.2, p = 0.038). The maximum cIMT was smaller in HT users (1.98 ± 0.56 mm, n = 190) than in non-users (2.16 ± 0.74 mm, n = 156, p = 0.036). Conclusions: The results of our population-based study suggest that BMD is related to AS, at least in carotid arteries. They indirectly support the hypothesis of partially shared pathophysiological mechanisms between these two disorders. © 2014 Published by Elsevier Ireland Ltd.
Osteoporosis (OP) and atherosclerosis (AS) are both common in elderly people [1]. Their consequences, like osteoporotic fractures, myocardial infarction, and cerebrovascular stroke reduce quality of life and lead to functional decline and excess mortality in developed countries [2,3].
Abbreviations: AS, atherosclerosis; OP, osteoporosis. ∗ Corresponding author. Tel.: +358 503655083; fax: +358 17 172 611. E-mail address: [email protected].fi (M. Värri).
Ultrasonographic determination of carotid intima-media thickness (cIMT) is a non-invasive and reliable screening method to detect subclinical AS and predict future cardiovascular disease (CVD) events and stroke [4–8]. In women, the incidence of coronary heart disease (CHD) and stroke increases substantially after menopause, when estrogen production is decreasing, marking the end of the protective effect of endogenous estrogens against CVD [9]. Previous studies have demonstrated a relationship between bone loss, fractures, and vascular changes. Low bone mass or a prior vertebral fracture has been found to increase the risk of CVD and cardiovascular morbidity and mortality [10,11]. Low bone mass has
http://dx.doi.org/10.1016/j.maturitas.2014.05.017 0378-5122/© 2014 Published by Elsevier Ireland Ltd.
Please cite this article in press as: Värri M, et al. Carotid intima-media thickness and calcification in relation to bone mineral density in postmenopausal women—The OSTPRE-BBA study. Maturitas (2014), http://dx.doi.org/10.1016/j.maturitas.2014.05.017
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been associated with increased cIMT and carotid artery calcification (CAC) in postmenopausal women, but the randomly selected population-based studies are scarce [12–14]. The intimal calcification of arteries is one facet of atherosclerotic vascular disease, while numerous mechanisms and mediators are responsible for calcium deposition, including several bone-forming mediators [15,16]. In intimal calcification, calcium deposits on the intima layer of the vessel wall, especially in advanced atherosclerotic plaques and, in some cases, it increases the risk of a plaque rupture [16]. The calcification of the arterial wall media layer is unrelated to AS and is observed in patients with diabetes or chronic renal disease [16]. Concerning postmenopausal women and vascular atherosclerotic changes, hormone therapy (HT) seem to associates with reduced cIMT values in postmenopausal women [17–19], but opposite results have also been found [20]. Similarly, results about the effects of HT on intimal atherosclerotic calcification are consistent; calcification-reducing effects and no effects have both been reported [16,21,22]. The aim of this cross-sectional study was to examine the associations between cIMT, CAC and BMD in a representative population sample of postmenopausal women. According to our hypothesis: BMD is associated with subclinical atherosclerosis markers despite the differences in the use of HT, life style factors and age.
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2. Methods
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2.1. Population
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The data were obtained from the Kuopio Osteoporosis Risk Factor and Prevention (OSTPRE) Study cohort, consisting of all the 14,220 women (aged 47–56 years) who lived in the Province of Kuopio, Eastern Finland in February 1989. A baseline questionnaire was sent to these women in May 1989 and returned by 13,100 women [23]. A stratified random sample of 3222 women out of 11,055 respondents willing to undergo bone densitometry underwent the procedure in 1989–1992 (Fig. 1). The random part of the sample was 2025 women. A random subsample (n = 506) underwent hip, spine, and total body BMD follow-up measurements in 1994–1997, 1999–2002, and 2005–2007 and 458 participants of them were alive in 2009. In 2009–2011, femoral and total body BMD were measured. The OSTPRE (Bone, Brain, and Atherosclerosis) study (OSTPREBBA) has been designed to investigate the associations between adiposity, bone, and brain functions in 458 randomly selected postmenopausal women from the original OSTPRE densitometry study population. The final study sample (n = 290) includes women who participated in BMD and cIMT measurements (Fig. 1).
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2.2. IMT measurements
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IMT measurements were conducted on 346 OSTPRE-BBA participants in 2009. Ultrasound scans were conducted at the Bone and Cartilage Research Unit (BCRU), University of Eastern Finland, Kuopio. The examinations were performed by an experienced radiographer (JT) using the Technos MP ESAOTE ultrasound device (Esaote, Italy), with a B-type linear transducer at the 9 MHz frequency. The scanning area was from the base of the neck to a carotid bulb, following the common carotid artery (CCA) all the way. The technique has been used in previous studies [24]. All scanning materials were digitally recorded. The recordings were read to produce several variables: the maximum and mean cIMT; and calcifications on the arterial wall. IMT was measured over a 1-cm long segment from the distal CCA just before the bifurcation from the digitally recorded scanning
Women aged 47-56 (n=14220) in 1989 located in Kuopio province. Out of 13100 women 11055 were willing to undergo DXA.
Stratified random sample (n=3686) including high risk and random groups. 464 women did not participate.
Baseline densitometry in 1989-92, n=3222
Stratified high risk group was excluded (n=1197) Random sample, n=2025
25 % random sample n=506 for OSTPRE-BBA sample.
112 women did not participate and 48 died before the IMT measurements. Final OSPTRE-BBA study population with valid IMT measurements in 2009, n=346. 55 women did not participate and 1 died before the DXA measurements. Final study sample with valid DXA and IMT measurements, n=290
Fig. 1. Study population. OSTPRE-BBA = Kuopio Osteoporosis Risk and Prevention Study – Bone, Brain and Atherosclerosis.
images, using the Prowin computer software (Medical Technologies International Inc., Palm Desert, California, USA). Intima-media interface lines were manually traced as continuous lines. The cIMT operator was not aware of the final use of the scanning material. The main interests were on the maximum and mean cIMT and plaque calcifications (maximum cIMT >1.2 mm). The mean cIMT was computed from the means of the right and left cIMTs measured over the measurement area and it was used to describe the overall stage of AS. The maximum cIMT was the single highest point in the distal CCA IMT and it was used to demonstrate the highest protrusion and obstruction of the intima into the lumen. The left and right artery values were used as separate and combined variables. The combined maximum cIMT was the average of the maximum cIMT of both arteries. If either cIMT value was missing (n = 5), only the available value was used. The measurement points are shown in Fig. 2. Carotid calcifications were categorized into two different groups (no/yes): women who had intimal calcifications on their carotid artery walls (yes); and women who had no intimal calcifications (no). Four right maximum cIMTs and one left maximum cIMT were excluded, because of the anatomically difficult characteristics in some of the study subjects. 2.3. DXA measurements Both the hip and the total body BMD were measured by DXA at the OSTPRE 20-year follow-up study visit in 2009–2011 for 290 participants, whose cIMT was measured earlier. The femoral neck BMD was measured from the left femoral neck (n = 282). If the participant had a prosthesis in her left hip (n = 8), the BMD was
Please cite this article in press as: Värri M, et al. Carotid intima-media thickness and calcification in relation to bone mineral density in postmenopausal women—The OSTPRE-BBA study. Maturitas (2014), http://dx.doi.org/10.1016/j.maturitas.2014.05.017
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Table 1 Characteristics of the study population (n = 290).
Fig. 2. The intima-media thickness measurement points of the common carotid arteries. cIMT = Carotid artery Intima-Media Thickness.
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measured from the right femoral neck. The DXA data were missing for 56 women, because 50 of them did not attend the measurement, five had a prosthesis in both hips, and one woman died before the measurement. Measurements were carried out at the University of Eastern Finland, BCRU, using the General Electrics Lunar Prodigy DXA device (Madison, WI, USA). BMD results were reported as T-scores. T-scores were also categorized into three groups according to the World Health Organization (WHO) criteria for diagnosing OP: normal BMD (T-score ≥−1 SD); osteopenic (T-score −1 to −2.5 SD); and osteoporotic (T-score ≤−2.5 SD) [2].
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2.4. Other variables
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The women’s weight and height were measured at each of the DXA densitometry measurements. The height was measured with a wall-mounted ruler. The BMI was calculated as body weight/height2 (kg/m2 ). The self-reported use of postmenopausal HT among participants was included (only systemic estrogen or combined estrogen-progestin treatment were accepted). HT users were categorized into two groups: women who had never used HT (no); and women who currently used or had used it (yes). The information concerning the use of HT, the history of diseases (stroke, asthma, diabetes, high serum cholesterol, arterial hypertension, CHD, rheumatoid arthritis, and transient ischemic attack [TIA]), medications, current smoking, blood pressure, physical exercise with shortness of breath (hours in a week), and dietary calcium intake (milligram per day) were based on a postal enquiry in 2009, with the question on chronic health disorders verified by a physician. CHD consisted of myocardial infarction and angina pectoris. Physical exercise data were missing for 56 participants who went through the cIMT measurement. The data were missing only for eight participants who went through both cIMT and BMD measurements. The missing values were replaced with the mean value of all participants. Dietary calcium intake was estimated by summing up intake from dairy products (cheese, milk, sour milk, yogurt, and sour whole milk).
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2.5. Statistical analysis
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Statistical analyses were performed using the SPSS software (version 19.0, SPSS Inc., Chicago, IL, USA). Values are expressed as percentage or mean ± SD. Natural logarithm modification was made for maximum cIMT values to ensure normal distribution for the analysis. The normality of the data (all cIMT and BMD variables) was confirmed with Kolmogorov-Smirnoff test or by inspecting the histograms. Means were compared using Student’s t-test, in analyses between chronic diseases, HT and cIMT as dependent variable, or analysis of variance, in analyses between categorized T-score and cIMT as dependent variable. Chi-square test was used in the
Characteristic
Mean ± SD
Age (years) Weight (kg) BMI (kg/m2 ) Time since menopause (years) Femoral neck BMD (g/cm2 ) Femoral neck T-score Total body BMD (g/cm2 ) Total body T-score Mean IMT of the right CCA (mm) Max IMT of the right CCA (mm) Mean IMT of the left CCA (mm) Max IMT of the left CCA (mm) Mean IMT in right and left CCA (mm) Max IMT in right and left CCA (mm) HT between 1989 and 2009 (months, n = 190) Calcium intake (mg/day) Physical exercise with shortness of breath (hours in a week, n = 244)
73.6 72.1 28.7 23.7 0.848 −1.1 1.095 −0.4 0.93 2.06 0.93 2.04 0.93 2.04 55.7
± ± ± ± ± ± ± ± ± ± ± ± ± ± ±
2.8 13.0 5.1 4.6 0.131 1.1 0.104 1.3 0.14 0.76 0.16 0.74 0.13 0.66 72.7
762 ± 301 0.98 ± 1.33
Range 69.2–79.2 45.5–126.2 18.7–45.1 14.2–42.9 0.534–1.423 −3.7–3.7 0.809–1.421 −3.9–3.7 0.65–1.78 1.0–5.8 0.61–1.59 1.0–5.0 0.64–1.47 1.00–4.95 0–248 0–2070 0–7.50
BMI, body mass index; IMT, intima-media thickness; CCA, common carotid artery; HT, hormone therapy.
analysis of categorical variables, between CAC and categorized Tscore. Pearson correlation was used to compare the repeated cIMT measurement reliability and to compare calcium dietary supplementation and continuous T-score. Linear regression was used to study the association of cIMT and the continuous T-score variables. Analysis of covariance was used to study the independent effect of total body or femoral BMD on cIMT as dependent variable. Participants’ age, BMI, current smoking (no, yes), HT use (no, yes), and systolic blood pressure were used as covariates. In addition, physical exercise with shortness of breath (hours in a week) was categorized into quartiles and used as covariate in analyses, which included femoral neck BMD. Only variables showing statistically significant association with dependent variables were included in the final model. Logistic regression was used to model dichotomous (no, yes) carotid calcification, as the dependent variable, explained by femoral neck or total body T-score, HT (0, 1–60, >60 months), BMI, age, and dietary calcium intake. Two-sided p-values lower than 0.05 were considered statistically significant. 3. Results Characteristics of the study population are shown in Table 1. In all, 0.3% of the women were underweight (<19.0 kg/m2 ) and 35.2% were obese (BMI >30 kg/m2 ); 3.8% were current smokers. In all, 47.6% of the women used statins, 1.7% used peroral corticosteroids, 5.5% used inhaled corticosteroids and 8.6% used osteoporosis medication. The coefficient of variation (CV) for femoral neck BMD after repositioning of the patient was 1.1% in two repeated BMD measurements from left femoral neck for 20 participants. There was significant correlation between 10 repeated mean cIMT (r = 0.977, p < 0.001) and maximum cIMT (r = 0.942, p < 0.001) measurements. The daily dietary calcium intake was significantly higher in women who had no CAC (832 ± 345 mg, n = 134) than in women who had CAC (734 ± 288 mg, n = 212, p = 0.004). There were no statistically significant correlations between dietary calcium intake and femoral neck T-score (p > 0.05) though the calcium intake were slightly different. The results were similar with total body T-score (data not shown). When comparing the study cohort (women who went through IMT and BMD measurements, n = 290) with all other women in the OSTPRE densitometry sample, who were measured at the 20-year
Please cite this article in press as: Värri M, et al. Carotid intima-media thickness and calcification in relation to bone mineral density in postmenopausal women—The OSTPRE-BBA study. Maturitas (2014), http://dx.doi.org/10.1016/j.maturitas.2014.05.017
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4 Table 2 Associations between BMD T-scores and vascular variables. Femoral neck T-score
Mean IMT in right and left CCA ± SD (mm)a Max IMT in right and left CCA ± SD (mm)a Max IMT in right CCA ± SD (mm)a Max IMT in left CCA ± SD (mm)a Intimal calcification, n (%)b
T-score <−2.5 n = 20
T-score −2.5 to −1 n = 148
T-score >−1 n = 122
p
pc
0.93 ± 0.15 2.51 ± 0.88 2.66 ± 1.19 2.36 ± 0.71 17 (85%)
0.92 ± 0.13 2.08 ± 0.61 2.08 ± 0.66 2.08 ± 0.80 97 (65.5%)
0.95 ± 0.13 1.93 ± 0.64 1.95 ± 0.73 1.93 ± 0.67 61 (50%)
0.192 0.001 0.001 0.025 0.002
0.166 0.010 0.008 0.138
T-score <−2.5 n = 13
T-score −2.5 to −1 n = 84
T-score >−1 n = 197
p
pc
0.89 ± 0.14 2.52 ± 0.86 2.55 ± 1.06 2.48 ± 0.84 9 (69.2%)
0.92 ± 0.13 2.10 ± 0.70 2.10 ± 0.85 2.09 ± 0.75 53 (62.1%)
0.94 ± 0.13 2.00 ± 0.62 2.02 ± 0.68 1.98 ± 0.73 113 (57.4%)
0.250 0.032 0.118 0.032 0.513
0.103 0.121 0.335 0.111
Total body T-score
Mean IMT in right and left CCA ± SD (mm)a Max IMT in right and left CCA ± SD (mm)a Max IMT in right CCA ± SD (mm)a Max IMT in left CCA ± SD (mm)a Intimal calcification, n (%)b
CCA, common carotid artery; IMT, intima-media thickness; pc = p with covariates: hormone therapy (no/yes), smoking (no/yes), BMI, age and systolic blood pressure (and physical exercise in quartiles in the femoral neck BMD model). a Analysis of variances. b Chi-square test.
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follow-up in 2009 (n = 1264), there were no significant differences in body weight (p = 0.587), height (p = 0.304), BMI (p = 0.079), femoral neck BMD (p = 0.384), or systolic blood pressure (p = 0.286).
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3.1. IMT, chronic diseases, risk factors, and the use of HT
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The mean cIMT was 0.98 ± 0.14 mm in women with diabetes (n = 37) and 0.92 ± 0.13 mm in women without diabetes (n = 309, p = 0.026). There was a similar trend between maximum cIMT and diabetes (p = 0.045). Women with arterial hypertension (n = 166) had a higher mean cIMT (0.94 ± 0.14 mm) and maximum cIMT (2.18 ± 0.61 mm) than women with normal blood pressure (n = 188, mean cIMT 0.91 ± 0.12 mm and maximum cIMT 1.95 ± 0.67 mm, p = 0.04 with mean cIMT and p = 0.001 with maximum cIMT). The maximum cIMT was significantly higher in women who had a history of stroke or TIA (2.46 ± 0.57 mm, n = 21) than women with no cerebrovascular disorders (2.04 ± 0.65 mm, n = 325) (p < 0.001), but there were no significant differences in mean cIMT (p = 0.179). Women who had a history of CHD had a higher maximum cIMT (2.34 ± 0.72 mm, n = 42) than women who did not have CHD (2.02 ± 0.63 mm, n = 304, p = 0.005), but there were no significant differences in mean cIMT (p = 0.913). Bronchial asthma (n = 45), high serum cholesterol (n = 123), and rheumatoid arthritis (n = 15) had no associations with cIMT (data not shown). Women with a positive history of HT use had a smaller maximum cIMT (1.98 ± 0.56 mm, n = 190) than non-users (2.16 ± 0.74 mm, n = 156, p = 0.036), but there were no significant associations with mean cIMT (p = 0.061).
−0.96 to −0.024). The result was similar between femoral neck Tscore and left maximum cIMT (ˇ = −0.195, p = 0.001, R2 = 0.038, 95% CI: −0.096 to −0.025). There was a significant association between femoral neck T-score and combined maximum cIMT (ˇ = −0.223, p < 0.001, R2 = 0.050, 95% CI: −0.094 to −0.031). The associations between intimal calcifications and femoral neck BMD are shown in Table 3. There was 4.2 times higher odd for CAC in the osteoporotic group than in the normal T-score group (OR 4.2, p = 0.038). HT was not associated with CAC (p > 0.05) (Table 3). There were no associations between carotid calcification (no/yes) and categorized physical exercise (p = 0.318) (data not shown). 3.3. Total body T-score, cIMT, and calcification The result on the total body T-score groups and IMT and intimal calcification are summarized in Table 2. When the right and left maximum cIMTs were combined in the same variable, there was a significant difference between total body T-score groups and combined maximum cIMT (p = 0.032), but the difference did not persist after adjustment for covariates (p = 0.121). In addition, there was a significant linear association between the right maximum cIMT and total body T-score (ˇ = −0.154, p = 0.009, R2 = 0.024, 95% CI: −0.071 to −0.010). Low total body T-score was also associated with left maximum cIMT (ˇ = −0.187, p = 0.001, R2 = 0.035, 95% CI: −0.078 to −0.019). The combined maximum cIMT was significantly associated with the total body T-score (ˇ = −0.195, p = 0.001, R2 = 0.038, 95% CI: −0.072 to −0.019). There were no associations between CAC and continuous total body T-score (data not shown).
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3.2. Femoral T-score, cIMT, and calcification 4. Discussion
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The results on femoral neck T-score groups and IMT and intimal calcifications are summarized in Table 2. When the right and left maximum cIMTs were combined in the same variable, there was a significant association between femoral neck T-score and combined maximum cIMT (p = 0.010), when adjusted for HT (no/yes), smoking (no/yes), BMI, age, systolic blood pressure, and categorized physical exercise. Statistically significant covariates in the model were age (p = 0.001), systolic blood pressure (p = 0.002), and categorized physical exercise (p = 0.004). In addition, the femoral neck T-score was inversely associated with right maximum cIMT (ˇ = −0.192, p = 0.001, R2 = 0.037, 95% CI:
In this cross-sectional, population-based study, we found that high maximum cIMT, but not mean cIMT, was associated with low femoral neck BMD in postmenopausal women. The odds for carotid calcification were over four-fold higher in osteoporotic women (5.8%) compared with women with a normal femoral Tscore (35.3%). The subjects of this study belong to the OSTPRE study which is a representative population based sample. Nevertheless, the final study sample (n = 290) represents a small part of the original OSTPRE study cohort (n = 14,220). The heavy selection process carries
Please cite this article in press as: Värri M, et al. Carotid intima-media thickness and calcification in relation to bone mineral density in postmenopausal women—The OSTPRE-BBA study. Maturitas (2014), http://dx.doi.org/10.1016/j.maturitas.2014.05.017
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Table 3 Correlates of carotid calcification according to binary logistic regression. Carotid calcification (no/yes)
FN T-score >−1 FN T-score = −2.5 to −1 FN T-score < −2.5 HT = 0 months HT = 1–60 months HT > 60 months Calcium intake mg/day Body mass index, kg/m2 Age, years
OR
p
95% CI
1.0 1.7 4.2 1.0 1.2 0.8 0.9 1.0 1.2
0.032 0.040 0.038 0.540 0.706 0.410 0.002 0.274 <0.001
Lower
Upper
1.0 1.1
2.9 15.9
0.6 0.4 0.9 1.0 1.1
2.4 1.4 1.0 1.1 1.3
FN, femoral neck; HT, hormone therapy; OR, odds ratio; CI, confidence interval. Femoral neck T-score >−1 and HT = 0 months were reference categories.
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the risk of selection bias. However, height, weight, BMI, systolic blood pressure, and femoral neck BMD were not different between OSTPRE-BBA women, who went through IMT and BMD measurements (n = 290), and all other OSTPRE cohort women who had their BMD measured at the 20-year follow-up in 2009 (n = 1264). It is unlikely that considerable selection bias has been introduced by the selection process. Thus the results might be generalized to other late postmenopausal women as well. As this is a population-based study, common chronic diseases and medications are not excluded. These may have had effect on the BMD or cIMT results. However, the statins should decrease, rather than increase the cIMT [25] and may attenuate the results observed. There were some limitations in the present study. The total daily intake of calcium might have been higher than we reported, because the use of calcium supplementation was not included in the present study. There was also lack of data considering the information about specific type of osteoporosis medication. In addition, some of women who participated in IMT measurements did not participate in the DXA measurements, which might have caused selection bias. One possible weakness of this study is the possible selection bias concerning HT users; they may represent healthier women in this age cohort. In addition, some women had stopped the use of HT years earlier, which may affect the results. Major conclusions cannot be drawn from the effect of HT use on IMT due to the cross-sectional study design. Several studies have shown that IMT, measured at carotid arteries with ultrasound, is a useful tool for estimating the presence of AS [5,6]. The method is widely used and generally approved [26,27]. It has been shown that atherosclerotic plaques and increased IMT predict the risk of CVD and stroke [4,7,8]. Our results about cIMT in people who had a stroke or CHD are in line with earlier, abovementioned studies, which support the method’s feasibility to reveal atherosclerosis. In addition, DXA is a widely used, reproducible, technique to measure BMD and the diagnostic criteria for OP are based on femoral neck BMD [2].Elevated systolic blood pressure and increased age were associated with increased cIMT, as in several other studies [14,24,28]. Age seemed to be a significant predictor of increased IMT even in the narrow age range of the present study, as presumed. In addition, diabetes was a risk factor for intima-media thickening and stroke, and CHD and arterial hypertension seemed to be connected with increased maximum cIMT, as presumed [4]. Smoking had no effect on IMT, but the small number of current smokers might have influenced the results. The use of postmenopausal HT has been associated with lower IMT at carotid arteries in earlier studies [17–19]. Our results showed that IMT values were smaller for HT users than for non-users. HT use had no effects on atherosclerotic calcification in our study, which is a similar result as found in some previous studies [21,22]. However, the selection bias might have had an impact on the HT results.
In addition, HT users might have had a healthier way of life than non-users. On the other hand, in a previous study of the OSTPRE population, the women who had used HT were not healthier than those who had not used it [29]. Several studies have demonstrated the connection between low BMD and cIMT. Low femoral neck and lumbar spine T-score were associated with increased cIMT in postmenopausal women who were consecutively enrolled among patients undergoing BMD measurement [14]. A negative correlation between total femoral BMD and cIMT was found in postmenopausal Moroccan women [12]. Low lumbar bone status has been associated with increased cIMT in early postmenopausal women [13]. Our study suggests that increased right cIMT is associated with low femoral neck T-score. This is in line with the results of earlier studies about the association between low BMD and cIMT. Significant differences between the association between right and left cIMTs and low BMD have not been reported elsewhere [12,14]. However, Fodor et al. [14] did find that the association between T-score values and right cIMT was stronger than the connection with left cIMT. More research is needed to explain the possible IMT differences between the right and left carotid arteries and their association with femoral neck T-score. Several studies have shown that low BMD is associated with intimal atherosclerotic calcification [30,31], and our study is in line with these results. Our results showed that carotid intimal calcification was associated with low femoral neck T-score, but not with the total body T-score. The reason why total body T-score was not associated with CAC can be partly explained by the fact that metabolically less active cortical bone is the main constituent of total body BMD measurement[32]. In addition, there may be lifestyle differences, for example, more physical exercise, which have more impact on femoral neck BMD than on total body BMD. Age has been positively associated with carotid calcification in other studies and our study confirms these results [30]. Our finding of the slightly protective effect of dairy calcium intake on carotid calcification is similar to that found in other studies, where only dietary calcium intake was evaluated [33]. However, the role of dietary supplements is more controversial with respect to cardiovascular disease [34]. There were differences in dietary calcium intake rates, which might be explained by lifestyle differences. In other words, women who had no CAC might have had a healthier way of life and diet than women who had a higher prevalence of CAC. The small difference of dietary calcium intake may explain why femoral neck or total body T-scores was not associated with dietary calcium intake. In conclusion, the results of our population-based study suggest that low BMD is related to atherosclerotic vascular changes, while indirectly supporting the hypothesis of partially shared pathophysiological mechanisms in these two disorders. More research
Please cite this article in press as: Värri M, et al. Carotid intima-media thickness and calcification in relation to bone mineral density in postmenopausal women—The OSTPRE-BBA study. Maturitas (2014), http://dx.doi.org/10.1016/j.maturitas.2014.05.017
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is needed to explore the metabolic connections between OP and vascular calcification. In addition, the long term follow-up of carotid arteries among osteoporotic women might be useful for the assessment of causality, including future prevention and treatment interventions.
[8]
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Authors’ roles: M.Tuppurainen, H.Kröger, and M.Värri were responsible for study design. M.Värri was responsible for study conduct. R.Honkanen, H.Kröger, and M.Tuppurainen were responsible for data collection. M.Värri, M.Tuppurainen and T.Rikkonen were responsible for data interpretation. M.Värri and M.Tuppurainen were responsible for drafting manuscript. TP.Tuomainen, R.Honkanen, L.Niskanen, T.Rikkonen, H.Kröger, and M.Tuppurainen were responsible for revising manuscript content. M.Värri takes responsibility for the integrity of the data analysis. We thank Jarmo Tiikkainen for performing IMT measurements and Kimmo Ronkainen for help in statistical analyses.
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Competing interests
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[11]
[12]
[13]
[14]
[15] [16] [17]
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L. Niskanen has received lecture fees from Amgen and Eli Lilly. All other authors state that they have no conflicts of interests. Funding
The study was supported by Kuopio University Hospital EVOQ4 grants (MT), Finnish Academy (HK), The Ministry of Education and 418 Culture of Finland, Kuopio University Hospital Funding (V.T.R.), and 419 Strategic Funding of the University of Eastern Finland. 420 Q3 417
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Ethical approval
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The willingness of the women to participate in the OSTPRE-BBA was asked by a postal enquiry. The study has been approved by the Ethics Committee of the North Savo Health Care District and all participants of the present study provided written informed consent. The study complies with the World Medical Association declaration of Helsinki ethical principles for medical research involving human subjects.
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We thank Jarmo Tiikkainen for performing IMT measurements and Kimmo Ronkainen for help in statistical analyses.
[19]
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[23]
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Panoramic images of white and black post-menopausal females evidencing carotid calcifications are at high risk of comorbid osteopenia of the femoral neck. Dentomaxillofac Radiol 2013;42:20120195. Greenspan SL, Maitland-Ramsey L, Myers E. Classification of osteoporosis in the elderly is dependent on site-specific analysis. Calcif Tissue Int 1996;58:409–14. Kim JH, Yoon JW, Kim KW, et al. Increased dietary calcium intake is not associated with coronary artery calcification. Int J Cardiol 2012;157:429–31. Pentti K, Tuppurainen MT, Honkanen R, et al. Use of calcium supplements and the risk of coronary heart disease in 52–62-year-old women: The Kuopio Osteoporosis Risk Factor and Prevention Study. Maturitas 2009;63:73–8.
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Contents lists available at ScienceDirect
Maturitas journal homepage: www.elsevier.com/locate/maturitas
Carotid intima-media thickness and calcification in relation to bone mineral density in postmenopausal women—The OSTPRE-BBA study
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Miika Värri a,∗ , Tomi-Pekka Tuomainen b , Risto Honkanen a,c , Toni Rikkonen a , Leo Niskanen d , Heikki Kröger a,e , Marjo T. Tuppurainen a,f a Bone and Cartilage Research Unit (BCRU), Surgery, Institute of Clinical Medicine, University of Eastern Finland, Mediteknia Building, P.O. Box 1627, FI-70211 Kuopio, Finland b Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Canthia Building, P.O.Box 1627, FI-70211 Kuopio, Finland c Lapland Hospital District, P.O. Box 8041, FI-96101 Rovaniemi, Finland d Institute of Clinical Medicine, University of Eastern Finland and Finnish Medicines Agency Fimea, Mannerheimintie 103b, FI-00280 Helsinki, Finland e Department of Orthopaedics, Traumatology and Hand Surgery, Kuopio University Hospital, Building 3, P.O. Box 100, FI-70029 Kuopio, Finland f Department of Obstetrics and Gynaecology, Kuopio University Hospital, Building 6, P.O. Box 100, FI-70029 Kuopio, Finland
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Article history: Received 23 February 2014 Received in revised form 17 May 2014 Accepted 21 May 2014 Available online xxx
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Keywords: DXA Osteoporosis Carotid calcification Intima-media thickness Postmenopausal hormone therapy
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1. Introduction
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Objectives: Atherosclerosis (AS) and osteoporosis are common diseases in elderly people and may be metabolically related. The aim of this cross-sectional population-based study was to explore the association between common carotid artery intima-media thickness (cIMT), carotid artery calcification (CAC), and BMD in postmenopausal women. In addition, the association of postmenopausal hormone therapy (HT) and selected diseases with cIMT and carotid calcification was studied. Study design: The 290 women (mean age 73.6 years) included in this Bone Brain Atherosclerosis study (OSTPRE-BBA) were randomly selected from the population-based Kuopio Osteoporosis Risk Factor and Prevention (OSTPRE) study cohort, Finland. Main outcome measures: For this cross-sectional study, cIMT was measured with B-mode ultrasound; femoral neck and total body BMD were measured with dual-energy X-ray absorptiometry. Results: There were no statistically significant associations between mean cIMT and femoral neck Tscore (p > 0.05). However, an increased maximum cIMT was significantly associated with low femoral neck T-score. In the osteoporotic group (T-score <−2.5, n = 20), the maximum cIMT was 2.51 ± 0.88 mm (mean ± SD); in the normal BMD group (T-score >−1, n = 122), it was 1.93 ± 0.64 mm (p = 0.001). The odds of having CAC were approximately four-fold higher in the osteoporotic group compared with the group with a normal femoral neck T-score (odds ratio [OR] = 4.2, p = 0.038). The maximum cIMT was smaller in HT users (1.98 ± 0.56 mm, n = 190) than in non-users (2.16 ± 0.74 mm, n = 156, p = 0.036). Conclusions: The results of our population-based study suggest that BMD is related to AS, at least in carotid arteries. They indirectly support the hypothesis of partially shared pathophysiological mechanisms between these two disorders. © 2014 Published by Elsevier Ireland Ltd.
Osteoporosis (OP) and atherosclerosis (AS) are both common in elderly people [1]. Their consequences, like osteoporotic fractures, myocardial infarction, and cerebrovascular stroke reduce quality of life and lead to functional decline and excess mortality in developed countries [2,3].
Abbreviations: AS, atherosclerosis; OP, osteoporosis. ∗ Corresponding author. Tel.: +358 503655083; fax: +358 17 172 611. E-mail address: [email protected].fi (M. Värri).
Ultrasonographic determination of carotid intima-media thickness (cIMT) is a non-invasive and reliable screening method to detect subclinical AS and predict future cardiovascular disease (CVD) events and stroke [4–8]. In women, the incidence of coronary heart disease (CHD) and stroke increases substantially after menopause, when estrogen production is decreasing, marking the end of the protective effect of endogenous estrogens against CVD [9]. Previous studies have demonstrated a relationship between bone loss, fractures, and vascular changes. Low bone mass or a prior vertebral fracture has been found to increase the risk of CVD and cardiovascular morbidity and mortality [10,11]. Low bone mass has
http://dx.doi.org/10.1016/j.maturitas.2014.05.017 0378-5122/© 2014 Published by Elsevier Ireland Ltd.
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been associated with increased cIMT and carotid artery calcification (CAC) in postmenopausal women, but the randomly selected population-based studies are scarce [12–14]. The intimal calcification of arteries is one facet of atherosclerotic vascular disease, while numerous mechanisms and mediators are responsible for calcium deposition, including several bone-forming mediators [15,16]. In intimal calcification, calcium deposits on the intima layer of the vessel wall, especially in advanced atherosclerotic plaques and, in some cases, it increases the risk of a plaque rupture [16]. The calcification of the arterial wall media layer is unrelated to AS and is observed in patients with diabetes or chronic renal disease [16]. Concerning postmenopausal women and vascular atherosclerotic changes, hormone therapy (HT) seem to associates with reduced cIMT values in postmenopausal women [17–19], but opposite results have also been found [20]. Similarly, results about the effects of HT on intimal atherosclerotic calcification are consistent; calcification-reducing effects and no effects have both been reported [16,21,22]. The aim of this cross-sectional study was to examine the associations between cIMT, CAC and BMD in a representative population sample of postmenopausal women. According to our hypothesis: BMD is associated with subclinical atherosclerosis markers despite the differences in the use of HT, life style factors and age.
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2.1. Population
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The data were obtained from the Kuopio Osteoporosis Risk Factor and Prevention (OSTPRE) Study cohort, consisting of all the 14,220 women (aged 47–56 years) who lived in the Province of Kuopio, Eastern Finland in February 1989. A baseline questionnaire was sent to these women in May 1989 and returned by 13,100 women [23]. A stratified random sample of 3222 women out of 11,055 respondents willing to undergo bone densitometry underwent the procedure in 1989–1992 (Fig. 1). The random part of the sample was 2025 women. A random subsample (n = 506) underwent hip, spine, and total body BMD follow-up measurements in 1994–1997, 1999–2002, and 2005–2007 and 458 participants of them were alive in 2009. In 2009–2011, femoral and total body BMD were measured. The OSTPRE (Bone, Brain, and Atherosclerosis) study (OSTPREBBA) has been designed to investigate the associations between adiposity, bone, and brain functions in 458 randomly selected postmenopausal women from the original OSTPRE densitometry study population. The final study sample (n = 290) includes women who participated in BMD and cIMT measurements (Fig. 1).
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2.2. IMT measurements
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IMT measurements were conducted on 346 OSTPRE-BBA participants in 2009. Ultrasound scans were conducted at the Bone and Cartilage Research Unit (BCRU), University of Eastern Finland, Kuopio. The examinations were performed by an experienced radiographer (JT) using the Technos MP ESAOTE ultrasound device (Esaote, Italy), with a B-type linear transducer at the 9 MHz frequency. The scanning area was from the base of the neck to a carotid bulb, following the common carotid artery (CCA) all the way. The technique has been used in previous studies [24]. All scanning materials were digitally recorded. The recordings were read to produce several variables: the maximum and mean cIMT; and calcifications on the arterial wall. IMT was measured over a 1-cm long segment from the distal CCA just before the bifurcation from the digitally recorded scanning
Women aged 47-56 (n=14220) in 1989 located in Kuopio province. Out of 13100 women 11055 were willing to undergo DXA.
Stratified random sample (n=3686) including high risk and random groups. 464 women did not participate.
Baseline densitometry in 1989-92, n=3222
Stratified high risk group was excluded (n=1197) Random sample, n=2025
25 % random sample n=506 for OSTPRE-BBA sample.
112 women did not participate and 48 died before the IMT measurements. Final OSPTRE-BBA study population with valid IMT measurements in 2009, n=346. 55 women did not participate and 1 died before the DXA measurements. Final study sample with valid DXA and IMT measurements, n=290
Fig. 1. Study population. OSTPRE-BBA = Kuopio Osteoporosis Risk and Prevention Study – Bone, Brain and Atherosclerosis.
images, using the Prowin computer software (Medical Technologies International Inc., Palm Desert, California, USA). Intima-media interface lines were manually traced as continuous lines. The cIMT operator was not aware of the final use of the scanning material. The main interests were on the maximum and mean cIMT and plaque calcifications (maximum cIMT >1.2 mm). The mean cIMT was computed from the means of the right and left cIMTs measured over the measurement area and it was used to describe the overall stage of AS. The maximum cIMT was the single highest point in the distal CCA IMT and it was used to demonstrate the highest protrusion and obstruction of the intima into the lumen. The left and right artery values were used as separate and combined variables. The combined maximum cIMT was the average of the maximum cIMT of both arteries. If either cIMT value was missing (n = 5), only the available value was used. The measurement points are shown in Fig. 2. Carotid calcifications were categorized into two different groups (no/yes): women who had intimal calcifications on their carotid artery walls (yes); and women who had no intimal calcifications (no). Four right maximum cIMTs and one left maximum cIMT were excluded, because of the anatomically difficult characteristics in some of the study subjects. 2.3. DXA measurements Both the hip and the total body BMD were measured by DXA at the OSTPRE 20-year follow-up study visit in 2009–2011 for 290 participants, whose cIMT was measured earlier. The femoral neck BMD was measured from the left femoral neck (n = 282). If the participant had a prosthesis in her left hip (n = 8), the BMD was
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Table 1 Characteristics of the study population (n = 290).
Fig. 2. The intima-media thickness measurement points of the common carotid arteries. cIMT = Carotid artery Intima-Media Thickness.
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measured from the right femoral neck. The DXA data were missing for 56 women, because 50 of them did not attend the measurement, five had a prosthesis in both hips, and one woman died before the measurement. Measurements were carried out at the University of Eastern Finland, BCRU, using the General Electrics Lunar Prodigy DXA device (Madison, WI, USA). BMD results were reported as T-scores. T-scores were also categorized into three groups according to the World Health Organization (WHO) criteria for diagnosing OP: normal BMD (T-score ≥−1 SD); osteopenic (T-score −1 to −2.5 SD); and osteoporotic (T-score ≤−2.5 SD) [2].
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The women’s weight and height were measured at each of the DXA densitometry measurements. The height was measured with a wall-mounted ruler. The BMI was calculated as body weight/height2 (kg/m2 ). The self-reported use of postmenopausal HT among participants was included (only systemic estrogen or combined estrogen-progestin treatment were accepted). HT users were categorized into two groups: women who had never used HT (no); and women who currently used or had used it (yes). The information concerning the use of HT, the history of diseases (stroke, asthma, diabetes, high serum cholesterol, arterial hypertension, CHD, rheumatoid arthritis, and transient ischemic attack [TIA]), medications, current smoking, blood pressure, physical exercise with shortness of breath (hours in a week), and dietary calcium intake (milligram per day) were based on a postal enquiry in 2009, with the question on chronic health disorders verified by a physician. CHD consisted of myocardial infarction and angina pectoris. Physical exercise data were missing for 56 participants who went through the cIMT measurement. The data were missing only for eight participants who went through both cIMT and BMD measurements. The missing values were replaced with the mean value of all participants. Dietary calcium intake was estimated by summing up intake from dairy products (cheese, milk, sour milk, yogurt, and sour whole milk).
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Statistical analyses were performed using the SPSS software (version 19.0, SPSS Inc., Chicago, IL, USA). Values are expressed as percentage or mean ± SD. Natural logarithm modification was made for maximum cIMT values to ensure normal distribution for the analysis. The normality of the data (all cIMT and BMD variables) was confirmed with Kolmogorov-Smirnoff test or by inspecting the histograms. Means were compared using Student’s t-test, in analyses between chronic diseases, HT and cIMT as dependent variable, or analysis of variance, in analyses between categorized T-score and cIMT as dependent variable. Chi-square test was used in the
Characteristic
Mean ± SD
Age (years) Weight (kg) BMI (kg/m2 ) Time since menopause (years) Femoral neck BMD (g/cm2 ) Femoral neck T-score Total body BMD (g/cm2 ) Total body T-score Mean IMT of the right CCA (mm) Max IMT of the right CCA (mm) Mean IMT of the left CCA (mm) Max IMT of the left CCA (mm) Mean IMT in right and left CCA (mm) Max IMT in right and left CCA (mm) HT between 1989 and 2009 (months, n = 190) Calcium intake (mg/day) Physical exercise with shortness of breath (hours in a week, n = 244)
73.6 72.1 28.7 23.7 0.848 −1.1 1.095 −0.4 0.93 2.06 0.93 2.04 0.93 2.04 55.7
± ± ± ± ± ± ± ± ± ± ± ± ± ± ±
2.8 13.0 5.1 4.6 0.131 1.1 0.104 1.3 0.14 0.76 0.16 0.74 0.13 0.66 72.7
762 ± 301 0.98 ± 1.33
Range 69.2–79.2 45.5–126.2 18.7–45.1 14.2–42.9 0.534–1.423 −3.7–3.7 0.809–1.421 −3.9–3.7 0.65–1.78 1.0–5.8 0.61–1.59 1.0–5.0 0.64–1.47 1.00–4.95 0–248 0–2070 0–7.50
BMI, body mass index; IMT, intima-media thickness; CCA, common carotid artery; HT, hormone therapy.
analysis of categorical variables, between CAC and categorized Tscore. Pearson correlation was used to compare the repeated cIMT measurement reliability and to compare calcium dietary supplementation and continuous T-score. Linear regression was used to study the association of cIMT and the continuous T-score variables. Analysis of covariance was used to study the independent effect of total body or femoral BMD on cIMT as dependent variable. Participants’ age, BMI, current smoking (no, yes), HT use (no, yes), and systolic blood pressure were used as covariates. In addition, physical exercise with shortness of breath (hours in a week) was categorized into quartiles and used as covariate in analyses, which included femoral neck BMD. Only variables showing statistically significant association with dependent variables were included in the final model. Logistic regression was used to model dichotomous (no, yes) carotid calcification, as the dependent variable, explained by femoral neck or total body T-score, HT (0, 1–60, >60 months), BMI, age, and dietary calcium intake. Two-sided p-values lower than 0.05 were considered statistically significant. 3. Results Characteristics of the study population are shown in Table 1. In all, 0.3% of the women were underweight (<19.0 kg/m2 ) and 35.2% were obese (BMI >30 kg/m2 ); 3.8% were current smokers. In all, 47.6% of the women used statins, 1.7% used peroral corticosteroids, 5.5% used inhaled corticosteroids and 8.6% used osteoporosis medication. The coefficient of variation (CV) for femoral neck BMD after repositioning of the patient was 1.1% in two repeated BMD measurements from left femoral neck for 20 participants. There was significant correlation between 10 repeated mean cIMT (r = 0.977, p < 0.001) and maximum cIMT (r = 0.942, p < 0.001) measurements. The daily dietary calcium intake was significantly higher in women who had no CAC (832 ± 345 mg, n = 134) than in women who had CAC (734 ± 288 mg, n = 212, p = 0.004). There were no statistically significant correlations between dietary calcium intake and femoral neck T-score (p > 0.05) though the calcium intake were slightly different. The results were similar with total body T-score (data not shown). When comparing the study cohort (women who went through IMT and BMD measurements, n = 290) with all other women in the OSTPRE densitometry sample, who were measured at the 20-year
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4 Table 2 Associations between BMD T-scores and vascular variables. Femoral neck T-score
Mean IMT in right and left CCA ± SD (mm)a Max IMT in right and left CCA ± SD (mm)a Max IMT in right CCA ± SD (mm)a Max IMT in left CCA ± SD (mm)a Intimal calcification, n (%)b
T-score <−2.5 n = 20
T-score −2.5 to −1 n = 148
T-score >−1 n = 122
p
pc
0.93 ± 0.15 2.51 ± 0.88 2.66 ± 1.19 2.36 ± 0.71 17 (85%)
0.92 ± 0.13 2.08 ± 0.61 2.08 ± 0.66 2.08 ± 0.80 97 (65.5%)
0.95 ± 0.13 1.93 ± 0.64 1.95 ± 0.73 1.93 ± 0.67 61 (50%)
0.192 0.001 0.001 0.025 0.002
0.166 0.010 0.008 0.138
T-score <−2.5 n = 13
T-score −2.5 to −1 n = 84
T-score >−1 n = 197
p
pc
0.89 ± 0.14 2.52 ± 0.86 2.55 ± 1.06 2.48 ± 0.84 9 (69.2%)
0.92 ± 0.13 2.10 ± 0.70 2.10 ± 0.85 2.09 ± 0.75 53 (62.1%)
0.94 ± 0.13 2.00 ± 0.62 2.02 ± 0.68 1.98 ± 0.73 113 (57.4%)
0.250 0.032 0.118 0.032 0.513
0.103 0.121 0.335 0.111
Total body T-score
Mean IMT in right and left CCA ± SD (mm)a Max IMT in right and left CCA ± SD (mm)a Max IMT in right CCA ± SD (mm)a Max IMT in left CCA ± SD (mm)a Intimal calcification, n (%)b
CCA, common carotid artery; IMT, intima-media thickness; pc = p with covariates: hormone therapy (no/yes), smoking (no/yes), BMI, age and systolic blood pressure (and physical exercise in quartiles in the femoral neck BMD model). a Analysis of variances. b Chi-square test.
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follow-up in 2009 (n = 1264), there were no significant differences in body weight (p = 0.587), height (p = 0.304), BMI (p = 0.079), femoral neck BMD (p = 0.384), or systolic blood pressure (p = 0.286).
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3.1. IMT, chronic diseases, risk factors, and the use of HT
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The mean cIMT was 0.98 ± 0.14 mm in women with diabetes (n = 37) and 0.92 ± 0.13 mm in women without diabetes (n = 309, p = 0.026). There was a similar trend between maximum cIMT and diabetes (p = 0.045). Women with arterial hypertension (n = 166) had a higher mean cIMT (0.94 ± 0.14 mm) and maximum cIMT (2.18 ± 0.61 mm) than women with normal blood pressure (n = 188, mean cIMT 0.91 ± 0.12 mm and maximum cIMT 1.95 ± 0.67 mm, p = 0.04 with mean cIMT and p = 0.001 with maximum cIMT). The maximum cIMT was significantly higher in women who had a history of stroke or TIA (2.46 ± 0.57 mm, n = 21) than women with no cerebrovascular disorders (2.04 ± 0.65 mm, n = 325) (p < 0.001), but there were no significant differences in mean cIMT (p = 0.179). Women who had a history of CHD had a higher maximum cIMT (2.34 ± 0.72 mm, n = 42) than women who did not have CHD (2.02 ± 0.63 mm, n = 304, p = 0.005), but there were no significant differences in mean cIMT (p = 0.913). Bronchial asthma (n = 45), high serum cholesterol (n = 123), and rheumatoid arthritis (n = 15) had no associations with cIMT (data not shown). Women with a positive history of HT use had a smaller maximum cIMT (1.98 ± 0.56 mm, n = 190) than non-users (2.16 ± 0.74 mm, n = 156, p = 0.036), but there were no significant associations with mean cIMT (p = 0.061).
−0.96 to −0.024). The result was similar between femoral neck Tscore and left maximum cIMT (ˇ = −0.195, p = 0.001, R2 = 0.038, 95% CI: −0.096 to −0.025). There was a significant association between femoral neck T-score and combined maximum cIMT (ˇ = −0.223, p < 0.001, R2 = 0.050, 95% CI: −0.094 to −0.031). The associations between intimal calcifications and femoral neck BMD are shown in Table 3. There was 4.2 times higher odd for CAC in the osteoporotic group than in the normal T-score group (OR 4.2, p = 0.038). HT was not associated with CAC (p > 0.05) (Table 3). There were no associations between carotid calcification (no/yes) and categorized physical exercise (p = 0.318) (data not shown). 3.3. Total body T-score, cIMT, and calcification The result on the total body T-score groups and IMT and intimal calcification are summarized in Table 2. When the right and left maximum cIMTs were combined in the same variable, there was a significant difference between total body T-score groups and combined maximum cIMT (p = 0.032), but the difference did not persist after adjustment for covariates (p = 0.121). In addition, there was a significant linear association between the right maximum cIMT and total body T-score (ˇ = −0.154, p = 0.009, R2 = 0.024, 95% CI: −0.071 to −0.010). Low total body T-score was also associated with left maximum cIMT (ˇ = −0.187, p = 0.001, R2 = 0.035, 95% CI: −0.078 to −0.019). The combined maximum cIMT was significantly associated with the total body T-score (ˇ = −0.195, p = 0.001, R2 = 0.038, 95% CI: −0.072 to −0.019). There were no associations between CAC and continuous total body T-score (data not shown).
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3.2. Femoral T-score, cIMT, and calcification 4. Discussion
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The results on femoral neck T-score groups and IMT and intimal calcifications are summarized in Table 2. When the right and left maximum cIMTs were combined in the same variable, there was a significant association between femoral neck T-score and combined maximum cIMT (p = 0.010), when adjusted for HT (no/yes), smoking (no/yes), BMI, age, systolic blood pressure, and categorized physical exercise. Statistically significant covariates in the model were age (p = 0.001), systolic blood pressure (p = 0.002), and categorized physical exercise (p = 0.004). In addition, the femoral neck T-score was inversely associated with right maximum cIMT (ˇ = −0.192, p = 0.001, R2 = 0.037, 95% CI:
In this cross-sectional, population-based study, we found that high maximum cIMT, but not mean cIMT, was associated with low femoral neck BMD in postmenopausal women. The odds for carotid calcification were over four-fold higher in osteoporotic women (5.8%) compared with women with a normal femoral Tscore (35.3%). The subjects of this study belong to the OSTPRE study which is a representative population based sample. Nevertheless, the final study sample (n = 290) represents a small part of the original OSTPRE study cohort (n = 14,220). The heavy selection process carries
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Table 3 Correlates of carotid calcification according to binary logistic regression. Carotid calcification (no/yes)
FN T-score >−1 FN T-score = −2.5 to −1 FN T-score < −2.5 HT = 0 months HT = 1–60 months HT > 60 months Calcium intake mg/day Body mass index, kg/m2 Age, years
OR
p
95% CI
1.0 1.7 4.2 1.0 1.2 0.8 0.9 1.0 1.2
0.032 0.040 0.038 0.540 0.706 0.410 0.002 0.274 <0.001
Lower
Upper
1.0 1.1
2.9 15.9
0.6 0.4 0.9 1.0 1.1
2.4 1.4 1.0 1.1 1.3
FN, femoral neck; HT, hormone therapy; OR, odds ratio; CI, confidence interval. Femoral neck T-score >−1 and HT = 0 months were reference categories.
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the risk of selection bias. However, height, weight, BMI, systolic blood pressure, and femoral neck BMD were not different between OSTPRE-BBA women, who went through IMT and BMD measurements (n = 290), and all other OSTPRE cohort women who had their BMD measured at the 20-year follow-up in 2009 (n = 1264). It is unlikely that considerable selection bias has been introduced by the selection process. Thus the results might be generalized to other late postmenopausal women as well. As this is a population-based study, common chronic diseases and medications are not excluded. These may have had effect on the BMD or cIMT results. However, the statins should decrease, rather than increase the cIMT [25] and may attenuate the results observed. There were some limitations in the present study. The total daily intake of calcium might have been higher than we reported, because the use of calcium supplementation was not included in the present study. There was also lack of data considering the information about specific type of osteoporosis medication. In addition, some of women who participated in IMT measurements did not participate in the DXA measurements, which might have caused selection bias. One possible weakness of this study is the possible selection bias concerning HT users; they may represent healthier women in this age cohort. In addition, some women had stopped the use of HT years earlier, which may affect the results. Major conclusions cannot be drawn from the effect of HT use on IMT due to the cross-sectional study design. Several studies have shown that IMT, measured at carotid arteries with ultrasound, is a useful tool for estimating the presence of AS [5,6]. The method is widely used and generally approved [26,27]. It has been shown that atherosclerotic plaques and increased IMT predict the risk of CVD and stroke [4,7,8]. Our results about cIMT in people who had a stroke or CHD are in line with earlier, abovementioned studies, which support the method’s feasibility to reveal atherosclerosis. In addition, DXA is a widely used, reproducible, technique to measure BMD and the diagnostic criteria for OP are based on femoral neck BMD [2].Elevated systolic blood pressure and increased age were associated with increased cIMT, as in several other studies [14,24,28]. Age seemed to be a significant predictor of increased IMT even in the narrow age range of the present study, as presumed. In addition, diabetes was a risk factor for intima-media thickening and stroke, and CHD and arterial hypertension seemed to be connected with increased maximum cIMT, as presumed [4]. Smoking had no effect on IMT, but the small number of current smokers might have influenced the results. The use of postmenopausal HT has been associated with lower IMT at carotid arteries in earlier studies [17–19]. Our results showed that IMT values were smaller for HT users than for non-users. HT use had no effects on atherosclerotic calcification in our study, which is a similar result as found in some previous studies [21,22]. However, the selection bias might have had an impact on the HT results.
In addition, HT users might have had a healthier way of life than non-users. On the other hand, in a previous study of the OSTPRE population, the women who had used HT were not healthier than those who had not used it [29]. Several studies have demonstrated the connection between low BMD and cIMT. Low femoral neck and lumbar spine T-score were associated with increased cIMT in postmenopausal women who were consecutively enrolled among patients undergoing BMD measurement [14]. A negative correlation between total femoral BMD and cIMT was found in postmenopausal Moroccan women [12]. Low lumbar bone status has been associated with increased cIMT in early postmenopausal women [13]. Our study suggests that increased right cIMT is associated with low femoral neck T-score. This is in line with the results of earlier studies about the association between low BMD and cIMT. Significant differences between the association between right and left cIMTs and low BMD have not been reported elsewhere [12,14]. However, Fodor et al. [14] did find that the association between T-score values and right cIMT was stronger than the connection with left cIMT. More research is needed to explain the possible IMT differences between the right and left carotid arteries and their association with femoral neck T-score. Several studies have shown that low BMD is associated with intimal atherosclerotic calcification [30,31], and our study is in line with these results. Our results showed that carotid intimal calcification was associated with low femoral neck T-score, but not with the total body T-score. The reason why total body T-score was not associated with CAC can be partly explained by the fact that metabolically less active cortical bone is the main constituent of total body BMD measurement[32]. In addition, there may be lifestyle differences, for example, more physical exercise, which have more impact on femoral neck BMD than on total body BMD. Age has been positively associated with carotid calcification in other studies and our study confirms these results [30]. Our finding of the slightly protective effect of dairy calcium intake on carotid calcification is similar to that found in other studies, where only dietary calcium intake was evaluated [33]. However, the role of dietary supplements is more controversial with respect to cardiovascular disease [34]. There were differences in dietary calcium intake rates, which might be explained by lifestyle differences. In other words, women who had no CAC might have had a healthier way of life and diet than women who had a higher prevalence of CAC. The small difference of dietary calcium intake may explain why femoral neck or total body T-scores was not associated with dietary calcium intake. In conclusion, the results of our population-based study suggest that low BMD is related to atherosclerotic vascular changes, while indirectly supporting the hypothesis of partially shared pathophysiological mechanisms in these two disorders. More research
Please cite this article in press as: Värri M, et al. Carotid intima-media thickness and calcification in relation to bone mineral density in postmenopausal women—The OSTPRE-BBA study. Maturitas (2014), http://dx.doi.org/10.1016/j.maturitas.2014.05.017
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is needed to explore the metabolic connections between OP and vascular calcification. In addition, the long term follow-up of carotid arteries among osteoporotic women might be useful for the assessment of causality, including future prevention and treatment interventions.
[8]
[9]
Contributors [10]
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Authors’ roles: M.Tuppurainen, H.Kröger, and M.Värri were responsible for study design. M.Värri was responsible for study conduct. R.Honkanen, H.Kröger, and M.Tuppurainen were responsible for data collection. M.Värri, M.Tuppurainen and T.Rikkonen were responsible for data interpretation. M.Värri and M.Tuppurainen were responsible for drafting manuscript. TP.Tuomainen, R.Honkanen, L.Niskanen, T.Rikkonen, H.Kröger, and M.Tuppurainen were responsible for revising manuscript content. M.Värri takes responsibility for the integrity of the data analysis. We thank Jarmo Tiikkainen for performing IMT measurements and Kimmo Ronkainen for help in statistical analyses.
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Competing interests
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[11]
[12]
[13]
[14]
[15] [16] [17]
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L. Niskanen has received lecture fees from Amgen and Eli Lilly. All other authors state that they have no conflicts of interests. Funding
The study was supported by Kuopio University Hospital EVOQ4 grants (MT), Finnish Academy (HK), The Ministry of Education and 418 Culture of Finland, Kuopio University Hospital Funding (V.T.R.), and 419 Strategic Funding of the University of Eastern Finland. 420 Q3 417
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Ethical approval
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The willingness of the women to participate in the OSTPRE-BBA was asked by a postal enquiry. The study has been approved by the Ethics Committee of the North Savo Health Care District and all participants of the present study provided written informed consent. The study complies with the World Medical Association declaration of Helsinki ethical principles for medical research involving human subjects.
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[18]
We thank Jarmo Tiikkainen for performing IMT measurements and Kimmo Ronkainen for help in statistical analyses.
[19]
[20]
[21] [22]
[23]
[24] [25]
[26]
[27]
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