Characteristics of Pathogenetic Links in Vascular Remodeling and Bone Tissue Destruction in Postmenopausal Women with Arterial Hypertension

Abstract

The role of nonspecific immune inflammatory vascular response as a link in general pathogenetic mechanisms with change in the elastic properties of the arteries and phenomena of destructive bone changes has attracted great attention. We examined 104 patients (mean age 54.03 ± 9.56) who were divided into three groups: healthy women, with arterial hypertension (AH) and osteopenia and with AH and osteoporosis. The immune inflammatory response markers, endothelial dysfunction, and hormonal and mineral-vitamin status were analyzed simultaneously with 24-hour ambulatory blood pressure monitoring, parameters of vascular wall stiffness, and densitometry to clarify the predictors of cardiovascular and degenerative bone changes in postmenopausal women. For patients with AH and osteopenia, significant parameter associated with the risk of osteoporosis was pulse wave velocity; increase of which exceeded 12.05 m/s was associated with increased risk of osteoporosis by 3.8 times. The levels of pro-inflammatory parameters, interleukin (IL) 6 and 8, tumor necrosis factor-α, high-sensitivity С-reactive protein, and parathyroid hormone were increased and the levels of progesterone and IL-10 were decreased. Timely specialized multidirectional studies of biochemical and instrumental parameters (pulse wave velocity and densitometry) can be the basis for the development of personalized prevention and treatment strategy for women to prevent dangerous cardiovascular and bone complications.

1. Introduction

Atherosclerosis (AS) and osteoporosis (OP) are currently considered chronic non-infectious epidemics of the 21st century. These diseases are age-related but they are associated with both increase in life expectancy and etiopathogenetic relationships. AS and OP have a number of common features and, above all, asymptomatic course at the onset and a high risk of delayed complications; for AS, these are heart attack and stroke, for OP, low-trauma fractures with a rate of 30–40% [1].

Modern medicine finds it extremely important to identify certain relationships and common pathogenetic mechanisms between various diseases in order to develop an integrated and individualized approach to the treatment and prevention of diseases. The results of experimental and clinical studies conducted over the last decade confirm that AS and OP with asymptomatic onset had common pathogenetic links resulting in manifested complications. A relationship was shown between the development of AS and decrease in bone mineral density (BMD), regardless of the age of patients and increased risk of morbidity and mortality due to AS complications in patients with OP [2].

Various factors affecting bone metabolism are involved in the mechanisms of vascular diseases. In order to assess the relationship between OP and cardiovascular diseases (CVD) caused by AS, surrogate markers of these diseases are commonly used, such as parameters of vascular wall stiffness or vascular calcification and BMD. The vascular and bone tissues appeared to have a number of common properties and vascular calcification consists of the same elements as the bone tissue: calcium salts, type I collagen, phosphates, bone morphogenetic protein, etc. It has been suggested that low BMD may be a direct risk factor for AS of the coronary arteries [3].

The relationship between AS and OP is most evident in postmenopausal women. In estrogen deficiency, the ability of endothelial cells to produce nitric oxide, which supports the elasticity of the arteries and has stimulating effects on the osteoblasts, decreases, which results in endothelial dysfunction and bone metabolism disorders [2, 3].

Together with the deficit of sex steroids, negative calcium balance caused by vitamin D deficiency and reduced absorption of calcium in the intestine is of great importance, which ultimately results in secondary hyperparathyroidism and increased bone resorption [4, 5]. Disorders leading to both OP and CVD include increased activity of the sympathetic autonomic nervous system, which, together with endothelial dysfunction, causes disorders of the microcirculation system. The most important mechanism for reducing BMD is deterioration of bone tissue perfusion associated with disorders of the microcirculation system. Microcirculation that determines the value of peripheral vascular resistance, due to the “steal” syndrome, significantly affects the state of perfusion of internal organs, including bone tissue [6].

The role of angiotensin II in the development of CVD is well known. In addition to the vasoconstrictor effects, it has significant pro-inflammatory activity in the vascular wall (stimulating the production of reactive oxidized particles, inflammatory cytokines, and adhesion molecules) and contributes to the formation and progression of AS. Angiotensin II receptors have been identified in the culture of bone tissue cells (osteoblasts and osteoclasts). Angiotensin II promotes the production of the receptor activator of nuclear factor kappa-B ligand (RANKL) by osteoblasts, which leads to additional activation of the osteoclasts and increased bone resorption, as well as inhibition of bone mineralization [7, 8].

The results of clinical studies of the relationships between BMD and arterial hypertension (AH) and blood pressure (BP) levels have been controversial. Some of them showed a negative relationship between BP and bone density, while others showed no relationship between BP and BMD [9, 10]. There are also published data showing that arterial stiffness is higher in women with moderate cardiovascular risk and postmenopausal OP and is closely associated with BMD and bone turnover markers. It was shown that decrease in BMD of the femoral neck is an independent factor for increase in arterial stiffness. The data obtained allowed us to assume that bone mineral metabolism disorders may be an additional risk factor for vascular wall damage, which must be taken into account when determining patients’ total cardiovascular risk [11, 12, 13, 14].

With steady aging of the population in the 21st century, data on the association of the processes of cardiovascular remodeling and bone tissue resorption in postmenopausal period remain of interest. More and more attention has been recently paid to the role of nonspecific immune inflammatory vascular response as a link in the common pathogenetic mechanisms of atherosclerotic lesions of the vascular bed with changes in the elastic properties of the arteries and the phenomena of degenerative bone changes, which is of great importance at subclinical level, to provide comprehensive measures for the prevention of complications of these comorbid conditions in general.

The purpose of our work was to study the role of nonspecific immune-inflammatory markers, parathyroid hormone, and female sex hormones as predictors of cardiovascular and degenerative bone changes in postmenopausal women with AH and OP.

2. Materials and methods

The study involved 104 patients (mean age 54.03 ± 9.56 years) who were divided into three groups. Group 1 included 39 healthy women, group 2 – 30 patients with AH and osteopenia, and group 3 – 35 women with AH and OP. The study protocol was approved by the Ethics Committee of Tyumen Cardiologic Research Center, Tomsk National Research Medical Center of the Russian Academy of Sciences, Tomsk, Russia. Before enrollment, each study participant gave a written informed consent to use the study results for scientific purposes.

Exclusion criteria included: presence of acute cerebrovascular accident less than 6 months ago, coronary artery disease, type 2 diabetes mellitus, chronic heart failure of functional class (FC) III-IV (according to the New York Heart Association classification–NYHA), cancer, and mental illness. AH was diagnosed according to the current recommendations of the European Society of Cardiology and Russian Society of Cardiology. The scope of diagnostic measures included: clinical examination, laboratory, and instrumental methods to evaluate the cardiovascular and skeletal systems. The study of the parameters of 24-hour ambulatory blood pressure monitoring (ABPM) was carried out for all examined patients according to the standard scheme, using the oscillometric method, on the equipment of BPLAB LLC “Petr Telegin” (Russian Federation), with the study of standard parameters.

The study of the elastic properties of the vascular walls was carried out using a sphygmograph Vasera VS-1000 Series (Fukuda Denishi, Japan), with the assessment of the following parameters: pulse wave velocity for the elastic-type arteries on the right or left (PWV-R/L) and ankle-brachial index (ABI-R, ABI-L) as a parameter of peripheral vascular blood flow and a screening parameter for the presence of AS of the vessels of the lower extremities. Osteodensitometry was performed using the Siemens Somatom Emotion spiral computed tomograph. Calcium content CA-HA and the standard deviation of the T-Score peak were assessed (standard values: from 2.0 to −1.0, normal values: from −1.0 to −2.5, and osteopenia: from −2.5 and lower - OP).

Ultrasound scanning of the brachiocephalic arteries was performed; the parameters of intima-media thickness (IMT) of the carotid artery, state of the vascular wall, and the presence of atherosclerotic plaques were taken into account. IMT was determined at a distance of 2 cm from the bifurcation of the common carotid artery on the posterior wall (normal – less than 0.8 mm, the upper limit of normal was 0.9 mm, the thickening was more than 0.9 mm). Atherosclerotic plaque was a local thickening of the arterial wall exceeding 50% or more of the thickness of the adjacent unchanged IMT, protruding into the lumen of the vessel and having different structure compared to unchanged arterial wall and/or thickening of the IMT of more than 1.3 mm [13]. Fasting venous blood was collected into the Vacuette disposable tubes (Japan); the blood was centrifuged for 15 min at 2500 rpm in the Sigma centrifuge (Germany). Patients’ blood serum was aliquoted for further freezing (at −70°C).

The parameters of lipid metabolism were studied using the Cobas Integra 400 plus automatic biochemical analyzer (Switzerland). Total cholesterol and triglycerides (TG) in blood serum were determined using the enzymatic colorimetric method; high-density lipoprotein (HDL) and low-density lipoprotein (LDL) were determined using the direct enzymatic colorimetric method; concentrations of apolipoprotein A-I (Apo A-I), apolipoprotein B (Apo-B), and lipoprotein a (Lp(a)) were obtained using immunoturbidimetry with the analytical kits and control materials by Roche Diagnostics Gmb (Germany).

The following biochemical markers of inflammation were determined: high-sensitivity C-reactive protein (hs-CRP) by immunoturbidimetric method using the “C-reactive protein hs” analytical kit (BioSystem, Spain) on the Clima MC-15 semi-automatic, open type analyzer (Spain); interleukin-1β (IL-1β), interleukin-6 (IL-6), interleukin-8 (IL-8), tumor necrosis factor-α (TNF-α) –“sandwich” and homocysteine (HYC) by competitive methods (solid-phase chemiluminescence enzyme immunoassay) using the following analytical kits: IL-1β, IL-6, IL-8, TNF-α, HYC, respectively. The level of sex hormones (estradiol, progesterone, testosterone) and parathyroid hormone were determined using a competitive, solid-phase, chemiluminescent ELISA method with the Siemens Diagnostics reagents; myeloperoxidase was investigated by the sandwich ELISA method using the eBioscience reagents.

Carbohydrate metabolism was assessed based on glucose and glycated hemoglobin (HbA1c) concentrations. Blood glucose was determined by the hexokinase method using the Cobas Integra 400 plus biochemical analyzer. Glycated hemoglobin was determined by chromatography using the Bio-Rad D10 analyzer, USA. The atherogenic coefficient (AC) was calculated as = Apo B/Apo A-I. The parameters of functional activity of endothelium in blood serum: nitrite levels were determined using the Humalyzer 2000 Human biochemical analyzer (Germany) and endothelin-1-21 using the Dynatech semi-automated immunoassay analyzer (Germany).

Statistical data processing was carried out using the Statistica software package (SPSS Inc., ver 11.5). Parameter distribution was tested using the Kolmogorov-Smirnov test. To determine the statistical significance of the differences in continuous values depending on the distribution parameters, one-factor analysis of variance with the Holm-Sidak correction for multiple comparisons or the Kruskal−Wallis criterion with the Bonferroni correction for multiple comparisons were used. Continuous variables represented as M ± SD (mean ± standard deviation) or Me [Q25; Q75] (median and interquartile range). To assess the differences in qualitative variables, the chi-square criterion and the Fisher exact criterion were used. Spearman and Pearson linear correlation coefficient, logistic regression method, and discriminant analysis were used to identify the relationship between the variables.

3. Results and discussion

Characteristics of clinical and anamnestic data of examined patients are presented in Table 1. The data presented in the table show that the age of the patients in Groups 2 and 3 significantly differed from Group 1 (p < 0.005; p < 0.001, respectively). There were no significant differences in smoking and body mass index (BMI) in all groups, or duration of AH in the groups with AH. The percentage of family history of AH in the groups with AH did not differ, but was significantly lower in the control group of healthy patients. Regarding the grade of AH, the maximum percentage of patients with grade 1 AH was in Group 2 and the maximum percentage of patients with grade 3 AH was in Group 3. In addition, patients in group with AH and OP had significantly longer postmenopausal period compared to the 1st group of patients (p < 0.001).

Parameter		Group 1 Healthy patients (n = 39)	Group 2 Patients with AH and osteopenia (n = 30)	Group 3 Patients with AH and osteoporosis (n = 35)	p(groups 1 and 3)
Age (years)		42.92 ± 13.41	58.91 ± 8.28***	62.68 ± 7.16***	<0.001
Smoking		0%	1 (3.4%)	3 (8.6%)	0.181
Non-smoking		39 (100%)	29 (96.6%)	32 (91.4%)
AH grade	1		11 (36.7%)	5 (14.3%)	0.029
	2		11 (36.7%)	17 (48.6%)	0.386
	3		8(26.6%)	13(37.1%)	0.259
BMI (kg/m^2)		25 ± 0.8	26.14 ± 2.48	25.48 ± 2.61	0.460
Waist volume (cm)		71.01 ± 6.08	83.83 ± 8.31	81.65 ± 12.38	0.165
Hips volume (cm)		93.01 ± 1.41	96.22 ± 7.28	97.51 ± 9.93	0.739
Family history of AH	Yes	17 (43.5%)	20 (66.7%)	29 (82.9%)	0.082
	No	22 (56.6%)	10 (33.3%)	6 (17.1%)
Postmenopausal period (years)		1.0 [1.0;1.75]	7.0 [4.0;10.0]***	10.0 [5.5;21.5]##	<0.001

Table 1.

Clinical and anamnestic characteristics in groups of examined patients.

***

p < 0.001 – comparison between groups 1 and 2.

##

p < 0.01 – comparison between groups 2 and 3.

p – comparison between groups 1 and 3.

According to ABPM, a significant difference in the parameters was observed for the levels of 24-hour systolic BP (SBP 24) and diastolic BP (DBP 24) between healthy subjects in Group 1 and patients in Group 2, as well as for the levels of SBP 24 variability and nighttime DBP between patients in Groups 2 and 3 (p < 0.01). The absence of other significant changes in ABPM parameters can be explained by sufficient adherence of patients with AH to antihypertensive therapy. The characteristics of structural and functional parameters of vascular wall and bone tissue in the groups of examined patients are presented in Table 2.

Parameter	Healthy patients	Patients with AH and osteopenia	Patients with AH and osteoporosis	p(groups 1 and 3)
	(n = 39)	(n = 30)	(n = 35)
PWV-R, m/s	11.29 ± 0.84	12.99 ± 1.52**	14.82 ± 2.81#	<0.001
PWV-L, m/s	9.60 ± 0.77	13.32 ± 1.44**	15.09 ± 2.97#	0.001
IMT CCA d, mm	0.70 [0.55; 0.80]	0.80 [0.75; 1.0]	0.90 [0.80; 0.90]	0.046
IMT CCA s, mm	0.70 [0.55; 0.75]	0.80 [0.70; 0.85]	0.90 [0.9; 1.00]	0.007
Т Score	−0.40 ± 0.22	−1.47 ± 0.93**	−3.08 ± 0.64##	<0.001
AC	—	110.56 ± 16.27	60.37 ± 26.79##	—

Table 2.

Structural and functional characteristics of the vascular wall and bone tissue in the groups of examined patients (M ± SD).

**

p < 0.01.

#

p < 0.05 – comparison between groups 2 and 3.

##

p < 0.01 – comparison between groups 2 and 3.

p – comparison between groups 1 and 3.

According to the results presented in Table 2, PWV-R/L is significantly higher in the groups of patients with AH compared to the control group. The maximum values were registered in Group 3, which significantly exceeded parameters in Groups 1 and 2, which is compliant with the data of other researchers who registered increase in the rigidity of the vascular wall in postmenopausal women [2, 3].

IMT of the common carotid artery (IMT CCA) d/s maximum values were observed in Group 3 of patients with AH and OP, which significantly exceeded the values in Group 1. T-Score and AC were naturally significantly reduced in Group 3 of patients with AH and OP compared to Groups 1 and 2. Correlation analysis of parameters presented in the table showed moderate relationships in Group 2 – PWV-R with IMT CCA d (r = 0.415, p < 0.06); in Group 3 – AC with PWV-R (r = 0.871, p < 0.06) and IMT CCA d (r = −0.673, p < 0.002).

We decided to study common relationships between the studied parameters by determining their relationships with the biochemical parameters of the lipid profile, inflammatory response, and endothelial dysfunction of the vascular wall, as well as parameters of hormonal and mineral-vitamin metabolism.

Laboratory biochemical parameters in the examined groups of patients are presented in Table 3.

Parameter	Healthy patients	Patients with AH and osteopenia	Patients with AH and osteoporosis	p(groups 1 and 3)
	(n = 39)	(n = 30)	(n = 35)
Lipid profile
TCh (mmol/L)	5.09 ± 1.01	5.54 ± 1.15	5.57 ± 1.18	0.124
HDL (mmol/L)	1.59 ± 0.39	1.54 ± 0.4	1.73 ± 0.52	0.230
LDL (mmol/L)	2.83 ± 0.76	3.32 ± 1.05	3.25 ± 1.17	0.081
ТG (mmol/L)	1.21 ± 0.75	1.44 ± 0.85	1.18 ± 0.43	0.246
Аpo-А (mg/dL)	187.26 ± 35.7	177.13 ± 27.64	178.7 ± 29.0	0.358
Аpo-В (mg/dL)	116.02 ± 139.8	105.75 ± 29.78	105.97 ± 29.42	0.261
Аpо-А1/Аpо-В (mg/dL)	0.53 ± 0.14	0.6 ± 0.19	0.61 ± 0.16	0.112
Myeloperoxidase (mg/dL)	7.69 [2.12; 11.87]	9.75 [7.13; 13.02]	10.07 [8.09; 13.7]	0.05
Inflammatory markers
High-sensitivity С-reactive protein (hs-СRP) (mg/L)	1.05 [0.45; 3.13]	2.10 * [1.01; 4.05]	3.11 [1.76; 5.51]	0.002
TNF-α (pg/ml)	4.47 ± 0.06	4.78 ± 1.35	5.04 ± 1.26	0.219
Homocysteine (μmol/L)	10.88 ± 2.28	12.42 ± 5.47	13.21 ± 5.21	0.076
IL-1β (pg/ml)	2.49 ± 0.46	2.54 ± 0.53	2.67 ± 1.04	0.539
IL-6 (pg/ml)	1.65 ± 0.41	2.05 ± 0.80	1.92 ± 0.67	0.285
IL-8 (pg/ml)	10.40 ± 4.27	10.42 ± 4.64	12.91 ± 4.75#	0.034
IL-10 (pg/ml)	3.71 ± 0.88	3.33 ± 0.81	3.17 ± 0.76*	0.020
Endothelial dysfunction
Endothelin-1 (fmol/L)	0.47 [0.13; 1.13]	0.32 [0.05; 0.99]	0.51 [0.24; 1.166]	0.269
Nitrites (μmol/L)	56.21 ± 31.13	68.36 ± 33.63	78.25 ± 40.23	0.036
Nitrates (μmol/L)	67.53 ± 38.22	77.61 ± 30.80	90.9 ± 40.33	0.037
Nitrites / Nitrates	34.11 ± 30.31	29.12 ± 22.53	31.5 ± 26.49	0.782
Parameters of hormonal and calcium metabolism, vitamin D
Estrogen (nmol/L)	35.54 ± 22.34	26.76 ± 9.54	26.7 ± 9.68	0.449
Progesterone (nmol/L)	1.99 [0.99; 4.9]	0.64 [0.64; 0.81]***	0.64 [0.64; 0.82]	<0.001
Testosterone (nmol/L)	0.70 [0.69; 1.01]	0.69 [0.69; 0.72]	0.69 [0.68; 0.69]	0.010
Parathyroid hormone (pg/mL)	22.5 [16.7; 39.5]	29.3 [21.1; 45.9]	37.7 [22.7; 59.0]	0.029
Calcitonin (pg/mL)	1.39 [1.31; 1.61]	1.26 [1.14; 1.56]	1.18 [1.13; 1.49]	0.152
Vitamin D (ng/mL)	46.24 ± 14.82	41.51 ± 21.96*	39.1 ± 15.14	0.01
Total calcium (mmol/L)	2.39 ± 0.11	2.44 ± 0.09	2.35 ± 0.18#	0.226
Ionized calcium (mmol/L)	1.14 ± 0.02	1.17 ± 0.03	1.17 ± 0.43	0.728

Table 3.

Characteristics of biochemical parameters in the examined groups of patients (M ± SD).

*

p < 0.05.

***

p < 0.001 – icomparison between groups 1 and 2.

#

p < 0.05 – comparison between groups 2 and 3.

p – comparison between groups 1 and 3.

According to the table, there is a persistent tendency to increase in the levels of total cholesterol and its atherogenic fractions in the groups with AH compared to the control group of patients. There is a clear tendency to increase in myeloperoxidase as a parameter reflecting increased peroxidation process in Group 3 of patients with AH and OP compared to Groups 1 and 2.

According to the results of vascular inflammatory response markers, the levels of hs-CRP, HYC, and IL-8 were significantly higher in Group 3. A tendency to increase in the levels of endothelin-1 and significant increase in nitrites in Group 3 indicate significant endothelial dysfunction in patients with AH and OP. Results in the study of the parameters of hormonal and mineral-vitamin metabolism showed the maximum levels of parathyroid hormone (p < 0.029) and decreased levels of estrogens, progesterone, testosterone, a tendency to decrease in calcitonin, total and ionized calcium and significantly low levels of vitamin D (p < 0.001) in Group 3 of patients. Our results are consistent with published data and reflect the severity of changes in the parameters of biochemical markers in different groups of patients [2, 3].

The study showed multiple multidirectional moderate correlations (r = 0.452, p < 0.05) between the presented structural, functional, and biochemical parameters; in Group 3, negative correlations were observed between the peak of T-Score and age, PWV-L/R, 24-hour and night SBP and DBP, duration of menopause, IL-6, hs-CRP and HYC, as well as between PWV-L and estradiol; positive correlations between T-Score and progesterone and between PWV-R/L and IL-6, LDL-cholesterol, hs-CRP, TNF-α, endothelin-1, mean 24-hour SBP, in daily variability of SBP and DBP.

Back in 1935, Allen et al. showed that estrogens dilate blood vessels, improve blood circulation, and normalize cardiac function, and in 1957, Popovici et al. stated that a decrease in estrogen levels resulted in decrease in acetylcholine, which in turn resulted in coronary and arterial ischemic syndrome. Modern data convincingly prove the existence of the relationships between the levels of sex hormones both with CVD and bone destructive processes, and prolonged vascular inflammatory response is considered a pathogenetically associated link in this relationship.

The risks of the development and progression of destructive changes were calculated using logistic regression for the group of AH with osteopenia and OP in postmenopausal period. Thus, for the patients with AH and osteopenia, statistically significant parameter associated with the risk of OP was PWV-R index, which increase by 1 point was associated with 3.8-time increase in the risk of OP (odds ratio (OR) 3.8, 95% confidence interval (CI) 1.81–7.97). There were no reliable relationships between biochemical parameters and the risk of OP at this stage of the study in this group.

In the group of AH with OP, risks of progression of the bone destructive process were observed with changes in certain biochemical markers. Thus, the risk of OP increased: by 2.5 times with increase in IL-6 by 1 pg./mL (OR 1.037 CI 1.01; 1.065, p = 0.048), by 2 times with increase in TNF-α by 1 pg./mL (OR 1.99 CI 1.107; 0.58, p = 0.022), by 6.5% with decrease in estrogen by 1 nmol/L (OR 0.967 CI 0.935; 1.00, p = 0.052), by 18% with increase in HYC by 1 μmol/L (OR 1.18 CI 1.023; 1.361, p = 0.023), by 65% with decrease in progesterone by 1 nmol/L (OR 0.348 95% CI 0.164; 0.739, p = 0.006), by 3.7% with increase in parathyroid hormone by 1 pg./mL (OR 1.037 95% CI 1.01; 1.065, p = 0.009), by 13.6% with increase in IL-8 by 1 pg./ml (OR 1.136 95% CI 1.016; 61.27, p = 0.025), by 54% with decrease in IL-10 by 1 pg./mL (OR 0.459 95% CI 0.252; 0.837, p = 0.011). As for functional parameters, the risk of OP increased by 6 times with increase in PWV by 1 m/s (OR 6.06 95% CI 2.203; 16.69, p = 0.00048).

The characteristics of OR that maximally determine the risk of OP in the groups of AH with osteopenia and OP are presented in Figures 1 and 2. According to the data presented in Figure 1, in the group of OP, the most reliable parameter that determined the risk of OP was PWV-R value. According to the data presented in Figure 2, increased levels of parathyroid hormone and inflammatory markers IL-6 and 8, TNF-α, hs-CRP, as well as decreased levels of progesterone and anti-inflammatory IL-10, were most actively involved in the aggravation of pre-existing destruction of bone tissue.

Figure 1.

The odds ratios that maximally determine the risk of osteoporosis in hypertensive patients with osteopenia.

Figure 2.

The odds ratios that maximize the risk of osteoporosis progression in hypertensive patients with pre-existing osteoporosis.

In addition, during the receiver operating characteristic (ROC) analysis in the group of patients with AH and OP, cut-off points for increased risk of OP progression were determined; for example, with decrease in progesterone levels below 0.93 nmol/L, the risk of OP increases by 9 times (sensitivity 76.9%, specificity 85.7); with increase in parathyroid hormone levels over 28.14 pg./mL, the risk of OP increases by 3.7% (sensitivity 68.6%, specificity 69.2%); with increase in IL-8 over 10.25 pg./mL, the risk of OP increases by 13.6% (sensitivity 71.4%, specificity 64.1); with decrease in IL-10 levels below 3.465 pg./mL, the risk of OP increases by 54.1% (sensitivity 66.7%, specificity 62.9%). As for functional parameters, with increase in PWV-R index over 12.05 m/s, the risk of OP increases by 6 times (sensitivity 87.1%, specificity 89.3).

The results of the discriminant analysis clarified that the most significant parameters for the progression of OP in Group 3 of patients were progesterone, parathyroid hormone, IL-8, and PWV-R. The model obtained as a result of the discriminant function calculations is statistically significant (the Wilks’ lambda is 0.201, p < 0.001) with a canonical correlation coefficient of 0.894.

At the same time, the greatest diagnostic contribution to the progression of OP is made by the level of progesterone (standardized coefficient 0.843). The standardized coefficients of parathyroid hormone (0.523), IL-8 (0.367) and PWV-RC (0.413) indicate approximately the same diagnostic significance of these variables. The equation of the resulting discriminant function is as follows: F = −2.618 + 42.951* progesterone +1.293* parathyroid hormone +0.749* IL-8 + 1.025* PWV-R.

The specificity of this model was 100%, the sensitivity was 92%; 96% of the original observations were classified correctly. To enable classification, centroids were calculated for each group and a cut-off point that allows for more accurate identification of group membership. The mean value of the function for Group 1 was −1.915, for Group 2 - 1.992; the cut-off point (or threshold value) was equal to the function value of 0.039.

4. Conclusion

The demographic situation worldwide is characterized by a steady increase in the number of elderly people. With steady aging of the population, the problem of increased number of socially significant diseases in women is gaining increased interest. The most common causes of disability and mortality in older postmenopausal women include clinical consequences of AS and OP: cardiovascular accidents and bone fractures. It is known that many factors influencing bone metabolism are involved in the mechanisms of vascular diseases. There is a similarity in the course of these diseases, since they can be asymptomatic for many years and often have clinical manifestations after menopause.

Recently, the role of a nonspecific immune inflammatory vascular response as a link in general pathogenetic mechanisms of atherosclerotic lesions of the vascular bed and phenomenon of destructive bone changes has attracted great attention.

The multimarker approach in the study of common links in the pathogenesis of socially significant diseases enabled the clarification of the main risk factors, laboratory levels of nonspecific immune inflammatory response markers, and parameters of hormonal and vitamin status, which determine a degree of impairment of the elastic properties of the vascular wall and the risk of progression of OP can be predictors of CVD and degenerative bone complications in postmenopausal women with AH.

In our study, the following markers of vascular inflammation were increased: hs-CRP, HYC, IL-8, endothelin-1, parathyroid hormone, total cholesterol, and atherogenic lipid fractions, with a simultaneous decrease in the levels of estrogen, progesterone, calcium, and vitamin D. Multiple regression relationships between inflammatory parameters and the parameters of lipid metabolism and hormonal-vitamin status were observed.

The results of the study indicate early examinations of women with AH to detect increased rigidity of the vascular wall and reduced bone mineral density, which create the conditions for increased risk of development and progression of subclinical AS and OP prior to postmenopause.

Timely in-depth examination of women with AH in premenopause should become the main strategy for the development of a personalized prevention and therapy for women in order to prevent socially significant cardiovascular and bone complications such as coronary artery disease, stroke, and low-trauma fractures.

4.1 Limitations of the study

This is a pilot project, which requires an expansion of the patient sample to clarify the subtle mechanisms of the interrelationship of the processes under study. The planned comparative characteristics of the studied parameters between groups of women and men will require an expansion of the range of statistical methods for processing the studied data.

4.2 Perspectives

It is planned to continue recruiting patients, expanding research methods, in particular, conducting a study on the effect of gut microbiota as an additional risk factor for vascular and degenerative bone complications in postmenopausal patients with arterial hypertension.