PROGNOSTIC VALUE OF OSTEOPROTEGERIN IN ASSESSING RISK OF CARDIOVASCULAR COMPLICATIONS AND OSTEOPOROTIC FRACTURES IN COMORBID PATHOLOGY Текст научной статьи по специальности «Клиническая медицина»

UDC: 616-06

PROGNOSTIC VALUE OF OSTEOPROTEGERININ ASSESSING RISK OF CARDIOVASCULAR COMPLICATIONS AND OSTEOPOROTIC FRACTURES IN

COMORBID PATHOLOGY

D. Sh. Chyngyshpaev, M. Kerimaly, A.M. Pasanova, A.T. Alymkulov, A.O. Uzakova,

O.J. Uzakov

International Higher School of Medicine, Bishkek, Kyrgyz Republic Abstract

Introduction. To study the predictive role of serum levels of osteoprotegerin (OPG) for risk stratification of adverse cardiovascular events and bone fractures in women with comorbid pathologies, including chronic heartfailure (CHF), type 2 diabetes mellitus (DM2) and osteoporosis.

Materials and methods. The study involved 78 women aged 50 to 65 years (mean age 57.1±4.9 years) with CHF, DM2 and osteoporosis, presented in two groups. Group 1 (n=41) includedpatients with OPG level < 6.8 pmol/l, group 2 (n=37) included patients with OPG level 6.8 pmol/l. The control group included 35 postmenopausal women, aged 50-65 years, without clinical disorders of hemodynamics, carbohydrate and mineral metabolism. The content of serum OPG was determined by solid-phase enzyme-linked immunoassay. Assessment of bone mineral density (BMD) was carried out by densitometry using dual X-ray absorptiometry.

Outcomes. In women with an OPG level 6.8 pmol/l, adverse cardiovascular events and osteoporotic fractures were significantly more frequently recorded. A significant (p0.001) increase in the OPG level was found in patients of the 1st and 2nd groups compared with the control group (2.3±0.4 pmol/l, p=0.001). A decrease in the risk of cardiovascular events was revealed at OPG concentration < 6.8 pmol/l: myocardial infarction (OR=0.91 [95% CI 0.83-0.98; p=0.04]), cerebral stroke (OR =0.87 [95% CI 0.81-0.98; p=0.01]), decompensated CHF (OR=0.84 [95% CI 0.77-0.92; p=0.02]), osteoporotic bone fractures (OR=0.81 [95% CI 0.72-0.90; p=0.01]); the risk of death from all the causes did not change significantly (OR: 0.98[95% CI0.94-1.05; p=0.223]).

An OPG level 6.8 pmol/l (sensitivity - 91%, specificity - 53%) makes it possible to predict the onset ofadverse cardiovascular events with a high probability in patients with IHD with CD 2 and osteoporosis (AUC (Area Under Curve) = 0, 83 (95% CI [0.72-0.93; p=0.001]).

Conclusion. Osteoprotegerin is an independent risk factor for the development of adverse cardiovascular events and bone fractures in women with comorbid pathologies, including CHF, type 2 diabetes, and osteoporosis. It seems clinically reasonable to determine the concentration of OPG in the blood to stratify the risk of adverse cardiovascular events and bone fractures in women with CHF associated with type 2 diabetes and osteoporosis.

Key words: osteoprotegerin, risk factors, heart failure, diabetes mellitus, osteoporosis, prognosis.

Corresponding author: Chygyshpaev D.Sh. daniluha@mail.ru

MYPOR-RAH ТАМЫР ООРУЛАРЫНЫН ТАТААЛДАШУУСУНУНЖАНА ОСТЕОПОРЕТИКАЛЫК СЫНЫКТАРДЫН КОМОРБИДДИК ПАТОЛОГИЯСЫНДА ТОБОКЕЛДИКТИ БААЛООДО ОСТЕОПРОТЕГЕРИНДИ

БОЛЖОЛДООНУН МААНИСИ

Д.Ш. Чынгышпаев, Керималы к.М., А.М. Пасанова, А.Т. Алымкулов, А.О. Узакова,

О.Ж. Узаков

Эл аралык Жогорку Медициналык Мектеби, Бишкек, Кыргызстан Аннотация

Максат. Коморбиддик патологиясы бар аялдарда журвк-кан тамыр оорулары жана сеектун сынуу коркунучун анын ичинде внвквт журвк жетишсиздиги (9ЖЖ), 2-типтеги (КД) кант диабети жана остеопорозду стратификациялоо YЧYн остеопротегериндин (OPG) сывороткадагы децгээлинин болжолдоочу ролун изилдвв.

Материалдар жана ыкмалар. Изилдввгв ОЖЖ, 2-типтеги КД жана остеопороз менен ооруган 50 жаштан 65 жашка чейинки (орточо жашы 57,1±4,9 жыл) эки топко бвлунгвн 78 аял катышкан. 1-топко (n=41) OPG децгээли < 6,8 пмоль/л болгон бейтаптар, 2-топко (n=37) OPG децгээли 6,8 пмоль/л болгон бейтаптар кирген. Контролдук топко гемодинамика, углевод жана минералдык зат алмашуунун клиникалык бузулушу жок 50-65 жаштагы 35 постменопаузадагы аялдар кирген. OPG сыворотканын тутумун катууфаздык иммуноферменттик метод менен аныкталган. Сввк тканынын минералдык тыгыздыгын баалоо кош энергиялык рентгендик абсорбциометрияны колдонуу менен денситометрияменен жYргYЗYлгвн.

Жыйынтыктар. OPG децгээли 6,8 пмоль/л болгон аялдарда жYрвк-кан тамыр системасынын ооруларын жана остеопороздук сыныктар кыйла квп катталган. 1-жана 2-топтогу бейтаптарда контролдук топко (2.3±0.4 пмоль/л, p=0.001) салыштырмалуу OPG децгээлинин олуттуу (p 0.001) жогорулашы табылган. OPG концентрациясы < 6,8pmol/l болгондо жYрвк-кан тамыр окуяларынын тобокелдигинин твмвндвшY аныкталган: миокард инфаркты (0R=0,91 [95% CI0,83-0,98; p=0,04]), мээнин инсульт (OR =0,87[95% CI0,81] -0,98;p = 0,01]), декомпенсацияланган CHF (OR = 0,84 [95% CI 0,77-0,92; p = 0,02]), остеопороздук сввк жаракалар (OR = 0,81 [95% CI 0,720,90; p = 0,01]); бардык себептерден улам влYм коркунучу олуттуу взгвргвн жок (ЖЕ: 0,98 [95% CI 0,94-1,05; p = 0,223]). OPG децгээли 6,8 пмоль/лден жогору (сезгичтик - 91%, взгвчвлYк - 53%) 2-типтеги кант диабети жана остеопороз (AUC (Area Under Curve)=0,83 (95% ДИ [0,72-0,93; р=0,001]) менен коронардык артерия оорусу бар бейтаптарда жYрвк-кан тамыр системасынын ооруларынын башталышын болжолдоогомYмкYндYк берет.

Корутунду. Аялдардын коморбиддик патологиясында остеопротегерин - жYрвк-кан тамыр системасынын оорулары жана сввк сыныктарынын внYгYШY анын ичинде ОЖЖ, КД 2-тиби жана остеопороз y^y^ квз карандысыз тобокелдик фактору болуп саналат. Бул ОЖЖ, КД 2 тиби жана остеопороз менен аялдардын жYрвк-кан тамыр ооруларынын жана сввк жаракаларынын коркунучун стратификациялоо y^y^ кандагы OPG концентрациясын аныктоо клиникалык жактан негиздYY кврYнвт.

Ачкыч свздвр: остеопротегерин, коркунуч факторлору, жYрвк жетишсиздиги, кант диабети, остеопороз, прогноз.

ПРОГНОСТИЧЕСКОЕ ЗНАЧЕНИЕ ОСТЕОПРОТЕГЕРИНА В ОЦЕНКЕ РИСКА КАРДИОВА СКУЛЯРНЫХ ОСЛОЖНЕНИЙ И ОСТЕОПОРЕТИЧЕСКИХПЕРЕЛОМОВ ПРИ КОМОРБИДНОЙ ПАТОЛОГИИ

Д.Ш. Чынгышпаев, Керималы к.М., А.М. Пасанова, А.Т. Алымкулов, А.О. Узакова,

О.Ж. Узаков

Международная высшая школа медицины, Бишкек, Кыргызстан Аннотация

Цель. Изучить предикторную роль сывороточных уровней остеопротегерина (OPG) для стратификации риска неблагоприятных сердечно-сосудистых событий и переломов костей у женщин с коморбидной патологией, включающей хроническую сердечную недостаточность (ХСН), сахарный диабет (СД2) типа и остеопороз.

Материалы и методы. Обследовано 78 женщин в возрасте от 50 до 65 лет (средний возраст 57,1±4,9 лет) с ХСН, СД 2 типа и остеопорозом, представленных в двух группах. В 1-ю группу (n=41) вошли пациентки с уровнем OPG < 6,8 пмоль/л, во 2-ю группу (n=37) включены пациентки с уровнем OPG 6,8 пмоль/л. В группу контроля вошли 35 женщин в постменопаузе, в возрасте 50-65 лет без клинических нарушений гемодинамики, углеводного и минерального обмена. Содержание сывороточного OPG определяли твердофазным иммуноферментным методом. Оценка минеральной плотности костной ткани (МПК) проводилась денситометрией с помощью двойной энергетической рентгеновской абсорбциометрии.

Результаты. У женщин с уровнем OPG 6,8 пмоль/л значимо чаще регистрировались неблагоприятные сердечно-сосудистые события и остеопоретические переломы. Установлено существенное (p0,001) повышение уровня ОPG у пациенток 1-й и 2-й групп по сравнению с группой контроля (2,3±0,4 пмоль/л, р=0,001). Выявлено снижение риска сердечно-сосудистых событий при концентрации ОPG < 6,8 пмоль/л: инфаркта миокарда (ОШ=0,91 [95% ДИ 0,83-0,98; р=0,04]), мозгового инсульта (ОШ=0,87 [95% ДИ 0,81-0,98; р=0,01]), декомпенсации ХСН (ОШ=0,84 [95% ДИ 0,77-0,92; р=0,02]), остеопоретических переломов костей (ОШ=0,81 [95% ДИ 0,72-0,90; р=0,01]); риск смерти от всех причин изменялся несущественно (ОШ: 0.98 [95% ДИ 0,94-1,05; р=0,223]). Уровень ОPG более 6,8 пмоль/л (чувствительность-91%, специфичность-53%) позволяет с высокой вероятностью прогнозировать наступление неблагоприятных сердечно-сосудистых событий у больных ИБС с СД 2 типа и остеопорозом (AUC (Area Under Curve)=0,83 (95% ДИ [0,72-0,93; р=0,001]).

Заключение. Остеопротегерин является независимым фактором риска развития неблагоприятных сердечно-сосудистых событий и переломов костей у женщин с коморбидной патологией, включающей ХСН, СД 2 типа и остеопороз. Представляется клинически-оправданным определение концентрации OPG в крови для стратификации риска неблагоприятных сердечнососудистых событий и переломов костей у женщин с ХСН, ассоциированной с СД 2 типа и остеопорозом.

Ключевые слова: остеопротегерин, факторы риска, сердечная недостаточность, сахарный диабет, остеопороз, прогноз.

Introduction

Glycoprotein osteoprotegerin (OPG) is a member of the superfamily of receptors of the pro-inflammatory cytokine tumor necrosis factor-a (TNF-a), which regulates osteoclastogenesis and stimulates cell apoptosis, inducing the transcription of genes involved in remodeling, proliferation, inflammation, hypertrophic reactions of the vascular wall and heart [1- 6].

The search for a link between increased osteoclastogenesis and atherosclerosis led to the discovery of the molecular biological ligand-receptor mechanism OPG/RANK/RANKL. At the same time, the main biological role of OPG is aimed at competitive interaction with the receptor activator of nuclear kappa-B-RANk for binding to its ligand, RANKL [6-9], which plays an important role in pathological and physiological remodeling of bone tissue and cardiovascular system.

It was established that an increase in OPG activity is associated with an increased risk of cardiovascular events [3-6, 16]. Thus, it has been shown that overexpression of OPG can be a marker of poor prognosis and a predictor of progression of heart failure (HF), peripheral occlusive atherosclerosis, stroke, and cardiovascular mortality in women with type 2 diabetes mellitus (DM 2) and osteoporosis [7-9, 11-13].

However, the predictive role of serum OPG levels, as well as the relationship with the risk of progression of chronic heart failure (CHF), coronary and peripheral atherosclerosis, and cardiovascular mortality for older postmenopausal women with DM 2 with osteoporosis was not determined.

In addition, the analysis of the literature indicates that only a few researches have studied the potential relationship between the levels of OPG expression and risk factors for ischemic myocardial remodeling, initiation and progression of HF, development of the metabolic syndrome in women with DM 2 and osteoporosis [1213].

The goal of the research was to study the predictive role of serum levels of osteoprotegerin for risk stratification of adverse cardiovascular events and bone fractures in women with comorbid pathology, including CHF, MD 2, and osteoporosis.

Materials and methods

To study the predictor role of OPG in stratifying the risk of developing long-term (36-month) adverse cardiovascular and osteoporotic events, 78 women aged 50 to 65 years (mean age 57.1±4.9 years) with CHF, MD 2 and osteoporosis were examined, presented in two groups. Group 1 (n=41) included patients with OPG level <6.8 pmol/l, group 2 (n=37) included patients with OPG level 6.8 pmol/l (Table 1) . The control group included 35 postmenopausal women, aged 50-65 years (mean age 56.0±4.1 years), without clinical disorders of hemodynamics, carbohydrate and mineral metabolism. All the patients were observed at the outpatient stage for CHF I-III FC (according to NYHA), type 2 diabetes and osteoporosis. Blood samples were taken from all the examined under standard conditions during the examination in the polyclinic. The content of serum OPG was determined by solid-phase enzyme-linked immunoassay (ELISA). Death from

cardiovascular causes was taken as the

primary endpoint. The composite endpoint

was death from common causes, non-fatal

myo c ardial infarc ti o n, stro ke ,

hospitalizations with decompensated CHF,

and osteoporotic bone fractures.

„ ! ^he functional class of CHF- severity Table 1. Clinical and demographic charact

eris

was assessed according to the classification of the New York Heart Association (NYHA, 1964). To objectify the FC CHF identification, a 6-minute walk test was used.

The state of intracardiac

hemodynamics! was assessed by »tics of patients divided into groups

depending on the levels of os teoprotegerin

Indicator Group 1 OPG <6,8 pmol/l n=41 Group 2 OPG >6,8 pmol/l n=37 p-value

Age 56,1±4,7 57,9±4,8 0,784

BMI, kg/m2 28,4±3,1 29,7,4±2,6 0.642

CHF, n (%) Grade II Grade III Grade IV 17 (41,5) 21 (51,2) 3 (7,3) 13 (35,2) 17 (45,9) 7 (18,9) 0,143 0, 265 0,002

LVEF, % 47,2±4,1 44,3±5,2 0,082

AH, n (%) 25 (61,0) 23 (62,2) 0,845

ABP syst., mm Hg. 129,3±9,3 132,8±5,8 0,621

ABP diast., mmHg. 84,0±4,2 86,5±5,2 0,485

Effort angina grade II-III, n (%) 18 (43,9) 23 (62,2) 0.023

Old MI, n (%) 4 (9,8) 8 (21,6) 0,001

AKVA, n (%) 2 (4,9) 3 (8,1) 0,024

PATE, n (%) 1 (2,4) 3 (8,1) 0,001

Osteoporosis fractures, n (%) 4 (9,8) 7 (18,9) 0,002

Note. BMI - body mass index; CHF - chronic heart failure; Left Ventricular Ejection Fraction, AH -arterial hypertension, ABP - arterial blood pressure, MI - Miocardial Infarction, AKVA - acute cerebrovascular accident, PATE - pulmonary artery thromboembolism.

echocardiography performed according to the standard protocol using the recommendations of the American Society of Echocardiography. In patients with MD 2, compensation of carbohydrate metabolism was assessed by the level of glycated hemoglobin (HbAlc). Bone mineral density (BMD) was assessed radiographically by dual-energy X-ray absorciometry of the lumbar spine and

proximal femoral neck. BMD status was characterized by T-criterion: the diagnosis of osteoporosis was identified with T-criterion -2.5 SD; decrease in BMD by T-criterion by more than 1 SD was considered as osteopenia.

The study did not include patients with hemodynamically significant lesions of the heart valves, pericarditis, myocarditis, diseases of the connective

tissue, kidneys, liver, oncological pathology.

The study protocol was approved by the local ethics committee. All patients gave their written informed consent to participate in the prospective study and to use the observation results.

Statistical processing of the results was carried out using the statistical software package STATISTICA. The mean value and standard error of the mean value of the studied quantitative variables were determined (M±m). Logistic regression was used to identify predictors of adverse endpoints. To identify factors that have a significant impact on the course and prognosis of the disease, the odds ratio (OR) was calculated. To identify predictors of the development of adverse endpoints, ROC analysis was used with the construction of characteristic curves and the calculation of AUC (area under the curve). The value of the area under the ROC-curve exceeding 0.70 was considered significant. For correlation analysis, Spearman's rank correlation coefficient (Spearman R) was used. The critical significance level p for all statistical

analysis procedures used was 0.05.

Outcomes

In the present study, CHF was diagnosed in all the cases (in group 2, grade IV by NYHA was registered more often than in group 1, p=0.002), associated with type 2 diabetes and osteoporosis. Analysis of the comorbid pathology development showed that in the 2nd group, at the time of inclusion in the study, significantly more patients suffered large-focal myocardial infarction (MI) (p=0.001), acute cerebrovascular accident (p=0.024), pulmonary artery thromboembolism (p=0.001 ), osteoporotic fractures of the vertebral bodies or proximal femurs (p=0.002).

Adverse events during 36 months of prospective follow-up in patients with comorbid pathology are presented in Table. 2. Women with an OPG level 6.8 pmol/l were significantly more likely to have adverse cardiovascular events and osteoporotic fractures. In the 2nd group, two patients died on the background of decompensated HF. There were no fatal events in the control group.

Table 2. Adverse cardiovascular events during the year of observation depending on the level of osteoprotegerin (n, %)

Adverse event Group 1 OPG <6,8 pmol/l n=41 Group 2 OPG >6,8 pmol/l n=37 p-value

Total number of adverse CVE 19 42 0,001

Progression of CHF (according to 6-minute walk test) 12 (29,3) 23 (62,2) 0,018

Repeated hospitalisations 7 (17,1) 14 (37,8) 0,005

PATE 1 (2,4) 2 (5,4) 0,0383

ACS 1 (2,4) 4 (10,8) 0,049

AKVA 1 (2,4) 3 (8,1) 0,014

Osteoporosis fractures 5 (12,2) 14 (37,8) 0,001

Fatality 0 2 (5,4) 0,372

Note. CCE - cardiovascular events, CHF - chronic heart failure, PATE - pulmonary artery thromboembolism, ACS - acute coronary syndrome, AKVA - acute cerebrovascular accident.

A highly significant (p0.001) increase in the level of OPG expression was found in patients of the 1st and 2nd groups compared with the control group (2.3±0.4 pmol/l, p=0.001).

Discussion

Odds ratio (OR) analysis and confidence interval (CI) 95% of the effect of increased OPG activation was calculated separately for each risk factor. In patients of the 1st group with OPG <6.8 pmol/l, compared with the group with OPG 6.8 pmol/l, the risk of cumulative effect (joint rate of the combined end point of cardiovascular events) was reduced (OR = 0.90 [95% CI 0.85-0.96; p=0.03]). Separate analysis of the risk of adverse cardiovascular outcomes showed a decrease in the risk of cardiovascular events at an OPG concentration < 6.8 pmol/l: MI (OR=0.91

[95% CI 0.83-0.98; p=0.04]) , stroke (OR=0.87 [95% CI 0.81-0.98; p=0.01]), decompensated CHF (OR=0.84 [95% CI 0.77-0.92; p=0.01]); =0.02]), osteoporotic bone fractures (OR=0.81 [95% CI 0.72-0.90; p=0.01]); the risk of death from all the causes did not change significantly (OR: 0.98 [95% CI 0.94-1.05; p=0.223]).

The use of ROC-analysis by the value of OPG revealed that the level of OPG more than 6.8 pmol/l (sensitivity - 91%, specificity - 53%) makes it possible to predict the onset of adverse cardiovascular events with a high probability in patients with coronary artery disease with type 2 diabetes and osteoporosis . The area under the curve for OPG was 0.83 (95% CI [0.720.93; p=0.001]), which exceeds that for classical conventional risk factors. Therefore, OPG blood level screening can

be used as an independent marker for risk stratification of adverse cardiovascular events in the comorbid pathology under consideration.

Evaluation of the diagnostic and prognostic significance of BMD disorders with increased OPG expression in conditions of CHF development in patients with DM according to ROC analysis showed that bone mineral density by the T-criterion = -2.5 SD has prognostic significance (area under the curve 0, 63 (95% CI 0.53-0.81; p = 0.03), predicting the probability of adverse clinical events with a sensitivity of 72.1%, a specificity of 42.1%. When taking BMD>-2,5 as CUT OFF value by the T-test, the sensitivity of the test was 79.2%, the specificity was 61% (area under the curve 0.69 (95% CI 0.57-0.84; p=0.01).

In addition, patients with OPG > 6.8 pmol/l had a higher (3 times) frequency of bone fractures. At the same time, in patients with a BMD deficiency level > -2.5 SD by the T-criterion, a 1.5-fold higher incidence of adverse clinical events (including recurrent MI, CHF decompensation, strokes) and bone fractures was recorded.

Thus, deciphering the pathogenetic mechanisms that determine the relationship between risk factors for a continuum of comorbid pathology, represented by CHF, MD 2 and osteoporosis, is important for the development of innovative, more effective and promising approaches for personalized diagnosis, prevention, and treatment of these diseases. The results of previous studies performed in various research centers have shown that metabolic syndrome and DM are the most important risk factors for ischemic and diabetic cardiomyopathy, obesity and osteoporosis in elderly and senile patients [14]. It was established that inflammation is one of the key pathogenetic processes that

play an important role in the initiation and development of CHF, insulin resistance, and osteoclastogenesis disorders. Horowitz M. [15] emphasizes the important role of proinflammatory cytokines (in particular, interleukins 1 and 6, tumor necrosis factor-a) in the regulation of osteoporosis; and draws attention to the fact that a number of inhibitory factors are involved in the control of these pathophysiological processes, one of which is osteoprotegerin.

The prognostic role of the new biomarker osteoprotegerin glycoprotein regarding the risks of developing adverse cardiovascular events and osteoporotic fractures in comorbid pathology, including CHF, type 2 diabetes, and osteoporosis, established in this work, allows not only improving the risk stratification of the involvement of conventional and non-conventional risk factors in the development of these diseases, but also provide full control as an objective independent criterion for the effectiveness of pathogenetic therapy. At the same time, the prognosis in women with CHF associated with diabetes, who make up the majority of patients hospitalized in hospitals, seems to be relevant for the tactics of managing decompensated heart failure.

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