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Bone Mineral Density and Metabolism in Very Elderly Patients with Congestive Heart Failure

  • S. V. TopolyanskayaEmail author
  • I. A. Osipovskaya
  • L. S. Lifanova
  • T. A. Eliseeva
  • O. N. Vakulenko
  • L. I. Dvoretsky
Medicine
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  1. Topical Collection on Medicine

Abstract

The study purpose was investigation of bone mineral density (BMD) and metabolism in very elderly patients with heart failure. The study enrolled 125 patients (aged 75–98 years) hospitalized with coronary artery disease (CAD). The study group comprised 61 patients with clinically significant congestive heart failure (CHF) and the control group — 64 age-matched patients without CHF symptoms. The main exclusion criteria were any other diseases that could cause osteoporosis and administration of medications reducing BMD. Lumbar spine and proximal femur BMD was measured by dual-energy X-ray absorptiometry. Serum osteocalcin concentration was measured by immunechemiluminescence, beta-Cross Laps level — by electrochemiluminescence. BMD in the CHF patients was lower versus the control group. Largest differences were recorded in proximal femur: BMD in the CHF patients was 719.8 ± 188.2 mg/cm3 versus 797.7 ± 161.7 mg/cm3 (p = 0.02) in the control group. Greater differences in BMD were detected in female patients. Proximal femur BMD had normal values only in 5% of the CHF patients, in the control group — in 31% of cases (p = 0.003). Reduced osteoblast function was observed in CHF patients: the mean osteocalcin level in the CHF patients was 1.2 ± 1.7 ng/ml versus 4.2 ± 4.1 ng/ml (р = 0.03) in the control group. Mean β-Cross Laps level in the CHF patients reached 0.73 ± 0.4 ng/ml versus 0.4 ± 0.1 ng/ml (p = 0.003) in the control group. These study findings suggest that bone mineral density in very elderly CHF patients is noticeably lower versus the patient group similar in age and main diseases. This study has demonstrated significantly reduced osteoblast function in CHF patients and slight increase in bone resorption.

Keywords

Congestive heart failure Osteoporosis Fractures Bone mineral density Osteocalcin β-Cross laps Very elderly 

Introduction

Congestive heart failure (CHF) is a steadily progressive cardiovascular disease. This pathological state is fairly common among elderly persons [1, 2, 3, 4]. CHF is considered a major reason for hospitalization and death in old age. The mortality rate of patients over 75 years is 50% 1 year after the CHF diagnosis [2]. According to major epidemiological studies, the prevalence of clinically significant CHF in very elderly patients reaches ~ 10–17% [3, 4]. CHF incidence is on the rise despite all advances in cardiovascular disease therapy and prevention. The significantly higher incidence of this pathology in old age groups is particularly noticeable [3, 4].

Osteoporosis is also a very common pathological state in old age. Osteoporosis is characterized by loss of bone mass and quality, which in turn results in bone fragility and a higher fracture risk both with little or no injuries [5]. Vertebral compression fractures, distal forearm fractures, and proximal femur fractures are typical for osteoporosis. Global clinical practice records presumably one osteoporosis-related fracture every 3 s. At least half of the women over 50 years may have such a fracture in the rest of their lifetimes [5].

According to expert assessment, osteoporosis may be diagnosed in ~ 30% of women in postmenopause [6]. Vertebral osteoporosis fractures occur in 10–12% of elderly persons of both sexes, whilst hip fractures are recorded in almost 2 million people annually [6]. Osteoporosis and its associated fractures is a challenge for world healthcare. Due to steady population aging, osteoporosis-related economic costs are bound to increase.

Hip fractures (the worst osteoporosis complication) are accompanied by 20% mortality in the first year after the fracture, with 45–50% mortality rate in some regions [5]. About one third of the rest are permanently bed-ridden, almost half of patients have very limited activities, and only 10% can recover their everyday activities [5]. Therefore, the prevention of osteoporosis-related fractures and the minimization of osteoporosis risk factors remain critical.

CHF is sometimes associated with osteoporosis and a higher fracture risk. Both fractures and CHF cause severe disability in elderly patients with repeated hospitalizations and longer hospital treatment periods, thus increasing economic costs significantly. According to some authors, over half of CHF patients (even relatively young) have low BMD, whilst the risk of osteoporosis-related fractures is 1.5–6 times higher with CHF versus the overall population [7, 8, 9, 10, 11].

There has been no consensus that would fully explain relationship between osteoporosis and CHF. Nevertheless, a number of common risk factors have been detected both for osteoporosis and CHF. They primarily include hyperparathyroidism, diabetes mellitus, vitamin D deficiency, sex hormone reduction (including the postmenopausal state in women), and low physical activity. Aging itself also predisposes to these pathological states. Some CHF medications, especially loop diuretics (and possibly anticoagulants), may also reduce BMD. It is possible that congestive changes in the liver and intestines, in the setting of right ventricle failure, help disrupt vitamin D absorption and synthesis. A major osteoporosis risk factor in CHF patients is chronic kidney disease as part the cardiorenal syndrome [10, 12, 13, 14].

Heart failure and osteoporosis are assumed to have some common pathogenetic mechanisms including the activation of the renin-angiotensin-aldosterone system (primarily, hyperaldosteronism) and oxidative stress. However, CHF is increasingly considered as a proinflammatory condition in which various proinflammatory mediators contribute to myocardium remodeling by participating in the processes of its hypertrophy and fibrosis, as well as in cardiomyocyte apoptosis. The same proinflammatory cytokines stimulate, in turn, bone resorption by activating osteoclasts and inhibit bone formation, acquiring the value of the prognostic risk factors of non-traumatic fractures in elderly patients. Osteoporosis is likely to progress with CHF also due to bone hypoperfusion during heart failure [13].

Scattered data published in medical literature underlay our attempt to study the relationship of osteoporosis and CHF among very elderly patients. The primary study objective is investigation of bone mineral density and metabolism in very elderly patients with CHF. Also, the study objectives are investigations of tumor necrosis factor-alfa (TNF-α) and leptin levels as well as assessment of associations between TNF-α and leptin and bone mineral density.

Materials and Methods

This research was done on the clinical basis of War Veterans Hospital (WVH) No.3 (Moscow, Russia). The study enrolled men and women over 75 years hospitalized in WVH No.3 with coronary artery disease (CAD) diagnosis. The study group comprised patients with clinically significant CHF (NYHA FC II-IV). The control group comprised CAD and arterial hypertension patients without clinically significant CHF symptoms. The main exclusion criteria were any other diseases that could have an evident impact on BMD and cause secondary osteoporosis (hyperthyroidism and other endocrine pathology, Stage 4–5 chronic kidney disease, chronic obstructive pulmonary diseases, clinically significant chronic liver diseases, malabsorption syndrome, rheumatic and other chronic inflammatory diseases, oncohematological and other malignant neoplasms in the active phase); administration of medications evidently reducing BMD (primarily, glucocorticoids).

The patients’ condition was evaluated with standard examination methods for CHF patients, the CHF clinical state assessment scale with scores ranging from 0 to 10 (10 indicates very severe CHF), and Borg Dyspnea Scale. Besides, the 6-min walk distance was measured, an echocardiogram was done, and quality of life was assessed by the Minnesota Living with Heart Failure Questionnaire.

Lumbar spine and proximal femur BMD was measured by dual-energy X-ray absorptiometry on the Lunar Prodigy Advance (GE) machine. The study measured the absolute BMD value (in mg/cm3), T- and Z-scores. The T-score is a BMD deviation from the peak bone mass value at a young age, and the Z-score is a patient’s BMD deviation from mean BMD values in the same age. Osteoporosis and osteopenia were diagnosed using WHO criteria under which BMD is measured by the T-score: 1, norm (T-score of − 1SD or above), 2, osteopenia (lower than − 1SD and greater than − 2.5SD), and 3, osteoporosis (− 2.5SD or lower). Also, the fracture risk was measured under FRAX (an estimate assessing fracture probability in the next 10 years [14]), the Timed Up and Go test was conducted, and osteoporosis risk factors were analyzed (previous fractures, predisposition to falling, heredity, early menopause in women, low body mass index, prolonged immobilization, low physical activity, and inadequate calcium consumption).

Osteocalcin concentration in the blood serum was measured by the immunechemiluminescent method (N, 0–22 ng/ml) and the beta-Cross Laps level (degradation products of collagen type I) by electrochemiluminescence (N < 1.008 ng/ml). Serum leptin concentration was detected by the immune-enzyme assay. Normal ranges for serum leptin levels in women were 3.6–11.1 ng/ml, in men, 2.0–5.6 ng/ml. Serum tumor necrosis factor-alfa levels were determined by the immune-enzyme assay. Normal ranges for sTNF-α levels were less than 8.1 pg/ml.

Data were analyzed using the Statistica 10.0 and SPSS 22.0 software. The study results were presented by descriptive statistics (mean and standard deviation for numerical variables, number and proportion for qualitative variables). The groups were compared by nonparametric methods (Mann-Whitney test, chi-square test, or Fisher’s exact test), with Spearman’s rank correlation coefficient and multiple regression analysis conducted.

Results

The study enrolled 125 patients (38 men and 87 women) aged 75–98 years; most of them (74%) were over 85 years. The study group comprised 61 patients (at the mean age of 86.9 ± 4.6 years) and the control group 64 patients (aged 86.3 ± 4.6 on average). Patients in both groups were compared in basic demographics, the body mass index, and main concomitant diseases. However, the CHF group featured much more frequent myocardial infarction (recorded in the history of 42% of the CHF patients and 19% of the control group patients, p = 0.005 by Fischer’s exact test) and atrial fibrillation (diagnosed in 62% of the CHF patients and 39% in the control group; p = 0.009) (Table 1).
Table 1

Baseline characteristics of study patients

 

Study group

Control group

p

Age, years

86.9 ± 4.6 y.

86.3 ± 4.6 y.

0.43

Men/women

21/40

17/47

0.34

Body mass index, kg/m2

29.5

28.9

0.52

Coronary artery disease, %

100%

100%

NS

Arterial hypertension, %

100%

100%

NS

Myocardial infarction, %

42%

19%

0.005

Atrial fibrillation < %

62%

39%

0.009

Creatinine levels, μmol/l

111.5

104.5

0.3

Glucose, mmol/l

5.5

5.8

0.3

Almost all study group patients had CHF with preserved ejection fraction (EF), whilst only 25% of the CHF patients had left ventricular EF at 50% and lower (with the group mean EF at 55%). Many CHF patients (86%) had biventricular heart failure of III–IV FC. The mean score by the CHF clinical state assessment scale was 7.2 points. Due to the patients’ severe somatic condition, the 6-min walk test applied only to some of them: its mean value was 73 m, and in 79% of cases the patients could not pass 100 m non-stop (some even a few steps). All the patients under study (in both groups) had frailty signs.

BMD in the CHF patients was lower versus the control group (both in absolute values and by the T-score). The largest differences were recorded in the proximal femur: BMD in the CHF patients was 719.8 ± 188.2 mg/cm3 versus 797.7 ± 161.7 mg/cm3 (p = 0.02) in the control group. Femoral neck BMD in the CHF patients was 649.4 ± 137.1 mg/cm3 on average versus 696.2 ± 121.8 mg/cm3 (p = 0.03) in the control group. There were no significant differences found in lumbar vertebrae BMD between the groups: the mean BMD of this skeleton region in the CHF patients was 1013 mg/cm3 versus 1037 mg/cm3 (p = 0.4) in the control group.

In the group under study, BMD differences were greater among women. Densitometric value comparison results in the CHF women and control group are shown in Table 2 and Fig. 1.
Table 2

Densitometric bone parameters in women with and without CHF

Densitometric bone parameters

Heart failure mean (SD)

Control mean (SD)

р

L2–L4, T-score (SD)

− 1.6 (± 1.7)

− 1.0 (± 1.7)

0.2

L2–L4, BMD (mg/cm3)

971 (± 212)

1033 (± 212)

0.2

Left femoral neck, T-score (SD)

− 2.5 (± 1.1)

− 2.0 (± 0.9)

0.1

Left femoral neck, BMD (mg/cm3)

628 (± 141)

683 (± 123)

0.03*

Left proximal femur, T-score (SD)

− 2.2 (± 1.1)

− 1.5 (± 1.2)

0.001*

Left proximal femur, BMD (mg/cm3)

680 (± 149)

776 (± 153)

0.005*

Right femoral neck, T-score (SD)

− 2.5 (± 0.9)

− 2.0 (± 0.8)

0.04*

Right femoral neck, BMD (mg/cm3)

629 (± 130)

678 (± 115)

0.009*

Right proximal femur, T-score (SD)

− 2.2 (± 1.3)

− 1.5 (± 1.1)

0.002*

Right proximal femur, BMD (mg/cm3)

688 (± 153)

768 (± 149)

0.007*

* − p<0.05 (level of significance)

Fig. 1

BMD in women with and without CHF

Bone mineral density in the proximal femur corresponded to normal values in 5% of patients with CHF; whereas in the control group, normal BMD values were observed in 31% of cases (p = 0.003). A similar trend was found with respect to the BMD of the lumbar spine, however, these differences between groups did not reach the degree of statistical significance (p = 0.11).

Regression analysis confirmed the effect of heart failure on bone mineral density. It has been demonstrated that the significant factors affecting femur BMD were chronic heart failure (β = 0.375, p = 0.005) and female sex (β = 0.698, p < 0.0001).

Osteocalcin and β-Cross Laps (bone metabolism indicators) serum concentration in the CHF patients and in the control group is shown in Fig. 2.
Fig. 2

Serum levels of osteocalcin and β-Cross Laps in patients with and without CHF

The mean level of osteocalcin in patients with CHF was 1.2 ± 1.7 ng/ml, in the control group — 4.2 ± 4.1 ng/ml (р = 0.03). In 60.6% of the examined patients with CHF, the osteocalcin concentration was below the lower limit of norm (p = 0.02 compared with the control). The mean concentration of β-Cross Laps in patients with CHF was 0.73 ± 0.4 ng/ml, in the control group — 0.4 ± 0.1 ng/ml (p = 0.003). An increase in β-Cross Laps was observed in 21.7% of patients with CHF, but in no case among the patients in the control group (p = 0.03). There was also a negative correlation between the concentration of β-Cross Laps and BMD, especially in the proximal femur (r = − 0.4, p = 0.03).

When analyzing other factors that could affect the condition of bone tissue in patients with CHF, the following data were obtained. A negative correlation was found between the level of tumor necrosis factor-alpha (TNF-a) and bone mineral density, especially in the proximal femur (r = − 0.9; p = 0.03). It was noteworthy that serum concentration levels of TNF-a were higher in patients with CHF (11.8 vs 8.1 pg/ml, p = 0.003). In patients with a low concentration of leptin, BMD values were lower than in patients with normal or elevated serum leptin levels (p = 0.006 for the proximal femur) (Fig. 3). Low levels of leptin (less than 3.6 ng/ml in women and < 2.0 ng/ml in men) were observed only in patients with CHF.
Fig. 3

Serum leptin levels and BMD

Among traditional osteoporosis risk factors, the CHF patients often (40.5% of cases) featured fractures (primarily, in the distal forearm), usually repeated. Predisposition to falling (51.4% of the patients) and very low physical activity (up to prolonged immobilization in 27% of the patients) were also frequent. The average Timed Up and Go test score was 16.5 ± 7.1 s reflecting a high risk of falling, whereas 70% of the CHF patients could not actually get up off the chair without relying on their hands. Patients in control group had same traditional osteoporosis factors excluding prolonged immobilization observed in 15% of cases (vs 27% in the study group, p = 0.03).

Discussion

Our findings show much lower bone mineral density in very elderly CHF patients versus age-matched patients with similar cardiovascular diseases (atherosclerosis, CAD, and arterial hypertension) but without clinically significant heart failure. Some study findings published also confirm that CHF can be seen as an additional osteoporosis risk factor [6, 7, 8, 9, 10, 11, 13, 15, 16]. However, our study stands out for its main characteristics of the patient group. Our patients are primarily characterized by their old age (86 years on average) and female predominance. Another important difference from other studies was prevalence of CHF with preserved EF (quite typical of very elderly patients), whilst the vast majority of other projects included patients with evident systolic dysfunction and even after heart transplantation [9, 13, 15, 17].

A significant result of this study can be stronger CHF effect on BMD in women versus men. Women are generally prone to greater BMD reduction with age. This assertion is confirmed by our study findings: for the group as a whole, osteoporosis was detected in 22.7% of men and normal BMD in 28%, whilst women featured osteoporosis in almost half of all the cases (45%) and normal BMD only in 19%. Greater loss of BMD in women is primarily due to decreased estrogen levels postmenopausal. Estrogens are key hormones to bone metabolism acting both directly by stimulating primarily the osteoblast function and indirectly by affecting proinflammatory cytokines and oxidized lipids [12, 18]. Androgens may also benefit BMD, although not as distinctly as estrogens [12].

More significant differences between the CHF patients and the control group under study were noted in proximal femur BMD versus the lumbar spine. The following concept can be suggested for clinical interpretation of our findings. Microcirculatory disorders in CHF patients are most pronounced in the limbs and can therefore reduce intraosseous microcirculation in the femur and decrease the related BMD. This assertion is also supported by the results of other studies of BMD status in patients with cardiovascular diseases, showing a greater femur BMD reduction versus the lumbar spine [12]. This concept is indirectly proved by our study revealing greater osteoblast function reduction versus bone resorption activation. Higher bone resorption during CHF can, in turn, result from subclinical inflammation and the hyperproduction of some proinflammatory cytokines in CHF patients, as confirmed in our study as well [19, 20]. The CHF patient group under our study featured a significantly higher level of such a proinflammatory cytokine as TNF-a versus the control group. Alongside this, there is negative correlation found between TNF-a and BMD, especially in the femur.

Leptin may be a connecting factor between osteoporosis and CHF. Our study has confirmed the already known fact of leptin level reduction in CHF patients, probably due to the activation of catabolic processes during heart failure and malnutrition [21]. However, in our patient group, leptin reduction was significantly associated with lower BMD. According to relevant literature, leptin’s effects on bone metabolism are quite diverse: first of all, it can stimulate osteoblast differentiation, inhibit osteoclasts, and facilitate osteocalcin release by osteoblasts [22, 23].

Additional factors influencing on BMD reduction should include frailty or senile asthenia. This asthenia generally typical of old age is further exacerbated with clinically significant heart failure [16], as was also observed in our CHF patient group with very low physical activity and predisposition to frequent falls partially facilitating fractures in nearly half of the patients.

Despite quite meaningful results of this study [24], it has some limitations. Unlike most similar studies including younger patients, our study involved very elderly patients with not only clinically significant cardiovascular diseases but also multiple comorbid pathology. The cognitive characteristics of the patient group under study did not allow adequate assessment of the role of lifestyles, administered medications, and other factors possibly affecting BMD status. Furthermore, for organizational reasons, the project did not study parathormone, vitamin D, and sex hormones whose levels may also significantly affect bone metabolism. Another limitation of this study is its cross-sectional rather than prospective nature disabling analysis of BMD status dynamics and assessment of the fracture risk as CHF progresses.

Conclusion

The results of this study suggest that bone mineral density in very elderly patients with heart failure is markedly reduced compared with a group of patients similar in age and the presence of the underlying pathology (primarily, coronary artery disease, and arterial hypertension). In the course of this study, patients with CHF showed a significant decrease in osteoblast function with a slight increase in bone resorption. It is advisable to further study the condition of bone tissue in patients with CHF involving a large sample of patients, as well as conducting scientific research aimed at studying the mechanisms of interrelation of osteoporosis and heart failure.

Notes

Compliance with Ethical Standards

Conflict of Interest

On behalf of all authors, the corresponding author states that there is no conflict of interest.

Ethical Approval

All procedures conducted in the study complied with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Informed consent was obtained from all individual participants included in the study. This study was approved by the Independent Review Board; the IRB approval number is 05-2017.

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Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Hospital Therapy Department No.2I.M. Sechenov First Moscow State Medical University (Sechenov University)MoscowRussia
  2. 2.War Veterans Hospital (WVH) No.3MoscowRussia

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