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European Journal of Heart Failure 2009 11(1):28-38; doi:10.1093/eurjhf/hfn004
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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2009. For permissions please email: journals.permissions@oxfordjournals.org.

Bone mineral status and bone loss over time in men with chronic systolic heart failure and their clinical and hormonal determinants

Ewa A. Jankowska1,2,*, Justyna Jakubaszko3, Aldona Cwynar1, Jacek Majda1, Beata Ponikowska4, Dorota Kustrzycka-Kratochwil1, Krzysztof Reczuch1, Ludmila Borodulin-Nadzieja4, Waldemar Banasiak1, Philip A. Poole-Wilson5 and Piotr Ponikowski1

1 Cardiology Department, Military Hospital, ul. Weigla 5, 50-981 Wroclaw, Poland
2 Institute of Anthropology, Polish Academy of Sciences, Wroclaw, Poland
3 Endocrinology Department, Military Hospital, Wroclaw, Poland
4 Physiology Department, Wroclaw Medical University, Poland
5 Cardiac Medicine, National Heart and Lung Institute, Imperial College London, London, UK

* Corresponding author. Tel:/Fax: +48 71 7660 250, Email: ewa.jankowska{at}antro.pan.wroc.pl


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 Conclusions
 Funding
 References
 
Aims: Bone status has not been comprehensively studied in chronic heart failure (CHF). In CHF men, we evaluated bone status, bone loss over time, and their clinical and hormonal determinants.

Methods and results: Bone mineral content (BMC) and bone mineral density (BMD) of arms, legs, trunk, and total body were examined using dual-energy X-ray absorptiometry in 187 men with CHF [age: 60±11 years, left ventricular ejection fraction (LVEF): 32±7%, New York Heart Association (NYHA) class (I/II/III/IV): 20/76/76/15] and in 21 age-matched male controls without CHF. Men with CHF had reduced BMD and BMC compared with controls (P < 0.05). Reduced BMD and BMC were independently determined by CHF severity (high NYHA class and impaired LVEF), reduced lean tissue mass, low serum dehydroepiandrosterone sulphate, total testosterone (TT), and estimated free testosterone (eFT) (all P < 0.05). Bone status was reassessed in 60 patients who survived >2 years from the initial evaluation. Significant bone loss over time (a reduction in BMC total ≥1%/year) occurred in 35% of CHF men. Advanced NYHA class (P < 0.05) and reduced serum TT and eFT (P < 0.0001) at baseline predicted augmented bone loss.

Conclusion: In CHF men, reduced BMD and BMC constitute an element of generalized body wasting, determined mainly by advanced heart failure and androgen deficiencies. Significant bone loss over time frequently occurs in CHF men and is related to testosterone depletion and disease severity.

Key Words: Chronic heart failure • Bone density • Bone loss • Anabolic hormones • Androgens

Received January 13, 2008; Revised July 3, 2008; Accepted August 19, 2008


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 Conclusions
 Funding
 References
 
Metabolic disorders of bone tissue, among which osteoporosis is most widely recognized, are frequently present in male subjects and constitute a clinically relevant problem.1 Reduced bone mineral density (BMD) and loss of bone mass are characteristics of physiological ageing2 and commonly co-exist with chronic diseases (e.g. chronic bronchitis, liver cirrhosis, and Parkinson's disease), having an unfavourable impact on quality of life.1

Chronic heart failure (CHF) is a chronic disorder associated with a myriad of metabolic disturbances, many of which may unfavourably affect bone metabolism and predispose to an exaggerated bone loss. Surprisingly though, status of the bone tissue in CHF has been rarely investigated.3–6 Patients with advanced stages of the disease, particularly with co-existing cachexia, often demonstrate reduced bone mass.4,7 Reduced BMD with subsequent increased susceptibility to fractures has been described in heart transplant recipients, but in this group, augmented bone loss is primarily mediated by high dose glucocorticoid and cyclosporin therapy.8,9 It has been hypothesized that low mobility, cachexia-induced loss of muscle mass, specific drugs, impaired renal function, and hypogonadism might be risk factors for low bone mass in pre-transplant patients with CHF.6,10 However, available data on the aetiology of reduced bone mass and BMD in patients with CHF are scanty, and prospective studies are lacking.

We evaluated bone mineral status and bone loss over time in an unselected cohort of male CHF patients and identified their clinical or hormonal determinants.


   Methods
Top
 Abstract
 Introduction
 Methods
Results
 Discussion
 Conclusions
 Funding
 References
 
Study population
Between October 2000 and September 2004, we evaluated consecutive male patients who were hospitalized in our department or attended the outpatient CHF clinic. The criteria for study inclusion were: (i) a more than 6-month documented history of CHF due to coronary artery disease (CAD) or idiopathic dilated cardiomyopathy; (ii) left ventricular ejection fraction (LVEF) below 45% as assessed by echocardiography; (iii) clinical stability and unchanged medications for at least 1 month preceding the study. As a control group, we investigated age-matched men with hypertension or CAD with LVEF ≥50% as assessed by echocardiography, with no signs or symptoms of CHF. Exclusion criteria for both groups were: (i) acute coronary syndrome or coronary revascularization within 6 months preceding the study; (ii) any hormonal treatment either at the time of the study or in the past; and (iii) history of any chronic, non-cardiac disease that may affect bone metabolism [thyroid disease, hypercortisolism, or any endocrine pathology that might interfere with bone status, chronic renal failure (serum creatinine exceeding 3 mg/dL or regularly performed haemodialysis), chronic obstructive pulmonary disease, autoimmune diseases, significant liver failure, cancer, etc.]. All patients were Caucasian.

The study protocol was approved by the local Ethics Committee, and all subjects gave written informed consent. The study was conducted in accordance with the Helsinki Declaration.

Bone, lean, and fat tissue densitometry measurements
Densitometry measurements were performed using dual-energy X-ray absorptiometry (DEXA) using a scan mode for total body composition assessment (scanner: LUNAR DPXIQ 7339, Madison, WI, USA). DEXA is a widely applied, non-invasive method of bone densitometry, which allows precise detection of bone mineral mass and BMD and involves only a minimal exposure to ionizing radiation.11–13

For the evaluation of bone status, the following indices were used: (1) bone mineral content (BMC), describing the amount of bone tissue within the examined body regions, and (ii) BMD, reflecting the planimetric density of bone tissue.

The trunk region was delineated by an upper horizontal border below the chin, vertical borders lateral to the ribs, and a lower border formed by oblique lines passing through the hip joints. The leg region was defined as tissue below the oblique line passing through the hip joints.

BMC and BMD were measured for both arms [BMC arms (g) and BMD arms (g·cm–2), respectively], both legs [BMC legs (g) and BMD legs (g·cm–2), respectively], the trunk [BMC trunk (g) and BMD trunk (g·cm–2), respectively], and the total body [BMC total (g) and BMD total (g·cm–2), respectively]. BMC total was adjusted for body size [i.e. calculated per m2 of body surface area (BSA)], estimated using an anthropometric equation.14 The amount of total bone calcium was estimated (g).

BMD was additionally expressed by Z and T scores. Using the Z scores, we compared BMD in the total body (BMD total) and in all anatomical regions (BMD trunk, BMD arms, and BMD legs) of the examined patients with the mean values of BMD in the age- and weight-matched male healthy subjects from the general population (and with the reference values provided by the DEXA scanner manufacturer). The reference population used by the manufacturer consists of a cohort of healthy Caucasian men with a broad age range, living in the USA and Europe, which is accepted as being representative for a European male population (including a Polish population).15,16 Z score expressed in standard deviation (SD) units was defined as the difference between individual BMD and mean BMD of the age-matched male reference group divided by the SD of BMD for this reference group. Using the T scores, we compared BMD of examined patients with peak values of BMD of young healthy adult men from the general population.17,18 T score expressed in SD units was defined as the difference between individual BMD and peak BMD of the healthy young adult men divided by an SD of their BMD.

The precision of densitometric parameters was assessed by repeated DEXA measurements in 14 CHF patients (mean duration between assessments 4±1 days, range 2–7). Coefficients of variance for repeated measurements for all parameters were below 3%, which was in accordance with other studies showing a short-term variability of <5%.11,13,19

In all subjects, lean and fat tissue mass for the total body, legs, and arms (all in kilogram) was also assessed using DEXA.

In order to evaluate changes in bone densitometric parameters over time in CHF, we aimed to repeat the DEXA scans in those patients who had survived at least 2 years after the initial assessment. Taking into account the fact that age-related bone loss in healthy men may reach up to 10% per decade,2 we prospectively defined significant bone loss in men with CHF as a reduction in BMC total of ≥1%/year.

All DEXA examinations were evaluated independently by two experienced investigators (E.A.J. and J.J.), and the inter-observer variability was below 2%.

Cardiopulmonary exercise test
Exercise capacity was assessed by measuring peak oxygen consumption (peak VO2) during a symptom-limited cardiopulmonary exercise test, as described elsewhere.20

Laboratory assessments
Venous blood samples were taken in the morning following an overnight fast and after a supine rest of ≥15 min. Blood samples were always taken between 7 and 9 am, taking into account the importance of marked circadian rhythms in hormone secretion.21 After centrifugation, serum was collected and frozen at –70°C until being analysed.

Serum levels of hormones [dehydroepiandrosterone sulphate (DHEAS), total testosterone (TT), insulin-like growth factor 1 (IGF-1)] were measured with immunoassays (Diagnostic Products Corporation, San Francisco, CA, USA). The inter- and intra-assay variability coefficients were 12.0 and 6.8% for DHEAS, 9.8 and 7.4% for TT, and 6.2 and 3.1% for IGF-1, respectively. Serum level of total oestradiol (TE2) was measured using electrochemiluminescence on the Elecsys 1010/2010 System (Roche Diagnostics GmbH, Mannheim, Germany) and expressed in pg/mL. The inter- and intra-assay variability coefficients were 2.0 and 3.3% for TE2, respectively.

In order to estimate the circulating fraction of free testosterone and oestradiol which may express more accurately the biological activity of circulating testosterone and oestradiol, in all subjects, the serum level of sex hormone-binding globulin was measured using an immunoassay (Diagnostic Products Corporation) and expressed in nmol/L (the inter- and intra-assay variability coefficients were 5.2 and 3.0%, respectively). The serum level of estimated free testosterone (eFT) was calculated using the validated equation of Vermeulen et al.,22 whereas the serum level of estimated free oestradiol (eFE2) was calculated using the validated equation of Södergård et al.23

Measurement of serum levels of osteocalcin (OCL, a bone-specific non-collagenous protein) was used as a biochemical marker of bone formation and of serum levels of cross-linked β-isomerized type I collagen C-terminal telopeptide fragments (β-CTx) as a biochemical marker of bone resorption. Moreover, we assessed serum levels of parathormone (PTH) and vitamin 25(OH)D2, hormones directly related to bone metabolism. Serum levels of OCL and PTH were measured using the Immulite automated immunoassay systems (Diagnostic Products Corporation). The inter- and intra-assay variability coefficients were 4.7 and 3.2% for OCL and 5.7 and 5.3% for PTH, respectively. Serum levels of β-CTx were measured using the Elecsys 2010 automated immunoassay system (Roche Diagnostic Corporation, Indianapolis, IN, USA). The inter- and intra-assay variability coefficients were 3.1 and 2.4% for β-CTx, respectively.

Renal function was expressed as estimated glomerular filtration rate (eGFR, mL/min/1.73 m2) calculated from the Modification in Diet in Renal Disease equation.24

Statistical analyses
All continuous variables were tested for a normal distribution using the Kolmogorow–Smirnov test. Continuous variables with a normal distribution were expressed as mean±SD (x±SD). The inter-group differences were tested using the unpaired Student's t-test, the {chi}2 test, or the one-way analysis of variance with post hoc comparisons (Scheffe test), where appropriate. Correlations between variables were assessed using a simple or multiple linear regression analysis (r) or Spearman rank correlations (R). Only serum DHEAS and eFT had a skewed distribution. These variables were described using median with interquartile range (IQR). For the regression models, these variables were log-transformed, which enabled to achieve their normal distributions.

For the evaluation of clinical and hormonal determinants of BMC and BMD, we applied multivariable forward stepwise linear regression models, in which P = 0.10 was used for both inclusion and exclusion of variables into the model. During the construction of multivariable models, we included all variables that had been shown to be significant determinants of bone densitometric indices in single predictor models.

Differences in two repeated DEXA measurements of bone parameters were assessed using the paired Student's t-test. We expressed changes in bone densitometric parameters in absolute units and in percentages. In order to adjust for changes in bone status for time diversity between two measurements, we calculated an average annual rate of bone loss and expressed changes in bone parameters in absolute values (g/year, g·cm2/year) and in percentages (%/year).

A value of P < 0.05 was considered statistically significant.


   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 Conclusions
 Funding
 References
 
During the study period, we prospectively recruited 187 men with CHF and 21 controls (nine men with hypertension and 12 men with CAD), whose baseline clinical characteristics are shown in Table 1. Mean values of bone densitometric parameters were lower in men with CHF when compared with male subjects without CHF (Table 2).


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  		Table 1 Baseline clinical characteristics in men with and without chronic heart failure

 


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  		Table 2 Baseline bone densitometric parameters in men with and without chronic heart failure

 
Bone mineral status and clinical indices
There were modest, but statistically significant, correlations between most of the bone densitometric parameters and New York Heart Association (NYHA) class, peak VO2 (mL·min–1), and LVEF (Tables 3 and 4). BMC and BMD in subjects in NYHA class IV were significantly lower when compared with men with CHF in NYHA classes I, II, and III, whereas there were no differences in bone densitometric parameters between men with CHF across NYHA classes I–III. No relationship was found between bone densitometric parameters, and age and eGFR (r < 0.1, P > 0.2 in all correlations). Neither therapy with furosemide nor with thiazide diuretics was related to bone mineral status in CHF. Subjects treated with spironolactone had lower BMC arms, BMC total, total bone calcium, and BMD trunk (P < 0.05) when compared with men not receiving spironolactone. There were no differences in bone densitometric parameters between CHF patients with ischaemic or non-ischaemic aetiologies (all P > 0.2).


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  		Table 3 Relationships between bone parameters and clinical characteristics and serum levels of total testosterone, estimated free testosterone, and dehydroepiandrosterone sulphate in men with chronic heart failure

 


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  		Table 4 Bone densitometric parameters in total body and all body regions in men with chronic heart failure according to New York Heart Association class (results of analysis of variance)

 
Bone mineral status and body composition
BMC total and BMD total correlated with total lean and total fat tissue mass (for BMC total: r = 0.55 and 0.39, for BMD total: r = 0.32 and 0.27, respectively, all P < 0.0001). These relationships between bone, fat and lean tissue mass were present within the arms and the legs. BMC arms and BMD arms correlated with lean tissue mass in the arms (r = 0.66 and 0.45, respectively, both P < 0.0001) and with fat tissue mass in the arms (r = 0.33 and 0.30, respectively, both P < 0.0001). BMC legs and BMD legs correlated with lean tissue mass in the legs (r = 0.59 and 0.29, respectively, both P < 0.0001) and with fat tissue mass in the legs (r = 0.43 and 0.20, both P < 0.01).

Bone mineral status and serum anabolic hormones
In a subgroup of 111 men with CHF, clinically representative of the whole CHF population [mean age: 61±11 years, mean LVEF: 33±7%, NYHA class I/II/III/IV: 8/51/45/7 (7/46/41/6%), all P > 0.2 in comparison with the whole group of 187 men with CHF], we measured levels of circulating anabolic hormones. Mean serum levels (with limits) were 4.47±1.70 ng/mL (limits 0.20–8.93) for TT, 83.5 pg/mL (IQR: 62.2–127.0, limits: 3.3–349.3) for eFT, 533 ng/mL (IQR: 308–952, limits: 89–2800) for DHEAS, 22.8±15.3 pg/mL (limits: 0.2–75.4) for TE2, 0.76±0.50 pg/mL (limits: 0.006–2.24) for eFE2, and 141.4±73.9 ng/mL (18.7–310.3) for IGF-1, respectively.

The majority of bone densitometric parameters positively correlated with serum levels of TT, eFT, and DHEAS (Table 3), but not with serum IGF-1, TE2, FE2 (all r < 0.1 and P > 0.1).

Bone mineral status and serum bone metabolism markers in men with chronic heart failure
In a subgroup of 60 male CHF patients, clinically representative of the whole CHF population (mean age: 59±11 years, LVEF: 32±7%, NYHA class I/II/III/IV: 6/29/18/7—all P > 0.2 in comparison with the whole group of 187 men with CHF), we quantified biochemical and hormonal markers of bone turnover and metabolism. Mean serum levels (with limits) were: for PTH 82.6±48.7 pg/mL (20.7–225.8), for OCL 5.85±3.42 ng/mL (1.0–15.60), for β-CTx 624±173 pg/mL (285–994), and for 25(OH)D2 16.2±9.4 ng/mL (0.1–38.1).

We found that in men with CHF, most bone densitometric parameters correlated with serum PTH, 25(OH)D2, and β-CTx in single predictor regression models (Table 5), but not with serum OCL (all P > 0.1).


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  		Table 5 Relationships between bone parameters and serum levels of PTH, 25(OH)D2, and β-CTx in men with chronic heart failure

 
Clinical and hormonal determinants of bone mineral status (multivariable analyses)
In the multivariable model, in men with CHF, reduced BMC total was independently determined by higher NYHA class (β = 0.24, P < 0.01), more impaired LVEF (β = 0.21, P < 0.01), reduced total lean mass (β = 0.50, P < 0.0001), reduced serum levels of DHEAS (β = 0.24, P < 0.01), and TT (β = 0.22, P < 0.01). In the multivariable model, BMD total in men with CHF was independently related to serum levels of DHEAS (β = 0.30, P < 0.01), TT (β = 0.28, P < 0.01), NYHA class (β = 0.32, P < 0.01), total lean mass (β = 0.22, P < 0.05), and LVEF (β = 0.19, P < 0.05).

Analogous results were obtained when serum TT, as a measure of gonadal androgen activity, was replaced by serum eFT. Namely, in the multivariable model, in men with CHF, reduced BMC total was independently determined by higher NYHA class (β = 0.19, P < 0.05), more impaired LVEF (β = 0.19, P < 0.05), reduced total lean mass (β = 0.52, P < 0.0001), reduced serum levels of DHEAS (β = 0.20, P < 0.05), and eFT (β = 0.17, P < 0.05). Similarly, in a multivariable model, BMD total in men with CHF was related to serum levels of DHEAS (β = 0.24, P < 0.05), eFT (β = 0.28, P < 0.01), NYHA class (β = 0.27, P < 0.01), total lean mass (β = 0.23, P < 0.05), and borderline LVEF (β = 0.17, P = 0.07).

Changes in bone mass in men over the course of chronic heart failure
During 2 years of clinical follow-up, 51 (27%) men with CHF died. Those, who had died, had more advanced CHF as evidenced by higher NYHA class (P < 0.0001), lower LVEF (P = 0.0002), and reduced peak VO2 (P = 0.001) when compared with survivors. Moreover, deceased patients had also higher serum PTH (P = 0.004), lower BMI (P = 0.06), and reduced total fat mass (P = 0.03). There were no differences in bone densitometric parameters between those who died and those who survived the 2-year period after the baseline DEXA assessment (all P > 0.2).

Eighty-five (46%) men with CHF survived the 2-year period after the baseline DEXA assessment [the remaining 51 (27%) patients did not reach the 2-year time-point of clinical follow-up during the study time] and were invited for the second DEXA assessment.

Finally, 60 of the 85 (71%) surviving men with CHF agreed to participate. The studied subgroup did not differ in any clinical, hormonal, or bone densitometric parameter from the whole group of alive men with CHF [mean age: 59±11 years, mean LVEF: 32±6%, NYHA class I–II/III–IV: 38/22 (63/37%)] (all P > 0.2). The mean time between both DEXA evaluations was 3.0±0.8 years.

There was a significant reduction in all bone densitometric parameters over time in men with CHF (Table 6).


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  		Table 6 Changes over time in bone densitometric parameters expressed in absolute units, percentages, and annualized in 60 men with chronic heart failure

 
Accelerated bone loss over time (defined prospectively as a reduction in BMC total ≥1%/year) occurred in 21 (35%) of these patients. They had more advanced NYHA class (NYHA III–IV: 78 vs. 14%, P = 0.001) and lower serum TT levels (3.46±2.23 vs. 5.06±1.58 ng/mL, P = 0.03, respectively, men with a reduction in BMC total ≥1 vs. <1%/year). There were no differences in other clinical and hormonal parameters and treatment between these two groups (all P > 0.2).

During the 3-year follow-up period, there was a significant increase in fat mass (fat mass in arms, legs, and total body, respectively: 1.89±0.83 vs. 2.16±1.04 kg, P = 0.0004; 6.12±2.92 vs. 6.57±2.88 kg, P = 0.003; 22.51±9.17 vs. 24.68±9.47 kg, P = 0.001) and no change in lean mass (arms, legs, and total body—all P > 0.2) in men with CHF.

Determinants of the rate of bone loss in men with chronic heart failure
Only two baseline parameters predicted the increased rate of bone loss during follow-up: advanced CHF expressed as NYHA class [change in BMD total (g·cm2/year) and BMD total (%/year): r = –0.22, P = 0.08 for both; change in BMC total (g/year): r = –0.26, P = 0.049; change in BMC total (%/year): r = –0.27, P = 0.04], reduced serum TT [change in BMD total (g·cm2/year): r = 0.39, P = 0.03; change in BMD total (%/year): r = 0.44, P = 0.01; change in BMC total (g/year): r = 0.59, P = 0.001; change in BMC total (%/year): r = 0.60, P < 0.0001] (Figure 1), and reduced serum eFT [change in BMD total (g·cm2/year): r = 0.64, P < 0.0001; change in BMD total (%/year): r = 0.68, P < 0.0001; change in BMC total (g/year): r = 0.64, P < 0.0001; change in BMC total (%/year): r = 0.66, P < 0.0001]. All remaining parameters assessed at baseline [age, LVEF, peak VO2, CHF aetiology, fat tissue mass, lean tissue mass, serum levels of DHEAS, TE2, eFE2, and IGF-1, serum levels of PTH, 25(OH)D2, OCL, and β-CTx] were not related to a subsequent rate of bone loss in men with CHF (all P > 0.1). Changes in bone densitometric parameters did not correlate with changes over time in fat or lean tissue mass in men with CHF (all P > 0.2).


Figure 1
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  		Figure 1 Changes in bone mineral content total in men with chronic heart failure determined by baseline serum levels of total testosterone.

 

   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
Conclusions
 Funding
 References
 
The following are the main findings of this study. Men with CHF demonstrate reduced BMD and BMC when compared with age-matched male subjects without CHF. In male CHF subjects, low bone mass and reduced BMD are independently determined by CHF severity (as evidenced by higher NYHA class, greater impairment of LVEF, and reduced peak oxygen consumption), depleted gonadal and adrenal drive (as evidenced by low serum levels of TT, eFT, and DHEAS) and constitute a part of general body wasting (correlating with low lean and fat tissue mass). Enhanced bone loss over time is a common finding in men with CHF, particularly among patients with advanced NYHA class and testosterone deficiency.

We have demonstrated that reduced bone mass and bone density in male patients with CHF are accompanied by reduced fat and lean tissue mass. Attenuation of BMD in the course of general body wasting has been previously described in chronic diseases.1 Anker et al.4 found positive relationships between total body BMC and total fat and lean tissue mass in 58 CHF patients, one-third of them with cardiac cachexia. Our study confirms these cross-sectional relationships in a larger CHF cohort with fewer cachectic patients. To the best of our knowledge, this is the first study that, using a detailed analysis of body composition, has demonstrated a relationship between decreased bone densitometric parameters and reduced lean and fat tissue in the total body and in all body regions. Although one can presume that in the course of CHF changes in different tissue compartments are interrelated, we have not observed such relationships between longitudinal changes in lean, fat, and bone tissue mass in 60 men with CHF whom we followed up for between 2 and 4 years. A reduction in bone mass was accompanied by an increase in fat mass (arms, legs, and total body), and no changes in lean mass (arms, legs, and total body). Taking into account that bone tissue is very sensitive to deficient anabolic stimuli (more than muscle and fat tissues), we may presume that bone tissue is the body compartment where wasting due to anabolic depletion occurs first.

In healthy men, a strong relationship between sex steroids and bone metabolism exists.25 Several authors have reported that in healthy men BMD correlates with serum DHEAS and testosterone levels.26–28 In the course of CHF, decreased levels of TT and DHEAS have been documented,29 particularly in those with severe CHF30 and cardiac cachexia.31 It has been demonstrated that testosterone therapy reveals favourable effects in men with CHF (e.g. improvement in exercise capacity, amelioration of neurohumoral activation, improvement in insulin sensitivity, and anti-inflammatory effects).32–35 Direct anabolic properties of testosterone or indirect effects of this therapy (mentioned earlier) may also potentially improve bone homeostasis in men with CHF, but this has not yet been investigated. Our study demonstrated for the first time that low serum levels of DHEAS and testosterone (both TT and eFT) independently predict reduced bone mass and bone density. In contrast, in men with CHF, we did not confirm links between circulating oestradiol (both TE2 and eFE2) and bone densitometric indices, associations being demonstrated in ageing men by several authors.26,36

Some authors postulated associations of reduced BMD with high PTH and low 25(OH)D2 in a small group of patients with CHF (both men and women).6 In contrast, we found only weak associations between most bone densitometric parameters and serum PTH, 25(OH)D2, and β-CTx (but not serum OCL) in single predictor regression models in men with CHF (Table 5), being of a marginal importance for BMC and BMD variance, when compared with much stronger impact of disease severity and testosterone deficiency.

Reduced baseline serum testosterone (both TT and eFT) remained the only anabolic hormone that predicted enhanced bone loss in men in the course of CHF. In contrast, serum IGF-1, known to predict bone mass in healthy men,37,38 was related to neither BMD nor BMC in men with CHF. None of the bone metabolism markers (serum levels of PTH, 25(OH)D2, β-CTx, and OCL) predicted bone loss during follow-up in men with CHF. Our findings indicate that the reduction in bone mass in the course of CHF may be secondary to anabolic androgen depletion, in particular testosterone deficiency. This concurs with the results of clinical and experimental studies, demonstrating direct and indirect effects of anabolic steroids on bone tissue in male subjects.39–46 Gonadal and adrenal androgen replacement therapy can improve BMD in older men with testosterone or DHEA deficiency, respectively,39,41,47,48 and favourable changes in bone mass are accompanied by decreased bone resorption markers and increased bone formation markers in the peripheral blood.49 However, favourable effects of testosterone on bone mass have not been confirmed in all published studies.49 Low circulating testosterone results in an accelerated bone loss in longitudinal analyses50 and is considered as a risk factor of skeletal fractures in elderly men.51 In experimental models, both testosterone and DHEA stimulate proliferation, differentiation, and bone metabolic activity of human osteoblasts; all these effects are related to the modified expression of osteoprotegerin/receptor activator of the NF–kappaB ligand system and are secondary to androgen receptor-mediated mechanisms.42,43,45,49 Testosterone can also inhibit osteoclast formation and bone resorption in a dose-dependent manner, acting as well through androgen receptor-mediated mechanisms.44,49 Additionally, DHEA is a precursor of oestrogens and androgens synthesized in the peripheral tissues and is known to increase bone formation and to reduce bone resorption acting indirectly through interactions with oestrogen and androgen receptors.40,41

More studies are required to prove that testosterone deficiency may be the mechanistic explanation for the bone loss in male CHF patients. A desirable methodological approach here would be an assessment of whether correction of testosterone deficiency could improve bone mass in these patients. We believe that the results of our study form a strong background for such interventions.

Study limitations
The observational character of our study needs to be acknowledged. Limitations of the longitudinal part of the study result from a relatively short period between the two DEXA scans (on average 3 years). Changes in the bone mass tend to occur as a long-term process, but such a long-term project may not be feasible in CHF due to the high mortality rates in these patients. Moreover, those patients who survived until the second assessment had less advanced NYHA class and higher circulating TT levels, as both these factors are strongly related to increased mortality in men with CHF.29 Hence, we can presume that unfavourable changes in bone mineral status would have been even greater if they had been analysed in high-risk CHF patients.

The other limitation of our study is a relatively small control group. Still, we were able to demonstrate that men with CHF had significantly lower BMC and BMD when compared with age-matched men with CAD or hypertension but without CHF. It should be emphasized that in all analyses we additionally used Z-score values, reflecting BMD derived from healthy age-matched male subjects. The reference population used by the manufacturer consists of a cohort of healthy Caucasian men with a broad age range, which is accepted as a valid comparator for a Polish male population. The BMD of each individual case of CHF is compared with a reference value in an analogous age group. We revealed a lower Z-score in men with CHF when compared with those without CHF (P < 0.05), indicating that BMD values of men with CHF were in a greater distance from normal values than analogous BMD values of male subjects without CHF. A significant reduction in the Z-score values in our longitudinal observation further confirms a strong trend towards a reduction in BMD in the natural course of CHF.

It should be emphasized that the primary aim of our analysis was to evaluate the bone status in men with CHF in the context of changes in body composition (fat and lean tissue mass) seen in the course of heart disease. Therefore, we analysed all these parameters of body composition separately in major body regions using a specific mode of total body scanning and intentionally did not measure BMD in selected regions (such as hip or lumbar spine). In the context of precise bone status assessment, lack of standard BMD within hip or lumbar spine should be considered as a study limitation.

Physical activity exerts trophic effects on bone tissue in humans. In our study, the patients' physical activity was entirely related to their everyday habitual activity (during the period preceding the baseline assessments and during the clinical follow-up). As we are not able to quantify precisely the amount of physical activity performed by CHF subjects, we consider lack of such data as a limitation of our analyses.

Clinical perspective
In recent years, there has been an increasing interest in osteoporosis and reduced BMD affecting not only post-menopausal women, but also men, particularly with co-existing chronic diseases. These observations have a practical impact on the precise definition of the target population in whom screening measures and prophylactic actions should be taken. Prevention is crucial, as osteoporosis is a debilitating condition that significantly reduces quality of life. Our paper provides the first ever evidence that men with CHF develop accelerated bone loss in the course of heart disease. Hence, CHF itself should be considered, along with chronic obstructive pulmonary disease, neurological disease, rheumatoid arthritis, and so on, as another clinically significant risk factor of accelerated bone loss in a general male population.

Putting our results into clinical perspective, we believe that assessment of bone status may be considered in male CHF patients when other predictors of low bone mass and/or accelerated bone loss co-exist, i.e. another chronic illness (chronic obstructive pulmonary disease, severe renal dysfunction, and rheumatoid arthritis), severe CHF (evidenced by severe symptoms and impaired LVEF), low lean tissue mass (in other words, low BMI), and low circulating testosterone. In particular, we would like to point out the importance of hypogonadism as an important pathophysiological background of male osteoporosis in the clinical setting of heart failure. We have reported previously that ~25% of the men with CHF have testosterone deficiency, which is independently related to poor outcome.29 In the present study, we have demonstrated that testosterone deficiency is accompanied by a reduced bone mass and results in an accelerated bone loss during 3-year follow-up. We believe it corroborates our previous argument that male CHF patients should be screened for testosterone deficiency.


   Conclusions
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Conclusions
Funding
 References
 
The present study demonstrates that in an unselected cohort of male CHF patients, deficiency in bone mineral status is more prevalent among those with advanced disease, is accompanied by reduced lean tissue mass, and decreased serum levels of gonadal and adrenal androgens. Significant bone loss occurs in one-third of men with CHF, and its magnitude is determined mainly by disease severity and testosterone deficiency.

Conflict of interest: none declared.


   Funding
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Conclusions
 Funding
References
 
The research was financially supported by the State Committee for Scientific Research (Poland) grant no. 3 T11F 008 30. E.A.J. was supported by British Council (British-Polish Young Scientists' Program) and European Society of Cardiology Training Fellowship.


   References
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 Methods
 Results
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 Funding
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A new pathway? Failure, fragility and fractures
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