Relevance of serum sclerostin concentrations in critically ill patients

Relevance of serum sclerostin concentrations in critically ill patients

Journal of Critical Care 37 (2017) 38–44 Contents lists available at ScienceDirect Journal of Critical Care journal homepage: www.jccjournal.org Re...

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Journal of Critical Care 37 (2017) 38–44

Contents lists available at ScienceDirect

Journal of Critical Care journal homepage: www.jccjournal.org

Relevance of serum sclerostin concentrations in critically ill patients Alexander Koch, MD a, Ralf Weiskirchen, PhD b, Sebastian Ludwig, MD a, Lukas Buendgens, MD a, Jan Bruensing, MD a, Eray Yagmur, MD c, Christer Baeck, MD, PhD a, Ulf Herbers, MD a, Christian Trautwein, MD a, Frank Tacke, MD, PhD a,⁎ a b c

Department of Medicine III, RWTH-University Hospital Aachen, Aachen, Germany Institute of Molecular Pathobiochemistry, Experimental Gene Therapy and Clinical Chemistry, RWTH-University Hospital Aachen, Aachen, Germany Medical Care Center, Dr Stein and Colleagues, Mönchengladbach, Germany

a r t i c l e

i n f o

Keywords: Sclerostin Organ failure Sepsis Cirrhosis Prognosis Bone metabolism

a b s t r a c t Purpose: Sclerostin is a negative regulator of bone metabolism and associated with chronic morbidities. We investigated circulating sclerostin in critically ill patients. Methods: A total of 264 patients (170 with sepsis) were studied prospectively upon admission to the medical intensive care unit (ICU) and on day 7. Patients' survival was followed for up to 3 years. Results: Sclerostin serum levels were significantly elevated in critically ill patients at ICU admission compared with 99 healthy controls. Unlike in healthy controls, sclerostin did not depend on sex or age of ICU patients. Sclerostin was associated with disease severity, independent of the presence of sepsis. Sclerostin levels increased during the first week of treatment at the ICU but were not a predictor of mortality. Sclerostin was elevated in patients with preexisting chronic kidney disease or liver cirrhosis, but was not related to diabetes, obesity, or cardiovascular disease. Circulating sclerostin in ICU patients correlated with biomarkers reflecting renal, hepatic and cardiac dysfunction, and biomarkers reflecting bone metabolism. Conclusion: Serum sclerostin concentrations are significantly elevated in critically ill patients, linked to renal or hepatic organ failure, and associated with bone resorption markers, supporting its value as a potential tool for the assessment of ICU-related metabolic bone disease. © 2016 Elsevier Inc. All rights reserved.

1. Introduction Metabolic bone disease in the intensive care unit (ICU) is considered as a potentially devastating consequence of critical illness. Routinely used laboratory parameters related to bone metabolism such as calcium, phosphate, alkaline phosphatase, or parathyroid hormone have limited value in the ICU setting due to confounding influences by organ dysfunction, comorbidities, and therapeutic measures [1]. Sclerostin has emerged as a key negative regulator of bone metabolism [2]. It is an inhibitor of the anabolic Wnt/β-catenin signaling pathway that is specifically produced by osteocytes [3]. Sclerostin decreases bone formation by repressing osteoblast differentiation and proliferation [3]. The ability to measure sclerostin levels in the blood has led to the further investigation of circulating sclerostin as a biomarker of bone metabolism [4]. Several independent clinical studies have

⁎ Corresponding author at: Department of Medicine III, RWTH-University Hospital Aachen, Pauwelsstraße 30, 52074 Aachen, Germany. Tel.: +49 241 80 35848; fax: +49 241 80 82455. E-mail address: [email protected] (F. Tacke).

http://dx.doi.org/10.1016/j.jcrc.2016.08.019 0883-9441/© 2016 Elsevier Inc. All rights reserved.

suggested associations between sclerostin levels and bone mineral density changes, fracture risk, responses to hyperparathyreoidism, or bisphosphonate therapy as well as vascular calcification [2,4-6]. These clinical associations imply that serum sclerostin measurements could be useful in predicting patient-specific outcomes. This has been exemplarily demonstrated in hemodialysis patients. However, these studies yielded conflicting results. In 2 large cohorts of hemodialysis patients from the Netherlands (n = 673) as well as from Belgium (n = 100), high serum sclerostin was identified as a prognostic indicator for improved cardiovascular and all-cause survival [7,8]. On the other hand, a study from Brazil comprising n = 99 hemodialysis patients reported that the long-term mortality (10-year observation period) was significantly increased in patients with high sclerostin levels [9]. High sclerostin have also been reported in patients with advanced liver disease [10], type 2 diabetes [11], obesity [12], and cardiovascular diseases [6], indicating that sclerostin has implications in various types of chronic diseases. The regulation of sclerostin in conditions of critical illness is currently unknown. We therefore assessed serum sclerostin levels in a large cohort of 264 critically ill patients at a medical ICU at the time of admission as well as after the first week of ICU treatment. We herein demonstrate that sclerostin levels are significantly increased in critically

A. Koch et al. / Journal of Critical Care 37 (2017) 38–44

ill patients compared with controls, and we identified important clinical parameters influencing circulating sclerostin.

2. Materials and methods 2.1. Study design and patient characteristics We conducted a single-center prospective observational trial at the Medical ICU at the University Hospital Aachen, Germany. We included consecutively all patients on admission to the ICU. Patients for postinterventional ICU observation after elective procedures were excluded from this study [13]. We obtained written informed consent from the patient, his or her spouse, or the appointed legal guardian. The study protocol was approved by the local ethics committee (ethics committee of the University Hospital Aachen, RWTH-University, Aachen, Germany). Sepsis was defined following the Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3) [14]; all other patients were categorized as nonsepsis patients. The mortality during the ICU treatment was defined as “ICU mortality.” Furthermore, the patient's outcome was followed for approximately 2 years by contacting the patients, patients' relatives, and/or general practitioner, resulting in assessment of an “overall mortality” rate [15]. The Charlson Comorbidity Index (CCI) was retrospectively assessed [16]. Healthy blood donors with normal blood counts, normal liver enzymes, and negative serology for viral hepatitis and HIV served as controls [17].

2.2. Sclerostin measurements At the time point of admission to the ICU as well as in the morning of day 7 after admission, blood samples were collected, centrifuged, and frozen at −80°C until analysis. To exclude potential effects of treatment measures on sclerostin levels, the blood samples at admission were obtained before therapeutic interventions at the ICU [17]. Sclerostin serum concentrations were analyzed using a commercial enzyme immunoassay (Biomedica Medizinprodukte GmbH, Vienna, Austria). The intraassay coefficient of variation was 4% to 6%, and the interassay coefficient of variation was 5% to 7%. Sclerostin measurements were performed by a scientist, who was fully blinded to any clinical or other laboratory data of the patients or controls.

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2.3. Statistical analysis Clinical and experimental data from this study are presented as median and range due to the skewed distribution of most of the parameters. Mann-Whitney U test was used to determine differences between 2 groups. Box plot graphics were calculated to display the median, quartiles, range, and extreme values. Box-and-whisker plot reaches from the minimum to the maximum value excluding outside and far-out values which are displayed as separate points. An outside value (indicated by an open circle) was defined as a value that is smaller than the lower quartile minus 1.5 times the interquartile range, or larger than the upper quartile plus 1.5 times the interquartile range. A far-out value was defined as a value that is smaller than the lower quartile minus 3 times the interquartile range, or larger than the upper quartile plus 3 times the interquartile range [13]. Importantly, all values, including “outliers,” have been included for statistical analyses. Correlations between parameters were analyzed by Spearman rank correlation. Throughout this study, P values less than .05 were considered statistically significant. The prognostic value of sclerostin was tested by Cox regression analysis. All statistical analyses were performed with SPSS (SPSS, Chicago, Ill). 3. Results 3.1. Sclerostin serum levels are significantly up-regulated in critically ill patients and is related to disease severity We measured sclerostin serum concentrations in a large cohort of medical ICU patients at admission (=before therapeutic interventions) and on day 7 (Table 1). We enrolled 264 patients (158 men, 106 women with a median age of 63 years; range, 18-90 years) who were admitted to the General Internal Medicine ICU at the RWTH-University Hospital Aachen, Germany (Table 1). As a control population, we analyzed 99 healthy blood donors (66 men, 33 women; median age, 32 years; range 18-67 years). Sclerostin serum levels were significantly higher in ICU patients (n = 264; median, 33.6 pmol/L; range, 5.1-239.3 pmol/L) as compared with healthy controls (n = 99; median, 30.4 pmol/L; range, 10-84.1 pmol/L; P = .018; Fig. 1A). In our healthy control cohort, serum sclerostin levels correlated with age (r = 0.201, P = .047), and sclerostin was higher in male than in female individuals (median, 32.5 pmol/L vs 24.6 pmol/L; P = .006), in line with the literature [18]. No significant association between serum sclerostin and sex or age was found in critically ill patients (detailed data not shown).

Table 1 Baseline patient characteristics and sclerostin serum measurements Parameter

All patients

Nonsepsis

Sepsis

No. Sex (male:female) Age (y), median (range) APACHE II score, median (range) ICU days, median (range) Death during ICU, n (%) Death during follow-up (total), n (%) Mechanical ventilation, n (%) Preexisting diabetes, n (%) Preexisting cirrhosis, n (%) BMI (m2/kg), median (range) WBC (×103/μL), median (range) CRP (mg/dL), median (range) Procalcitonin (μg/L), median (range) Creatinine (mg/dL), median (range) INR, median (range) Sclerostin day 1 (pmol/L), median (range) Sclerostin week 1 (pmol/L), median (range)

264 158:106 63 (18-90) 17 (2-43) 8 (1-137) 65 (24.6) 125 (47.3) 180 (68.2) 80 (30.3) 25 (9.5) 26 (15.9-86.5) 12.7 (0-149) 97.5 (5-230) 0.9 (0.03-248) 1.33 (0.1-21.6) 1.18 (0.9-13) 33.6 (5.1-239.3) 45.4 (0.5-169.7)

94 57:37 60.5 (18-85) 14.5⁎ (2-33) 6⁎ (1-45) 16 (17)⁎ 32 (34)⁎ 57 (60.6)⁎

170 101:69 64 (20-90) 19⁎ (3-43) 10⁎ (1-137) 49 (28.8)⁎ 93 (54.7)⁎ 123 (72.4)⁎

30 (31.9) 18 (19.1)⁎ 26 (15.9-53.3) 11.7⁎ (1.8-29.6) 17⁎ (5-230) 0.2⁎ (0.03-100) 1.0⁎ (0.2-15) 1.18 (0.9-6.73) 33.4 (10-208) 36.9 (8.5-148.6)

50 (29.4) 7 (4.1)⁎ 26 (17.1-86.5) 13.2⁎ (0-149) 161.5⁎ (5-230) 3.1⁎ (0.1-248) 1.6⁎ (0.1-21.6) 1.17 (0.92-13) 33.6 (5.1-239.3) 47.3 (0.5-169.7)

For quantitative variables, median and range (in parenthesis) are given. BMI indicates body mass index; WBC, white blood cell count; CRP, C-reactive protein; INR, international normalized ratio. ⁎ P b .05 for the difference between sepsis and non-sepsis patients (U test for quantitative and chi-square test for qualitative variables).

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P = .018

sclerostin (pmol/L)

sclerostin (pmol/L)

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n=99 controls

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n=94 non-sepsis

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P = .001 200

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n=170 sepsis

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0

0 APACHE II ≤ 10

APACHE II > 10

APACHE II ≤ 20

APACHE II >20

Fig. 1. Sclerostin serum concentrations in critically ill patients. A, At admission to the Medical ICU, serum sclerostin levels were significantly (P = .018, U test) elevated in critically ill patients (n = 264) as compared with healthy controls (n = 99). B, Sclerostin serum levels at ICU admission did not differ between patients with or without sepsis. C and D, High sclerostin levels were associated with higher disease severity, as displayed by the APACHE II score.

Among the 264 critically ill patients enrolled in this study, 170 patients conformed to the criteria of sepsis (Table 1), according to the third international consensus definitions of sepsis and septic shock from 2016 [14]. Pneumonia was identified in most sepsis patients as origin of infection (Table 2). Nonsepsis patients were admitted to the ICU mainly due to cardiopulmonary diseases (myocardial infarction, pulmonary embolism, and acute decompensated heart failure), decompensated liver cirrhosis, acute pancreatitis, or other causes of critical illness (Table 2). Sclerostin serum levels did not differ between patients with or without sepsis (Table 1, Fig. 1B). Interestingly, patients with initially low Acute Table 2 Disease etiology of the study population leading to ICU admission Sepsis (n = 170) Nonsepsis (n = 94) Etiology of sepsis critical illness Site of infection, n (%) Pulmonary 94 (55.3) Abdominal 29 (17.1) Urogenital 7 (4.1) Other 37 (21.8) Etiology of nonsepsis critical illness, n (%) Cardiopulmonary disorder Acute pancreatitis Acute liver failure Decompensated liver cirrhosis Severe gastrointestinal hemorrhage Nonsepsis other

32 (34) 13 (13.8) 4 (4.3) 16 (17) 7 (7.4) 22 (23.4)

Physiology and Chronic Health Evaluation II (APACHE II) scores (b10), indicating less severe critical illness, displayed significantly lower sclerostin serum levels than ICU patients with a higher initial APACHE II score (N10; median, 22.9 pmol/L vs 39.8 pmol/L; P = .001; Fig. 1C). Patients with highest disease severity, defined by APACHE II score higher than 20, were found to have the highest sclerostin levels (median, 41.9 pmol/L vs 32.8 pmol/L in patients with APACHE II score b20; P = .020; Fig. 1D). 3.2. Sclerostin levels increase during the first week of treatment at the ICU, but do not predict outcome In 90 patients, paired blood samples were available for sclerostin measurements at ICU admission and at day 7 of ICU treatment. Remarkably, individual sclerostin levels increased during the first week of ICU therapy (Table 1, Fig. 2A; P = .015, paired Wilcoxon test). In line with our findings for admission measurements, sclerostin levels at day 7 did not differ between patients with or without sepsis and remained independent of age and sex in ICU patients (data not shown). The observed association between sclerostin serum levels and severity of critical illness at ICU admission prompted us to investigate the potential of sclerostin for predicting the outcome. However, sclerostin levels were not different between patients who died during the course of ICU treatment (ICU mortality rate was about 25%; Table 1) and ICU survivors (median, 43.1 pmol/L vs 31.4 pmol/L; P = .23; Fig. 2B). Also, patients who died during the long-term follow-up (overall mortality

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sclerostin (pmol/L)

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41

150

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0

0 day 1

survivors ICU

day 7

C

deaths ICU

D 250

n.s.

sclerostin

survivor ICU

death ICU

total

decrease

28 (31%)

9 (10%)

37

increase

41 (46%)

12 (13%)

53

total

69

21

90

survivor overall

death overall

total

decrease

17 (19%)

20 (22%)

37

increase

26 (29%)

27 (30%)

53

total

43

47

90

sclerostin (pmol/L)

200

day 1 – day 7 150

sclerostin

100

day 1 – day 7 50

0 survivors

deaths

overall survival Fig. 2. Longitudinal sclerostin measurements and outcome. A, In 90 patients, sclerostin levels were measured at admission (day 1) and at 1 week (day 7) of ICU therapy. Sclerostin levels increased during the first week of ICU treatment (paired Wilcoxon test). B and C, Sclerostin serum concentrations at ICU admission did not differ between patients who died during the ICU treatment (B) or who died during the total observation period (C) compared with surviving patients. D, Similarly, the increase or decrease of sclerostin levels during the first week of ICU treatment did not predict ICU or overall mortality. Patient numbers are given in the cross-table.

rate was 47%; Table 1) did not show altered sclerostin levels (median, 36 pmol/L vs 33.3 pmol/L in overall survivors; P = .688; Fig. 2C). Sclerostin measurements obtained at day 7 after ICU admission did not predict prognosis either (data not shown). We next investigated whether longitudinal changes of serum sclerostin over the first week of ICU treatment may be predictive for the patients' prognosis. However, as depicted by cross-table analysis (Fig. 2D), neither the increase nor the decrease of serum sclerostin during the first week of ICU treatment was associated with ICU or overall mortality.

3.3. Impact of existing comorbidities on sclerostin levels Sclerostin levels were reported to be elevated in patients with metabolic disorders such as type 2 diabetes [11]. However, patients with preexisting type 2 diabetes (Fig. 3A), obesity as defined by body mass index exceeding 30 kg/m2 (Fig. 3B), or a medical history of coronary artery disease (Fig. 3C) had no altered sclerostin serum concentrations upon admission to the ICU. Strikingly, patients with liver cirrhosis (n = 25) had significantly higher serum sclerostin levels as compared with ICU patients without liver cirrhosis (median, 54.5 pmol/L vs 32.6 pmol/ L; P = .023; Fig. 3D). Nevertheless, in the subgroup of liver cirrhosis patients (n = 25), sclerostin levels did not differ between patients who

survived during the ICU (n = 14) or during long-term follow-up (n = 12; detailed data not shown). Previous studies indicated increased sclerostin levels in patients with advanced stages of chronic kidney disease [19,20]. In line with these findings, we observed significantly higher sclerostin levels at ICU admission in patients with end-stage renal failure undergoing hemodialysis on a regular basis (median, 58.2 pmol/L vs 33.1 pmol/L in patients without regular hemodialysis; P = .005; Fig. 3E). To distinguish the influence of disease severity or comorbidities on sclerostin levels, we assessed retrospectively the CCI for all patients. In fact, serum sclerostin levels did not correlate with the CCI (r = 0.053, P = .397, Spearman rank correlation, not significant). Moreover, patients with a CCI b 2 did not display different sclerostin levels compared with patients with a CCI N 2 (P = .357, U test, not significant). Thus, disease severity and specific conditions (liver cirrhosis, renal failure), but not comorbidities per se impact circulating sclerostin levels in critically ill medical patients. 3.4. Association of serum sclerostin with other biomarkers reflecting organ dysfunction and metabolism We next assessed correlations between sclerostin serum levels at admission and clinically established biomarkers indicating disease severity, organ dysfunction, and metabolism in ICU patients (Table 3).

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A

B 250

250

n.s.

n.s. 200

sclerostin (pmol/L)

sclerostin (pmol/L)

200

150

100

150

100

50

50

0

0 no

no yes obesity (BMI >30 kg/m²)

yes

type 2 diabetes

C

D 250

250

n.s.

P = .023 200

sclerostin (pmol/L)

sclerostin (pmol/L)

200

150

100

150

100

50

50

0

0 no

yes

coronary artery disease

no

yes

liver cirrhosis

E 250

sclerostin (pmol/L)

P = .005 200

150

100

50

0 no

yes

chronic hemodialysis Fig. 3. Sclerostin levels and comorbidities in critically ill patients. A-E, When ICU patients were subdivided according to their preexisting comorbidities including type 2 diabetes (A), obesity (B), coronary artery disease (C), liver cirrhosis (D), and end-stage kidney disease with chronic hemodialysis (E), patients with liver cirrhosis and patients on chronic hemodialysis displayed increased sclerostin levels at admission to the ICU.

Sclerostin clearly correlated with markers representing renal function such as creatinine (r = 0.400, P b .001), cystatin C (r = 0.369, P b .001; Fig. 4A), urea (r = 0.288, P b .001), or the cystatin C–based glomerular filtration rate (r = −0.391, P b .001). Moreover, there were moderate associations between serum sclerostin and markers of disease

severity (APACHE II score, length of stay at the ICU, suPAR [21]) as well as markers of liver dysfunction (bilirubin, coagulation factors). More strikingly, we observed that serum sclerostin correlated with a variety of parameters involved in bone metabolism such as ionized calcium (r = −0.274, P b .001; Fig. 4B), phosphate (r = 0.135, P = .033),

A. Koch et al. / Journal of Critical Care 37 (2017) 38–44 Table 3 Correlations with sclerostin serum concentrations at admission day (Spearman rank correlation test, only significant results are shown) Parameters

ICU patients r

Disease severity APACHE II suPAR Renal function Urea Creatinine GFR (creatinine) Cystatin C GFR (cystatin C) Uric acid Liver function Bilirubin (conjugated) Prothrombin time aPTT Antithrombin III Metabolism Ionized calcium Phosphorus Alkaline phosphatase Parathyroid hormone Growth hormone C-peptide NT-proCNP NT-proBNP

P 0.235 0.341

.001 b.001

0.288 0.400 −0.364 0.369 −0.391 0.272

b.001 b.001 b.001 b.001 b.001 b.001

0.160 −0.124 0.172 −0.240

.037 .047 .006 .002

−0.274 0.135 0.145 0.222 0.221 0.232 0.426 0.243

b.001 .033 .023 .021 .027 .014 b.001 .004

NT-proCNP indicates amino-terminal pro-C-type natriuretic peptide; NT-proBNP, aminoterminal pro-brain natriuretic peptide; GFR, glomerular filtration rate.

alkaline phosphatase (r = 0.145, P = .023), parathyroid hormone (r = 0.221, P = .027), and growth hormone (r = 0.221, P = .027). Furthermore, we found correlations between sclerostin and C-peptide (r = 0.232, P = .014), N-terminal pro brain natriuretic peptide (NTproBNP) (r = 0.243, P = .004) and N-termin pro C-type natriuretic peptide (NT-proCNP) (r = 0.426, P b .001), indicating associations with other metabolic pathways as well. To address which factors independently influence sclerostin concentrations, we subjected selected parameters that were correlated with sclerostin serum levels by univariate analysis and were included in a multivariate regression analysis. When we included markers of renal function (ie, creatinine), bone metabolism (ie, ionized calcium, phosphate, and alkaline phosphatase), and liver function (ie, bilirubin), only creatinine (P b .001) and ionized calcium (P = .002) remained independent predictors of sclerostin concentrations (detailed data not shown).

4. Discussion This study demonstrates increased serum sclerostin concentrations in critically ill patients already at the time of admission to the ICU as compared with healthy controls. During the first week of ICU treatment, sclerostin levels even further increase in these patients. Prior studies on either healthy cohorts or patients with chronic metabolic or cardiovascular diseases have reported elevated levels of sclerostin in male sex, advanced age, obesity, type 2 diabetes, or coronary artery disease [2,4,18,22]. Although we could confirm some of these principal associations in our healthy control cohort, the significantly elevated sclerostin concentrations in patients with critical illness were independent from these known regulating factors. In ICU patients, we identified the severity of critical illness (as assessed by clinical scores) and renal and hepatic failure as main influences on circulating sclerostin. The association of chronic kidney disease and sclerostin levels is well established in the literature [5,8,9,19,20]. Increased sclerostin serum levels in patients with chronic kidney disease are likely not simply caused by decreased renal elimination [23]. Remarkably, uremia seems to stimulate sclerostin production, as observed in bone biopsies of patients with kidney disease [24]. In our cohort, highest sclerostin levels were found in ICU patients who were chronic hemodialysis patients. However, we observed a clear correlation between acute or chronic renal failure and sclerostin levels in the total cohort of ICU patients. This correlation remained independent from other confounding parameters by multivariate regression analysis, emphasizing the relevance of the kidney-bone axis for systemic sclerostin regulation. Another important observation of our study concerns the association between sclerostin and liver dysfunction. Although in the whole ICU cohort moderate correlations between sclerostin and parameters indicating the hepatic biosynthetic function could be observed, patients with decompensated liver cirrhosis showed highest sclerostin concentrations among all ICU patients. The exact route of sclerostin metabolism is unknown, but it has been suggested that the liver contributes to its elimination [10]. Also, increased estrogen levels as a typical feature of end-stage liver disease may further cause increased sclerostin in cirrhosis [25]. More recently, sclerostin expression was reported to be upregulated in serum as well as in the liver of patients with primary biliary cholangitis [26]. Interestingly, sclerostin expression in the liver was mainly detected in the bile ducts [26]. Because critically ill patients oftentimes develop patterns of cholestatic liver injury [27], altered

B

A 250

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r= -0.274 P < .001

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cystatin C (mg/L)

6

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ionized calcium (mmol/L)

Fig. 4. Serum sclerostin concentrations in critically ill patients are correlated with renal failure and ionized calcium. A and B, Serum sclerostin levels at ICU admission correlated highly significantly with renal failure (cystatin C) and ionized calcium. Spearman rank correlation test, and r and p values are given in the figure.

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sclerostin expression by inflamed or injured bile ducts may further contribute to high circulating levels in our cohort. The clinical and pathogenic consequences of elevated circulating sclerostin levels in critically ill patients are currently unknown. In our cohort, we observed correlations between sclerostin and parameters reflecting bone metabolism (ie, ionized calcium, phosphorus, alkaline phosphatase, parathyroid hormone, and growth hormone). In the ICU setting, critically ill patients are at risk for developing ICU-related metabolic bone disease, characterized by significant loss of bone mineral density [28]. At present, inflammatory cytokines (particularly tumor necrosis factor, interleukin 6, and interleukin 1), immobilization, vitamin D deficiency, common medications (eg, heparinoids, steroids), and hormonal irregularities affecting adrenocorticotropic hormone (ACTH), cortisol, or growth hormone are key factors that promote osteoclast-mediated bone resorption [1]. Our data now indicate that elevated sclerostin as a negative regulator of bone metabolism could possibly further contribute to this vicious circle of inflammation, accelerated bone resorption, and impaired bone formation in critically ill patients. The importance of bone metabolism for the overall prognosis at the ICU was recently demonstrated in a large retrospective study on 7830 ICU patients, in which patients who had been on bisphosphonate therapy before ICU admission displayed improved survival and decreased bone loss, despite an older age and more comorbidities [29]. Therefore, sclerostin should be further investigated for the assessment of ICU-related metabolic bone disease and for identification of patients at particular risk that might benefit from specific therapeutic interventions. Competing interests None of the authors declare competing interests. Acknowledgments We sincerely thank Philip Kim for excellent technical assistance. This work was supported by the German Research Foundation (DFG Ta434/5-1 and SFB/TRR57) and the Interdisciplinary Centre for Clinical Research (IZKF) within the faculty of Medicine at the RWTH Aachen University. References [1] Hollander JM, Mechanick JI. Bisphosphonates and metabolic bone disease in the ICU. Curr Opin Clin Nutr Metab Care 2009;12:190–5. [2] Honasoge M, Rao AD, Rao SD. Sclerostin: recent advances and clinical implications. Curr Opin Endocrinol Diabetes Obes 2014;21:437–46. [3] Winkler DG, Sutherland MK, Geoghegan JC, Yu C, Hayes T, Skonier JE, et al. Osteocyte control of bone formation via sclerostin, a novel BMP antagonist. EMBO J 2003;22: 6267–76. [4] Clarke BL, Drake MT. Clinical utility of serum sclerostin measurements. Bonekey Rep 2013;2:361. [5] Brandenburg VM, Kramann R, Koos R, Kruger T, Schurgers L, Muhlenbruch G, et al. Relationship between sclerostin and cardiovascular calcification in hemodialysis patients: a cross-sectional study. BMC Nephrol 2013;14:219. [6] Koos R, Brandenburg V, Mahnken AH, Schneider R, Dohmen G, Autschbach R, et al. Sclerostin as a potential novel biomarker for aortic valve calcification: an in-vivo and ex-vivo study. J Heart Valve Dis 2013;22:317–25.

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