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Prognostic Value of Bone Formation and Resorption Proteins in Heterotopic Ossification in Critically-Ill Patients. A Single-Centre Study

Alice Georgia Vassiliou

Alice Georgia Vassiliou

First Department of Critical Care Medicine and Pulmonary Services, School of Medicine, National and Kapodistrian University of Athens, Evangelismos HospitalAthens, Greece
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Vassiliou, Alice Georgia
, 
Edison Jahaj

Edison Jahaj

First Department of Critical Care Medicine and Pulmonary Services, School of Medicine, National and Kapodistrian University of Athens, Evangelismos HospitalAthens, Greece
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Jahaj, Edison
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Zafeiria Mastora

Zafeiria Mastora

First Department of Critical Care Medicine and Pulmonary Services, School of Medicine, National and Kapodistrian University of Athens, Evangelismos HospitalAthens, Greece
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Mastora, Zafeiria
, 
Ioannis Karnezis

Ioannis Karnezis

Department of Orthopedics, Evangelismos HospitalAthens, Greece
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Karnezis, Ioannis
, 
Ioanna Dimopoulou

Ioanna Dimopoulou

First Department of Critical Care Medicine and Pulmonary Services, School of Medicine, National and Kapodistrian University of Athens, Evangelismos HospitalAthens, Greece
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Dimopoulou, Ioanna
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Stylianos E. Orfanos

Stylianos E. Orfanos

First Department of Critical Care Medicine and Pulmonary Services, School of Medicine, National and Kapodistrian University of Athens, Evangelismos HospitalAthens, Greece
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Orfanos, Stylianos E.
 and 
Anastasia Kotanidou

Anastasia Kotanidou

First Department of Critical Care Medicine and Pulmonary Services, School of Medicine, National and Kapodistrian University of Athens, Evangelismos HospitalAthens, Greece
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Kotanidou, Anastasia
  
Jan 29, 2021
Prognostic Value of Bone Formation and Resorption Proteins in Heterotopic Ossification in Critically-Ill Patients. A Single-Centre Study's Cover Image
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Article Category: Research Article
Published Online: Jan 29, 2021
Page range: 37 - 45
Received: Aug 26, 2020
Accepted: Nov 26, 2020
DOI: https://doi.org/10.2478/jccm-2020-0046
Keywords
© 2021 Alice Georgia Vassiliou, Edison Jahaj, Zafeiria Mastora, Ioannis Karnezis, Ioanna Dimopoulou, Stylianos E. Orfanos, Anastasia Kotanidou, published by Sciendo
This work is licensed under the Creative Commons Attribution 4.0 International License.

Fig. 1

Study enrolment flow chart
Study enrolment flow chart

Fig. 2

BMP-2, RANKL and Osteoprotegerin levels on admission. a) BMP-2, b) RANKL, c) Osteoprotegerin and d) RANKL: Osteoprotegerin ratio were measured in 28 critically ill, initially non-septic patients on ICU admission. Patients were subsequently categorised as heterotopic ossification-positive (those who subsequently developed heterotopic ossification, yes, N= 9) and heterotopic ossification -negative (those who did not develop heterotopic ossification, no, N= 19). Two-group comparisons were performed with the non-parametric Mann-Whitney test, * p< 0.05. Data are presented as box plots. Line in the box, median value; box edges, 25th to 75th centiles; whiskers, range of values; bullet points, outliers. BMP-2= bone-morphogenetic protein 2, RANKL= receptor activator of nuclear factor kappa-Β ligand, OPG= osteoprotegerin.
BMP-2, RANKL and Osteoprotegerin levels on admission. a) BMP-2, b) RANKL, c) Osteoprotegerin and d) RANKL: Osteoprotegerin ratio were measured in 28 critically ill, initially non-septic patients on ICU admission. Patients were subsequently categorised as heterotopic ossification-positive (those who subsequently developed heterotopic ossification, yes, N= 9) and heterotopic ossification -negative (those who did not develop heterotopic ossification, no, N= 19). Two-group comparisons were performed with the non-parametric Mann-Whitney test, * p< 0.05. Data are presented as box plots. Line in the box, median value; box edges, 25th to 75th centiles; whiskers, range of values; bullet points, outliers. BMP-2= bone-morphogenetic protein 2, RANKL= receptor activator of nuclear factor kappa-Β ligand, OPG= osteoprotegerin.

Fig.3

Time course of BMP-2, RANKL and OPG levels during ICU stay and the follow-up period in the patients who developed heterotopic ossification. a) BMP-2, b) RANKL, c) OPG and d) RANKL: OPG ratio were measured in 9 patients who developed heterotopic ossification on ICU admission (0), and thereafter seven days post-admission (7) and 30 days following ICU discharge (30). Data are presented with box plots. Line in the box, median value; box edges, 25th to 75th centiles; whiskers, range of values. Comparisons were performed using one-way ANOVA followed by Dunn’s multiple comparisons. BMP-2= bone-morphogenetic protein 2, RANKL= receptor activator of nuclear factor kappa-Β ligand, OPG= osteoprotegerin.
Time course of BMP-2, RANKL and OPG levels during ICU stay and the follow-up period in the patients who developed heterotopic ossification. a) BMP-2, b) RANKL, c) OPG and d) RANKL: OPG ratio were measured in 9 patients who developed heterotopic ossification on ICU admission (0), and thereafter seven days post-admission (7) and 30 days following ICU discharge (30). Data are presented with box plots. Line in the box, median value; box edges, 25th to 75th centiles; whiskers, range of values. Comparisons were performed using one-way ANOVA followed by Dunn’s multiple comparisons. BMP-2= bone-morphogenetic protein 2, RANKL= receptor activator of nuclear factor kappa-Β ligand, OPG= osteoprotegerin.

Fig. 4

Time course of BMP-2, RANKL and OPG levels during ICU stay and the follow-up period in the patients who did not develop heterotopic ossification. a) BMP-2, b) RANKL, c) OPG and d) RANKL: OPG ratio were measured in 19 patients who did not develop heterotopic ossification on ICU admission (0), and thereafter seven days post-admission (7) and 30 days following ICU discharge (30). Data are presented with box plots. Line in the box, median value; box edges, 25th to 75th centiles; whiskers, range of values; bullet points, outliers. Comparisons were performed using one-way ANOVA followed by Dunn’s multiple comparisons. BMP-2= bone-morphogenetic protein 2, RANKL= receptor activator of nuclear factor kappa-Β ligand, OPG= osteoprotegerin.
Time course of BMP-2, RANKL and OPG levels during ICU stay and the follow-up period in the patients who did not develop heterotopic ossification. a) BMP-2, b) RANKL, c) OPG and d) RANKL: OPG ratio were measured in 19 patients who did not develop heterotopic ossification on ICU admission (0), and thereafter seven days post-admission (7) and 30 days following ICU discharge (30). Data are presented with box plots. Line in the box, median value; box edges, 25th to 75th centiles; whiskers, range of values; bullet points, outliers. Comparisons were performed using one-way ANOVA followed by Dunn’s multiple comparisons. BMP-2= bone-morphogenetic protein 2, RANKL= receptor activator of nuclear factor kappa-Β ligand, OPG= osteoprotegerin.

Fig. 5

Receiver operating characteristic (ROC) curve analysis. ROC curves were generated to determine the prognostic accuracy of a) BMP-2 and b) RANKL; the corresponding areas under the curve (AUC) and 95% confidence intervals (CI) were estimated as follows: BMP-2 at 0.823 (0.623-1.023, p= 0.038); RANKL at 0.767 (0.557-0.977, p= 0.048). The levels of both molecules were estimated on ICU admission. BMP-2= bone-morphogenetic protein 2, RANKL= receptor activator of nuclear factor kappa-Β ligand.
Receiver operating characteristic (ROC) curve analysis. ROC curves were generated to determine the prognostic accuracy of a) BMP-2 and b) RANKL; the corresponding areas under the curve (AUC) and 95% confidence intervals (CI) were estimated as follows: BMP-2 at 0.823 (0.623-1.023, p= 0.038); RANKL at 0.767 (0.557-0.977, p= 0.048). The levels of both molecules were estimated on ICU admission. BMP-2= bone-morphogenetic protein 2, RANKL= receptor activator of nuclear factor kappa-Β ligand.

Demographics on ICU admission and important outcomes of the patients who developed heterotopic ossification (HO) (HO-positive) versus those who did not (HO-negative)_

Demographics/Outcomes HO-positive patients HO-negative patients p-value
Number of patients (N) 9 19
Age 51(19) 51(14) ns
Sex ns
         Male 14
         Female 5
APACHE II, mean (SD) 16(6) 17(5) ns
SOFA, mean (SD) 7(1) 7(2) ns
CRP (mg/dl), (median, IQR) 5.1 (1.6-12.0) 5.5 (1.1-8.8) ns
PCT (ng/ml), (median, IQR) 1.1 (0.2-2.5) 0.1 (0.1-0.8) ns
Creatinine (mg/dl), mean (SD) 0.7(0.2) 0.9(0.3) ns
Vitamin D (ng/ml), (median, IQR) 6.8 (4.2-13.6) 12.7 (6.5-16.8) ns
Diagnosis ns
         Medical 0% 15.8%
         Surgery/Trauma 100% 84.2%
Medical 0 3
         Cerebral abscess - 1
         Subarachnoid haemorrhage - 1
         Cerebral haemorrhage - 1
Surgical Emergency 5 8
         Thoracic 0 0
         Neurosurgery 5 8
         Abdominal 0 0
Trauma 4 8
Comorbidities 3 7 ns
         CAD
         Arterial Hypertension
         Hypothyroidism
Mechanical ventilation (days) 20 (17-25) 22 (16-30) ns
ICU Length of Stay (days) 29 (21-35) 30 (22-40) ns
Sepsis 66.7% 84.2% ns
Day of sepsis 10 (7-12) 8 (5-10) ns
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