Role of Wnt/β-catenin and RANKL/OPG in bone healing of diabetic Charcot arthropathy patients

Figures & data

Table 1. Clinical and demographic data in Charcot patients, diabetes controls, and healthy subjects

	Charcot arthropathy at inclusion (n = 24)	Charcot arthropathy at end of study (n = 23)	Diabetic controls at inclusion (n = 20)	Diabetic controls at 2 years (n = 20)	Healthy subjects (n = 20)
Age, median (range), years	61 (42–87)	63 (42–87)	55 (20–94)	57 (20–94)	58 (24–78)
Gender, female/male, n	10/14	10/14	8/12	8/12	9/11
Diabetes type-1/type-2, n	10/14	10/14	6/14	6/14	-
Duration of diabetes, years	26 (4)	-	14 (6)	-	-
Debut foot symptoms, median (range), weeks	8.8 (1–24)	-	-	-	-
Systolic blood pressure, mmHg	151 (6)	150 (6)	127 (4)	-	138 (4)
Diastolic blood pressure, mmHg	80 (3)	78 (2)	76 (2)	-	81 (3)
Arterial toe pressure, mmHg
Charcot foot	118 (12)	123 (8)	115 (4)	-	-
Contralateral foot	131 (8)	119 (7)	114 (5)	-	-
Skin temperature, °C
Charcot foot	31.5 (0.7)^a	29.6 (0.7)	30.0 (0.4)	-	-
Contralateral foot	29.3 (0.8)	29.1 (0.7)	30.2 (0.4)	-	-
Pain at rest, n	4	0	0	-	-
Pain on bearing weight, n	16	0	0	-	-
Foot distortion, n	3	3	0	-	0
Total contact cast, months	-	7.6 (1.0)	-	-	-
Charcot pattern 1/2/3/4/5, n	2/15/4/0/3	-	-	-	-
Nephropathy/ cardiac disease, n	7/4	7/4	2/1	2/1	0/0
Hb, g/L	127 (3)	128 (3)	136 (2)	139 (3)	143 (5)
S-CRP, mg/L	11.2 (3)^b,c	9.9 (2)^d,e	3.6 (0.8)	3.8 (0.8)	2.7 (0.7)
SR, mm	31.0 (6)^f,g	24 (4)	11 (2)	10 (2)	6 (4)
S-creatinine, µmol/L	116 (19)	99 (12)	83 (8)	89 (7)	78 (5)
HbA1c, mmol/mol	59 (4)	67 (3)	58 (3)	56 (2)	-
HbA1c, %	7.5 (0.4)	8.3 (0.3)	7.5 (0.2)	7.3 (0.2)	-

Table data are mean (SEM) when not expressed differently.

^a p = 0.04 for Charcot foot vs. contralateral foot at inclusion.

^b p = 0.04 for Charcot foot patients at inclusion vs. diabetes controls at inclusion.

^c p = 0.01 for Charcot foot patients at inclusion vs. healthy subjects.

^d p = 0.04 for Charcot foot patients at end of study vs. diabetes controls at 2 years.

^e p = 0.03 for Charcot foot patients at end of study vs. healthy subjects.

^f p = 0.003 for Charcot foot patients at inclusion vs. diabetes controls at inclusion.

^g p < 0.001 for Charcot foot patients at inclusion vs. healthy subjects. All other differences were not significant.

Charcot pattern 1–5 on radiographs (see Papanas and Maltezos 2013).

Figure 1. A and B. Box plots of plasma osteoprotegerin values (OPG, ng/mL) in Charcot patients (n = 24), diabetic controls (n = 20), and healthy subjects (n = 20) at inclusion (A) and at termination of the study after 2 years (B). Inter-group comparison performed by 1-way repeated measures ANOVA and post-hoc Holm-Šidak test.

Figure 2. A and B. Box plots of plasma receptor activator of nuclear factor-κB ligand (RANKL, ng/mL) in Charcot patients (n = 24), diabetic controls (n = 20), and healthy subjects (n = 20) at inclusion (A) and at termination of the study after 2 years (B).

Figure 3. A and B.Box plots of plasma OPG-RANKL ratio in Charcot patients (n = 24), diabetic controls (n = 20), and healthy subjects (n = 20) at inclusion (A) and at termination of the study after 2 years (B).

Figure 5. A and B. Box plots of plasma sclerostin (ng/mL) in Charcot patients (n = 24), diabetic controls (n = 20), and healthy subjects (n = 20) at inclusion (A) and at termination of the study after 2 years (B).

Figure 6. A and B. Box plots of plasma Dickkopf-1 (Dkk-1, pg/mL) in Charcot patients (n = 24), diabetic controls (n = 20), and healthy subjects (n = 20) at inclusion (A) and at termination of the study after 2 years (B). C. Trajectory of plasma Dkk-1 in Charcot patients throughout the observation period of 2 years, based on repeated sampling over time and relative to diabetic controls and healthy subjects. Mean (SEM). ^a p = 0.009 for Charcot patients at 4 months vs. Charcot patients at inclusion; ^b p = 0.01 for Charcot patients at 2 years vs. Charcot patients at inclusion, as analyzed by Mann-Whitney rank sum test.

Figure 7. A and B. Box plots of plasma Wnt ligand-1 (Wnt-1, pg/mL) in Charcot patients (n = 24), diabetic controls (n = 20), and healthy subjects (n = 20) at inclusion (A) and at termination of the study after 2 years (B). C. Trajectory of plasma Wnt-1 in Charcot patients throughout the observation period of 2 years, based on repeated sampling over time and relative to diabetic controls and healthy subjects. Mean (SEM). ^a p = 0.003 for Charcot patients at 4 months vs. Charcot patients at inclusion; ^b p = 0.2 for Charcot patients at 2 years vs. Charcot patients at inclusion, as analyzed by Mann-Whitney rank sum test.

Figure 8. A and B. Box plots of plasma Wnt inhibitory factor-1 (Wif-1, pg/mL) in Charcot patients (n = 24), diabetic controls (n = 20), and healthy subjects (n = 20) at inclusion (A) and at termination of the study after 2 years (B).

Table 2. Staging of radiographic changes in the Charcot arthropathy foot as described by Sella and Barrette (1999) based on weight-bearing radiographic examinations of the diseased foot; also, inflammation/bone edema on MRI based on activity (see Chantelau and Grutzner 2014) . Numbers in the table are numbers of patients.

	At inclusion	1 week	6 months	12 months	18 months	24 months
Radiography
Stage 0	4	3	0	0	0	0
Stage 1	3	3	2	0	0	0
Stage 2	9	9	9	6	4	0
Stage 3	8	8	8	5	5	0
Stage 4	0	1	5	13	15	23
MRI
Inactive	7	9	12	15	18	23
Activite	17	15	12	9	6	0

Papanas N, Maltezos E. Etiology, pathophysiology and classifications of the diabetic Charcot foot. Diabet Foot Ankle 2013; 4.

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Sella EJ, Barrette C. Staging of Charcot neuroarthropathy along the medial column of the foot in the diabetic patient. J Foot Ankle Surg 1999; 38 (1): 34–40.

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