Changes in Angiogenesis and Bone Turnover Markers in Patients with Gaucher Disease Developing Osteonecrosis
Abstract
1. Introduction
2. Materials and Methods
2.1. Patients
2.2. Blood Sampling and Serum Storage
2.3. Biochemistry
2.4. Biomarker Assays
2.5. Bone Disease Assessment
2.6. Gaucher Disease Severity Scoring System
2.7. Statistical Analysis
3. Results
3.1. Characteristics of the Subjects
3.2. Circulating Markers of Angiogenesis and Bone Turnover Markers in Gaucher Disease Patients Stratified by Osteonecrosis Status
3.3. Sensitivity and Specificity of Angiogenesis and Bone Biomarkers for Detecting Osteonecrosis
4. Discussion
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Variable | Osteonecrosis—Free | Osteonecrosis—Historical | Osteonecrosis—Incident | p-Value |
---|---|---|---|---|
N | 73 (36M:37F) | 62 (28M:34F) | 11 (6M:5F) | |
Age, years, median (IQR) | 47 (34.4–60.3) | 47.7 (35.8–60.9) | 49.5 (39.2–66.8) | 0.446 |
GENOTYPE, N % | ||||
Homozygous N370S/N370S | 18 (25%) | 4 (6.5%) | 1 (9%) | 0.036 + |
Homozygous L444P/L444P | 3 (4%) | 6 (10%) | - | |
Homozygous other/other a | 1 (1%) | - | - | |
Heterozygous N370S/L444P | 14 (19%) | 11 (18%) | 2 (18%) | |
Heterozygous N370S/other a | 29 (39.7%) | 32 (52%) | 4 (36.5%) | |
Heterozygous L444P/other a | 1 (1%) | 4 (6.5%) | - | |
Heterozygous other/other a | 7 (10%) | 5 (8%) | 4 (36.5%) | |
TYPE OF GAUCHER DISEASE, N % | ||||
Type 1 | 68 (93%) | 55 (89%) | 10 (91%) | 0.665 + |
Type 3 | 5 (7%) | 7 (11%) | 1 (9%) | |
Age at Gaucher disease presentation, years, median (IQR) | 26.5 (13.8–37.8) | 8.2 (4.2–20.3) | 6.5 (4.4–25.3) | <0.001 1, 2 ≠ 0 ‡ |
OSTEONECROSIS, N % | ||||
Symptomatic osteonecrosis events | - | 36 | 9 | 0.001 + |
Asymptomatic osteonecrosis events | - | 30 | 11 | |
Age at first osteonecrosis, years, median (IQR) | - | 25.07 (11.88–37.43) | 21.95 (12.6–37.8) | 0.845 # |
FRACTURE, N % | ||||
No | 69 (94.5%) | 46 (74%) | 7 (64%) | 0.001 + |
Yes | 4 (5.5%) | 16 (26%) | 4 (36%) | |
Age at first fracture, years, median (IQR) | 57.65 (16.85–61.59) | 45.39 (25.15–52.95) | 23.9 (13.7–34.8) | 0.176 |
OSTEOARTHRITIS, N % | ||||
No | 42 (58%) | 27 (43.5%) | 1 (9%) | 0.007 + |
Yes | 31 (42%) | 35 (56.5%) | 10 (91%) | |
Age at osteoarthritis diagnosis, years, median (IQR) | 43 (34.3–53.7) | 41.8 (33.7–52.4) | 40.4 (32.9–53.9) | 0.885 |
ORTHOPEDIC PROCEDURE, N % | ||||
No | 66 (90%) | 34 (55%) | 4 (36%) | <0.001 + |
Yes | 7 (10%) | 28 (45%) | 7 (64%) | |
Age at first orthopaedic procedure, years, median (IQR) | 46.1 (13–55.2) | 33.3 (14.83–47.65) | 46.9 (19.1–54.3) | 0.281 |
Variable | Osteonecrosis—Free | Osteonecrosis—Historical | Osteonecrosis—Incident | p-Value |
ERLENMEYER FLASK DEFORMITY (EFD), N % | ||||
No | 49 (67%) | 22 (35.5%) | 4 (36%) | 0.001 + |
Yes | 24 (33%) | 40 (64.5%) | 7 (64%) | |
Age at EFD diagnosis, years, median (IQR) | 37.2 (25.5–48) | 36.02 (22.8–49.35) | 45.5 (34.3–49.4) | 0.567 |
LYTIC LESION, N % | ||||
No | 71 (97%) | 58 (94%) | 10 (91%) | 0.474 + |
Yes | 2 (3%) | 4 (6%) | 1 (9%) | |
Age at first lytic lesion, years, median (IQR) | 48.0 (27.3–68.8) | 30.6 (9.0–42.4) | 47.2 (47.2–47.2) | 0.343 |
GAUCHER DISEASE TYPE 1 SEVERITY SCORING SYSTEM (GD-DS3) | ||||
Bone domain, median (IQR) | 2 (0.3–3) | 4 (3–5) | 4.5 (3–6.3) | <0.001 1, 2 ≠ 0 |
Haematologic domain, median (IQR) | 0 (0–0.75) | 0 (0–0) | 0 (0–1) | 0.435 |
Visceral domain, median (IQR) | 0 (0–1) | 0 (0–2) | 1 (0–3.3) | 0.057 |
Total Gaucher DS3 score, median (IQR) | 2 (1–4) | 4 (3–6) | 6 (4–9) | <0.001 1, 2 ≠ 0 ‡ |
BONE MARROW TRANSPLANT, N % | ||||
No | 73 (100%) | 60 (97%) | 11 (100%) | 0.253 + |
Yes | - | 2 (3%) | - | |
Age at bone marrow transplant, years, median (IQR) | - | 6.3 (1.7–10.8) | - | - |
SPLENECTOMY, N % | ||||
No | 66 (90%) | 37 (60%) | 6 (55%) | <0.001 + |
Yes | 7 (10%) | 25 (40%) | 5 (45%) | |
Age at splenectomy, years, median (IQR) | 27 (24.09–54.05) | 11.72 (5.02–20.76) | 15.4 (7.2–21.7) | 0.011 1 ≠ 0 ‡ |
GAUCHER SPECIFIC TREATMENT, N % | ||||
No | 7 (10%) | 2 (3%) | - | 0.209 + |
Yes | 66 (90%) | 60 (97%) | 11 (100%) | |
Age at Gaucher specific treatment initiation, years, median (IQR) | 34.5 (25.4–45.01) | 29.25 (20.15–42.4) | 35.4 (20.4–45.9) | 0.555 |
Time from Gaucher disease presentation and treatment initiation, years, median (IQR) | 3 (0.9–10.3) | 15.4 (4.4–24.3) | 16.9 (1–30.4) | <0.001 1, 2 ≠ 0 ‡ |
BONE TREATMENT, N % | ||||
No | 28 (38%) | 20 (32%) | 3 (27%) | 0.652 + |
Yes | 45 (62%) | 42 (68%) | 8 (73%) | |
Variable | Osteonecrosis— Free | Osteonecrosis—Historical | Osteonecrosis—Incident | p-Value |
STEROID TREATMENT, N % | ||||
No | 59 (81%) | 52 (84%) | 11 (100%) | 0.277 + |
Yes | 14 (19%) | 10 (16%) | - |
Variable | Osteonecrosis—Free | Osteonecrosis—Historical | Osteonecrosis—Incident | p-Value |
---|---|---|---|---|
Haemoglobin, g/L, median (IQR) | 139 (129–146.5) | 136 (131–150) | 137 (128–152) | 0.873 |
White cell count, ×109/L, median (IQR) | 5.7 (4.7–7.5) | 6.4 (5.0–8.4) | 6.6 (3.7–9) | 0.319 |
Platelets, ×109/L, median (IQR) | 178 (145–219) | 194 (160–252) | 237 (152–325) | 0.043 2 ≠ 0 ‡ |
Alkaline phosphatase, U/L, median (IQR) | 67.5 (55.8–84) | 67 (56–83) | 73 (55.5–95.3) | 0.864 |
Calcium, mmol/L, median (IQR) | 2.3 (2.3–2.4) | 2.4 (2.3–2.4) | 2.3 (2.3–2.4) | 0.229 |
Corrected calcium, mmol/L, median (IQR) | 2.4 (2.3–2.5) | 2.4 (2.3–2.5) | 2.4 (2.4–2.4) | 0.300 |
Vitamin D, ug/L, median (IQR) | 61.1 (43–84.5) | 58.3 (39.8–82.0) | 56.8 (40.1–67.7) | 0.749 |
Vitamin B12, ng/L, median (IQR) | 405 (310–556) | 399 (317.5–507) | 425 (356–538) | 0.861 |
Ferritin, ug/L, median (IQR) | 153 (76.3–535.3) | 190 (119.2–371.1) | 73.8 (27.8–460.5) | 0.332 |
ACE, U/L, median (IQR) | 40 (25–58) | 51 (38–80) | 66 (35–87) | 0.040 2 ≠ 0 ‡ |
Chitotriosidase, umol/L/h, median (IQR) | 303 (125.5–878) | 519 (254.5–1301.5) | 479.5 (199.5–2138.3) | 0.128 |
PARC/CCL18, ng/mL, median (IQR) | 149.5 (104.3–251.5) | 209 (117.3–378.8) | 224 (171–391.8) | 0.055 |
Fibrinogen, g/L, median (IQR) | 2.67 (2.02–3.17) | 2.59 (2.16–2.83) | 2.92 (2.66–3.1) | 0.141 |
Variable | Osteonecrosis—Free | Osteonecrosis—Historical | Osteonecrosis—Incident | p-Value |
---|---|---|---|---|
Osteonectin, pg/mL, median (IQR) | 769,231 (508,562.5–971,934) | 785,403.5 (585,508–1,003,565) | 322,027 (124,400.5–857,722.5) | 0.306 |
Osteopontin, pg/mL, median (IQR) | 14,462 (10,057–22,202.5) | 18,474 (11,951.25–23,575.25) | 24,113 (13,754–34,091) | 0.010 1, 2 ≠ 0 ‡ |
Osteocalcin, pg/mL, median (IQR) | 28,629 (19,786–34,474.5) | 26,751 (19,038–35,658.5) | 28,341 (17,304–45,209) | 0.576 |
MMP-1, pg/mL, median (IQR) | 4945 (1699–11,427) | 5378.5 (2889.75–8872) | 3058 (980–6332) | 0.253 |
MMP-2, pg/mL, median (IQR) | 10,7193 (95,016.5–122,201) | 116,699.5 (102,860.8–129,362.3) | 119,970 (113,784–127,694) | 0.017 1, 2 ≠ 0 ‡ |
MMP-3, pg/mL, median (IQR) | 12,663 (7838.5–18,749.5) | 12,721.5 (9052.5–17,771.25) | 12,314 (10,295–18,204) | 0.627 |
MMP-9, pg/mL, median (IQR) | 121,223 (68,135.5–195,583.5) | 126,312 (58,997–165,988.3) | 38,711 (24,822–72,420) | 0.001 2 ≠ 1,0 ‡ |
MMP-10, pg/mL, median (IQR) | 1113 (745.5–1408) | 1095 (892.75–1425.25) | 919 (571–974) | 0.058 |
TIMP-1, pg/mL, median (IQR) | 299,558 (215,000.5–34,8074) | 306,410.5 (190,432.5–360,033.5) | 190,183 (161,362–285,583) | 0.147 |
Osteoprotegerin, pg/mL, median (IQR) | 297 (229–381) | 314 (251.75–407) | 284 (239–406) | 0.589 |
FGF, pg/mL, median (IQR) | 3 (1.85–5.1) | 3.8 (2.4–6.125) | 3 (2–3.7) | 0.156 |
FLT-1, pg/mL, median (IQR) | 92.7 (70.75–113.55) | 92.65 (72.1–116.8) | 83.6 (67.1–127.8) | 0.834 |
PLGF, pg/mL, median (IQR) | 6.8 (5.5–8.2) | 6.1 (4.875–7.5) | 5.8 (5.1–7.3) | 0.098 |
TIE-2, pg/mL, median (IQR) | 5162 (4314.5–5693.5) | 4786.5 (3964.75–5752.25) | 4820 (4348–5088) | 0.634 |
VEGF-A, pg/mL, median (IQR) | 185.7 (84.55–298.25) | 182.35 (69.225–504.68) | 73.1 (37–127) | 0.056 |
VEGF-C, pg/mL, median (IQR) | 342.4 (64.6–505.4) | 304.3 (81.05–471.4) | 80.9 (49.1–136.9) | 0.036 2 ≠ 1, 0 ‡ |
VEGF-D, pg/mL, median (IQR) | 1246 (1001.5–1880.5) | 1260 (966–1735) | 854 (696–1318) | 0.072 |
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D’Amore, S.; Poole, K.E.; Ramaswami, U.; Hughes, D.; Page, K.; Solimando, A.G.; Vacca, A.; Cox, T.M.; Deegan, P., on behalf of the MRC GAUCHERITE Consortium. Changes in Angiogenesis and Bone Turnover Markers in Patients with Gaucher Disease Developing Osteonecrosis. Metabolites 2024, 14, 601. https://doi.org/10.3390/metabo14110601
D’Amore S, Poole KE, Ramaswami U, Hughes D, Page K, Solimando AG, Vacca A, Cox TM, Deegan P on behalf of the MRC GAUCHERITE Consortium. Changes in Angiogenesis and Bone Turnover Markers in Patients with Gaucher Disease Developing Osteonecrosis. Metabolites. 2024; 14(11):601. https://doi.org/10.3390/metabo14110601
Chicago/Turabian StyleD’Amore, Simona, Kenneth Eric Poole, Uma Ramaswami, Derralynn Hughes, Kathleen Page, Antonio Giovanni Solimando, Angelo Vacca, Timothy Martin Cox, and Patrick Deegan on behalf of the MRC GAUCHERITE Consortium. 2024. "Changes in Angiogenesis and Bone Turnover Markers in Patients with Gaucher Disease Developing Osteonecrosis" Metabolites 14, no. 11: 601. https://doi.org/10.3390/metabo14110601
APA StyleD’Amore, S., Poole, K. E., Ramaswami, U., Hughes, D., Page, K., Solimando, A. G., Vacca, A., Cox, T. M., & Deegan, P., on behalf of the MRC GAUCHERITE Consortium. (2024). Changes in Angiogenesis and Bone Turnover Markers in Patients with Gaucher Disease Developing Osteonecrosis. Metabolites, 14(11), 601. https://doi.org/10.3390/metabo14110601