Sistemik Olarak Uygulanan Denosumab'ın Kemik Defektlerinin Onarımındaki Etkinliğinin Değerlendirilmesi
Öz
Bu çalışmada denosumab'ın tek başına ve farklı greft materyalleri ile kombinasyon halinde yeni kemik oluşumu üzerindeki etkisi araştırıldı. 20 Yeni Zelanda tavşanının kafatasında dört defekt oluşturuldu. Bir defekt boş bırakılırken diğerlerine otogreft, xenogreft ve kalsiyum fosfat (BKF) greftleri uygulandı. Tavşanlar deney(n=10) ve kontrol(n=10) gruplarına ayrıldı. Deney grup, iki ay boyunca ayda bir kez 10 mg/kg denosumab aldı; kontrol grubuna ise aynı dozda fizyolojik serum verildi. Sekiz hafta sonunda sakrifiye edilen hayvanların kemik dokuları histomorfometrik analiz için incelendi. Kemik hacmi yüzdesi(PBV), olgun kemik dokusu alanının toplam doku alanına bölünmesiyle hesaplanmıştır. Denosumab ile tedavi edilen boş defektlerde kemik hacmi yüzdesi(PBV), kontrol grubuna kıyasla anlamlı derecede yüksek bulundu (p=0.037; p<0.05). Ayrıca, denosumab ve otogreft kombinasyonu yeni kemik formasyonunu(YKF) anlamlı şekilde artırdı(p<0.05). Denosumab’ın kemik oluşumunu destekleyici etkisi tespit edilmiştir. Ancak klinik kullanım öncesi, dozaj ve tedavi süresine dair daha fazla çalışma gerekmektedir.
Anahtar Kelimeler
Bifazik kalsiyum fosfat Denosumab Kalvaryal defekt Ksenogreft Otogreft.
Etik Beyan
This study was approved by the Inonu University Medical Faculty Experimental Animals Ethics Committee with the decision dated 20-06-2013 and numbered 2013/A-52.
Destekleyen Kurum
It was supported by the Scientific Research Projects Unit of İnönü University under project number 2013/184.
Proje Numarası
2013/184
Teşekkür
We would like to thank Scientific Research Projects Unit of İnönü University for their support and contributions.
Kaynakça
- Ahern, E., Smyth, M. J., Dougall, W. C. & Teng, M. W. L. (2018). Roles of the RANKL–RANK axis in antitumour immunity—implications for therapy. Nature Reviews Clinical Oncology, 15(11), 676–693.
- Antunes, A. A., Oliveira Neto, P., de Santis, E., Caneva, M., Botticelli, D. & Salata, L. A. (2013). Comparisons between Bio-Oss® and Straumann® Bone Ceramic in immediate and staged implant placement in dogs mandible bone defects. Clinical Oral Implants Research, 24(2), 135–142.
- Artzi, Z., Weinreb, M., Givol, N., Rohrer, M. D., Nemcovsky, C. E., Prasad, H. S. & Tal, H. (2004). Biomaterial resorption rate and healing site morphology of inorganic bovine bone and beta-tricalcium phosphate in the canine: a 24-month longitudinal histologic study and morphometric analysis. The International Journal of Oral & Maxillofacial Implants, 19(3), 357–368.
- Banwart, J. C., Asher, M. A. & Hassanein, R. S. (1995). Iliac crest bone graft harvest donor site morbidity: A statistical evaluation. In Spine (Vol. 20, Issue 9, pp. 1055–1066).
- Becker, W., Becker, B. E. & Caffesse, R. (1994). A Comparison of Demineralized Freeze‐Dried Bone and Autologous Bone to Induce Bone Formation in Human Extraction Sockets. Journal of Periodontology, 65(12), 1128–1133.
- Bone, H. G., Bolognese, M. A., Yuen, C. K., Kendler, D. L., Wang, H., Liu, Y. & San Martin, J. (2008). Effects of denosumab on bone mineral density and bone turnover in postmenopausal women. Journal of Clinical Endocrinology and Metabolism, 93(6), 2149–2157.
- Briot, K., Paccou, J., Beuzeboc, P., Bonneterre, J., Bouvard, B., Confavreux, C. B., … Debiais, F. (2019). French recommendations for osteoporosis prevention and treatment in patients with prostate cancer treated by androgen deprivation. Joint Bone Spine, 86(1), 21–28.
- Cordaro, L., Bosshardt, D. D., Palattella, P., Rao, W., Serino, G. & Chiapasco, M. (2008). Maxillary sinus grafting with Bio-Oss® or Straumann® Bone Ceramic: Histomorphometric results from a randomized controlled multicenter clinical trial. Clinical Oral Implants Research, 19(8), 796–803.
- Cummings, S. R., Martin, J. S., McClung, M. R., Siris, E. S., Eastell, R., Reid, I. R., … Christiansen, C. (2009). Denosumab for prevention of fractures in postmenopausal women with osteoporosis. Obstetrical and Gynecological Survey, 64(12), 805–807.
- Deeks, E. D. (2018). Denosumab: A Review in Postmenopausal Osteoporosis. Drugs and Aging, 35(2), 163–173.
- Erbe, E., Marx, J., Clineff, T. & Bellincampi, L. (2001). Potential of an ultraporous β-tricalcium phosphate synthetic cancellous bone void filler and bone marrow aspirate composite graft. European Spine Journal, 10(SUPPL. 2), 141–146.
- Friedlaender, G. E., Strong, D. M. & Sell, K. W. Studies on the antigenicity of bone. I. Freeze-dried and deep frozenbone allografts in rabbits. J Bone Joint Surg Am. 1976;58(6):854-858.
- Gerstenfeld, L. C., Sacks, D. J., Pelis, M., Mason, Z. D., Graves, D. T., Barrero, M., … Einhorn, T. A. (2009). Comparison of effects of the bisphosphonate alendronate versus the RANKL inhibitor denosumab on murine fracture healing. Journal of Bone and Mineral Research, 24(2), 196–208.
- Giannoudis, P. V., Dinopoulos, H. & Tsiridis, E. (2005). Bone substitutes: an update. Injury, 36 Suppl 3, 20–27.
- Goldhahn, J., Féron, J. M., Kanis, J., Papapoulos, S., Reginster, J. Y., Rizzoli, R., … Boonen, S. (2012). Implications for fracture healing of current and new osteoporosis treatments: An ESCEO consensus paper. Calcified Tissue International, 90(5), 343–353.
- Gül, M., Bayat, N., Gül, S., Hüz, M., Yıldız, A. & Otlu, A. (2014). A Comparison of Three Different Agents of Decalcification for a Histological Examination of Bone Tissues. J Turgut Ozal Med Cent, 21(4), 274-9.
- Hokugo, A., Sawada, Y., Hokugo, R., Iwamura, H., Kobuchi, M., Kambara, T., … Tabata, Y. (2007). Controlled release of platelet growth factors enhances bone regeneration at rabbit calvaria. Oral Surgery Oral Medicine, Oral Pathology, Oral Radiology, and Endodontology, 104(1), 44–48.
- Hollinger, G. C. B. (1986). Biodegradable bone repair materials. Synthetic polymers and ceramics. Clinical Orthopaedics and Related Researc, 207, 290–305.
- Iwamoto, N., Okamoto, M., Tsuji, S., Endo, Y., Takatani, A., Shimizu, T., … Kawakami, A. (2019). Denosumab is effective toward glucocorticoid-induced osteoporosis patients complicated with rheumatic diseases regardless of prior anti-osteoporotic drugs. Journal of Bone and Mineral Metabolism, 37(3), 554–562.
- Jamshidi, K., Gharehdaghi, M., Hajialiloo, S. S., Mirkazemi, M., Ghaffarzadehgan, K. & Izanloo, A. (2018). Denosumab in patients with giant cell tumor and its recurrence: A systematic review. Archives of Bone and Joint Surgery, 6(4), 260–268.
- Kahnberg, K. E. (2008). Bone grafting techniques for maxillary implants. John Wiley & Sons.
- Kent, J. N. & Davenport, W. (1987). Block MS, Kent JN, Ardoin RC, Davenport W. Mandibular Augmentation in Dogs with Hydroxylapatite Combined with Demineralized Bone. J. Oral Maxillofac. Surg 1987, 45 : 414-20. 414–420.
- Kostenuik, P. J., Nguyen, H. Q., McCabe, J., Warmington, K. S., Kurahara, C., Sun, N., … Sullivan, J. K. (2009). Denosumab, a fully human monoclonal antibody to RANKL, inhibits bone resorption and increases BMD in knock-in mice that express chimeric (murine/human) RANKL. Journal of Bone and Mineral Research, 24(2), 182–195.
- Kostenuik, P. J., Smith, S. Y., Jolette, J., Schroeder, J., Pyrah, I. & Ominsky, M. S. (2011). Decreased bone remodeling and porosity are associated with improved bone strength in ovariectomized cynomolgus monkeys treated with denosumab, a fully human RANKL antibody. Bone, 49(2), 151–161.
- Lewiecki, E. M., Miller, P. D., McClung, M. R., Cohen, S. B., Bolognese, M. A., Liu, Y., Wang, A., Siddhanti, S. & Fitzpatrick, L. A. (2007). Two-year treatment with denosumab (AMG 162) in a randomized phase 2 study of postmenopausal women with low BMD. Journal of Bone and Mineral Research, 22(12), 1832–1841.
- Miller, P. D., Bolognese, M. A., Lewiecki, E. M., McClung, M. R., Ding, B., Austin, M., Liu, Y. & San Martin, J. (2008). Effect of denosumab on bone density and turnover in postmenopausal women with low bone mass after long-term continued, discontinued, and restarting of therapy: A randomized blinded phase 2 clinical trial. Bone, 43(2), 222–229.
- Nemcovsky, C. E. & Serfaty, V. (1996). Alveolar Ridge Preservation Following Extraction of Maxillary Anterior Teeth. Report on 23 Consecutive Cases. Journal of Periodontology, 67(4), 390–395.
- Ominsky, M. S., Stouch, B., Schroeder, J., Pyrah, I., Stolina, M., Smith, S. Y. & Kostenuik, P. J. (2011). Denosumab, a fully human RANKL antibody, reduced bone turnover markers and increased trabecular and cortical bone mass, density, and strength in ovariectomized cynomolgus monkeys. Bone, 49(2), 162–173.
- Özer, T., Başlarlı, Ö., Aktaş, A., Barış, E., Çelik, H. H. & Ocak, M. (2019). Locally administrated single-dose teriparatide affects critical-size rabbit calvarial defects: A histological, histomorphometric and micro-CT study. Acta Orthopaedica et Traumatologica Turcica, 53(6), 478–484.
- Özer, T., Başlarlı, Ö., Aktaş, A., Barış, E. & Ocak, M. (2022). Effect of Locally Administered Denosumab on Bone Graft Healing in Rabbit Critical-Size Calvarial Defects. In Indian Journal of Orthopaedics (Vol. 56, Issue 8, pp. 1424–1430).
- Pandit, N., Pandit, I., Malik, R., Bali, D. & Jindal, S. (2012). Autogenous bone block in the treatment of teeth with hopeless prognosis. Contemporary Clinical Dentistry, 3(4), 437–442.
- Raghoebar, G. M., Timmenga, N. M., Reintsema, H., Stegenga, B. & Vissink, A. (2001). Maxillary bone grafting for insertion of endosseous implants: Results after 12-124 months. Clinical Oral Implants Research, 12(3), 279–286.
- Schwarz, E. M. & Ritchlin, C. T. (2007). Clinical development of anti-RANKL therapy. Arthritis Research and Therapy, 9(SUPPL.1).
- Stavropoulos, A. & Karring, T. (2010). Guided tissue regeneration combined with a deproteinized bovine bone mineral (Bio-Oss ®) in the treatment of intrabony periodontal defects: 6-year results from a randomized-controlled clinical trial. Journal of Clinical Periodontology, 37(2), 200–210.
- Suresh, E. & Abrahamsen, B. (2015). Denosumab: A novel antiresorptive drug for osteoporosis. Cleveland Clinic Journal of Medicine, 82(2), 105–114.
- Tsourdi, E., Makras, P., Rachner, T. D., Polyzos, S., Rauner, M., Mandanas, S., Hofbauer, L. C. & Anastasilakis, A. D. (2019). Denosumab effects on bone density and turnover in postmenopausal women with low bone mass with or without previous treatment. Bone, 120, 44–49.
- Von Arx, T. & Buser, D. (2006). Horizontal ridge augmentation using autogenous block grafts and the guided bone regeneration technique with collagen membranes: A clinical study with 42 patients. Clinical Oral Implants Research, 17(4), 359–366.
- Younger, E. M. & Chapman, M. W. Morbidity at bone graft donor sites. J Orthop Trauma. 1989;3(3):192-195.
Öz
This study investigated the effect of denosumab on new bone formation, both alone and in combination with different graft materials. To this end, four defects were created in the skulls of 20 New Zealand rabbits. One defect was left empty, while the other three were treated with autograft, xenograft, and calcium phosphate (BCP) grafts. The animals were divided into an experimental group (n=10), which received 10 mg/kg of denosumab subcutaneously once a month for 2 months, and a control group (n=10), which was administered the same dose of physiological saline. After 8 weeks, the animals were sacrificed, and their bone tissue samples were analyzed histomorphometrically. The percentage of bone volume (PBV) was calculated by dividing the area of mature bone tissue by the total tissue area. The PBV in empty defects treated with denosumab was significantly higher than in the control group (p < 0.05). Moreover, the combination of denosumab and autograft resulted in a significant increase in new bone formation (NBF) (p < 0.05), thus demonstrating the positive effect of denosumab on bone formation. However, further research with larger experimental groups would be needed to determine the practicality, dosage, and duration of this treatment before clinical application.
Anahtar Kelimeler
Autograft Biphasic calcium phosphate Calvarial defect Denosumab Xenograft
Etik Beyan
This study was approved by the Inonu University Medical Faculty Experimental Animals Ethics Committee with the decision dated 20-06-2013 and numbered 2013/A-52.
Destekleyen Kurum
It was supported by the Scientific Research Projects Unit of İnönü University under project number 2013/184.
Proje Numarası
2013/184
Teşekkür
We would like to thank Scientific Research Projects Unit of İnönü University for their support and contributions.
Kaynakça
- Ahern, E., Smyth, M. J., Dougall, W. C. & Teng, M. W. L. (2018). Roles of the RANKL–RANK axis in antitumour immunity—implications for therapy. Nature Reviews Clinical Oncology, 15(11), 676–693.
- Antunes, A. A., Oliveira Neto, P., de Santis, E., Caneva, M., Botticelli, D. & Salata, L. A. (2013). Comparisons between Bio-Oss® and Straumann® Bone Ceramic in immediate and staged implant placement in dogs mandible bone defects. Clinical Oral Implants Research, 24(2), 135–142.
- Artzi, Z., Weinreb, M., Givol, N., Rohrer, M. D., Nemcovsky, C. E., Prasad, H. S. & Tal, H. (2004). Biomaterial resorption rate and healing site morphology of inorganic bovine bone and beta-tricalcium phosphate in the canine: a 24-month longitudinal histologic study and morphometric analysis. The International Journal of Oral & Maxillofacial Implants, 19(3), 357–368.
- Banwart, J. C., Asher, M. A. & Hassanein, R. S. (1995). Iliac crest bone graft harvest donor site morbidity: A statistical evaluation. In Spine (Vol. 20, Issue 9, pp. 1055–1066).
- Becker, W., Becker, B. E. & Caffesse, R. (1994). A Comparison of Demineralized Freeze‐Dried Bone and Autologous Bone to Induce Bone Formation in Human Extraction Sockets. Journal of Periodontology, 65(12), 1128–1133.
- Bone, H. G., Bolognese, M. A., Yuen, C. K., Kendler, D. L., Wang, H., Liu, Y. & San Martin, J. (2008). Effects of denosumab on bone mineral density and bone turnover in postmenopausal women. Journal of Clinical Endocrinology and Metabolism, 93(6), 2149–2157.
- Briot, K., Paccou, J., Beuzeboc, P., Bonneterre, J., Bouvard, B., Confavreux, C. B., … Debiais, F. (2019). French recommendations for osteoporosis prevention and treatment in patients with prostate cancer treated by androgen deprivation. Joint Bone Spine, 86(1), 21–28.
- Cordaro, L., Bosshardt, D. D., Palattella, P., Rao, W., Serino, G. & Chiapasco, M. (2008). Maxillary sinus grafting with Bio-Oss® or Straumann® Bone Ceramic: Histomorphometric results from a randomized controlled multicenter clinical trial. Clinical Oral Implants Research, 19(8), 796–803.
- Cummings, S. R., Martin, J. S., McClung, M. R., Siris, E. S., Eastell, R., Reid, I. R., … Christiansen, C. (2009). Denosumab for prevention of fractures in postmenopausal women with osteoporosis. Obstetrical and Gynecological Survey, 64(12), 805–807.
- Deeks, E. D. (2018). Denosumab: A Review in Postmenopausal Osteoporosis. Drugs and Aging, 35(2), 163–173.
- Erbe, E., Marx, J., Clineff, T. & Bellincampi, L. (2001). Potential of an ultraporous β-tricalcium phosphate synthetic cancellous bone void filler and bone marrow aspirate composite graft. European Spine Journal, 10(SUPPL. 2), 141–146.
- Friedlaender, G. E., Strong, D. M. & Sell, K. W. Studies on the antigenicity of bone. I. Freeze-dried and deep frozenbone allografts in rabbits. J Bone Joint Surg Am. 1976;58(6):854-858.
- Gerstenfeld, L. C., Sacks, D. J., Pelis, M., Mason, Z. D., Graves, D. T., Barrero, M., … Einhorn, T. A. (2009). Comparison of effects of the bisphosphonate alendronate versus the RANKL inhibitor denosumab on murine fracture healing. Journal of Bone and Mineral Research, 24(2), 196–208.
- Giannoudis, P. V., Dinopoulos, H. & Tsiridis, E. (2005). Bone substitutes: an update. Injury, 36 Suppl 3, 20–27.
- Goldhahn, J., Féron, J. M., Kanis, J., Papapoulos, S., Reginster, J. Y., Rizzoli, R., … Boonen, S. (2012). Implications for fracture healing of current and new osteoporosis treatments: An ESCEO consensus paper. Calcified Tissue International, 90(5), 343–353.
- Gül, M., Bayat, N., Gül, S., Hüz, M., Yıldız, A. & Otlu, A. (2014). A Comparison of Three Different Agents of Decalcification for a Histological Examination of Bone Tissues. J Turgut Ozal Med Cent, 21(4), 274-9.
- Hokugo, A., Sawada, Y., Hokugo, R., Iwamura, H., Kobuchi, M., Kambara, T., … Tabata, Y. (2007). Controlled release of platelet growth factors enhances bone regeneration at rabbit calvaria. Oral Surgery Oral Medicine, Oral Pathology, Oral Radiology, and Endodontology, 104(1), 44–48.
- Hollinger, G. C. B. (1986). Biodegradable bone repair materials. Synthetic polymers and ceramics. Clinical Orthopaedics and Related Researc, 207, 290–305.
- Iwamoto, N., Okamoto, M., Tsuji, S., Endo, Y., Takatani, A., Shimizu, T., … Kawakami, A. (2019). Denosumab is effective toward glucocorticoid-induced osteoporosis patients complicated with rheumatic diseases regardless of prior anti-osteoporotic drugs. Journal of Bone and Mineral Metabolism, 37(3), 554–562.
- Jamshidi, K., Gharehdaghi, M., Hajialiloo, S. S., Mirkazemi, M., Ghaffarzadehgan, K. & Izanloo, A. (2018). Denosumab in patients with giant cell tumor and its recurrence: A systematic review. Archives of Bone and Joint Surgery, 6(4), 260–268.
- Kahnberg, K. E. (2008). Bone grafting techniques for maxillary implants. John Wiley & Sons.
- Kent, J. N. & Davenport, W. (1987). Block MS, Kent JN, Ardoin RC, Davenport W. Mandibular Augmentation in Dogs with Hydroxylapatite Combined with Demineralized Bone. J. Oral Maxillofac. Surg 1987, 45 : 414-20. 414–420.
- Kostenuik, P. J., Nguyen, H. Q., McCabe, J., Warmington, K. S., Kurahara, C., Sun, N., … Sullivan, J. K. (2009). Denosumab, a fully human monoclonal antibody to RANKL, inhibits bone resorption and increases BMD in knock-in mice that express chimeric (murine/human) RANKL. Journal of Bone and Mineral Research, 24(2), 182–195.
- Kostenuik, P. J., Smith, S. Y., Jolette, J., Schroeder, J., Pyrah, I. & Ominsky, M. S. (2011). Decreased bone remodeling and porosity are associated with improved bone strength in ovariectomized cynomolgus monkeys treated with denosumab, a fully human RANKL antibody. Bone, 49(2), 151–161.
- Lewiecki, E. M., Miller, P. D., McClung, M. R., Cohen, S. B., Bolognese, M. A., Liu, Y., Wang, A., Siddhanti, S. & Fitzpatrick, L. A. (2007). Two-year treatment with denosumab (AMG 162) in a randomized phase 2 study of postmenopausal women with low BMD. Journal of Bone and Mineral Research, 22(12), 1832–1841.
- Miller, P. D., Bolognese, M. A., Lewiecki, E. M., McClung, M. R., Ding, B., Austin, M., Liu, Y. & San Martin, J. (2008). Effect of denosumab on bone density and turnover in postmenopausal women with low bone mass after long-term continued, discontinued, and restarting of therapy: A randomized blinded phase 2 clinical trial. Bone, 43(2), 222–229.
- Nemcovsky, C. E. & Serfaty, V. (1996). Alveolar Ridge Preservation Following Extraction of Maxillary Anterior Teeth. Report on 23 Consecutive Cases. Journal of Periodontology, 67(4), 390–395.
- Ominsky, M. S., Stouch, B., Schroeder, J., Pyrah, I., Stolina, M., Smith, S. Y. & Kostenuik, P. J. (2011). Denosumab, a fully human RANKL antibody, reduced bone turnover markers and increased trabecular and cortical bone mass, density, and strength in ovariectomized cynomolgus monkeys. Bone, 49(2), 162–173.
- Özer, T., Başlarlı, Ö., Aktaş, A., Barış, E., Çelik, H. H. & Ocak, M. (2019). Locally administrated single-dose teriparatide affects critical-size rabbit calvarial defects: A histological, histomorphometric and micro-CT study. Acta Orthopaedica et Traumatologica Turcica, 53(6), 478–484.
- Özer, T., Başlarlı, Ö., Aktaş, A., Barış, E. & Ocak, M. (2022). Effect of Locally Administered Denosumab on Bone Graft Healing in Rabbit Critical-Size Calvarial Defects. In Indian Journal of Orthopaedics (Vol. 56, Issue 8, pp. 1424–1430).
- Pandit, N., Pandit, I., Malik, R., Bali, D. & Jindal, S. (2012). Autogenous bone block in the treatment of teeth with hopeless prognosis. Contemporary Clinical Dentistry, 3(4), 437–442.
- Raghoebar, G. M., Timmenga, N. M., Reintsema, H., Stegenga, B. & Vissink, A. (2001). Maxillary bone grafting for insertion of endosseous implants: Results after 12-124 months. Clinical Oral Implants Research, 12(3), 279–286.
- Schwarz, E. M. & Ritchlin, C. T. (2007). Clinical development of anti-RANKL therapy. Arthritis Research and Therapy, 9(SUPPL.1).
- Stavropoulos, A. & Karring, T. (2010). Guided tissue regeneration combined with a deproteinized bovine bone mineral (Bio-Oss ®) in the treatment of intrabony periodontal defects: 6-year results from a randomized-controlled clinical trial. Journal of Clinical Periodontology, 37(2), 200–210.
- Suresh, E. & Abrahamsen, B. (2015). Denosumab: A novel antiresorptive drug for osteoporosis. Cleveland Clinic Journal of Medicine, 82(2), 105–114.
- Tsourdi, E., Makras, P., Rachner, T. D., Polyzos, S., Rauner, M., Mandanas, S., Hofbauer, L. C. & Anastasilakis, A. D. (2019). Denosumab effects on bone density and turnover in postmenopausal women with low bone mass with or without previous treatment. Bone, 120, 44–49.
- Von Arx, T. & Buser, D. (2006). Horizontal ridge augmentation using autogenous block grafts and the guided bone regeneration technique with collagen membranes: A clinical study with 42 patients. Clinical Oral Implants Research, 17(4), 359–366.
- Younger, E. M. & Chapman, M. W. Morbidity at bone graft donor sites. J Orthop Trauma. 1989;3(3):192-195.
Ayrıntılar
| Birincil Dil | İngilizce |
|---|---|
| Konular | Tıp Eğitimi |
| Bölüm | Araştırma Makalesi |
| Yazarlar | |
| Proje Numarası | 2013/184 |
| Erken Görünüm Tarihi | 17 Haziran 2025 |
| Yayımlanma Tarihi | 25 Haziran 2025 |
| Gönderilme Tarihi | 18 Ekim 2024 |
| Kabul Tarihi | 10 Mart 2025 |
| Yayımlandığı Sayı | Yıl 2025 Cilt: 13 Sayı: 2 |
