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Systemic Effect of Metformin on Bone Healing at Bone Defect in Rabbits Using Radiographical and Serum Alkaline Phosphatase Assessment

Yıl 2022, Cilt: 17 Sayı: 3, 91 - 97, 06.01.2023
https://doi.org/10.5152/VetSciPract.2022.223353

Öz

Clinical therapy for disorders of bone healing present serious challenges. The delivery of the bone filling materials
necessitates surgical implantation at the fracture site, which could lead to local complications. As a result,
taking osteogenic medications will offer a great way to heal bone lesions. Increased osteoblasts and decreased
osteoclasts are 2 ways that metformin has an osteogenic impact. The aim of the study is to determine the
systemic impact of metformin on bone healing at the site of a bony defect using radiographic and serum alkaline
phosphatase testing. A total of 20 mature male rabbits, divided into 2 groups of 10 each for the treatment
group and the control group, were utilized. All rabbits underwent identical surgical procedures under general
anesthesia. Two holes that were 3 mm in diameter and 3 mm deep were created and left empty after the femur
has been surgically exposed. The study was conducted over 28 days. The rabbits in the treatment group
received 50 mg/kg of metformin orally daily for 28 days. The animals were sacrificed at 2 different time points,
according to their groups, on the 14th and 28th day after surgery. Bone samples from the defect site of the femur
were isolated, sectioned, assessed radiographically, and blood was drawn for serum alkaline phosphatase
measurement. There was an increase in bone mineral density and osseointegration. In addition, serum alkaline
phosphatase increased in the animals of the group treated with metformin than in the control group at both
study time periods. Metformin increases bone healing and regeneration at the bone defect sites and enhances
the process of osteogenesis and osseointegration more than the control untreated rabbits.

Kaynakça

  • 1. Toosi S, Behravan J. Osteogenesis and bone remodeling: A focus on growth factors and bioactive peptides. Biofactors, 2020;46(3), 326- 340. [Crossref]
  • 2. Schlundt C, Bucher CH, Tsitsilonis S, Schell H, Duda GN, Schmidt- Bleek K. Clinical and research approaches to treat non-union fracture. Curr Osteoporos Rep, 2020;16(2),155-168. [Crossref]
  • 3. Pajarinen J, Lin T, Gibon E, Kohno Y, Maruyama M, Nathan K. and Goodman, S. B. Mesenchymal stem cell-macrophage crosstalk and bone healing. Biomaterials, 2019;196,80-89. [Crossref]
  • 4. Raggatt LJ, and Partridge NC. Cellular and molecular mechanisms of bone remodeling. J Biol Chem, 2010;285(33), 25103-25108. [Crossref]
  • 5. Voller T, Ahmed M, Ho S, Kozhikunnath A, Bendall S. Measuring bone healing in fractures and fusions. Orthop Trauma, 2022;36(4), 218-222. [Crossref]
  • 6. Nauth A, Schemitsch E, Norris B, Nollin Z, Watson JT. Critical-size bone defects: is there a consensus for diagnosis and treatment?. J Orthop Trauma, 2018;32,7-11. [Crossref]
  • 7. Rothe R, Schulze S, Neuber C, Hauser S, Rammelt S, Pietzsch J. Adjuvant drug-assisted bone healing: Part III–Further strategies for local and systemic modulation. Clin Hemorheol Microcirc, 2019;73(3),439- 488. [Crossref]
  • 8. Bucher S, Bauduceau B, Benattar-Zibi L, Bertin P, Berrut G, Corruble E, Becquemont L. Primary care management of non-institutionalized elderly diabetic patients: The S. AGES cohort–Baseline data. Prim Care Diabetes. 2015;9(4),267-274. [Crossref]
  • 9. Andrews M, Soto N, Arredondo M. Effect of metformin on the expression of tumor necrosis factor-α, Toll like receptors 2/4 and C reactive protein in obese type-2 diabetic patients. Rev Med Chil, 2012;140(11), 1377-1382. [Crossref]
  • 10. Ren C, Hao X, Wang L, Hu Y, Meng L, Zheng S, Sun H. Metformin Carbon Dots for Promoting Periodontal Bone Regeneration via Activation of ERK/AMPK Pathway. Adv Healthc Mater, 2021;10(12), 2100196. [Crossref]
  • 11. Sanchez-Rangel E, Inzucchi SE. Metformin: clinical use in type 2 diabetes. Diabetologia, 60(9), 1586-1593 (2017). [Crossref]
  • 12. Vasikaran S, Eastell R, Bruyere O, Foldes AJ, Garnero P, Griesmacher A, Kanis JA. Markers of bone turnover for the prediction of fracture risk and monitoring of osteoporosis treatment: a need for international reference standards. Osteoporos Int, 2011;22(2),391-420. [Crossref]
  • 13. De Lima Santos A, da Silva CG, de Sá Barreto LS, Leite KRM, Tamaoki MJS, Ferreira LM, Faloppa F. A new decellularized tendon scaffold for rotator cuff tears–evaluation in rabbits. BMC Musculoskelet Disord, 2020;21(1), 1-12. [Crossref]
  • 14. Kumar AB, Mohan S, Sakthi RS, Ramkanth S. A Review On Clinical Pharmacokinetic And Pharmacodynamic Profile Of Metformin (2020).
  • 15. Ikewuchi CC, Ikewuchi JC, Ifeanacho MO. Restoration of plasma markers of liver and kidney functions/integrity in alloxan-induced diabetic rabbits by aqueous extract of Pleurotus tuberregium sclerotia. Biomed Pharmacother. 2017;95, 1809-1814. [Crossref]
  • 16. Ahirwar LK, Kalra P, Sharma S, Mohamed A, Mittal R, Das S, Bagga B. Linezolid shows high safety and efficacy in the treatment of Pythium insidiosum keratitis in a rabbit model. Exp Eye Res, 2021;202,108345. [Crossref]
  • 17. Jiron JM, Mendieta Calle JL, Castillo EJ, Abraham AM, Messer JG, Malphurs WL, Aguirre JI. Comparison of isoflurane, ketamine–dexmedetomidine, and ketamine–xylazine for general anesthesia during oral procedures in rice rats (Oryzomys palustris). J Am Assoc Lab Anim Sci, 2019;58(1),40-49. [Crossref]
  • 18. Nguyen-Thanh T, Nguyen-Tran BS, Cruciani S, Dang-Cong T, Maioli M. A rabbit femoral trochlear defect model for chondral and osteochondral regeneration. Acta Veterinaria Brno, 2022;91(3), 293-301. [Crossref]
  • 19. Sipani AK, Dhar A, Sungte N. Serum alkaline phosphatase: A prospective biomarker for assessment of progress of fracture healing in diaphyseal fractures of long bones in adult patients. Int J Orthop, 2020;6(2),248-251. [Crossref]
  • 20. Seibel MJ. Biochemical markers of bone turnover part I: biochemistry and variability. The Clinical biochemist. Reviews/Australian Association of Clinical Biochemists., 2005;26(4),97.
  • 21. Castells L, Cassanello P, Muñiz F, de Castro MJ, Couce ML. Neonatal lethal hypophosphatasia: A case report and review of literature. Medicine, 2018;97(48). [Crossref]
  • 22. Pinart M, Kunath F, Lieb V, Tsaur I, Wullich B, Schmidt S. Prognostic models for predicting overall survival in metastatic castration-resistant prostate cancer: a systematic review. World J Urol, 2020;38(3), 613-635. [Crossref]
  • 23. Abe Y, Chiba M, Yaklai S, Pechayco RS, Suzuki H, Takahashi T. Increase in bone metabolic markers and circulating osteoblast-lineage cells after orthognathic surgery. Sci Rep, 2019;9(1),1-10. [Crossref]
  • 24. Reddy GAK, Kumar VG, Raghavender, KBP, Kumar DP. Evaluation of haemato-biochemical parameters for assessment of fracture healing in dogs. Pharma Innovation J, 2020;9(9),123-125. [Crossref]
  • 25. Wang P, Ma T, Guo D, Hu K, Shu Y, Xu HH, Schneider, A. Metformin induces osteoblastic differentiation of human induced pluripotent stem cell‐derived mesenchymal stem cells. J Tissue Eng Regen Med, 2018;12(2),437-446. [Crossref]
  • 26. Molinuevo MS, Schurman L, McCarthy AD, Cortizo AM, Tolosa MJ, Gangoiti MV, Sedlinsky C. Effect of metformin on bone marrow progenitor cell differentiation: in vivo and in vitro studies. J Bone Miner Res, 2010;25(2),211-221. [Crossref]
  • 27. Jang WG, Kim EJ, Bae IH, Lee KN, Kim YD, Kim DK, Koh JT. Metformin induces osteoblast differentiation via orphan nuclear receptor SHP-mediated transactivation of Runx2. Bone, 2011;48(4), 885-893. [Crossref]
  • 28. Śmieszek A, Tomaszewski KA, Kornicka K, Marycz K. Metformin Promotes Osteogenic Differentiation of Adipose-Derived Stromal Cells and Exerts Pro-Osteogenic Effect Stimulating Bone Regeneration. J. Clin. Med, 2018;7,482. [Crossref]
  • 29. Luo T, Nocon A, Fry J, Sherban A, Rui X, Jiang B, Zang M. AMPK activation by metformin suppresses abnormal extracellular matrix remodeling in adipose tissue and ameliorates insulin resistance in obesity. Diabetes, 2016;65(8), 2295-2310. [Crossref]
  • 30. Sun J, Liu Q, He H, Jiang L, Lee KO, Li D, Ma J. Metformin treatment is associated with an increase in bone mineral density in type 2 diabetes mellitus patients in China: a retrospective single-center study. Diabetes Metab, 2022;101350. [Crossref]
  • 31. Mai QG, Zhang ZM, Xu S, Lu M, Zhou RP, Zhao L, Bai XC. Metformin stimulates osteoprotegerin and reduces RANKL expression in osteoblasts and ovariectomized rats. J Cell Biochem, 2011;112(10),2902- 2909. [Crossref]
  • 32. Kendler D, Chines A, Clark P, Ebeling PR, McClung M, Rhee Y, Stad RK. Bone mineral density after transitioning from denosumab to alendronate. J Clin Endocrinol Metab, 2020;105(3), e255-e264. [Crossref]
  • 33. Zhou Q, Guan Z, Liu S, Xuan Y, Han G, Chen H, Guan Z. The effects of metformin and alendronate in attenuating bone loss and improving glucose metabolism in diabetes mellitus mice. Aging (Albany NY), 2022;14(1), 272. [Crossref]
  • 34. Zheng L, Shen X, Ye J, Xie Y, Yan S. Metformin alleviates hyperglycemia- induced apoptosis and differentiation suppression in osteoblasts through inhibiting the TLR4 signaling pathway. Life sciences, 2019;216, 29-38. [Crossref]
  • 35. Wang YG, Qu XH, Yang Y, Han XG, Wang L, Qiao H, Dai KR. AMPK promotes osteogenesis and inhibits adipogenesis through AMPK-Gfi1- OPN axis. Cell Signal, 2016;28(9),1270-1282. [Crossref]
  • 36. Gonnelli S, Caffarelli C, Giordano N, Nuti R. The prevention of fragility fractures in diabetic patients. Aging Clin and Exp Res, 2015;27(2), 115- 124. [Crossref]
  • 37. Yang P, Feng J, Peng Q, Liu X, Fan Z. Advanced glycation end products: potential mechanism and therapeutic target in cardiovascular complications under diabetes. Oxid Med Cell Longev, (2019). [Crossref]
  • 38. Yıldırım TT, Dündar S, Bozoğlan A, Karaman T, Kahraman OE, Özcan EC. The effects of metformin on the bone filling ration around of TiAl6Va4 implants in non diabetic rats. J Oral Biol Craniofac Res, 2020;10(4),474-477. [Crossref]
  • 39. Afshari K, Dehdashtian A, Haddadi NS, Haj-Mirzaian A, Iranmehr A, Ebrahimi MA, et al. Anti-inflammatory effects of metformin improve the neuropathic pain and locomotor activity in spinal cord injured rats: introduction of an alternative therapy. Spinal cord, 2018;56(11), 1032-1041. [Crossref]

Kemik Defektli Tavşanlarda Metforminin Kemik İyileşmesi Üzerindeki Sistemik Etkisinin Radyografik ve Serum Alkalin Fosfataz Kullanılarak Değerlendirilmesi

Yıl 2022, Cilt: 17 Sayı: 3, 91 - 97, 06.01.2023
https://doi.org/10.5152/VetSciPract.2022.223353

Öz

Kemik iyileşme bozukluklarının klinik tedavisi ciddi zorluklar barındırır. Ancak, kemik dolgu malzemelerinin
uygulanması yaralanma yerinde cerrahi implantasyon gerektirir, bu da yerel komplikasyonlara yol açabilir. Bu
nedenle, osteojenik ilaçları almak kemik lezyonlarının iyileşmesine yardımcı olacaktır. Artan osteoblast ve azalan
osteoklastlar metforminin osteojenik etkisini temsil eden iki yoldur. Çalışmanın amacı, metformin uygulamasının
kemik defekti bölgesinde kemik iyileşmesi üzerindeki sistemik etkisini radyografik ve serum alkalin
fosfataz testleri kullanarak belirlemektir. Çalışmada, toplam 20 yetişkin erkek tavşan onarlı iki gruba bölünerek
kullanılmıştır. Tavşanların tamamı genel anestezi altında aynı cerrahi prosedüre maruz kaldılar. Femur cerrahi
olarak ekspoze edildikten sonra üzerine 3 mm çapında ve 3 mm derinliğinde iki delik açıldı ve delikler boş
bırakıldı. Çalışma 28 gün sürdü. Çalışma grubundaki tavşanlar, operasyonun ardından 28 gün boyunca günde
50 mg/kg oral metformin aldı. Hayvanlar araştırmadaki numaralarına ve gruplarına göre iki farklı zaman aralığında,
operasyondan sonraki 14'üncü ve 28'inci günlerde sakrifiye edildiler. Femur defekt bölgesinden alınan
kemik örnekleri, ayrıştırıldı, kesildi, radyografik olarak değerlendirildi ve serum alkalin fosfataz ölçümü için kan
alındı. Metformin alan hayvanların kontrol grubuna kıyasla çalışma zamanlarının her ikisinde de kemik mineral
yoğunluğu ve osseointegrasyon artışı olduğunu ve ayrıca serum alkalin fosfataz artışı olduğunu göstermiştir.
Sonuç olarak, metformin, kontrol grubunda tedavi uygulanmayan tavşanlara kıyasla kemik defekti bölgesinde
kemik iyileşmesini ve yenilenmesini artırmakta ve osteogenezis ve osseointegrasyon sürecini daha fazla
güçlendirmektedir.

Kaynakça

  • 1. Toosi S, Behravan J. Osteogenesis and bone remodeling: A focus on growth factors and bioactive peptides. Biofactors, 2020;46(3), 326- 340. [Crossref]
  • 2. Schlundt C, Bucher CH, Tsitsilonis S, Schell H, Duda GN, Schmidt- Bleek K. Clinical and research approaches to treat non-union fracture. Curr Osteoporos Rep, 2020;16(2),155-168. [Crossref]
  • 3. Pajarinen J, Lin T, Gibon E, Kohno Y, Maruyama M, Nathan K. and Goodman, S. B. Mesenchymal stem cell-macrophage crosstalk and bone healing. Biomaterials, 2019;196,80-89. [Crossref]
  • 4. Raggatt LJ, and Partridge NC. Cellular and molecular mechanisms of bone remodeling. J Biol Chem, 2010;285(33), 25103-25108. [Crossref]
  • 5. Voller T, Ahmed M, Ho S, Kozhikunnath A, Bendall S. Measuring bone healing in fractures and fusions. Orthop Trauma, 2022;36(4), 218-222. [Crossref]
  • 6. Nauth A, Schemitsch E, Norris B, Nollin Z, Watson JT. Critical-size bone defects: is there a consensus for diagnosis and treatment?. J Orthop Trauma, 2018;32,7-11. [Crossref]
  • 7. Rothe R, Schulze S, Neuber C, Hauser S, Rammelt S, Pietzsch J. Adjuvant drug-assisted bone healing: Part III–Further strategies for local and systemic modulation. Clin Hemorheol Microcirc, 2019;73(3),439- 488. [Crossref]
  • 8. Bucher S, Bauduceau B, Benattar-Zibi L, Bertin P, Berrut G, Corruble E, Becquemont L. Primary care management of non-institutionalized elderly diabetic patients: The S. AGES cohort–Baseline data. Prim Care Diabetes. 2015;9(4),267-274. [Crossref]
  • 9. Andrews M, Soto N, Arredondo M. Effect of metformin on the expression of tumor necrosis factor-α, Toll like receptors 2/4 and C reactive protein in obese type-2 diabetic patients. Rev Med Chil, 2012;140(11), 1377-1382. [Crossref]
  • 10. Ren C, Hao X, Wang L, Hu Y, Meng L, Zheng S, Sun H. Metformin Carbon Dots for Promoting Periodontal Bone Regeneration via Activation of ERK/AMPK Pathway. Adv Healthc Mater, 2021;10(12), 2100196. [Crossref]
  • 11. Sanchez-Rangel E, Inzucchi SE. Metformin: clinical use in type 2 diabetes. Diabetologia, 60(9), 1586-1593 (2017). [Crossref]
  • 12. Vasikaran S, Eastell R, Bruyere O, Foldes AJ, Garnero P, Griesmacher A, Kanis JA. Markers of bone turnover for the prediction of fracture risk and monitoring of osteoporosis treatment: a need for international reference standards. Osteoporos Int, 2011;22(2),391-420. [Crossref]
  • 13. De Lima Santos A, da Silva CG, de Sá Barreto LS, Leite KRM, Tamaoki MJS, Ferreira LM, Faloppa F. A new decellularized tendon scaffold for rotator cuff tears–evaluation in rabbits. BMC Musculoskelet Disord, 2020;21(1), 1-12. [Crossref]
  • 14. Kumar AB, Mohan S, Sakthi RS, Ramkanth S. A Review On Clinical Pharmacokinetic And Pharmacodynamic Profile Of Metformin (2020).
  • 15. Ikewuchi CC, Ikewuchi JC, Ifeanacho MO. Restoration of plasma markers of liver and kidney functions/integrity in alloxan-induced diabetic rabbits by aqueous extract of Pleurotus tuberregium sclerotia. Biomed Pharmacother. 2017;95, 1809-1814. [Crossref]
  • 16. Ahirwar LK, Kalra P, Sharma S, Mohamed A, Mittal R, Das S, Bagga B. Linezolid shows high safety and efficacy in the treatment of Pythium insidiosum keratitis in a rabbit model. Exp Eye Res, 2021;202,108345. [Crossref]
  • 17. Jiron JM, Mendieta Calle JL, Castillo EJ, Abraham AM, Messer JG, Malphurs WL, Aguirre JI. Comparison of isoflurane, ketamine–dexmedetomidine, and ketamine–xylazine for general anesthesia during oral procedures in rice rats (Oryzomys palustris). J Am Assoc Lab Anim Sci, 2019;58(1),40-49. [Crossref]
  • 18. Nguyen-Thanh T, Nguyen-Tran BS, Cruciani S, Dang-Cong T, Maioli M. A rabbit femoral trochlear defect model for chondral and osteochondral regeneration. Acta Veterinaria Brno, 2022;91(3), 293-301. [Crossref]
  • 19. Sipani AK, Dhar A, Sungte N. Serum alkaline phosphatase: A prospective biomarker for assessment of progress of fracture healing in diaphyseal fractures of long bones in adult patients. Int J Orthop, 2020;6(2),248-251. [Crossref]
  • 20. Seibel MJ. Biochemical markers of bone turnover part I: biochemistry and variability. The Clinical biochemist. Reviews/Australian Association of Clinical Biochemists., 2005;26(4),97.
  • 21. Castells L, Cassanello P, Muñiz F, de Castro MJ, Couce ML. Neonatal lethal hypophosphatasia: A case report and review of literature. Medicine, 2018;97(48). [Crossref]
  • 22. Pinart M, Kunath F, Lieb V, Tsaur I, Wullich B, Schmidt S. Prognostic models for predicting overall survival in metastatic castration-resistant prostate cancer: a systematic review. World J Urol, 2020;38(3), 613-635. [Crossref]
  • 23. Abe Y, Chiba M, Yaklai S, Pechayco RS, Suzuki H, Takahashi T. Increase in bone metabolic markers and circulating osteoblast-lineage cells after orthognathic surgery. Sci Rep, 2019;9(1),1-10. [Crossref]
  • 24. Reddy GAK, Kumar VG, Raghavender, KBP, Kumar DP. Evaluation of haemato-biochemical parameters for assessment of fracture healing in dogs. Pharma Innovation J, 2020;9(9),123-125. [Crossref]
  • 25. Wang P, Ma T, Guo D, Hu K, Shu Y, Xu HH, Schneider, A. Metformin induces osteoblastic differentiation of human induced pluripotent stem cell‐derived mesenchymal stem cells. J Tissue Eng Regen Med, 2018;12(2),437-446. [Crossref]
  • 26. Molinuevo MS, Schurman L, McCarthy AD, Cortizo AM, Tolosa MJ, Gangoiti MV, Sedlinsky C. Effect of metformin on bone marrow progenitor cell differentiation: in vivo and in vitro studies. J Bone Miner Res, 2010;25(2),211-221. [Crossref]
  • 27. Jang WG, Kim EJ, Bae IH, Lee KN, Kim YD, Kim DK, Koh JT. Metformin induces osteoblast differentiation via orphan nuclear receptor SHP-mediated transactivation of Runx2. Bone, 2011;48(4), 885-893. [Crossref]
  • 28. Śmieszek A, Tomaszewski KA, Kornicka K, Marycz K. Metformin Promotes Osteogenic Differentiation of Adipose-Derived Stromal Cells and Exerts Pro-Osteogenic Effect Stimulating Bone Regeneration. J. Clin. Med, 2018;7,482. [Crossref]
  • 29. Luo T, Nocon A, Fry J, Sherban A, Rui X, Jiang B, Zang M. AMPK activation by metformin suppresses abnormal extracellular matrix remodeling in adipose tissue and ameliorates insulin resistance in obesity. Diabetes, 2016;65(8), 2295-2310. [Crossref]
  • 30. Sun J, Liu Q, He H, Jiang L, Lee KO, Li D, Ma J. Metformin treatment is associated with an increase in bone mineral density in type 2 diabetes mellitus patients in China: a retrospective single-center study. Diabetes Metab, 2022;101350. [Crossref]
  • 31. Mai QG, Zhang ZM, Xu S, Lu M, Zhou RP, Zhao L, Bai XC. Metformin stimulates osteoprotegerin and reduces RANKL expression in osteoblasts and ovariectomized rats. J Cell Biochem, 2011;112(10),2902- 2909. [Crossref]
  • 32. Kendler D, Chines A, Clark P, Ebeling PR, McClung M, Rhee Y, Stad RK. Bone mineral density after transitioning from denosumab to alendronate. J Clin Endocrinol Metab, 2020;105(3), e255-e264. [Crossref]
  • 33. Zhou Q, Guan Z, Liu S, Xuan Y, Han G, Chen H, Guan Z. The effects of metformin and alendronate in attenuating bone loss and improving glucose metabolism in diabetes mellitus mice. Aging (Albany NY), 2022;14(1), 272. [Crossref]
  • 34. Zheng L, Shen X, Ye J, Xie Y, Yan S. Metformin alleviates hyperglycemia- induced apoptosis and differentiation suppression in osteoblasts through inhibiting the TLR4 signaling pathway. Life sciences, 2019;216, 29-38. [Crossref]
  • 35. Wang YG, Qu XH, Yang Y, Han XG, Wang L, Qiao H, Dai KR. AMPK promotes osteogenesis and inhibits adipogenesis through AMPK-Gfi1- OPN axis. Cell Signal, 2016;28(9),1270-1282. [Crossref]
  • 36. Gonnelli S, Caffarelli C, Giordano N, Nuti R. The prevention of fragility fractures in diabetic patients. Aging Clin and Exp Res, 2015;27(2), 115- 124. [Crossref]
  • 37. Yang P, Feng J, Peng Q, Liu X, Fan Z. Advanced glycation end products: potential mechanism and therapeutic target in cardiovascular complications under diabetes. Oxid Med Cell Longev, (2019). [Crossref]
  • 38. Yıldırım TT, Dündar S, Bozoğlan A, Karaman T, Kahraman OE, Özcan EC. The effects of metformin on the bone filling ration around of TiAl6Va4 implants in non diabetic rats. J Oral Biol Craniofac Res, 2020;10(4),474-477. [Crossref]
  • 39. Afshari K, Dehdashtian A, Haddadi NS, Haj-Mirzaian A, Iranmehr A, Ebrahimi MA, et al. Anti-inflammatory effects of metformin improve the neuropathic pain and locomotor activity in spinal cord injured rats: introduction of an alternative therapy. Spinal cord, 2018;56(11), 1032-1041. [Crossref]
Toplam 39 adet kaynakça vardır.

Ayrıntılar

Birincil Dil Türkçe
Konular Veteriner Bilimleri
Bölüm Araştırma Makaleleri
Yazarlar

Raad Mahmood Husseın Bu kişi benim

Ghada Abdulrahman Taqa Bu kişi benim

Yayımlanma Tarihi 6 Ocak 2023
Yayımlandığı Sayı Yıl 2022 Cilt: 17 Sayı: 3

Kaynak Göster

APA Mahmood Husseın, R., & Abdulrahman Taqa, G. (2023). Kemik Defektli Tavşanlarda Metforminin Kemik İyileşmesi Üzerindeki Sistemik Etkisinin Radyografik ve Serum Alkalin Fosfataz Kullanılarak Değerlendirilmesi. Veterinary Sciences and Practices, 17(3), 91-97. https://doi.org/10.5152/VetSciPract.2022.223353
AMA Mahmood Husseın R, Abdulrahman Taqa G. Kemik Defektli Tavşanlarda Metforminin Kemik İyileşmesi Üzerindeki Sistemik Etkisinin Radyografik ve Serum Alkalin Fosfataz Kullanılarak Değerlendirilmesi. Veterinary Sciences and Practices. Ocak 2023;17(3):91-97. doi:10.5152/VetSciPract.2022.223353
Chicago Mahmood Husseın, Raad, ve Ghada Abdulrahman Taqa. “Kemik Defektli Tavşanlarda Metforminin Kemik İyileşmesi Üzerindeki Sistemik Etkisinin Radyografik Ve Serum Alkalin Fosfataz Kullanılarak Değerlendirilmesi”. Veterinary Sciences and Practices 17, sy. 3 (Ocak 2023): 91-97. https://doi.org/10.5152/VetSciPract.2022.223353.
EndNote Mahmood Husseın R, Abdulrahman Taqa G (01 Ocak 2023) Kemik Defektli Tavşanlarda Metforminin Kemik İyileşmesi Üzerindeki Sistemik Etkisinin Radyografik ve Serum Alkalin Fosfataz Kullanılarak Değerlendirilmesi. Veterinary Sciences and Practices 17 3 91–97.
IEEE R. Mahmood Husseın ve G. Abdulrahman Taqa, “Kemik Defektli Tavşanlarda Metforminin Kemik İyileşmesi Üzerindeki Sistemik Etkisinin Radyografik ve Serum Alkalin Fosfataz Kullanılarak Değerlendirilmesi”, Veterinary Sciences and Practices, c. 17, sy. 3, ss. 91–97, 2023, doi: 10.5152/VetSciPract.2022.223353.
ISNAD Mahmood Husseın, Raad - Abdulrahman Taqa, Ghada. “Kemik Defektli Tavşanlarda Metforminin Kemik İyileşmesi Üzerindeki Sistemik Etkisinin Radyografik Ve Serum Alkalin Fosfataz Kullanılarak Değerlendirilmesi”. Veterinary Sciences and Practices 17/3 (Ocak 2023), 91-97. https://doi.org/10.5152/VetSciPract.2022.223353.
JAMA Mahmood Husseın R, Abdulrahman Taqa G. Kemik Defektli Tavşanlarda Metforminin Kemik İyileşmesi Üzerindeki Sistemik Etkisinin Radyografik ve Serum Alkalin Fosfataz Kullanılarak Değerlendirilmesi. Veterinary Sciences and Practices. 2023;17:91–97.
MLA Mahmood Husseın, Raad ve Ghada Abdulrahman Taqa. “Kemik Defektli Tavşanlarda Metforminin Kemik İyileşmesi Üzerindeki Sistemik Etkisinin Radyografik Ve Serum Alkalin Fosfataz Kullanılarak Değerlendirilmesi”. Veterinary Sciences and Practices, c. 17, sy. 3, 2023, ss. 91-97, doi:10.5152/VetSciPract.2022.223353.
Vancouver Mahmood Husseın R, Abdulrahman Taqa G. Kemik Defektli Tavşanlarda Metforminin Kemik İyileşmesi Üzerindeki Sistemik Etkisinin Radyografik ve Serum Alkalin Fosfataz Kullanılarak Değerlendirilmesi. Veterinary Sciences and Practices. 2023;17(3):91-7.

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