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. 2022 Dec 5;14(12):e32204.
doi: 10.7759/cureus.32204. eCollection 2022 Dec.

Effects of Linagliptin and Pioglitazone on Fracture Healing in an Experimental Type 2 Diabetes Rat Model

Hamisi M Mraja  1 , Sever Caglar  2 , Muhammed Uslu  2 , Bilal Yilmaz  3 , Mustafa Fatih Dasci  4 , Elif Yaprak Sarac  5 , Metehan Demirkol  6
Affiliations

Effects of Linagliptin and Pioglitazone on Fracture Healing in an Experimental Type 2 Diabetes Rat Model

Hamisi M Mraja et al. Cureus. .

Abstract

Aim: Our study aimed to examine the effects of Linagliptin, Pioglitazone, and their combination on fracture healing in a diabetes rat femur fracture model.

Material and methods: Type 2 diabetes mellitus (T2DM) induced rats were randomly divided into four groups: non-treated diabetes group (TD), Pioglitazone group (P), Linagliptin group (L), and Pioglitazone and Linagliptin group (PL). Daily oral dosage of pioglitazone (10 mg/kg/day), linagliptin (10 mg/kg/day), and their combination were administered. Femur fractures were stabilized intramedullary. At weeks 2 and 6, rats were sacrificed for evaluation radiologically, biomechanically, histopathologically, histomorphometrically, and immunohistochemically.

Results: Flexural strength of the L and PL groups were significantly higher compared to the P group. The highest healing score was in the L group and lowest in the P group, while the highest inflammation score was in the P group and lowest in the L group. A cluster of differentiation (CD) CD 34 reactivity was highest in the L group and lowest in the PL group.

Conclusion: Linagliptin treatment significantly increased histological healing scores, callus volume, biomechanical strength, and vascularity, however, minimized the inflammatory process, which was increased by pioglitazone. The combination of linagliptin and pioglitazone restored BMD and increased biomechanical strength. Linagliptin monotherapy is rarely indicated; hence, T2DM patients with a high risk of bone fractures can be considered for combined therapy of pioglitazone and linagliptin.

Keywords: bone healing; linagliptin; pioglitazone; streptozotocin; type 2 diabetes.

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Conflict of interest statement

The authors have declared that no competing interests exist.

Figures

Figure 1
Figure 1. Micro-computed tomography images obtained in the second and sixth weeks. Non-treated diabetes group (TD), Pioglitazone group (P), Linagliptin group (L), and Pioglitazone and Linagliptin group (PL). Arrow head demonstrating soft callus and arrow demonstrating hard callus.
Figure 2
Figure 2. Radiologic evaluations of callus volumes calculated at 2 and 6 weeks. Y-axis presents the callus volumes of non-treated diabetes group (TD), Pioglitazone group (P), Linagliptin group (L), and Pioglitazone and Linagliptin group (PL). All data are represented as Mean ± SD.
*L vs PL group p < 0.05; **P and L groups vs TD group p < 0.05.
Figure 3
Figure 3. Radiological evaluations of bone mineral densities (BMD) at 2 and 6 weeks. Y-axis presents BMDs of non-treated diabetes group (TD), Pioglitazone group (P), Linagliptin group (L), and Pioglitazone and Linagliptin group (PL).
All data are represented as Mean ± SD. *P group vs PL and TD groups p < 0.05; **L group vs PL and TD groups p < 0.05.
Figure 4
Figure 4. Biomechanical analysis of the flexural strength (σbend) value of healing bone at 6-week in non-treated diabetes group (TD), Pioglitazone group (P), Linagliptin group (L), and Pioglitazone and Linagliptin group (PL).
*L and PL groups vs P group p < 0.05. MPa (Megapascal)
Figure 5
Figure 5. Histopathologic image showing the bone healing after 2 and 6 weeks of treatments in non-treated diabetes group (TD), Pioglitazone group (P), Linagliptin group (L), and Pioglitazone and Linagliptin group (PL). Hematoxylin and eosin staining (H&E, x40)
Figure 6
Figure 6. Histopathologic image showing the bone healing after 2 and 6 weeks of treatments in non-treated diabetes group (TD), Pioglitazone group (P), Linagliptin group (L), and Pioglitazone and Linagliptin group (PL). Masson trichrome staining (x40).
Figure 7
Figure 7. Histopathological evaluations of fracture healing scores calculated at 2 and 6 weeks of treatment in non-treated diabetes group (TD), Pioglitazone group (P), Linagliptin group (L), and Pioglitazone and Linagliptin group (PL).
All data are represented as Mean ± SD. *P group vs L group p < 0.05.
Figure 8
Figure 8. Histopathological evaluations of inflammations at 2 and 6 weeks of treatments in Non-treated diabetes group (TD), Pioglitazone group (P), Linagliptin group (L), and Pioglitazone and Linagliptin group (PL). All data are represented as Mean ± SD.
*L group vs P group p < 0.05. **L group vs PL group p < 0.05. ***P group vs TD group p < 0.05.
Figure 9
Figure 9. Microscopical images of cluster of differentiation (CD) CD 34 immunoreactivities detected at 2 and 6 weeks of treatments in non-treated diabetes group (TD), Pioglitazone group (P), Linagliptin group (L), and Pioglitazone and Linagliptin group (PL). (x40 magnification)
Figure 10
Figure 10. Microscopical images of vascular endothelial growth factor (VEGF) immunoreactivities detected at 2 and 6 weeks of treatments in non-treated diabetes group (TD), Pioglitazone group (P), Linagliptin group (L), and Pioglitazone and Linagliptin group (PL). (x40 magnification)
See this image and copyright information in PMC

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References

    1. Bone mineral density and fracture risk in type-2 diabetes mellitus: the Rotterdam Study. de Liefde II, van der Klift M, de Laet CE, van Daele PL, Hofman A, Pols HA. Osteoporos Int. 2005;16:1713–1720. - PubMed
    1. Bone, sweet bone--osteoporotic fractures in diabetes mellitus. Hamann C, Kirschner S, Günther KP, Hofbauer LC. Nat Rev Endocrinol. 2012;8:297–305. - PubMed
    1. Bone metabolism in male patients with type 2 diabetes. Achemlal L, Tellal S, Rkiouak F, et al. Clin Rheumatol. 2005;24:493–496. - PubMed
    1. Osteoporosis-associated fracture and diabetes. Kurra S, Fink DA, Siris ES. Endocrinol Metab Clin North Am. 2014;43:233–243. - PubMed
    1. Bone quality assessment in type 2 diabetes mellitus. Dhaliwal R, Cibula D, Ghosh C, Weinstock RS, Moses AM. Osteoporos Int. 2014;25:1969–1973. - PubMed

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