Effect of an oral antidiabetic, sitagliptin, a DPP-4 inhibitor, on bone remodeling: study in ovariectomized rats
DOI:
https://doi.org/10.5902/2236583493205Palabras clave:
Dipeptidyl Peptidase 4, Dipeptidyl Peptidase IV Inhibitors, Osteoporosis, Bone Fractures, BoneResumen
Objective: To evaluate the effects of sitagliptin, a DPP-4 inhibitor, on bone remodeling using dynamic histomorphometry and assess DPP4 gene expression in bone tissue of ovariectomized (OVX) rats, a model of hypoestrogenism. Method: Non-diabetic female Wistar rats were divided into five groups: OVX-S (ovariectomized, sitagliptin-treated, n=9), OVX (ovariectomized, saline-treated, n=7), SHAM-S (sham-operated, sitagliptin-treated, n=10), SHAM (sham-operated, saline-treated, n=7), and control (n=7). Sitagliptin (25 mg/kg) or saline was administered daily via gavage for 13 weeks post-surgery. Bone histomorphometry of the right tibia assessed structural (BV/TV, Tb.Th, Tb.Sp, Tb.N), remodeling static (OS/BS, O.Th, ES/BS) and dynamic (MS/BS, MAR, BFR/BS) parameters. DPP4 gene expression in the right femur was analyzed using RT-qPCR. Statistical analyses included ANCOVA and Kruskal-Wallis tests (p<0.05). Results: Sitagliptin mitigated bone resorption in OVX-S compared to OVX. Structural parameters showed lower BV/TV and Tb.N, and higher Tb.Sp in OVX and OVX-S versus SHAM, SHAM-S, and control, with OVX-S having smaller Tb.Sp than OVX (p=0.012). Static parameters indicated higher OS/BS in OVX-S versus SHAM-S (p<0.04). Dynamic parameters revealed that the ovariectomized (OVX) group demonstrated greater number of fluorescent labels and therefore a higher mineralized surface (MS/BS) than the OVX-S (p<0.01), indicative that sitagliptin effectively mitigated increased bone resorption associated with hypoestrogenism. Dynamic parameters also revealed greater BFR/BS in OVX compared to all groups (p<0.001). DPP4 expression was significantly lower in OVX-S and SHAM-S versus OVX (p<0.01). Conclusion: Sitagliptin reduces bone remodeling in hypoestrogenic states, likely by decreasing resorption, as shown by histomorphometry and reduced DPP4 expression, suggesting its potential to prevent bone loss in conditions like menopause.
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Röhrborn D, Wronkowitz N, Eckel J. DPP4 in diabetes. Front Immunol. 2015;6:1–20. DOI: https://doi.org/10.3389/fimmu.2015.00386
Mulvihill EE, Drucker DJ. Pharmacology, physiology, and mechanisms of action of dipeptidyl peptidase-4 inhibitors. Endocr Rev. 2014;35(6):992–1019. DOI: https://doi.org/10.1210/er.2014-1035
Drucker DJ. The role of gut hormones in glucose homeostasis. J Clin Invest [Internet]. 2007 [cited 2018 Jun 27];117(1):24–32. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1716213/pdf/JCI0730076.pdf DOI: https://doi.org/10.1172/JCI30076
Compston J. Type 2 diabetes mellitus and bone. J Intern Med. 2018;283(2):140–53. DOI: https://doi.org/10.1111/joim.12725
Bonaccorsi G, Piva I, Greco P, Cervellati C. Oxidative stress as a possible pathogenic cofactor of post-menopausal osteoporosis: Existing evidence in support of the axis oestrogen deficiency-redox imbalance-bone loss. Indian J Med Res. 2018;147(4):341–51. DOI: https://doi.org/10.4103/ijmr.IJMR_524_18
Xue C, Luo H, Wang L, Deng Q, Kui W, Da W, et al. Aconine attenuates osteoclast-mediated bone resorption and ferroptosis to improve osteoporosis via inhibiting NF-κB signaling. Front Endocrinol. 2023;14. DOI: https://doi.org/10.3389/fendo.2023.1234563
Weivoda MM, Chew CK, Monroe DG, Farr JN, Atkinson EJ, Geske JR, et al. Identification of osteoclast-osteoblast coupling factors in humans reveals links between bone and energy metabolism. Nat Commun. 2020;11(1):87. DOI: https://doi.org/10.1038/s41467-019-14003-6
Glorie L, Behets GJ, Baerts L, Meester I De, Haese PCD, Verhulst A. DPP IV inhibitor treatment attenuates bone loss and improves mechanical bone strength in male diabetic rats. Am J Physiol Endocrinol Metab. 2014;307(5):447–55. DOI: https://doi.org/10.1152/ajpendo.00217.2014
Wang C, Xiao F, Qu X, Zhai Z, Hu G, Chen X, et al. Sitagliptin, an anti-diabetic drug, suppresses estrogen deficiency-induced osteoporosis in vivo and inhibits RANKL-induced osteoclast formation and bone resorption in vitro. Front Pharmacol. 2017;8:407. DOI: https://doi.org/10.3389/fphar.2017.00407
Kyle KA, Willett TL, Baggio LL, Drucker DJ, Grynpas MD. Differential Effects of PPAR- ␥ Activation versus Chemical or Genetic Reduction of DPP-4 Activity on Bone Quality in Mice. Endocrinology. 2011;152(2):457-67. DOI: https://doi.org/10.1210/en.2010-1098
Yang Y, Zhao C, Liang J, Yu M, Qu X. Effect of Dipeptidyl Peptidase-4 Inhibitors on Bone Metabolism and the Possible Underlying Mechanisms. Front Pharmacol. 2017;8:1–9. DOI: https://doi.org/10.3389/fphar.2017.00487
Chai S, Liu F, Yang Z, Yu S, Liu Z, Yang Q, et al. Risk of Fracture With Dipeptidyl Peptidase-4 Inhibitors, Glucagon-like Peptide-1 Receptor Agonists, or Sodium-Glucose Cotransporter-2 Inhibitors in Patients With Type 2 Diabetes Mellitus: A Systematic Review and Network Meta-analysis Combining 177 Randomized Controlled Trials With a Median Follow-Up of 26 weeks. Front Pharmacol. 2022 Jul 1;13:825417. DOI: https://doi.org/10.3389/fphar.2022.825417
Fu J, Zhu J, Hao Y, et al. Dipeptidyl peptidase-4 inhibitors and fracture risk: an updated meta-analysis of randomized clinical trials. Sci Rep. 2016;6:29104. doi:10.1038/srep29104. DOI: https://doi.org/10.1038/srep29104
Zhang YS, Zheng YD, Yuan Y, Chen SC, Xie BC. Effects of Anti-Diabetic Drugs on Fracture Risk: A Systematic Review and Network Meta-Analysis. Front Endocrinol (Lausanne). 2021;12. DOI: https://doi.org/10.3389/fendo.2021.735824
Yang J, Huang C, Wu S, Xu Y, Cai T, Chai S, et al. The effects of dipeptidyl peptidase-4 inhibitors on bone fracture among patients with type 2 diabetes mellitus: A network meta-analysis of randomized controlled trials. PLoS One. 2017;12(12). DOI: https://doi.org/10.1371/journal.pone.0187537
Mosenzon O, Wei C, Davidson J, Scirica BM, Yanuv I, Rozenberg A, et al. Incidence of fractures in patients with type 2 diabetes in the SAVOR-TIMI 53 trial. Diabetes Care. 2015;38(11):2142–50. DOI: https://doi.org/10.2337/dc15-1068
Kalaitzoglou E, Fowlkes JL, Popescu I, Thrailkill KM. Diabetes pharmacotherapy and effects on the musculoskeletal system. Diabetes Metab Res Rev. 2019;35(2). DOI: https://doi.org/10.1002/dmrr.3100
Glorie L, Haese PCD, Verhulst A. Boning up on DPP4, DPP4 substrates, and DPP4-adipokine interactions: Logical reasoning and known facts about bone related effects of DPP4 inhibitors. Bone [Internet]. 2016;92:37–49. Available from: http://dx.doi.org/10.1016/j.bone.2016.08.009 DOI: https://doi.org/10.1016/j.bone.2016.08.009
Baggio LL, Varin EM, Koehler JA, Cao X, Lokhnygina Y, Stevens SR, et al. Plasma levels of DPP4 activity and sDPP4 are dissociated from inflammation in mice and humans. Nat Commun. 2020;11(1). DOI: https://doi.org/10.1038/s41467-020-17556-z
Dempster DW, Compston JE, Drezner MK, Glorieux FH, Kanis JA, Malluche H, et al. Standardized Nomenclature, Symbols, and Units for the ASBMR Histomorphometry Nomenclature Committee. Journal of Bone and Mineral Research. 2013;28(1):1–16. DOI: https://doi.org/10.1002/jbmr.1805
Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2-ΔΔCT method. Methods. 2001;25(4):402–8. DOI: https://doi.org/10.1006/meth.2001.1262
Blanca MJ, Arnau J, López-Montiel D, Bono R, Bendayan R. Skewness and kurtosis in real data samples. Methodology. 2013;9(2):78–84. doi:10.1027/1614-2241/a000057. DOI: https://doi.org/10.1027/1614-2241/a000057
El-Marasy SA, Abdel-Rahman RF, Abd-Elsalam RM, Ogaly HA, Allam RM. Anti-osteoporotic effect of sitagliptin in an osteoporosis model of ovariectomized rats: role of RUNX2 and RANKL/OPG ratio. Naunyn Schmiedebergs Arch Pharmacol. 2025 May 21. doi:10.1007/s00210-025-04145-4. DOI: https://doi.org/10.1007/s00210-025-04145-4
T. Cusick. Bone loss in the oestrogen-depleted rat is not exacerbated by sitagliptin, either alone or in combination with a thiazolidinedione. Diabetes Obes Metab. 2013;15(954):954–7. DOI: https://doi.org/10.1111/dom.12109
He J, Zhao D, Peng B, Wang X, Wang S, Zhao X, et al. A novel mechanism of Vildagliptin in regulating bone metabolism and mitigating osteoporosis. Int Immunopharmacol. 2024;130. DOI: https://doi.org/10.1016/j.intimp.2024.111671
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Derechos de autor 2025 Luciana Muniz Pechmann, Vicente Florentino Castaldo Andrade, Thais Andrade Costa Casagrande, Rafaela Ceron, Leticia Capote dos Santos, Edneia Amancio de Souza Ramos Cavalieiri, Gabriela Casani Cardoso, Regiane Stafim da Cunha, Carolina Aguiar Moreira
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