{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,14]],"date-time":"2026-02-14T11:14:27Z","timestamp":1771067667904,"version":"3.50.1"},"reference-count":54,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2023,5,31]],"date-time":"2023-05-31T00:00:00Z","timestamp":1685491200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Medicina"],"abstract":"<jats:p>In this experimental study, the prophylactic effect of systemically administered erythropoietin (EPO) in medication-related osteonecrosis of the jaw (MRONJ) was evaluated. The osteonecrosis model was established using 36 Sprague Dawley rats. EPO was systemically applied before and\/or after tooth extraction. Groups were formed based on the application time. All samples were evaluated histologically, histomorphometrically, and immunohistochemically. A statistically significant difference in new bone formation was observed between the groups (p &lt; 0.001). When new bone-formation rates were compared, no significant differences were observed between the control group and the EPO, ZA+PostEPO, and ZA+Pre-PostEPO groups (p = 1, 0.402, and 1, respectively); however, this rate was significantly lower in the ZA+PreEPO group (p = 0.021). No significant differences in new bone formation were observed between the ZA+PostEPO and ZA+PreEPO groups (p = 1); however, this rate was significantly higher in the ZA+Pre-PostEPO group (p = 0.009). The ZA+Pre-PostEPO group demonstrated significantly higher intensity level in VEGF protein expression than the other groups (p &lt; 0.001). Administering EPO two weeks pre-extraction and continuing EPO treatment for three weeks post-extraction in ZA-treated rats optimized the inflammatory reaction, increased angiogenesis by inducing VEGF, and positively affected bone healing. Further studies are needed to determine the exact durations and doses.<\/jats:p>","DOI":"10.3390\/medicina59061059","type":"journal-article","created":{"date-parts":[[2023,6,1]],"date-time":"2023-06-01T01:40:56Z","timestamp":1685583656000},"page":"1059","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Evaluation of Preventive Role of Systemically Applied Erythropoietin after Tooth Extraction in a Bisphosphonate-Induced MRONJ Model"],"prefix":"10.3390","volume":"59","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5564-5776","authenticated-orcid":false,"given":"Gonca","family":"Duygu","sequence":"first","affiliation":[{"name":"Oral and Maxillofacial Surgery Department, Faculty of Dentistry, Tekirdag Nam\u0131k Kemal University, Tekirdag 59030, T\u00fcrkiye"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7438-5834","authenticated-orcid":false,"given":"G\u00fcl Merve","family":"Yalcin-\u00dclker","sequence":"additional","affiliation":[{"name":"Oral and Maxillofacial Surgery Department, Faculty of Dentistry, Istanbul Okan University, Istanbul 34947, T\u00fcrkiye"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Murat","family":"G\u00fcnbatan","sequence":"additional","affiliation":[{"name":"Oral and Maxillofacial Surgery Department, Faculty of Dentistry, Istanbul Okan University, Istanbul 34947, T\u00fcrkiye"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7178-3335","authenticated-orcid":false,"given":"Merva","family":"Soluk-Tekkesin","sequence":"additional","affiliation":[{"name":"Department of Tumour Pathology, Institute of Oncology, Istanbul University, Istanbul 34093, T\u00fcrkiye"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ceyda","family":"\u00d6zcakir-Tomruk","sequence":"additional","affiliation":[{"name":"Oral and Maxillofacial Surgery Department, Faculty of Dentistry, Yeditepe University, Istanbul 34728, T\u00fcrkiye"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,5,31]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"297","DOI":"10.1016\/0002-9343(93)90282-T","article-title":"Single-dose intravenous therapy with pamidronate for the treatment of hypercalcemia of malignancy: Comparison of 30-, 60-, and 90-mg dosages","volume":"95","author":"Nussbaum","year":"1993","journal-title":"Am. J. Med."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1016\/j.ctrv.2018.06.007","article-title":"Medication-related osteonecrosis of the jaw: Prevention, diagnosis and management in patients with cancer and bone metastases","volume":"69","author":"Otto","year":"2018","journal-title":"Cancer Treat. Rev."},{"key":"ref_3","first-page":"2","article-title":"American Association of Oral and Maxillofacial Surgeons position paper on bisphosphonate-related osteonecrosis of the jaws\u20142009 update","volume":"67","author":"Ruggiero","year":"2009","journal-title":"J. Oral Maxillofac. Surg."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1938","DOI":"10.1016\/j.joms.2014.04.031","article-title":"American Association of Oral and Maxillofacial Surgeons position paper on medication-related osteonecrosis of the jaw\u20142014 update","volume":"72","author":"Ruggiero","year":"2014","journal-title":"J. Oral Maxillofac. Surg."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"920","DOI":"10.1016\/j.joms.2022.02.008","article-title":"American Association of Oral and Maxillofacial Surgeons\u2019 Position Paper on Medication-Related Osteonecrosis of the Jaws-2022 Update","volume":"80","author":"Ruggiero","year":"2022","journal-title":"J. Oral Maxillofac. Surg."},{"key":"ref_6","first-page":"237","article-title":"Effect of pamidronate on bone blood flow in oophorectomized rats","volume":"47","author":"Kapitola","year":"1998","journal-title":"Physiol. Res."},{"key":"ref_7","first-page":"1080","article-title":"Pamidronate induces modifications of circulating angiogenetic factors in cancer patients","volume":"8","author":"Santini","year":"2002","journal-title":"Clin. Cancer Res."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"806","DOI":"10.1093\/annonc\/mdg194","article-title":"Bisphosphonates: New antiangiogenic molecules in cancer treatment?","volume":"14","author":"Vincenzi","year":"2003","journal-title":"Ann. Oncol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1093\/ndt\/14.suppl_2.22","article-title":"The molecular biology of erythropoietin","volume":"14","author":"Lacombe","year":"1999","journal-title":"Nephrol. Dial. Transplant."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1890","DOI":"10.1096\/fj.14-259085","article-title":"Erythropoietin directly stimulates osteoclast precursors and induces bone loss","volume":"29","author":"Liron","year":"2015","journal-title":"FASEB J."},{"key":"ref_11","first-page":"829","article-title":"Erythropoietin induces the osteogenesis of periodontal mesenchymal stem cells from healthy and periodontitis sources via activation of the p38 MAPK pathway","volume":"41","author":"Wang","year":"2018","journal-title":"Int. J. Mol. Med."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"22","DOI":"10.3109\/08977194.2011.637034","article-title":"Effects of erythropoietin on the bone microenvironment","volume":"30","author":"McGee","year":"2012","journal-title":"Growth Factors"},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Shiozawa, Y., Jung, Y., Ziegler, A.M., Pedersen, E.A., Wang, J., Wang, Z., Song, J., Wang, J., Lee, C.H., and Sud, S. (2010). Erythropoietin couples hematopoiesis with bone formation. PLoS ONE, 5.","DOI":"10.1371\/journal.pone.0010853"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"2095","DOI":"10.1089\/ten.tea.2011.0742","article-title":"Erythropoietin modulates the structure of bone morphogenetic protein 2-engineered cranial bone","volume":"18","author":"Sun","year":"2012","journal-title":"Tissue Eng. Part A"},{"key":"ref_15","first-page":"465","article-title":"Erythropoietin is a multifunctional tissue-protective cytokine","volume":"2","author":"Erbayraktar","year":"2003","journal-title":"Curr. Hematol. Rep."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1","DOI":"10.3109\/17453674.2013.869716","article-title":"The effect of erythropoietin on bone","volume":"85","author":"Rolfing","year":"2014","journal-title":"Acta Orthop."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"2337","DOI":"10.1016\/j.joms.2008.06.082","article-title":"Effects of recombinant human erythropoietin on mandibular distraction osteogenesis","volume":"67","author":"Mihmanli","year":"2009","journal-title":"J. Oral Maxillofac. Surg."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1037","DOI":"10.1016\/j.bone.2011.08.004","article-title":"Erythropoietin stimulates bone formation, cell proliferation, and angiogenesis in a femoral segmental defect model in mice","volume":"49","author":"Holstein","year":"2011","journal-title":"Bone"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1002\/jor.21219","article-title":"Low dose erythropoietin stimulates bone healing in mice","volume":"29","author":"Garcia","year":"2011","journal-title":"J. Orthop. Res."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"386","DOI":"10.5812\/traumamon.7099","article-title":"Local erythropoietin injection in tibiofibular fracture healing","volume":"17","author":"Bakhshi","year":"2013","journal-title":"Trauma Mon."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"840","DOI":"10.3892\/ijmm.2014.1644","article-title":"Administration of erythropoietin exerts protective effects against glucocorticoid-induced osteonecrosis of the femoral head in rats","volume":"33","author":"Chen","year":"2014","journal-title":"Int. J. Mol. Med."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"425","DOI":"10.1080\/17453674.2016.1198200","article-title":"Increased bone formation in a rabbit long-bone defect model after single local and single systemic application of erythropoietin","volume":"87","author":"Omlor","year":"2016","journal-title":"Acta Orthop."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"329","DOI":"10.1016\/j.oooo.2013.11.490","article-title":"Does an alkaline environment prevent the development of bisphosphonate-related osteonecrosis of the jaw? An experimental study in rats","volume":"117","author":"Dayisoylu","year":"2014","journal-title":"Oral Surg. Oral Med. Oral Pathol. Oral Radiol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"854","DOI":"10.1016\/j.bjoms.2014.07.256","article-title":"Leucocyte-rich and platelet-rich fibrin for the treatment of bisphosphonate-related osteonecrosis of the jaw: A prospective feasibility study","volume":"52","author":"Kim","year":"2014","journal-title":"Br. J. Oral Maxillofac. Surg."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1176","DOI":"10.1016\/j.joms.2016.12.005","article-title":"Does the Addition of Bone Morphogenetic Protein 2 to Platelet-Rich Fibrin Improve Healing after Treatment for Medication-Related Osteonecrosis of the Jaw?","volume":"75","author":"Park","year":"2017","journal-title":"J. Oral Maxillofac. Surg."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"2971","DOI":"10.1200\/JCO.19.02192","article-title":"Teriparatide Promotes Bone Healing in Medication-Related Osteonecrosis of the Jaw: A Placebo-Controlled, Randomized Trial","volume":"38","author":"Sim","year":"2020","journal-title":"J. Clin. Oncol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"789","DOI":"10.1080\/0284186X.2020.1730004","article-title":"Mesenchymal stromal cells administration for osteonecrosis of the jaw caused by bisphosphonate: Report of two cases","volume":"59","author":"Orellana","year":"2020","journal-title":"Acta Oncol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"56","DOI":"10.4103\/2155-8213.183767","article-title":"Topikal erythropoietin as a novel preventive and therapeutic agent in bisphosphonate-related osteonecrosis of the jaw","volume":"7","author":"Nazeman","year":"2016","journal-title":"Dent. Hypotheses"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1111\/j.1365-2796.2008.02024.x","article-title":"Erythropoietin-mediated tissue protection: Reducing collateral damage from the primary injury response","volume":"264","author":"Brines","year":"2008","journal-title":"J. Intern. Med."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1111\/j.1365-2141.2008.07014.x","article-title":"The non-haematopoietic biological effects of erythropoietin","volume":"141","author":"Arcasoy","year":"2008","journal-title":"Br. J. Haematol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"3049","DOI":"10.1096\/fj.08-109991","article-title":"Effects of erythropoietin in skin wound healing are dose related","volume":"23","author":"Sorg","year":"2009","journal-title":"FASEB J."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"893","DOI":"10.1016\/j.lfs.2006.11.023","article-title":"Erythropoietin (EPO): EPO-receptor signaling improves early endochondral ossification and mechanical strength in fracture healing","volume":"80","author":"Holstein","year":"2007","journal-title":"Life Sci."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1607","DOI":"10.1007\/s00784-015-1639-5","article-title":"Evaluation of carbon nanotubes functionalized with sodium hyaluronate in the inflammatory processes for oral regenerative medicine applications","volume":"20","author":"Reis","year":"2016","journal-title":"Clin. Oral Investig."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"5481","DOI":"10.1002\/jcb.26710","article-title":"HMGB1-induced inflammatory response promotes bone healing in murine tooth extraction socket","volume":"119","author":"Aoyagi","year":"2018","journal-title":"J. Cell. Biochem."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"S4","DOI":"10.1097\/00005131-200511101-00002","article-title":"The science of fracture healing","volume":"19","author":"Einhorn","year":"2005","journal-title":"J. Orthop. Trauma"},{"key":"ref_36","first-page":"c265","article-title":"Inflammation\u2014A double edged sword in high-energy fractures?","volume":"87","author":"Bunn","year":"2005","journal-title":"J. Bone Joint Surg. Br."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1016\/S8756-3282(99)00236-7","article-title":"Reduction in bone formation and elevated bone resorption in ovariectomized rats with special reference to acute inflammation","volume":"26","author":"Tanizawa","year":"2000","journal-title":"Bone"},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Mag\u00e1n-Fern\u00e1ndez, A., Rasheed Al-Bakri, S.M., O\u2019Valle, F., Benavides-Reyes, C., Abad\u00eda-Molina, F., and Mesa, F. (2020). Neutrophil Extracellular Traps in Periodontitis. Cells, 9.","DOI":"10.3390\/cells9061494"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1042","DOI":"10.3346\/jkms.2007.22.6.1042","article-title":"Erythropoietin attenuates hyperoxia-induced lung injury by down-modulating inflammation in neonatal rats","volume":"22","author":"Lee","year":"2007","journal-title":"J. Korean Med. Sci."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"735","DOI":"10.1111\/jre.12870","article-title":"Resveratrol enhances bone formation by modulating inflammation in the mouse periodontitis model","volume":"56","author":"Adhikari","year":"2021","journal-title":"J. Periodontal Res."},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Kim, T.Y., Park, J.K., Prasad Aryal, Y., Lee, E.S., Neupane, S., Sung, S., Pokharel, E., Yeon, C.Y., Kim, J.Y., and Jung, J.K. (2020). Facilitation of Bone Healing Processes Based on the Developmental Function of Meox2 in Tooth Loss Lesion. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21228701"},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Kim\u00e1kov\u00e1, P., Sol\u00e1r, P., Sol\u00e1rov\u00e1, Z., Komel, R., and Debeljak, N. (2017). Erythropoietin and Its Angiogenic Activity. Int. J. Mol. Sci., 18.","DOI":"10.3390\/ijms18071519"},{"key":"ref_43","first-page":"189","article-title":"Erythropoietin does not affect TNF and IL-6 production directly","volume":"27","author":"Cervellini","year":"2013","journal-title":"J. Biol. Regul. Homeost. Agents"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"2354","DOI":"10.1016\/j.joms.2017.04.017","article-title":"Preventive Effect of Phosphodiesterase Inhibitor Pentoxifylline Against Medication-Related Osteonecrosis of the Jaw: An Animal Study","volume":"75","author":"Cumbul","year":"2017","journal-title":"J. Oral Maxillofac. Surg."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"556","DOI":"10.1016\/j.injury.2011.03.035","article-title":"Angiogenesis in bone regeneration","volume":"42","author":"Hankenson","year":"2011","journal-title":"Injury"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"541","DOI":"10.1177\/0003319709358697","article-title":"Review of the role of erythropoietin in critical leg ischemia","volume":"61","author":"Joshi","year":"2010","journal-title":"Angiology"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1007\/s11420-009-9129-4","article-title":"Vascular endothelial growth factor: An essential component of angiogenesis and fracture healing","volume":"6","author":"Beamer","year":"2009","journal-title":"HSS J."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1007","DOI":"10.1002\/jor.21083","article-title":"Endothelial progenitor cells promote fracture healing in a segmental bone defect model","volume":"28","author":"Atesok","year":"2010","journal-title":"J. Orthop. Res."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"434","DOI":"10.1016\/j.bone.2008.05.001","article-title":"Circulating endothelial\/skeletal progenitor cells for bone regeneration and healing","volume":"43","author":"Matsumoto","year":"2008","journal-title":"Bone"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"987625","DOI":"10.3389\/fphys.2022.987625","article-title":"Effects of erythropoietin on osteoblast in the tooth extraction socket in mice periodontitis model","volume":"13","author":"Bae","year":"2022","journal-title":"Front. Physiol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"509","DOI":"10.1172\/JCI82585","article-title":"Osteoblast-derived VEGF regulates osteoblast differentiation and bone formation during bone repair","volume":"126","author":"Hu","year":"2016","journal-title":"J. Clin. Investig."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"8755","DOI":"10.3892\/mmr.2017.7735","article-title":"Administration of erythropoietin prevents bone loss in osteonecrosis of the femoral head in mice","volume":"16","author":"Xu","year":"2017","journal-title":"Mol. Med. Rep."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"1139","DOI":"10.1097\/01.CCM.0000206468.18653.EC","article-title":"Recombinant human erythropoietin improves angiogenesis and wound healing in experimental burn wounds","volume":"34","author":"Galeano","year":"2006","journal-title":"Crit. Care Med."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"1470","DOI":"10.1359\/jbmr.2002.17.8.1470","article-title":"Localization of nitric oxide synthases during fracture healing","volume":"17","author":"Zhu","year":"2002","journal-title":"J. Bone Miner. Res."}],"container-title":["Medicina"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1648-9144\/59\/6\/1059\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T19:46:18Z","timestamp":1760125578000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1648-9144\/59\/6\/1059"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,5,31]]},"references-count":54,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2023,6]]}},"alternative-id":["medicina59061059"],"URL":"https:\/\/doi.org\/10.3390\/medicina59061059","relation":{},"ISSN":["1648-9144"],"issn-type":[{"value":"1648-9144","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,5,31]]}}}