{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,31]],"date-time":"2026-08-31T12:00:05Z","timestamp":1788177605512,"version":"build-2803163510"},"reference-count":55,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2021,9,28]],"date-time":"2021-09-28T00:00:00Z","timestamp":1632787200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Animals"],"abstract":"<jats:p>Nonsteroidal anti-inflammatory drugs (NSAIDs) are among the most commonly used postoperative analgesics, antipyretics, and anti-inflammatories, and they help prevent blood clotting. However, most NSAIDs delay bone healing. This study was aimed to investigate bone healing in a rabbit animal model by assessing the ability of flunixin meglumine (FM) and ketoprofen to induce fracture healing by examining histology, radiological changes, and vascular endothelial growth factor (VEGF) immunostaining during bone healing. For this purpose, 24 New Zealand rabbits were assigned to three groups: the control group, the FM group, and the ketoprofen group. Our results revealed that there were no intraoperative complications, and all surviving rabbits achieved full-weight bearing. Significant periosteal reaction and callus formation were confirmed at 2 postoperative weeks. Interestingly, FM enhanced callus formation, bone union, and remodeling in the FM group compared to the control and ketoprofen groups. FM enhanced bone healing through early collagen deposition and marked angiogenesis process activation by increasing the expression of VEGF. Our findings demonstrated, for the first time, the potential imperative action of FM in the bone healing process rather than other NSAIDs in animals.<\/jats:p>","DOI":"10.3390\/ani11102834","type":"journal-article","created":{"date-parts":[[2021,9,28]],"date-time":"2021-09-28T12:29:14Z","timestamp":1632832154000},"page":"2834","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Flunixin Meglumine Enhanced Bone Fracture Healing in Rabbits Associated with Activation of Early Collagen Deposition and Enhancement of Vascular Endothelial Growth Factor Expression"],"prefix":"10.3390","volume":"11","author":[{"given":"Mohamed","family":"Elgendy","sequence":"first","affiliation":[{"name":"Department of Surgery, Anesthesiology and Radiology, Faculty of Veterinary Medicine, Kafrelsheikh University, Kafrelsheikh 33516, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gamal","family":"Elsayad","sequence":"additional","affiliation":[{"name":"Department of Surgery, Anesthesiology and Radiology, Faculty of Veterinary Medicine, Kafrelsheikh University, Kafrelsheikh 33516, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Magdi","family":"Seleim","sequence":"additional","affiliation":[{"name":"Department of Surgery, Anesthesiology and Radiology, Faculty of Veterinary Medicine, Kafrelsheikh University, Kafrelsheikh 33516, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Walied","family":"Abdo","sequence":"additional","affiliation":[{"name":"Department of Pathology, Faculty of Veterinary Medicine, Kafrelsheikh University, Kafr Elsheikh 33516, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5324-0014","authenticated-orcid":false,"given":"Roua S.","family":"Baty","sequence":"additional","affiliation":[{"name":"Department of Biotechnology, College of Science, Taif University, P.O. Box 11099, Taif 21944, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4484-3678","authenticated-orcid":false,"given":"Ehab Kotb","family":"Elmahallawy","sequence":"additional","affiliation":[{"name":"Department of Zoonoses, Faculty of Veterinary Medicine, Sohag University, Sohag 82524, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8870-9652","authenticated-orcid":false,"given":"Ayman","family":"Atiba","sequence":"additional","affiliation":[{"name":"Department of Surgery, Anesthesiology and Radiology, Faculty of Veterinary Medicine, Kafrelsheikh University, Kafrelsheikh 33516, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,9,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"944","DOI":"10.14202\/vetworld.2018.944-952","article-title":"Effectiveness of platelet-rich fibrin matrix treated with silver nanoparticles in fracture healing in rabbit model","volume":"11","author":"Salih","year":"2018","journal-title":"Vet. World"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"935","DOI":"10.1517\/14740338.2011.589833","article-title":"The effect of antibiotics on bone healing: Current evidence","volume":"10","author":"Pountos","year":"2011","journal-title":"Expert Opin. Drug Saf."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1668","DOI":"10.3390\/ph3051668","article-title":"Effect of non-steroidal anti-inflammatory drugs on bone healing","volume":"3","author":"Cottrell","year":"2010","journal-title":"Pharmaceuticals"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"e330","DOI":"10.5435\/JAAOS-D-17-00727","article-title":"Effect of NSAIDs on bone healing rates: A meta-analysis","volume":"27","author":"Wheatley","year":"2019","journal-title":"J. Am. Acad. Orthop. Surg."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"116","DOI":"10.2106\/00004623-200401000-00017","article-title":"Effect of COX-2-specific inhibition on fracture-healing in the rat femur","volume":"86","author":"Brown","year":"2004","journal-title":"JBJS"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1809","DOI":"10.2147\/DDDT.S164565","article-title":"Positives and negatives of nonsteroidal anti-inflammatory drugs in bone healing: The effects of these drugs on bone repair","volume":"12","author":"Lisowska","year":"2018","journal-title":"Drug Des. Dev. Ther."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"606404","DOI":"10.1100\/2012\/606404","article-title":"Do nonsteroidal anti-inflammatory drugs affect bone healing? A critical analysis","volume":"2012","author":"Pountos","year":"2012","journal-title":"Sci. World J."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1016\/j.jphs.2016.11.003","article-title":"Celecoxib inhibits osteoblast maturation by suppressing the expression of Wnt target genes","volume":"133","author":"Nagano","year":"2017","journal-title":"J. Pharmacol. Sci."},{"key":"ref_9","first-page":"e4","article-title":"Nonsteroidal anti-inflammatory drugs and bone-healing: A systematic review of research quality","volume":"4","author":"Hutchinson","year":"2016","journal-title":"JBJS Rev."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"488","DOI":"10.2106\/JBJS.L.00462","article-title":"Effect of aspirin on bone healing in a rabbit ulnar osteotomy model","volume":"95","author":"Lack","year":"2013","journal-title":"JBJS"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"835","DOI":"10.1007\/s00167-009-0763-7","article-title":"Negative effects of parecoxib and indomethacin on tendon healing: An experimental study in rats","volume":"17","author":"Dimmen","year":"2009","journal-title":"Knee Surg. Sports Traumatol. Arthrosc."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"343","DOI":"10.1016\/j.mehy.2013.03.042","article-title":"NSAIDs can have adverse effects on bone healing","volume":"81","author":"Kool","year":"2013","journal-title":"Med. Hypotheses"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"545","DOI":"10.1002\/jor.24498","article-title":"Influence of Ibuprofen on Bone Healing After Colles\u2019 Fracture: A Randomized Controlled Clinical Trial","volume":"38","author":"Aliuskevicius","year":"2020","journal-title":"J. Orthop. Res."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"472","DOI":"10.1302\/2046-3758.810.BJR-2018-0341.R1","article-title":"Short-term perioperative parecoxib is not detrimental to shaft fracture healing in a rat model","volume":"8","author":"Hjorthaug","year":"2019","journal-title":"Bone Jt. Res."},{"key":"ref_15","first-page":"655","article-title":"Selective COX-2 Inhibitors: A Review of Their Structure-Activity Relationships","volume":"10","author":"Zarghi","year":"2011","journal-title":"Iran. J. Pharm. Res."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1121","DOI":"10.1038\/sj.bjp.0702897","article-title":"Cyclo-oxygenase-2: Pharmacology, physiology, biochemistry and relevance to NSAID therapy","volume":"128","author":"Mitchell","year":"1999","journal-title":"Br. J. Pharmacol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"442","DOI":"10.1046\/j.1365-2044.2000.01271.x","article-title":"Cyclo-oxygenase isoenzymes: Physiological and pharmacological role","volume":"55","author":"Kam","year":"2000","journal-title":"Anaesthesia"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"eaaw2108","DOI":"10.1126\/sciadv.aaw2108","article-title":"Cyclooxygenase 2 augments osteoblastic but suppresses chondrocytic differentiation of CD90+ skeletal stem cells in fracture sites","volume":"5","author":"Wasnik","year":"2019","journal-title":"Sci. Adv."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1753","DOI":"10.2147\/DDDT.S164562","article-title":"Lights and shadows of NSAIDs in bone healing: The role of prostaglandins in bone metabolism","volume":"12","author":"Lisowska","year":"2018","journal-title":"Drug Des. Dev. Ther."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1111\/j.1742-7843.2007.00149.x","article-title":"Non-steroidal anti-inflammatory drugs, cyclooxygenase-2 and the bone healing process","volume":"102","author":"Vuolteenaho","year":"2008","journal-title":"Basic Clin. Pharmacol. Toxicol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"3310","DOI":"10.1016\/j.actbio.2010.01.042","article-title":"A non-steroidal anti-inflammatory drug (ketoprofen) does not delay \u03b2-TCP bone graft healing","volume":"6","author":"Nyangoga","year":"2010","journal-title":"Acta Biomater."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"631","DOI":"10.3171\/SPI-07\/12\/631","article-title":"The effect of ketoprophen on lumbar spinal fusion healing in a rabbit model","volume":"7","author":"Urrutia","year":"2007","journal-title":"J. Neurosurg. Spine"},{"key":"ref_23","first-page":"233","article-title":"Effects of flunixin meglumine on experimental tendon wound healing: A histopathological and mechanical study in rabbits","volume":"4","author":"Behfar","year":"2013","journal-title":"Vet. Res. Forum Int. Q. J."},{"key":"ref_24","first-page":"2247","article-title":"Effect of flunixin meglumine on surgical wound strength and healing in the rat","volume":"47","author":"Donner","year":"1986","journal-title":"Am. J. Vet. Res."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"309","DOI":"10.1111\/jvp.12756","article-title":"Pharmacokinetics and pharmacodynamics of intravenous and transdermal flunixin meglumine in meat goats","volume":"42","author":"Reppert","year":"2019","journal-title":"J. Vet. Pharmacol. Ther."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"100210","DOI":"10.1016\/j.bonr.2019.100210","article-title":"Inhibition of vascular endothelial growth factor in young adult mice causes low bone blood flow and bone strength with no effect on bone mass in trabecular regions","volume":"10","author":"Lane","year":"2019","journal-title":"Bone Rep."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1753","DOI":"10.1007\/s00018-013-1282-8","article-title":"Vascular endothelial growth factors (VEGFs) and stroke","volume":"70","author":"Greenberg","year":"2013","journal-title":"Cell. Mol. Life Sci."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1007\/s12565-009-0026-1","article-title":"Regulation of endothelial cell differentiation and arterial specification by VEGF and Notch signaling","volume":"84","author":"Hirashima","year":"2009","journal-title":"Anat. Sci. Int."},{"key":"ref_29","first-page":"6917958","article-title":"Platelet-rich plasma, hydroxyapatite, and chitosan in the bone and cartilaginous regeneration of femoral trochlea in rabbits: Clinical, radiographic, and histomorphometric evaluations","volume":"2018","year":"2018","journal-title":"J. Healthc. Eng."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"99","DOI":"10.22203\/eCM.v034a07","article-title":"Reamed locked intramedullary nailing for studying femur fracture and its complications","volume":"34","author":"Yoshino","year":"2017","journal-title":"Eur. Cell Mater."},{"key":"ref_31","first-page":"37","article-title":"Management of femoral fracture with the use of horn peg in canine","volume":"3","author":"Gahlod","year":"2010","journal-title":"Vet. World"},{"key":"ref_32","unstructured":"Suvarna, K.S., Layton, C., and Bancroft, J.D. (2019). Bancroft\u2019s Theory and Practice of Histological Techniques, Elsevier. [8th ed.]."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1016\/S0030-5898(20)30381-3","article-title":"Biology of cancellous bone grafts","volume":"18","author":"Heiple","year":"1987","journal-title":"Orthop. Clin. N. Am."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1007\/s10195-008-0006-6","article-title":"Xenogenic demineralized bone matrix and fresh autogenous cortical bone effects on experimental bone healing: Radiological, histopathological and biomechanical evaluation","volume":"9","author":"Bigham","year":"2008","journal-title":"J. Orthop. Traumatol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"120","DOI":"10.1016\/j.taap.2018.12.020","article-title":"Olmesartan ameliorates chemically-induced ulcerative colitis in rats via modulating NF\u03baB and Nrf-2\/HO-1 signaling crosstalk","volume":"364","author":"Saber","year":"2019","journal-title":"Toxicol. Appl. Pharmacol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1038\/nrrheum.2012.1","article-title":"Fracture healing under healthy and inflammatory conditions","volume":"8","author":"Claes","year":"2012","journal-title":"Nat. Rev. Rheumatol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"140","DOI":"10.1177\/1460408613486571","article-title":"Factors influencing fracture healing","volume":"15","author":"Mirhadi","year":"2013","journal-title":"Trauma"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1151","DOI":"10.1016\/j.injury.2008.12.011","article-title":"Factors Affecting the Fracture Healing in Treatment of Tibial Shaft Fractures With Circular External Fixator","volume":"40","author":"Iltar","year":"2009","journal-title":"Injury"},{"key":"ref_39","first-page":"53","article-title":"Histpathological Anti-inflammatory Effects of Flunixin Meglumine and Ketoprofen on Excised Rat Tendon","volume":"10","author":"Jarolmasjed","year":"2015","journal-title":"Iran. J. Vet. Surg."},{"key":"ref_40","first-page":"69","article-title":"Effect of Ketoprofen and Paracetamol on Bone Mineral Density in Rabbits","volume":"7","author":"Yaseen","year":"2018","journal-title":"Int. J. Enhanc. Res. Sci. Technol. Eng."},{"key":"ref_41","first-page":"99","article-title":"Evaluation of Adverse Effects of Ketoprofen Following Experimental Tibial Osteotomy in Cats","volume":"12","author":"Moarabi","year":"2016","journal-title":"Iran. Vet. J."},{"key":"ref_42","first-page":"234","article-title":"X-ray diagnosis of healing fractures in rabbits","volume":"142","author":"Nicholls","year":"1979","journal-title":"Clin. Orthop. Relat. Res."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"634","DOI":"10.2460\/ajvr.72.5.634","article-title":"Effects of long-term administration of carprofen on healing of a tibial osteotomy in dogs","volume":"72","author":"Ochi","year":"2011","journal-title":"Am. J. Vet. Res."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1038\/nrrheum.2014.164","article-title":"Fracture healing: Mechanisms and interventions","volume":"11","author":"Einhorn","year":"2015","journal-title":"Nat. Rev. Rheumatol."},{"key":"ref_45","first-page":"169","article-title":"Effect of flunixin meglumine on surgical skin wound healing in the rabbit","volume":"24","author":"Tovar","year":"1992","journal-title":"Arch. Med. Vet."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"120","DOI":"10.1016\/j.jmbbm.2015.08.012","article-title":"A direct role of collagen glycation in bone fracture","volume":"52","author":"Poundarik","year":"2015","journal-title":"J. Mech. Behav. Biomed. Mater."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"104766","DOI":"10.1016\/j.jmbbm.2021.104766","article-title":"Removal of glycosaminoglycans affects the in situ mechanical behavior of extrafibrillar matrix in bone","volume":"123","author":"Han","year":"2021","journal-title":"J. Mech. Behav. Biomed. Mater."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1016\/j.actbio.2021.02.042","article-title":"Cryptic ligand on collagen matrix unveiled by MMP13 accelerates bone tissue regeneration via MMP13\/Integrin \u03b13\/RUNX2 feedback loop","volume":"125","author":"Arai","year":"2021","journal-title":"Acta Biomater."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1304","DOI":"10.1002\/biot.201400305","article-title":"Bioactive nanoparticles stimulate bone tissue formation in bioprinted three-dimensional scaffold and human mesenchymal stem cells","volume":"9","author":"Gao","year":"2014","journal-title":"Biotechnol. J."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"101096","DOI":"10.1016\/j.bonr.2021.101096","article-title":"Plant-derived soybean peroxidase stimulates osteoblast collagen biosynthesis, matrix mineralization, and accelerates bone regeneration in a sheep model","volume":"14","author":"Barker","year":"2021","journal-title":"Bone Rep."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"233","DOI":"10.4067\/S0716-97602003000200013","article-title":"Effects of steroidal and non steroidal drugs on the neovascularization response induced by tumoral TA3 supernatant on CAM from chick embryo","volume":"36","author":"Zuniga","year":"2003","journal-title":"Biol. Res."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1016\/j.archoralbio.2018.05.006","article-title":"Inhibition of VEGF gene expression in osteoblast cells by different NSAIDs","volume":"92","author":"Ruiz","year":"2018","journal-title":"Arch. Oral Biol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"1168","DOI":"10.1016\/j.orthres.2004.03.015","article-title":"Effect of ketoprofen in topical formulation on vascular endothelial growth factor expression and tumor growth in nude mice with osteosarcoma","volume":"22","author":"Sakayama","year":"2004","journal-title":"J. Orthop. Res."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1002\/jor.24170","article-title":"Cellular biology of fracture healing","volume":"37","author":"Bahney","year":"2019","journal-title":"J. Orthop. Res."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"821","DOI":"10.1002\/jor.24267","article-title":"VEGF-loaded mineral-coated microparticles improve bone repair and are associated with increased expression of epo and RUNX-2 in murine non-unions","volume":"37","author":"Orth","year":"2019","journal-title":"J. Orthop. Res."}],"container-title":["Animals"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-2615\/11\/10\/2834\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T07:06:31Z","timestamp":1760166391000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-2615\/11\/10\/2834"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,9,28]]},"references-count":55,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2021,10]]}},"alternative-id":["ani11102834"],"URL":"https:\/\/doi.org\/10.3390\/ani11102834","relation":{},"ISSN":["2076-2615"],"issn-type":[{"value":"2076-2615","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,9,28]]}}}