A Model for Osteonecrosis of the Jaw with Zoledronate Treatment following Repeated Major Trauma
This study aims to develop a reproducible rat model for post-traumatic bisphosphonate-related osteonecrosis of the jaw (BRONJ). In our previous studies using dental extraction as an inducing factor, only 30%-60% of zoledronate-treated animals fulfilled the definition of clinical BRONJ. We modified t...
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| creator | Howie, R Nicole Borke, James L Kurago, Zoya Daoudi, Asma Cray, James Zakhary, Ibrahim E Brown, Tara L Raley, J Nathan Tran, Loan T Messer, Regina Medani, Fardous Elsalanty, Mohammed E |
| description | This study aims to develop a reproducible rat model for post-traumatic bisphosphonate-related osteonecrosis of the jaw (BRONJ). In our previous studies using dental extraction as an inducing factor, only 30%-60% of zoledronate-treated animals fulfilled the definition of clinical BRONJ. We modified the zoledronate regimen and introduced repeated surgical extraction to illicit quantifiable BRONJ in all animals. Eighty retired-breeder female Sprague-Dawley rats were divided between the treatment (i.v. zoledronate; 80 μg/kg/week for 13 weeks) and control (saline) groups. On week 13, the left mandibular first molar was surgically extracted, followed by the second molar a week later. Animals were euthanized at 1-week, 2-weeks, and 8-weeks following extraction. The occurrence and severity of BRONJ were scored in each animal based on gross and MicroCT analysis. Parameters of bone formation and osteoclast functions at the extraction site were compared between groups. All zoledronate-treated animals developed a severe case of BRONJ that fulfilled the clinical definition of the condition in humans. Osteoclast attachment continued to be defective eight weeks after stopping the treatment. There were no signs of kidney or liver toxicity. Our data confirmed that repeated surgical extraction (major trauma) by itself consistently precipitated massive bone necrosis in ZA-treated animals, eliminating the need to induce pre-existing infection or comorbidity. These results will be the basis for further studies examining the in-vivo pathogenesis and prevention of BRONJ. |
| doi_str_mv | 10.1371/journal.pone.0132520 |
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In our previous studies using dental extraction as an inducing factor, only 30%-60% of zoledronate-treated animals fulfilled the definition of clinical BRONJ. We modified the zoledronate regimen and introduced repeated surgical extraction to illicit quantifiable BRONJ in all animals. Eighty retired-breeder female Sprague-Dawley rats were divided between the treatment (i.v. zoledronate; 80 μg/kg/week for 13 weeks) and control (saline) groups. On week 13, the left mandibular first molar was surgically extracted, followed by the second molar a week later. Animals were euthanized at 1-week, 2-weeks, and 8-weeks following extraction. The occurrence and severity of BRONJ were scored in each animal based on gross and MicroCT analysis. Parameters of bone formation and osteoclast functions at the extraction site were compared between groups. All zoledronate-treated animals developed a severe case of BRONJ that fulfilled the clinical definition of the condition in humans. Osteoclast attachment continued to be defective eight weeks after stopping the treatment. There were no signs of kidney or liver toxicity. Our data confirmed that repeated surgical extraction (major trauma) by itself consistently precipitated massive bone necrosis in ZA-treated animals, eliminating the need to induce pre-existing infection or comorbidity. These results will be the basis for further studies examining the in-vivo pathogenesis and prevention of BRONJ.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0132520</identifier><identifier>PMID: 26186665</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Acid Phosphatase - metabolism ; Analysis ; Animals ; Auditory defects ; Biocompatibility ; Biomedical materials ; Bisphosphonate-Associated Osteonecrosis of the Jaw - diagnostic imaging ; Bisphosphonate-Associated Osteonecrosis of the Jaw - etiology ; Bisphosphonate-Associated Osteonecrosis of the Jaw - pathology ; Bone disorder agents ; Bone growth ; Comorbidity ; Computed tomography ; Dentistry ; Diphosphonates - adverse effects ; Disease Models, Animal ; Drug dosages ; Female ; Imidazoles - adverse effects ; Infections ; Isoenzymes - metabolism ; Jaw ; Kidney - drug effects ; Kidney - pathology ; Kidneys ; Liver ; Liver - drug effects ; Liver - pathology ; Mandible ; Mandible - diagnostic imaging ; Mandible - drug effects ; Mandible - pathology ; Medicine ; Osteoclasts - drug effects ; Osteoclasts - pathology ; Osteogenesis ; Osteonecrosis ; Pathogenesis ; Rats ; Rats, Sprague-Dawley ; Rodents ; Studies ; Surgeons ; Surgery ; Systematic review ; Tartrate-Resistant Acid Phosphatase ; Tooth Extraction ; Toxicity ; Trauma ; Wound Healing - drug effects ; Wounds and Injuries - complications ; X-Ray Microtomography ; Zoledronic Acid</subject><ispartof>PloS one, 2015-07, Vol.10 (7), p.e0132520</ispartof><rights>COPYRIGHT 2015 Public Library of Science</rights><rights>2015 Howie et al. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2015 Howie et al 2015 Howie et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c718t-20f8bd38d552e84f17e8d3137f8ec2feb3515d1e991f65db946f0339b7db8a343</citedby><cites>FETCH-LOGICAL-c718t-20f8bd38d552e84f17e8d3137f8ec2feb3515d1e991f65db946f0339b7db8a343</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4505856/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4505856/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,2095,2914,23846,27903,27904,53770,53772,79347,79348</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/26186665$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Heymann, Dominique</contributor><creatorcontrib>Howie, R Nicole</creatorcontrib><creatorcontrib>Borke, James L</creatorcontrib><creatorcontrib>Kurago, Zoya</creatorcontrib><creatorcontrib>Daoudi, Asma</creatorcontrib><creatorcontrib>Cray, James</creatorcontrib><creatorcontrib>Zakhary, Ibrahim E</creatorcontrib><creatorcontrib>Brown, Tara L</creatorcontrib><creatorcontrib>Raley, J Nathan</creatorcontrib><creatorcontrib>Tran, Loan T</creatorcontrib><creatorcontrib>Messer, Regina</creatorcontrib><creatorcontrib>Medani, Fardous</creatorcontrib><creatorcontrib>Elsalanty, Mohammed E</creatorcontrib><title>A Model for Osteonecrosis of the Jaw with Zoledronate Treatment following Repeated Major Trauma</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>This study aims to develop a reproducible rat model for post-traumatic bisphosphonate-related osteonecrosis of the jaw (BRONJ). In our previous studies using dental extraction as an inducing factor, only 30%-60% of zoledronate-treated animals fulfilled the definition of clinical BRONJ. We modified the zoledronate regimen and introduced repeated surgical extraction to illicit quantifiable BRONJ in all animals. Eighty retired-breeder female Sprague-Dawley rats were divided between the treatment (i.v. zoledronate; 80 μg/kg/week for 13 weeks) and control (saline) groups. On week 13, the left mandibular first molar was surgically extracted, followed by the second molar a week later. Animals were euthanized at 1-week, 2-weeks, and 8-weeks following extraction. The occurrence and severity of BRONJ were scored in each animal based on gross and MicroCT analysis. Parameters of bone formation and osteoclast functions at the extraction site were compared between groups. All zoledronate-treated animals developed a severe case of BRONJ that fulfilled the clinical definition of the condition in humans. Osteoclast attachment continued to be defective eight weeks after stopping the treatment. There were no signs of kidney or liver toxicity. Our data confirmed that repeated surgical extraction (major trauma) by itself consistently precipitated massive bone necrosis in ZA-treated animals, eliminating the need to induce pre-existing infection or comorbidity. These results will be the basis for further studies examining the in-vivo pathogenesis and prevention of BRONJ.</description><subject>Acid Phosphatase - metabolism</subject><subject>Analysis</subject><subject>Animals</subject><subject>Auditory defects</subject><subject>Biocompatibility</subject><subject>Biomedical materials</subject><subject>Bisphosphonate-Associated Osteonecrosis of the Jaw - diagnostic imaging</subject><subject>Bisphosphonate-Associated Osteonecrosis of the Jaw - etiology</subject><subject>Bisphosphonate-Associated Osteonecrosis of the Jaw - pathology</subject><subject>Bone disorder agents</subject><subject>Bone growth</subject><subject>Comorbidity</subject><subject>Computed tomography</subject><subject>Dentistry</subject><subject>Diphosphonates - adverse effects</subject><subject>Disease Models, Animal</subject><subject>Drug dosages</subject><subject>Female</subject><subject>Imidazoles - adverse effects</subject><subject>Infections</subject><subject>Isoenzymes - metabolism</subject><subject>Jaw</subject><subject>Kidney - drug effects</subject><subject>Kidney - pathology</subject><subject>Kidneys</subject><subject>Liver</subject><subject>Liver - drug effects</subject><subject>Liver - pathology</subject><subject>Mandible</subject><subject>Mandible - diagnostic imaging</subject><subject>Mandible - drug effects</subject><subject>Mandible - pathology</subject><subject>Medicine</subject><subject>Osteoclasts - drug effects</subject><subject>Osteoclasts - pathology</subject><subject>Osteogenesis</subject><subject>Osteonecrosis</subject><subject>Pathogenesis</subject><subject>Rats</subject><subject>Rats, Sprague-Dawley</subject><subject>Rodents</subject><subject>Studies</subject><subject>Surgeons</subject><subject>Surgery</subject><subject>Systematic review</subject><subject>Tartrate-Resistant Acid Phosphatase</subject><subject>Tooth Extraction</subject><subject>Toxicity</subject><subject>Trauma</subject><subject>Wound Healing - drug effects</subject><subject>Wounds and Injuries - complications</subject><subject>X-Ray Microtomography</subject><subject>Zoledronic Acid</subject><issn>1932-6203</issn><issn>1932-6203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2015</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><sourceid>DOA</sourceid><recordid>eNqNkl2L1DAYhYso7rr6D0QLguDFjPlo2vRmYVj8GNllYB298CakzZtOhrYZk9TRf2_G6S5TUJBeJLx5zml6epLkOUZzTAv8dmsH18t2vrM9zBGmhBH0IDnHJSWznCD68GR_ljzxfosQozzPHydnJMdxk7PzRCzSG6ugTbV16coHiG61s9741Oo0bCD9JPfp3oRN-s22oJztZYB07UCGDvoQdW1r96Zv0lvYxSGo9EZuo9nayaGTT5NHWrYeno3rRfLl_bv11cfZ9erD8mpxPasLzMOMIM0rRblijADPNC6AKxq_U3OoiYaKMswUhrLEOmeqKrNcI0rLqlAVlzSjF8nLo--utV6M2XiB85IjklHKIrE8EsrKrdg500n3S1hpxJ-BdY2QLpi6BQFa1YTLosSlynBWyYoinhUKySKHAlT0uhzfNlQdqDoG4WQ7MZ2e9GYjGvtDZAwxzvJo8Go0cPb7AD7848oj1ch4K9NrG83qzvhaLDJCMM1LVkRq_hcqPgo6U8f_qU2cTwRvJoLIBPgZGjl4L5afb_-fXX2dsq9P2A3INmy8bYdgbO-nYHYED03zDvR9chiJQ7nv0hCHcoux3FH24jT1e9Fdm-lvpD70yQ</recordid><startdate>20150717</startdate><enddate>20150717</enddate><creator>Howie, R Nicole</creator><creator>Borke, James L</creator><creator>Kurago, Zoya</creator><creator>Daoudi, Asma</creator><creator>Cray, James</creator><creator>Zakhary, Ibrahim E</creator><creator>Brown, Tara L</creator><creator>Raley, J Nathan</creator><creator>Tran, Loan T</creator><creator>Messer, Regina</creator><creator>Medani, Fardous</creator><creator>Elsalanty, Mohammed E</creator><general>Public Library of Science</general><general>Public Library of Science (PLoS)</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>IOV</scope><scope>ISR</scope><scope>3V.</scope><scope>7QG</scope><scope>7QL</scope><scope>7QO</scope><scope>7RV</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TG</scope><scope>7TM</scope><scope>7U9</scope><scope>7X2</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FD</scope><scope>8FE</scope><scope>8FG</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABJCF</scope><scope>ABUWG</scope><scope>AEUYN</scope><scope>AFKRA</scope><scope>ARAPS</scope><scope>ATCPS</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BGLVJ</scope><scope>BHPHI</scope><scope>C1K</scope><scope>CCPQU</scope><scope>D1I</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>KB.</scope><scope>KB0</scope><scope>KL.</scope><scope>L6V</scope><scope>LK8</scope><scope>M0K</scope><scope>M0S</scope><scope>M1P</scope><scope>M7N</scope><scope>M7P</scope><scope>M7S</scope><scope>NAPCQ</scope><scope>P5Z</scope><scope>P62</scope><scope>P64</scope><scope>PATMY</scope><scope>PDBOC</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>PTHSS</scope><scope>PYCSY</scope><scope>RC3</scope><scope>5PM</scope><scope>DOA</scope></search><sort><creationdate>20150717</creationdate><title>A Model for Osteonecrosis of the Jaw with Zoledronate Treatment following Repeated Major Trauma</title><author>Howie, R Nicole ; Borke, James L ; Kurago, Zoya ; Daoudi, Asma ; Cray, James ; Zakhary, Ibrahim E ; Brown, Tara L ; Raley, J Nathan ; Tran, Loan T ; Messer, Regina ; Medani, Fardous ; Elsalanty, Mohammed E</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c718t-20f8bd38d552e84f17e8d3137f8ec2feb3515d1e991f65db946f0339b7db8a343</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2015</creationdate><topic>Acid Phosphatase - metabolism</topic><topic>Analysis</topic><topic>Animals</topic><topic>Auditory defects</topic><topic>Biocompatibility</topic><topic>Biomedical materials</topic><topic>Bisphosphonate-Associated Osteonecrosis of the Jaw - diagnostic imaging</topic><topic>Bisphosphonate-Associated Osteonecrosis of the Jaw - etiology</topic><topic>Bisphosphonate-Associated Osteonecrosis of the Jaw - pathology</topic><topic>Bone disorder agents</topic><topic>Bone growth</topic><topic>Comorbidity</topic><topic>Computed tomography</topic><topic>Dentistry</topic><topic>Diphosphonates - adverse effects</topic><topic>Disease Models, Animal</topic><topic>Drug dosages</topic><topic>Female</topic><topic>Imidazoles - adverse effects</topic><topic>Infections</topic><topic>Isoenzymes - metabolism</topic><topic>Jaw</topic><topic>Kidney - drug effects</topic><topic>Kidney - pathology</topic><topic>Kidneys</topic><topic>Liver</topic><topic>Liver - drug effects</topic><topic>Liver - pathology</topic><topic>Mandible</topic><topic>Mandible - 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In our previous studies using dental extraction as an inducing factor, only 30%-60% of zoledronate-treated animals fulfilled the definition of clinical BRONJ. We modified the zoledronate regimen and introduced repeated surgical extraction to illicit quantifiable BRONJ in all animals. Eighty retired-breeder female Sprague-Dawley rats were divided between the treatment (i.v. zoledronate; 80 μg/kg/week for 13 weeks) and control (saline) groups. On week 13, the left mandibular first molar was surgically extracted, followed by the second molar a week later. Animals were euthanized at 1-week, 2-weeks, and 8-weeks following extraction. The occurrence and severity of BRONJ were scored in each animal based on gross and MicroCT analysis. Parameters of bone formation and osteoclast functions at the extraction site were compared between groups. All zoledronate-treated animals developed a severe case of BRONJ that fulfilled the clinical definition of the condition in humans. Osteoclast attachment continued to be defective eight weeks after stopping the treatment. There were no signs of kidney or liver toxicity. Our data confirmed that repeated surgical extraction (major trauma) by itself consistently precipitated massive bone necrosis in ZA-treated animals, eliminating the need to induce pre-existing infection or comorbidity. These results will be the basis for further studies examining the in-vivo pathogenesis and prevention of BRONJ.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>26186665</pmid><doi>10.1371/journal.pone.0132520</doi><oa>free_for_read</oa></addata></record> |
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| language | eng |
| recordid | cdi_plos_journals_1698024335 |
| source | MEDLINE; DOAJ Directory of Open Access Journals; Public Library of Science (PLoS); EZB-FREE-00999 freely available EZB journals; PubMed Central; Free Full-Text Journals in Chemistry |
| subjects | Acid Phosphatase - metabolism Analysis Animals Auditory defects Biocompatibility Biomedical materials Bisphosphonate-Associated Osteonecrosis of the Jaw - diagnostic imaging Bisphosphonate-Associated Osteonecrosis of the Jaw - etiology Bisphosphonate-Associated Osteonecrosis of the Jaw - pathology Bone disorder agents Bone growth Comorbidity Computed tomography Dentistry Diphosphonates - adverse effects Disease Models, Animal Drug dosages Female Imidazoles - adverse effects Infections Isoenzymes - metabolism Jaw Kidney - drug effects Kidney - pathology Kidneys Liver Liver - drug effects Liver - pathology Mandible Mandible - diagnostic imaging Mandible - drug effects Mandible - pathology Medicine Osteoclasts - drug effects Osteoclasts - pathology Osteogenesis Osteonecrosis Pathogenesis Rats Rats, Sprague-Dawley Rodents Studies Surgeons Surgery Systematic review Tartrate-Resistant Acid Phosphatase Tooth Extraction Toxicity Trauma Wound Healing - drug effects Wounds and Injuries - complications X-Ray Microtomography Zoledronic Acid |
| title | A Model for Osteonecrosis of the Jaw with Zoledronate Treatment following Repeated Major Trauma |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-22T23%3A09%3A36IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_plos_&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=A%20Model%20for%20Osteonecrosis%20of%20the%20Jaw%20with%20Zoledronate%20Treatment%20following%20Repeated%20Major%20Trauma&rft.jtitle=PloS%20one&rft.au=Howie,%20R%20Nicole&rft.date=2015-07-17&rft.volume=10&rft.issue=7&rft.spage=e0132520&rft.pages=e0132520-&rft.issn=1932-6203&rft.eissn=1932-6203&rft_id=info:doi/10.1371/journal.pone.0132520&rft_dat=%3Cgale_plos_%3EA422136957%3C/gale_plos_%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=1698024335&rft_id=info:pmid/26186665&rft_galeid=A422136957&rft_doaj_id=oai_doaj_org_article_efdc28a7919d414bab30847d0a76e7ed&rfr_iscdi=true |