{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,6]],"date-time":"2026-05-06T02:37:06Z","timestamp":1778035026943,"version":"3.51.4"},"reference-count":30,"publisher":"Oxford University Press (OUP)","issue":"8","license":[{"start":{"date-parts":[[2012,6,20]],"date-time":"2012-06-20T00:00:00Z","timestamp":1340150400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"name":"Italian Public Health Ministry","award":["PRIN 2007LT5X87_004"],"award-info":[{"award-number":["PRIN 2007LT5X87_004"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2012,8,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>Background.<\/jats:title>\n                  <jats:p>Bisphosphonate-related osteonecrosis of the jaw (BRONJ) is a well-documented adverse event from treatment with nitrogen-containing bisphosphonates (NBPs). During a preliminary histomorphometric study aimed at assessing the rate of bone remodeling in the jaws of patients with surgically resected BRONJ, we found a defect of bone mineralization (unpublished data). We hypothesized that osteomalacia could be a risk factor for BRONJ in patients taking NBPs. Therefore, we looked for static and dynamic histomorphometric evidence of osteomalacia in biopsies from subjects with and without BRONJ.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods.<\/jats:title>\n                  <jats:p>This case-control study used histomorphometric analysis of bone specimens of patients using NBPs (22 patients with BRONJ and 21 patients without BRONJ) who required oral surgical interventions for the treatment\/prevention of osteonecrosis. Patients were given tetracycline hydrochloride according to a standardized protocol before taking bone biopsies from their jaws. Biopsies with evidence of osteomyelitis or necrosis at histology were excluded from the study. Osteomalacia was defined as a mineralization lag time &amp;gt;100 days, a corrected mean osteoid thickness &amp;gt;12.5 mm, and an osteoid volume &amp;gt;10%.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results.<\/jats:title>\n                  <jats:p>In all, 77% of patients with BRONJ were osteomalacic compared with 5% of patients without BRONJ, according to histomorphometry. Because osteomalacia was found almost exclusively in NBP users with BRONJ, this is likely to be a generalized process in which the use of NBPs further deteriorates mechanisms of bone repair.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusions.<\/jats:title>\n                  <jats:p>Osteomalacia represents a new and previously unreported risk factor for disease development. This finding may contribute to a better understanding of the pathogenesis of this disease and help with the development of strategies to increase the safety of NBP administration.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1634\/theoncologist.2012-0141","type":"journal-article","created":{"date-parts":[[2012,6,21]],"date-time":"2012-06-21T13:58:04Z","timestamp":1340287084000},"page":"1114-1119","source":"Crossref","is-referenced-by-count":29,"title":["Osteomalacia: The Missing Link in the Pathogenesis of Bisphosphonate-Related Osteonecrosis of the Jaws?"],"prefix":"10.1093","volume":"17","author":[{"given":"Alberto","family":"Bedogni","sequence":"first","affiliation":[{"name":"a Unit of Oral and Maxillofacial Surgery, Department of Surgery, Clinic of Internal Medicine, Azienda Ospedaliera Universitaria Integrata, Verona, Italy;"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Giorgia","family":"Saia","sequence":"additional","affiliation":[{"name":"c Unit of Maxillofacial Surgery, Department of Neurosciences, University of Padova, Padova, Italy;"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Giordana","family":"Bettini","sequence":"additional","affiliation":[{"name":"c Unit of Maxillofacial Surgery, Department of Neurosciences, University of Padova, Padova, Italy;"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anita","family":"Tronchet","sequence":"additional","affiliation":[{"name":"c Unit of Maxillofacial Surgery, Department of Neurosciences, University of Padova, Padova, Italy;"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andrea","family":"Totola","sequence":"additional","affiliation":[{"name":"a Unit of Oral and Maxillofacial Surgery, Department of Surgery, Clinic of Internal Medicine, Azienda Ospedaliera Universitaria Integrata, Verona, Italy;"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Giorgio","family":"Bedogni","sequence":"additional","affiliation":[{"name":"e Clinical Epidemiology Unit, Liver Research Centre, Basovizza, Trieste, Italy;"},{"name":"f Department of Maternal and Pediatric Sciences, University of Milan, Fondazione IRCCS C\u00e0 Granda, Ospedale Maggiore Policlinico, Milan, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Paolo","family":"Tregnago","sequence":"additional","affiliation":[{"name":"a Unit of Oral and Maxillofacial Surgery, Department of Surgery, Clinic of Internal Medicine, Azienda Ospedaliera Universitaria Integrata, Verona, Italy;"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maria Teresa","family":"Valenti","sequence":"additional","affiliation":[{"name":"b Department of Medicine, Clinic of Internal Medicine, Azienda Ospedaliera Universitaria Integrata, Verona, Italy;"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Francesco","family":"Bertoldo","sequence":"additional","affiliation":[{"name":"b Department of Medicine, Clinic of Internal Medicine, Azienda Ospedaliera Universitaria Integrata, Verona, Italy;"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Giuseppe","family":"Ferronato","sequence":"additional","affiliation":[{"name":"c Unit of Maxillofacial Surgery, Department of Neurosciences, University of Padova, Padova, Italy;"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pier Francesco","family":"Nocini","sequence":"additional","affiliation":[{"name":"a Unit of Oral and Maxillofacial Surgery, Department of Surgery, Clinic of Internal Medicine, Azienda Ospedaliera Universitaria Integrata, Verona, Italy;"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stella","family":"Blandamura","sequence":"additional","affiliation":[{"name":"d Institute of Pathology, University of Padova, Padova, Italy;"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Luca","family":"Dalle Carbonare","sequence":"additional","affiliation":[{"name":"b Department of Medicine, Clinic of Internal Medicine, Azienda Ospedaliera Universitaria Integrata, Verona, Italy;"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2012,6,20]]},"reference":[{"key":"2021122308123019500_B1","doi-asserted-by":"crossref","first-page":"1117","DOI":"10.1007\/s00432-010-0907-7","article-title":"Bisphosphonate-induced osteonecrosis of the jaw: A review of 2,400 patient cases","volume":"136","author":"Filleul","year":"2010","journal-title":"J Cancer Res Clin Oncol"},{"key":"2021122308123019500_B2","doi-asserted-by":"crossref","first-page":"1115","DOI":"10.1016\/S0278-2391(03)00720-1","article-title":"Pamidronate (Aredia) and zoledronate (Zometa) induced avascular necrosis of the jaws: A growing epidemic","volume":"61","author":"Marx","year":"2003","journal-title":"J Oral Maxillofac Surg"},{"key":"2021122308123019500_B3","first-page":"2","article-title":"American Association of Oral and Maxillofacial Surgeons position paper on bisphosphonate-related osteonecrosis of the jaws\u20132009 update","volume":"67","author":"Ruggiero","year":"2009","journal-title":"J Oral Maxillofac Surg"},{"key":"2021122308123019500_B4","doi-asserted-by":"crossref","first-page":"5356","DOI":"10.1200\/JCO.2009.21.9584","article-title":"Longitudinal cohort study of risk factors in cancer patients of bisphosphonate-related osteonecrosis of the jaw","volume":"27","author":"Vahtsevanos","year":"2009","journal-title":"J Clin Oncol"},{"key":"2021122308123019500_B5","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1016\/j.joms.2009.01.007","article-title":"The pathogenesis of bisphosphonate-related osteonecrosis of the jaw: So many hypotheses, so few data","volume":"67","author":"Allen","year":"2009","journal-title":"J Oral Maxillofac Surg"},{"key":"2021122308123019500_B6","doi-asserted-by":"crossref","first-page":"280","DOI":"10.2353\/ajpath.2010.090592","article-title":"Bisphosphonates cause osteonecrosis of the jaw-like disease in mice","volume":"177","author":"Bi","year":"2010","journal-title":"Am J Pathol"},{"key":"2021122308123019500_B7","doi-asserted-by":"crossref","first-page":"1336","DOI":"10.1093\/annonc\/mdl045","article-title":"Could the long-term persistence of low serum calcium levels and high serum parathyroid hormone levels during bisphosphonate treatment predispose metastatic breast cancer patients to undergo osteonecrosis of the jaw?","volume":"17","author":"Ardine","year":"2006","journal-title":"Ann Oncol"},{"key":"2021122308123019500_B8","doi-asserted-by":"crossref","first-page":"625","DOI":"10.1136\/jcp.35.6.625","article-title":"Value of plasma calcium, phosphate, and alkaline phosphatase measurements in the diagnosis of histological osteomalacia","volume":"35","author":"Peach","year":"1982","journal-title":"J Clin Pathol"},{"key":"2021122308123019500_B9","doi-asserted-by":"crossref","first-page":"420","DOI":"10.1016\/j.oraloncology.2011.02.024","article-title":"Long-term outcomes of surgical resection of the jaws in cancer patients with bisphosphonate-related osteonecrosis","volume":"47","author":"Bedogni","year":"2011","journal-title":"Oral Oncol"},{"key":"2021122308123019500_B10","doi-asserted-by":"crossref","first-page":"797","DOI":"10.1016\/j.joms.2009.10.026","article-title":"Occurrence of bisphosphonate-related osteonecrosis of the jaw after surgical tooth extraction","volume":"68","author":"Saia","year":"2010","journal-title":"J Oral Maxillofac Surg"},{"key":"2021122308123019500_B11","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1139\/y63-005","article-title":"Measurement of human bone formation by means of tetracycline labelling","volume":"41","author":"Frost","year":"1963","journal-title":"Can J Biochem Physiol"},{"key":"2021122308123019500_B12","doi-asserted-by":"crossref","first-page":"358","DOI":"10.1016\/j.tripleo.2007.08.040","article-title":"Bisphosphonate-associated jawbone osteonecrosis: A correlation between imaging techniques and histopathology","volume":"105","author":"Bedogni","year":"2008","journal-title":"Oral Surg Oral Med Oral Pathol Oral Radiol Endod"},{"key":"2021122308123019500_B13","first-page":"56","article-title":"Histomorphometry of periarticular bone in rheumatoid arthritis","volume":"83","author":"Kr\u00f6ger","year":"1994","journal-title":"Ann Chir Gynaecol"},{"key":"2021122308123019500_B14","doi-asserted-by":"crossref","first-page":"595","DOI":"10.1002\/jbmr.5650020617","article-title":"Bone histomorphometry: Standardization of nomenclature, symbols, and units. Report of the ASBMR Histomorphometry Nomenclature Committee","volume":"2","author":"Parfitt","year":"1987","journal-title":"J Bone Miner Res"},{"key":"2021122308123019500_B15","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1111\/j.1749-6632.2010.05771.x","article-title":"Epidemiology and risk factors for osteonecrosis of the jaw in cancer patients","volume":"1218","author":"Hoff","year":"2011","journal-title":"Ann N Y Acad Sci"},{"key":"2021122308123019500_B16","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1038\/nrendo.2010.195","article-title":"Osteonecrosis of the jaw and bisphosphonates in cancer: A narrative review","volume":"7","author":"Migliorati","year":"2011","journal-title":"Nat Rev Endocrinol"},{"key":"2021122308123019500_B17","doi-asserted-by":"crossref","first-page":"1479","DOI":"10.1359\/jbmr.0707onj","article-title":"Bisphosphonate-associated osteonecrosis of the jaw: Report of a task force of the American Society for Bone and Mineral Research","volume":"22","author":"Khosla","year":"2007","journal-title":"J Bone Miner Res"},{"key":"2021122308123019500_B18","doi-asserted-by":"crossref","first-page":"266","DOI":"10.1056\/NEJMra070553","article-title":"Vitamin D deficiency","volume":"357","author":"Holick","year":"2007","journal-title":"N Engl J Med"},{"key":"2021122308123019500_B19","doi-asserted-by":"crossref","first-page":"305","DOI":"10.1359\/jbmr.090728","article-title":"Bone mineralization defects and vitamin D deficiency: Histomorphometric analysis of iliac crest bone biopsies and circulating 25-hydroxyvitamin D in 675 patients","volume":"25","author":"Priemel","year":"2010","journal-title":"J Bone Miner Res"},{"key":"2021122308123019500_B20","doi-asserted-by":"crossref","first-page":"1337","DOI":"10.1002\/jbmr.23","article-title":"Increased prevalence of bisphosphonate-related osteonecrosis of the jaw with vitamin D deficiency in rats","volume":"25","author":"Hokugo","year":"2010","journal-title":"J Bone Miner Res"},{"key":"2021122308123019500_B21","doi-asserted-by":"crossref","first-page":"2151","DOI":"10.1200\/JCO.2008.19.6162","article-title":"High prevalence of vitamin D deficiency despite supplementation in premenopausal women with breast cancer undergoing adjuvant chemotherapy","volume":"27","author":"Crew","year":"2009","journal-title":"J Clin Oncol"},{"key":"2021122308123019500_B22","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1007\/s00198-008-0650-y","article-title":"Vitamin D status and response to treatment in post-menopausal osteoporosis","volume":"20","author":"Adami","year":"2009","journal-title":"Osteoporosis International"},{"key":"2021122308123019500_B23","doi-asserted-by":"crossref","first-page":"363","DOI":"10.1007\/s00432-009-0662-9","article-title":"Disease-specific risk for an osteonecrosis of the jaw under bisphosphonate therapy","volume":"136","author":"Jung","year":"2010","journal-title":"J Cancer Res Clin Oncol"},{"key":"2021122308123019500_B24","doi-asserted-by":"crossref","first-page":"8580","DOI":"10.1200\/JCO.2005.02.8670","article-title":"Osteonecrosis of the jaw in cancer after treatment with bisphosphonates: Incidence and risk factors","volume":"23","author":"Bamias","year":"2005","journal-title":"J Clin Oncol"},{"key":"2021122308123019500_B25","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1016\/S0140-6736(11)61226-9","article-title":"Denosumab and bone-metastasis-free survival in men with castration-resistant prostate cancer: Results of a phase 3, randomised, placebo-controlled trial","volume":"379","author":"Smith","year":"2012","journal-title":"Lancet"},{"key":"2021122308123019500_B26","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1016\/j.jcms.2007.06.008","article-title":"\u201cBis-phossy jaws\u201d: High and low risk factors for bisphosphonate-induced osteonecrosis of the jaw","volume":"36","author":"Abu-Id","year":"2008","journal-title":"J Craniomaxillofac Surg"},{"key":"2021122308123019500_B27","doi-asserted-by":"crossref","first-page":"1459","DOI":"10.1016\/0140-6736(93)92935-M","article-title":"Mineralisation defects with pamidronate therapy for Paget's disease","volume":"342","author":"Adamson","year":"1993","journal-title":"Lancet"},{"key":"2021122308123019500_B28","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1359\/jbmr.070906","article-title":"Effects of intravenous zoledronic acid once yearly on bone remodeling and bone structure","volume":"23","author":"Recker","year":"2008","journal-title":"J Bone Min Res"},{"key":"2021122308123019500_B29","doi-asserted-by":"crossref","first-page":"418","DOI":"10.1016\/j.joms.2010.05.062","article-title":"Effects of short-term zoledronic acid treatment on bone remodeling and healing at surgical sites in the maxilla and mandible of aged dogs","volume":"69","author":"Huja","year":"2011","journal-title":"J Oral Maxillofac Surg"},{"key":"2021122308123019500_B30","doi-asserted-by":"crossref","first-page":"1799","DOI":"10.1056\/NEJMoa074941","article-title":"Zoledronic acid and clinical fractures and mortality after hip fracture","volume":"357","author":"Lyles","year":"2007","journal-title":"N Engl J Med"}],"container-title":["The Oncologist"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1634\/theoncologist.2012-0141","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1634\/theoncologist.2012-0141","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/academic.oup.com\/oncolo\/article-pdf\/17\/8\/1114\/41858293\/oncolo_17_8_1114.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/oncolo\/article-pdf\/17\/8\/1114\/41858293\/oncolo_17_8_1114.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,12,23]],"date-time":"2021-12-23T20:02:05Z","timestamp":1640289725000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/oncolo\/article\/17\/8\/1114\/6400956"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2012,6,20]]},"references-count":30,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2012,6,20]]},"published-print":{"date-parts":[[2012,8,1]]}},"URL":"https:\/\/doi.org\/10.1634\/theoncologist.2012-0141","relation":{},"ISSN":["1083-7159","1549-490X"],"issn-type":[{"value":"1083-7159","type":"print"},{"value":"1549-490X","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2012,8,1]]},"published":{"date-parts":[[2012,6,20]]}}}