Correlations between Immune Response and Etiopathogenic Factors of Medication-Related Osteonecrosis of the Jaw in Cancer Patients Treated with Zoledronic Acid

Impairment of the immune response in MRONJ (medication-related osteonecrosis of the jaws) is one of the still unclear etiopathogenic mechanisms of this condition encountered in cancer patients treated with bisphosphonates, with negative effects on the patient’s quality of life. The aim of the present study was to correlate the immune response with etiopathogenic factors via immunohistochemical evaluation of the maxillary tissues in zoledronic acid osteonecrosis. The retrospective study included a group of 51 patients with various types of cancers, diagnosed with stage 2 or 3 MRONJ at zoledronic acid and treated surgically. Immunohistochemical expressions of αSMA, CD3, CD4, CD8, CD20, CD79α, CD68, CD204, and tryptase were evaluated. Immunohistochemical markers expressions were statistically analyzed according to the duration of the treatment, the trigger factor, the location of the MRONJ, and the healing status. Analysis of the immune response included T lymphocytes, B lymphocytes, plasma cells, macrophages, and mast cells. The duration of treatment significantly influenced the immunohistochemical expression of most markers (p < 0.05). For an increasing trend in treatment duration, a decreasing trend in marker score was observed, suggesting an inverse correlation. The expression of the markers was different depending on the trigger factor, on MRONJ localization (maxilla/mandible), and the healing status, being more intense in patients cured per primam compared to those who had relapses. The patient’s immune response was negatively influenced by the duration of the treatment, the trigger factor, the location of the lesion in the mandible, and the recurrence of MRONJ.

[1]  L. Chivu,et al.  Risk Factors for Medication-Related Osteonecrosis of the Jaw—A Binomial Analysis of Data of Cancer Patients from Craiova and Constanta Treated with Zoledronic Acid , 2023, Journal of clinical medicine.

[2]  L. Mogoantă,et al.  Clinical and Histopathological Aspects of MRONJ in Cancer Patients , 2023, Journal of clinical medicine.

[3]  F. Mussano,et al.  Immune Dysfunction in Medication-Related Osteonecrosis of the Jaw , 2023, International journal of molecular sciences.

[4]  S. Olate,et al.  Medication-Related Osteonecrosis of the Jaws (MRONJ) in Children and Young Patients—A Systematic Review , 2023, Journal of clinical medicine.

[5]  Hiroko Wada,et al.  Actin alpha 2, smooth muscle, a transforming growth factor-β1-induced factor, regulates collagen production in human periodontal ligament cells via Smad2/3 pathway. , 2022, Journal of dental sciences.

[6]  A. Giannì,et al.  Medication-Related Osteonecrosis of the Jaw in Dental Practice: A Retrospective Analysis of Data from the Milan Cohort , 2022, Dentistry journal.

[7]  S. Park,et al.  Effects of Type 2 Diabetes Mellitus on Osteoclast Differentiation, Activity, and Cortical Bone Formation in POSTmenopausal MRONJ Patients , 2022, Journal of clinical medicine.

[8]  N. Park,et al.  Indigenous microbiota protects development of medication-related osteonecrosis induced by periapical disease in mice , 2022, International journal of oral science.

[9]  G. Campisi,et al.  One changing and challenging scenario: the treatment of cancer patients with bone metastases by bisphosphonates and denosumab, the cost–benefit evaluation of different options, and the risk of medication-related osteonecrosis of the jaw (MRONJ) , 2022, Supportive Care in Cancer.

[10]  F. Bertoldo,et al.  The preventive care of medication-related osteonecrosis of the jaw (MRONJ): a position paper by Italian experts for dental hygienists , 2022, Supportive Care in Cancer.

[11]  C. Dobó-Nagy,et al.  Targeted histological evaluation shows high incidence of actinomyces infection in medication-related osteonecrosis of the jaws , 2022, Scientific Reports.

[12]  N. Chattipakorn,et al.  Impacts of bisphosphonates on the bone and its surrounding tissues: mechanistic insights into medication-related osteonecrosis of the jaw , 2022, Archives of Toxicology.

[13]  K. Miyamoto,et al.  Osteonecrosis development by tooth extraction in zoledronate treated mice is inhibited by active vitamin D analogues, anti-inflammatory agents or antibiotics , 2022, Scientific reports.

[14]  S. Tetradis,et al.  Macrophage Involvement in Medication-Related Osteonecrosis of the Jaw (MRONJ): A Comprehensive, Short Review , 2022, Cancers.

[15]  E. C. Sung,et al.  Mechanism of bisphosphonate-related osteonecrosis of the jaw (BRONJ) revealed by targeted removal of legacy bisphosphonate from jawbone using competing inert hydroxymethylene diphosphonate , 2021, medRxiv.

[16]  A. Gaudio,et al.  Early Changes of VEGF Levels After Zoledronic Acid in Women With Postmenopausal Osteoporosis: A Potential Role of Vitamin D , 2021, Frontiers in Medicine.

[17]  H. Y. Kim Review and Update of the Risk Factors and Prevention of Antiresorptive-Related Osteonecrosis of the Jaw , 2021, Endocrinology and metabolism.

[18]  S. Abrams,et al.  Discovering Myeloid Cell Heterogeneity in Mandibular Bone – Cell by Cell Analysis , 2021, Frontiers in Physiology.

[19]  P. Gándara-Vila,et al.  Medication-Related Osteonecrosis of the Jaw: A Critical Narrative Review , 2021, Journal of clinical medicine.

[20]  C. Giachelli,et al.  Engineered Osteoclasts Resorb Necrotic Alveolar Bone in Anti-RANKL Antibody-Treated Mice. , 2021, Bone.

[21]  M. Ehrenfeld,et al.  Infection as an Important Factor in Medication-Related Osteonecrosis of the Jaw (MRONJ) , 2021, Medicina.

[22]  Byoung-Eun Yang,et al.  Various Therapeutic Methods for the Treatment of Medication-Related Osteonecrosis of the Jaw (MRONJ) and Their Limitations: A Narrative Review on New Molecular and Cellular Therapeutic Approaches , 2021, Antioxidants.

[23]  S. Popescu,et al.  Mandibulectomy Reconstruction with Pectoralis Major Island Flap Associated with Primary Reconstruction Plate for Mandibular Medication-Related Osteonecrosis , 2021, Current health sciences journal.

[24]  A. Munz,et al.  Microarchitecture of medication-related osteonecrosis of the jaw (MRONJ); a retrospective micro-CT and morphometric analysis. , 2021, Journal of cranio-maxillo-facial surgery : official publication of the European Association for Cranio-Maxillo-Facial Surgery.

[25]  Ling Gao,et al.  The Role of the Immune Response in the Development of Medication-Related Osteonecrosis of the Jaw , 2021, Frontiers in Immunology.

[26]  Li-Hang Shen,et al.  Exosomes from Adipose-Derived Stem Cells Can Prevent Medication-Related Osteonecrosis of the Jaw , 2021, Medical science monitor : international medical journal of experimental and clinical research.

[27]  J. Yates,et al.  Systematic review of medication related osteonecrosis of the jaw (MRONJ) in patients undergoing only antiangiogenic drug therapy: surgery or conservative therapy? , 2020, The British journal of oral & maxillofacial surgery.

[28]  C. Moinpour,et al.  Association of Osteonecrosis of the Jaw With Zoledronic Acid Treatment for Bone Metastases in Patients With Cancer. , 2020, JAMA oncology.

[29]  F. Baudi,et al.  The Case of Medication-Related Osteonecrosis of the Jaw Addressed from a Pathogenic Point of View. Innovative Therapeutic Strategies: Focus on the Most Recent Discoveries on Oral Mesenchymal Stem Cell-Derived Exosomes , 2020, Pharmaceuticals.

[30]  Y. Niu,et al.  Pathogenesis and multidisciplinary management of medication-related osteonecrosis of the jaw , 2020, International journal of oral science.

[31]  F. Baudi,et al.  Dose-Dependent Effects of Zoledronic Acid on Human Periodontal Ligament Stem Cells: An In Vitro Pilot Study , 2020, Cell transplantation.

[32]  H. Essig,et al.  Antimicrobial peptide gene expression in medication-related osteonecrosis of the jaw. , 2020, Pathology, research and practice.

[33]  K. Pereira,et al.  Bisphosphonate-related osteonecrosis induced change in alveolar bone architecture in rats with participation of Wnt signaling , 2020, Clinical Oral Investigations.

[34]  P. Vescovi,et al.  Medication-Related Osteonecrosis of Jaws (MRONJ) Prevention and Diagnosis: Italian Consensus Update 2020 , 2020, International journal of environmental research and public health.

[35]  M. Siddique,et al.  Teriparatide Promotes Bone Healing in Medication-Related Osteonecrosis of the Jaw: A Placebo-Controlled, Randomized Trial. , 2020, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[36]  B. Hutton,et al.  Long-term impact of bone-modifying agents for the treatment of bone metastases: a systematic review , 2020, Supportive Care in Cancer.

[37]  M. Bornstein,et al.  Medication-related osteonecrosis of the jaws (MRONJ) in cancer patients treated with denosumab VS. zoledronic acid: A systematic review and meta-analysis , 2020, Medicina oral, patologia oral y cirugia bucal.

[38]  M. Osaki,et al.  Bisphosphonates induced reactive oxygen species inhibit proliferation and migration of oral fibroblast: A pathogenesis of bisphosphonate-related osteonecrosis of the Jaw. , 2019, Journal of periodontology.

[39]  Wenjie Zhang,et al.  Decreased osteogenic ability of periodontal ligament stem cells leading to impaired periodontal tissue repair in BRONJ patients. , 2019, Stem cells and development.

[40]  N. Yarom,et al.  Medication-Related Osteonecrosis of the Jaw: MASCC/ISOO/ASCO Clinical Practice Guideline. , 2019, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[41]  Nicole M. Chapman,et al.  Helper T cell differentiation , 2019, Cellular & Molecular Immunology.

[42]  George Bullock Tissue engineering approaches to the treatment of bisphosphonate-related osteonecrosis of the jaw , 2019 .

[43]  K. Roszkowski,et al.  Biphosphonates-related osteonecrosis of the jaw , 2019, Medical Research Journal.

[44]  M. Iriti,et al.  Development and validation of a method using ultra performance liquid chromatography coupled to tandem mass spectrometry for determination of zoledronic acid concentration in human bone , 2019, Journal of pharmaceutical and biomedical analysis.

[45]  C. Pautke,et al.  Medication-related osteonecrosis of the jaw: Prevention, diagnosis and management in patients with cancer and bone metastases. , 2018, Cancer treatment reviews.

[46]  A. E. Hakam,et al.  Current Understanding of the Pathophysiology of Osteonecrosis of the Jaw , 2018, Current Osteoporosis Reports.

[47]  S. Patntirapong,et al.  Alteration of macrophage viability, differentiation, and function by bisphosphonates. , 2018, Oral diseases.

[48]  S. Ivanovski,et al.  Risk factors for medication-related osteonecrosis of the jaws: A systematic review. , 2018, Oral diseases.

[49]  G. Garlet,et al.  RANKL Triggers Treg-Mediated Immunoregulation in Inflammatory Osteolysis , 2018, Journal of dental research.

[50]  C. Politis,et al.  Microbial population changes in patients with medication-related osteonecrosis of the jaw treated with systemic antibiotics. , 2017, Oral surgery, oral medicine, oral pathology and oral radiology.

[51]  J. Konkel,et al.  Tissue-Specific Immunity at the Oral Mucosal Barrier. , 2017, Trends in immunology.

[52]  G. Dryden,et al.  Immunopathophysiology of inflammatory bowel disease: how genetics link barrier dysfunction and innate immunity to inflammation , 2017, Innate immunity.

[53]  S. Kalyan It May Seem Inflammatory, but Some T Cells Are Innately Healing to the Bone , 2016, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[54]  A. Neff,et al.  Impact of Soft Tissue Pathophysiology in the Development and Maintenance of Bisphosphonate-Related Osteonecrosis of the Jaw (BRONJ) , 2016, Dentistry journal.

[55]  E. Wagner,et al.  Chronic skin inflammation leads to bone loss by IL-17–mediated inhibition of Wnt signaling in osteoblasts , 2016, Science Translational Medicine.

[56]  H. Takayanagi,et al.  IL-17-producing γδ T cells enhance bone regeneration , 2016, Nature Communications.

[57]  N. Dutzan,et al.  Characterization of the human immune cell network at the gingival barrier , 2015, Mucosal Immunology.

[58]  J. Fantasia The Role of Antiangiogenic Therapy in the Development of Osteonecrosis of the Jaw. , 2015, Oral and maxillofacial surgery clinics of North America.

[59]  S. Tetradis,et al.  Pathophysiology of Osteonecrosis of the Jaws. , 2015, Oral and maxillofacial surgery clinics of North America.

[60]  Liqing Yang,et al.  Efficacy and Safety of Zoledronic Acid and Pamidronate Disodium in the Treatment of Malignant Skeletal Metastasis , 2015, Medicine.

[61]  Jun Wang,et al.  Systemic immunity shapes the oral microbiome and susceptibility to bisphosphonate-associated osteonecrosis of the jaw , 2015, Journal of Translational Medicine.

[62]  J. Sayre,et al.  Osteonecrosis of the Jaw Developed in Mice , 2015, The Journal of Biological Chemistry.

[63]  A. Pabst,et al.  In vitro effects of bisphosphonates on chemotaxis, phagocytosis, and oxidative burst of neutrophil granulocytes , 2014, Clinical Oral Investigations.

[64]  G. Scagliotti,et al.  Delaying skeletal-related events in a randomized phase 3 study of denosumab versus zoledronic acid in patients with advanced cancer: an analysis of data from patients with solid tumors , 2014, Supportive Care in Cancer.

[65]  J. Hodges,et al.  Periodontal disease as a risk factor for bisphosphonate-related osteonecrosis of the jaw. , 2014, Journal of periodontology.

[66]  Akinobu Matsumoto,et al.  Zoledronic Acid Enhances Lipopolysaccharide-Stimulated Proinflammatory Reactions through Controlled Expression of SOCS1 in Macrophages , 2013, PloS one.

[67]  S. Shi,et al.  IL-17–Mediated M1/M2 Macrophage Alteration Contributes to Pathogenesis of Bisphosphonate-Related Osteonecrosis of the Jaws , 2013, Clinical Cancer Research.

[68]  Joanne L Welton,et al.  Monocytes and γδ T cells control the acute‐phase response to intravenous zoledronate: Insights from a phase IV safety trial , 2013, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[69]  D. Kabelitz,et al.  Defining the nature of human γδ T cells: a biographical sketch of the highly empathetic , 2012, Cellular and Molecular Immunology.

[70]  L. Idolazzi,et al.  Long-Term Effects of Amino-Bisphosphonates on Circulating γδ T Cells , 2012, Calcified Tissue International.

[71]  V. Denaro,et al.  Serum VEGF levels as predictive marker of bisphosphonate-related osteonecrosis of the jaw , 2012, Journal of Hematology & Oncology.

[72]  P. Kostenuik,et al.  Bench to bedside: elucidation of the OPG–RANK–RANKL pathway and the development of denosumab , 2012, Nature Reviews Drug Discovery.

[73]  K. Gasser,et al.  Drug-induced osteonecrosis of the jaw , 2012, memo - Magazine of European Medical Oncology.

[74]  D. Carson,et al.  Cutting Edge: Nitrogen Bisphosphonate-Induced Inflammation Is Dependent upon Mast Cells and IL-1 , 2012, The Journal of Immunology.

[75]  R. Baron,et al.  Denosumab and bisphosphonates: different mechanisms of action and effects. , 2011, Bone.

[76]  A. Pabst,et al.  Bisphosphonates affect migration ability and cell viability of HUVEC, fibroblasts and osteoblasts in vitro. , 2011, Oral diseases.

[77]  T. Junt,et al.  Th17 Cells, Not IL-17+ γδ T Cells, Drive Arthritic Bone Destruction in Mice and Humans , 2011, The Journal of Immunology.

[78]  M. Pazianas Osteonecrosis of the jaw and the role of macrophages. , 2011, Journal of the National Cancer Institute.

[79]  E. Seeman,et al.  Teriparatide therapy for alendronate-associated osteonecrosis of the jaw. , 2010, The New England journal of medicine.

[80]  S. Hoefert,et al.  Importance of microcracks in etiology of bisphosphonate-related osteonecrosis of the jaw: a possible pathogenetic model of symptomatic and non-symptomatic osteonecrosis of the jaw based on scanning electron microscopy findings , 2010, Clinical Oral Investigations.

[81]  R. Rizzoli,et al.  Bisphosphonate-associated osteonecrosis of the jaw: a key role of inflammation? , 2009, Bone.

[82]  C. Shuler,et al.  Microbial biofilms in osteomyelitis of the jaw and osteonecrosis of the jaw secondary to bisphosphonate therapy. , 2009, Journal of the American Dental Association.

[83]  J. Lo,et al.  Intravenous bisphosphonate-related osteonecrosis of the jaw: bone scintigraphy as an early indicator. , 2009, Journal of oral and maxillofacial surgery : official journal of the American Association of Oral and Maxillofacial Surgeons.

[84]  L. Assael,et al.  Comprehensive review of bisphosphonate therapy: implications for the oral and maxillofacial surgery patient. , 2009, Journal of oral and maxillofacial surgery : official journal of the American Association of Oral and Maxillofacial Surgeons.

[85]  L. Assael,et al.  American Association of Oral and Maxillofacial Surgeons position paper on bisphosphonate-related osteonecrosis of the jaws--2009 update. , 2009, Journal of oral and maxillofacial surgery : official journal of the American Association of Oral and Maxillofacial Surgeons.

[86]  R. Medzhitov Origin and physiological roles of inflammation , 2008, Nature.

[87]  N. Watts,et al.  Mechanisms of action of bisphosphonates: similarities and differences and their potential influence on clinical efficacy , 2008, Osteoporosis International.

[88]  E. Elm,et al.  The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: guidelines for reporting observational studies , 2007, The Lancet.

[89]  S. Pocock,et al.  Strengthening the reporting of observational studies in epidemiology (STROBE) statement: guidelines for reporting observational studies , 2007, BMJ : British Medical Journal.

[90]  M. Rogers,et al.  Molecular Mechanisms of Action of Bisphosphonates: Current Status , 2006, Clinical Cancer Research.

[91]  A. Vecchione,et al.  Bisphosphonates and oral cavity avascular bone necrosis: a review of twelve cases. , 2006, Anticancer research.

[92]  T. Hansen,et al.  Osteonecrosis of the jaws in patients treated with bisphosphonates - histomorphologic analysis in comparison with infected osteoradionecrosis. , 2006, Journal of oral pathology & medicine : official publication of the International Association of Oral Pathologists and the American Academy of Oral Pathology.

[93]  P. Clézardin,et al.  Bisphosphonates inhibit angiogenesis in vitro and testosterone-stimulated vascular regrowth in the ventral prostate in castrated rats. , 2002, Cancer research.

[94]  L. Devy,et al.  Novel Antiangiogenic Effects of the Bisphosphonate Compound Zoledronic Acid , 2002, Journal of Pharmacology and Experimental Therapeutics.

[95]  M. Rogers,et al.  Bisphosphonates: from the laboratory to the clinic and back again. , 1999, Bone.

[96]  S. Ruggiero Medication-Related Osteonecrosis of the Jaw – 2022 Update , 2022 .

[97]  I. Kaplan,et al.  Comparison of the histopathological characteristics of osteomyelitis, medication-related osteonecrosis of the jaw, and osteoradionecrosis. , 2019, International journal of oral and maxillofacial surgery.

[98]  C. Popescu,et al.  Clinical, statistical, histological and immunohistochemical aspects of periodontal changes in patients with diabetes mellitus. , 2019, Romanian journal of morphology and embryology = Revue roumaine de morphologie et embryologie.

[99]  C. Busuioc,et al.  Histological and immunohistochemical study on the apical granuloma. , 2018, Romanian journal of morphology and embryology = Revue roumaine de morphologie et embryologie.

[100]  T. Dodson,et al.  Medication-Related Osteonecrosis of the Jaw—2014 Update , 2014 .

[101]  T. Ikebe Pathophysiology of BRONJ: Drug-related osteoclastic disease of the jaw , 2013 .

[102]  American Association of Oral and Maxillofacial Surgeons position paper on bisphosphonate-related osteonecrosis of the jaws. , 2007, Journal of oral and maxillofacial surgery : official journal of the American Association of Oral and Maxillofacial Surgeons.

[103]  L. Weeda Drug induced osteonecrosis of the jaws. , 2006, The Journal of the Tennessee Dental Association.