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1.
J Bone Miner Metab ; 38(6): 819-825, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32507944

RESUMO

INTRODUCTION: Our aim is to track the development of the epidemiological characteristics in patient populations diagnosed with MRONJ at the Sheba Medical Center. MATERIALS AND METHODS: The files of patients diagnosed with MRONJ from 2003 until December 2017 were retrieved. Data on demographics, medical background, type and duration of drug use and triggering events at presentation was collected. RESULTS: The study included 448 patients, 336 females and 112 males. A decrease in the proportion of multiple myeloma patients (p < 0.05) and an increase in the proportion of patients with bone metastases of solid tumors has been observed recently. An increase in the proportion of cases in osteoporosis patients compared with oncology patients is evident (p < 0.01). Overtime a higher proportion of patients presented at an earlier stage of MRONJ (p < 0.01). CONCLUSIONS: As a result of changes in treatment protocols and increased awareness of oncology caregivers, including referral and consultation with Oral Medicine specialists, there has been a change in the demographics and presentation of the disease.


Assuntos
Osteonecrose da Arcada Osseodentária Associada a Difosfonatos/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Osteonecrose da Arcada Osseodentária Associada a Difosfonatos/diagnóstico , Osteonecrose da Arcada Osseodentária Associada a Difosfonatos/terapia , Conservadores da Densidade Óssea/uso terapêutico , Comorbidade , Difosfonatos/uso terapêutico , Prescrições de Medicamentos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Osteoporose/tratamento farmacológico , Fatores de Risco
4.
Sci Rep ; 9(1): 18896, 2019 12 11.
Artigo em Inglês | MEDLINE | ID: mdl-31827217

RESUMO

Medication-related osteonecrosis of the jaw (MRONJ) is a serious adverse effect of antiresorptive and antiangiogenic therapies. MRONJ is identified by chronic wounds in the oral mucosa associated with exposed necrotic bone. We hypothesized that zoledronic acid (ZOL) impairs keratinocyte and fibroblast function and reduces soft tissue vascularization; therefore, treating MRONJ with proangiogenic cells may benefit MRONJ patients. The effect of ZOL and dexamethasone (DEX) on gingival fibroblasts and keratinocytes was investigated. In-vitro, ZOL inhibited fibroblast and keratinocyte proliferation, delaying scratch healing. In-vivo, exposed bone was detected at tooth extraction sites, mainly in ZOL(+)/DEX(+) rats; and was associated with significantly decreased soft tissue vascularization, serum-VEGF, and tissue-VEGF. Local injection of early and late endothelial progenitor cells (EPCs) healed 13 of 14 MRONJ lesions compared with 2/7 lesions in the mesenchymal stem cells, and 2/6, in culture-medium group. The EPCs reduced necrotic bone area, increased serum and tissue VEGF levels. EPCs engraftment was minimal, suggesting their paracrine role in MRONJ healing. The EPC-conditioned medium improved scratch healing of keratinocytes and fibroblasts via VEGF pathway and elevated mRNA of VEGFA and collagen1A1. In conclusion, a novel MRONJ treatment with EPCs, increased vascularization and improved epithelial and fibroblast functions as well as cured the lesion.


Assuntos
Osteonecrose da Arcada Osseodentária Associada a Difosfonatos/terapia , Proliferação de Células/efeitos dos fármacos , Transplante de Células , Dexametasona/farmacologia , Células Progenitoras Endoteliais/transplante , Ácido Zoledrônico/farmacologia , Animais , Osteonecrose da Arcada Osseodentária Associada a Difosfonatos/patologia , Conservadores da Densidade Óssea/farmacologia , Difosfonatos/farmacologia , Modelos Animais de Doenças , Fibroblastos/efeitos dos fármacos , Humanos , Queratinócitos/efeitos dos fármacos , Ratos , Cicatrização/efeitos dos fármacos
5.
Int J Med Sci ; 16(12): 1534-1540, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31839740

RESUMO

The aim of this study was to elucidate the role of fibroblasts in bisphosphonate-related osteonecrosis of the jaw (BRONJ), evaluating the effect of zoledronate, alendronate, and ibandronate on the proliferation of fibroblasts and on their expression of genes essential for fibroblast physiology. Human CCD-1064Sk epithelial fibroblast cells were incubated in culture medium with 10-5, 10-7, or 10-9 M zoledronate, alendronate, or ibandronate. The proliferative capacity of fibroblasts was determined by spectrophotometry (MTT) at 24 of culture. Real-time polymerase chain reaction (RT-PCR) was used to study the effects of BPs at a dose of 10-9 M on the expression of FGF, CTGF, TGF-ß1, TGFßR1, TGFßR2, TGFßR3, DDR2, α-actin, fibronectin, decorin, and elastin. Fibroblasts proliferation was significantly increased at the lowest dose (10-9M) of each BP but was not affected at the higher doses (10-5 and 10-7M). The proliferation increase may be related to the rise in TGF-ß1 and TGFßR1 expression detected after the treatment of cells with 10-9M of zoledronate, alendronate, or ibandronate. However, the expression of CTGF, DDR2, α-actin, fibronectin, and decorin decreased versus controls. The results of this in vitro study indicate that a very low BP dose (10-9 M) can significantly affect the physiology of fibroblasts, increasing their proliferative capacity and modulating the expression of multiple genes involved in their growth and differentiation.


Assuntos
Osteonecrose da Arcada Osseodentária Associada a Difosfonatos/tratamento farmacológico , Proliferação de Células/efeitos dos fármacos , Difosfonatos/farmacologia , Fibroblastos/efeitos dos fármacos , Alendronato/farmacologia , Osteonecrose da Arcada Osseodentária Associada a Difosfonatos/genética , Osteonecrose da Arcada Osseodentária Associada a Difosfonatos/patologia , Diferenciação Celular/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Ácido Ibandrônico/farmacologia , Arcada Osseodentária/efeitos dos fármacos , Arcada Osseodentária/metabolismo , Arcada Osseodentária/patologia , Osteoblastos/efeitos dos fármacos , Reação em Cadeia da Polimerase em Tempo Real , Ácido Zoledrônico/farmacologia
6.
Future Oncol ; 15(30): 3503-3511, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31580147

RESUMO

Aim: To investigate the risk factors for developing osteonecrosis of jaw (ONJ) in advanced cancer patients with bone metastases underwent zoledronic acid (ZA) treatment. Materials & methods: Univariate and multivariate logistic regression analyses were performed to investigate factors associated with developing ONJ in advanced cancer patients. Results: A total of 2214 advanced cancer patients were included. Univariate and multivariate logistic regression analyses for risk factors associated with ONJ were older age (≥66 years, hazards ratio [HR]: 3.21; p = 0.007), anemia (HR: 3.29; p = 0.006) and duration of ZA exposure (between 1 and 2 years, HR: 3.91, p = 0.01; ≥2 years, HR: 8.07, p < 0.001), respectively. Conclusion: Patients with older age, anemia and/or more than 1 year of ZA treatment are at high risk of developing ONJ.


Assuntos
Osteonecrose da Arcada Osseodentária Associada a Difosfonatos/epidemiologia , Conservadores da Densidade Óssea/administração & dosagem , Neoplasias Ósseas/tratamento farmacológico , Ácido Zoledrônico/administração & dosagem , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Anemia/epidemiologia , Osteonecrose da Arcada Osseodentária Associada a Difosfonatos/etiologia , Osteonecrose da Arcada Osseodentária Associada a Difosfonatos/patologia , Conservadores da Densidade Óssea/efeitos adversos , Neoplasias Ósseas/secundário , Ensaios Clínicos Fase III como Assunto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Ácido Zoledrônico/efeitos adversos
7.
Int J Mol Sci ; 20(19)2019 Oct 04.
Artigo em Inglês | MEDLINE | ID: mdl-31590328

RESUMO

Bone physiology relies on the delicate balance between resorption and formation of its tissue. Bone resorption depends on a process called osteoclastogenesis in which bone-resorbing cells, i.e., osteoclasts, are produced by the differentiation of more undifferentiated progenitors and precursors. This process is governed by two main factors, monocyte colony-stimulating factor (M-CSF) and receptor activator of NFκB ligand (RANKL). While the former exerts a proliferating effect on progenitors/precursors, the latter triggers a differentiation effect on more mature cells of the same lineage. Bone homeostasis requires a perfect space-time coordination of the involved signals. When osteoclastogenesis is poorly balanced with the differentiation of the bone forming counterparts, i.e., osteoblasts, physiological bone remodelling can turn into a pathological state, causing the systematic disruption of bone tissue which results in osteopenia or osteolysis. Examples of these conditions are represented by osteoporosis, Paget's disease, bone metastasis, and multiple myeloma. Therefore, drugs targeting osteoclastogenesis, such as bisphosphonates and an anti-RANKL monoclonal antibody, have been developed and are currently used in the treatment of such diseases. Despite their demonstrated therapeutic efficacy, these agents are unfortunately not devoid of side effects. In this regard, a condition called osteonecrosis of the jaw (ONJ) has been recently correlated with anti-resorptive therapy. In this review we will address the involvement of osteoclasts and osteoclast-related factors in the pathogenesis of ONJ. It is to be hoped that a better understanding of the biological mechanisms underlying bone remodelling will help in the design a medical therapeutic approach for ONJ as an alternative to surgical procedures.


Assuntos
Osteonecrose da Arcada Osseodentária Associada a Difosfonatos/metabolismo , Diferenciação Celular , Osteoclastos/metabolismo , Animais , Osteonecrose da Arcada Osseodentária Associada a Difosfonatos/epidemiologia , Osteonecrose da Arcada Osseodentária Associada a Difosfonatos/patologia , Humanos , Osteoclastos/citologia
8.
Head Neck ; 41(12): 4209-4228, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31502752

RESUMO

BACKGROUND: We investigated the efficacy of hyperbaric oxygen (HBO), low-intensity laser (LIL), and platelet-rich plasma (PRP) in the management of medication-related osteonecrosis of the jaws (MRONJ). METHODS: A literature search was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement. Two examiners independently assessed eligibility and risk of bias and extracted data. RESULTS: There was improvement in 75.6% of the 41 patients submitted to HBO, with positive effects on pain relief and decreased size and number of lesions at a faster rate, with better effects when the drug was discontinued. For LIL, 158 (64.2%) of the 246 patients/sites improved the symptoms and 98 (39.8%) healed completely. Fourteen (17.3%) of the 81 patients treated with PRP significantly improved the symptoms and 65 (80.2%) completely healed. CONCLUSIONS: These therapies served as safe and effective adjuvant modalities for MRONJ treatment. The lack of randomized clinical trials evidences the need for more high-quality investigations on the subject.


Assuntos
Osteonecrose da Arcada Osseodentária Associada a Difosfonatos/terapia , Oxigenação Hiperbárica/métodos , Terapia a Laser/métodos , Plasma Rico em Plaquetas , Idoso , Idoso de 80 Anos ou mais , Osteonecrose da Arcada Osseodentária Associada a Difosfonatos/patologia , Conservadores da Densidade Óssea/efeitos adversos , Terapia Combinada , Denosumab/efeitos adversos , Difosfonatos/efeitos adversos , Feminino , Humanos , Doenças Maxilomandibulares/induzido quimicamente , Doenças Maxilomandibulares/terapia , Masculino , Pessoa de Meia-Idade , Osteonecrose/induzido quimicamente , Osteonecrose/terapia , Manejo da Dor , Pamidronato/efeitos adversos , Ensaios Clínicos Controlados Aleatórios como Assunto
9.
Macromol Biosci ; 19(11): e1900226, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31549786

RESUMO

Medication-related osteonecrosis of the jaw (MRONJ) poses an ongoing challenge for clinicians and researchers. Currently, there is a lack of preventative measures available for at-risk patients undergoing tooth extractions, especially those with prior bisphosphonate treatment due to osteoporosis or bone metastasis diagnoses. Here, these issues are addressed using a preventative tissue engineering strategy against MRONJ development. This study evaluates the efficacy of a poly(ethylene glycol)-heparin hydrogel as a tool for the delivery of arginylglycylaspartic acid (RGD) and recombinant human bone morphogenic protein-2 (rhBMP-2). Three groups of skeletally mature rats each receive two doses of intravenous zoledronic acid prior to surgery and undergo extraction of the right first mandibular molar with gingival closure. Experimental groups either have the sockets left empty, filled with hydrogel minus rhBMP-2, or filled with hydrogel plus rhBMP-2. Eight weeks postoperatively specimens are analyzed using radiological, histological, and scanning electron microscopy (SEM) techniques. µCT analysis shows increased bone formation with hydrogel/rhBMP-2 delivery compared to the empty socket. Hydrogel-treated groups display increased presence of osteocytes and increased osteoclastic action compared to the empty sockets. These results represent the first step toward improved delivery of rhBMP-2 and a potential MRONJ preventative for patients undergoing bisphosphonate treatment.


Assuntos
Osteonecrose da Arcada Osseodentária Associada a Difosfonatos/prevenção & controle , Proteína Morfogenética Óssea 2/farmacocinética , Preparações de Ação Retardada/farmacocinética , Liberação Controlada de Fármacos , Fator de Crescimento Transformador beta/farmacocinética , Animais , Osteonecrose da Arcada Osseodentária Associada a Difosfonatos/patologia , Proteína Morfogenética Óssea 2/administração & dosagem , Células Cultivadas , Quimioprevenção/métodos , Preparações de Ação Retardada/administração & dosagem , Modelos Animais de Doenças , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/prevenção & controle , Humanos , Hidrogéis/farmacocinética , Osteócitos/efeitos dos fármacos , Osteócitos/fisiologia , Ratos , Ratos Sprague-Dawley , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/farmacocinética , Fator de Crescimento Transformador beta/administração & dosagem
10.
Braz Oral Res ; 33: e050, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-31269114

RESUMO

The present study aimed to investigate the use of platelet-rich plasma (PRP) on tooth extraction sites in rats treated with bisphosphonates. Thirty Albinus Wistar male rats were administered 0.035 mg/kg zoledronic acid intravenously for 8 weeks, divided into four administrations with a 2-week interval between each application, after which their upper right central incisors were extracted to induce the development of bisphosphonate-related osteonecrosis of the jaw (BRONJ). The samples were divided into the following two groups: Group 1 (G1) underwent marginal resection of BRONJ followed by the use of PRP, while Group 2 (G2) underwent resection of BRONJ but without the use of PRP. The treatment groups were evaluated after 14, 28, and 42 days. Clinical, microtomographic, microscopic, and immunohistochemical (IHC) evaluations were performed. Microtomography results revealed no significant difference between the groups (p <0.05) in any time period. Histomorphometric analysis showed increased bone formation over time for both groups (p < 0.001). G1 demonstrated a greater amount of new bone formation than G2 at 28 and 42 days (p < 0.001), with G1 presenting greater vascularization and a slightly higher VEGF expression. For both groups, RANKL/OPG expression levels were sufficient as a parameter for indicating the rate of bone remodeling in a previously treated area of osteonecrosis groups. Taken together, our findings indicated that the use of PRP improves the resolution process of BRONJ.


Assuntos
Osteonecrose da Arcada Osseodentária Associada a Difosfonatos/terapia , Conservadores da Densidade Óssea/uso terapêutico , Difosfonatos/uso terapêutico , Plasma Rico em Plaquetas , Animais , Osteonecrose da Arcada Osseodentária Associada a Difosfonatos/patologia , Osteonecrose da Arcada Osseodentária Associada a Difosfonatos/fisiopatologia , Modelos Animais de Doenças , Masculino , Osteoclastos/efeitos dos fármacos , Ratos , Ratos Wistar , Extração Dentária/efeitos adversos , Cicatrização
12.
Stem Cell Res Ther ; 10(1): 169, 2019 06 13.
Artigo em Inglês | MEDLINE | ID: mdl-31196208

RESUMO

BACKGROUND: Due to its complex pathogenesis and low clinical cure rate, bisphosphonate-related osteonecrosis of the jaw (BRONJ) poses a substantial challenge for oral and maxillofacial surgeons. Therefore, the treatment of BRONJ should focus on prevention. In clinical studies, primary wound closure can significantly reduce the incidence of BRONJ. Whether local stem cell transplantation can promote primary gingival healing in patients with a medication history and prevent BRONJ has not been reported. METHODS: In this study, animals were divided into a healthy group (non-drug treatment), a BP group, a hydroxyapatite (HA) group, and an adipose-derived stem cell (ADSC) group. All groups except the healthy group were treated with BPs and immunosuppressive drugs once per week for 8 weeks, simulating clinical use for the treatment of cancer patients with bone metastasis, to induce BRONJ-like animals. After the sixth drug treatment, the bilateral premolars were extracted in all groups. In contrast to the healthy and BP groups, the extraction sockets in the HA and ADSC groups were filled with HA or HA + ADSCs simultaneously post extraction to observe the preventive effect of ADSCs on the occurrence of BRONJ. At 2 and 8 weeks post extraction, animals from all groups were sacrificed. RESULTS: At 8 weeks post transplantation, ADSCs prevented the occurrence of BRONJ, mainly through accelerating healing of the gingival epithelium at 2 weeks post extraction. We also found that ADSCs could upregulate the expression of transforming growth factor ß1 (TGF-ß1) and fibronectin in tissue from animals with a medication history by accelerating gingival healing of the extraction socket. A rescue assay further demonstrated that TGF-ß1 and fibronectin expression decreased in TGF-ß1-deficient ADSC-treated animals, which partially abolished the preventive effect of ADSCs on the onset of BRONJ. CONCLUSION: ADSCs prevent the onset of BRONJ, mainly by upregulating the expression of TGF-ß1 and fibronectin to promote primary gingival healing, ultimately leading to bone regeneration in the tooth extraction socket. Our new findings provide a novel stem cell treatment for the prevention of BRONJ.


Assuntos
Osteonecrose da Arcada Osseodentária Associada a Difosfonatos/terapia , Fibronectinas/genética , Transplante de Células-Tronco Mesenquimais , Fator de Crescimento Transformador beta1/genética , Animais , Osteonecrose da Arcada Osseodentária Associada a Difosfonatos/genética , Osteonecrose da Arcada Osseodentária Associada a Difosfonatos/patologia , Modelos Animais de Doenças , Regulação da Expressão Gênica no Desenvolvimento , Gengiva/lesões , Gengiva/patologia , Gengiva/transplante , Humanos , Células-Tronco Mesenquimais/citologia , Coelhos , Cicatrização/genética , Ácido Zoledrônico/farmacologia
14.
J Transl Med ; 17(1): 69, 2019 03 04.
Artigo em Inglês | MEDLINE | ID: mdl-30832685

RESUMO

BACKGROUND: With an increasing indication spectrum of antiresorptive drugs, the medication-related osteonecrosis of the jaw secondary to bisphosphonate therapy [MRONJ (BP)] is continuously gaining clinical relevance. Impaired osteoclast function, accompanied by altered cell morphology and expression of osteoclastic effector proteins, contributes to the pathogenesis of MRONJ (BP). However, the underlying regulatory mechanisms at a transcriptional level are unaddressed so far. These mechanisms are crucial to the development of disease-characteristic osteoclastic anomalies, that contribute to the pathogenesis of MRONJ (BP). NFATc1 is considered a master upstream osteoclastic activator, whereas BCL6 acts as osteoclastic suppressor. The present study aimed to elucidate the NFATc1 and BCL6 mediated osteoclastic regulation and activity in MRONJ (BP) compared to osteoradionecrosis (ORN) and osteomyelitis (OM) and normal jaw bone. METHODS: Formalin-fixed jaw bone specimens from 70 patients [MRONJ (BP) n = 30; OM: n = 15, ORN: n = 15, control: n = 10] were analyzed retrospectively for osteoclast expression of NFATc1 and BCL6. The specimens were processed for H&E staining and immunohistochemistry. The histological sections were digitalized and analyzed by virtual microscopy. RESULTS: Osteoclastic expression of NFATc1 and BCL6 was significantly higher in MRONJ (BP) specimens compared to OM and control specimens. NFATc1 and BCL6 labeling indices revealed no significant differences between MRONJ (BP) and ORN. The ratio of nuclear BCL6+ osteoclasts to cytoplasmic BCL6+ osteoclasts revealed significantly higher values for MRONJ (BP) specimens compared to OM and controls. CONCLUSION: This study displays that osteoclasts in MRONJ (BP) tissues feature increased expression of the higher-level regulators, paradoxically of both NFATc1 and BCL6. These observations can help to explain the genesis of morphologically altered and resorptive inactive osteoclasts in MRONJ (BP) tissues by outlining the transcriptional regulation of the pathomechanically relevant osteoclastic effector proteins. Furthermore, they strengthen the etiological delineation of MRONJ (BP) from OM and extend the osteoclast profiles of MRONJ (BP), OM and ORN and thus could lead to a better histopathological differentiation that can improve treatment decision and motivate new therapeutic concepts.


Assuntos
Osteonecrose da Arcada Osseodentária Associada a Difosfonatos/metabolismo , Fatores de Transcrição NFATC/metabolismo , Osteoclastos/metabolismo , Osteomielite/metabolismo , Osteorradionecrose/metabolismo , Proteínas Proto-Oncogênicas c-bcl-6/metabolismo , Adulto , Idoso , Osteonecrose da Arcada Osseodentária Associada a Difosfonatos/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Osteoclastos/patologia , Osteomielite/patologia , Osteorradionecrose/patologia
15.
Tohoku J Exp Med ; 247(2): 75-86, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30713280

RESUMO

Bisphosphonates (BPs) have been used as antiresorptive agents to treat patients with osteoporosis or metastatic bone cancer, each of which is characterized by bone loss due to the increased bone resorption. However, BPs could cause osteonecrosis of the jaw (ONJ), known as bisphosphonate-related osteonecrosis of the jaw (BRONJ). ONJ is associated with severe pain and deteriorated quality of life. ONJ is also caused by administration of denosumab, a monoclonal antibody against receptor activator of NFκB ligand (RANKL), that functions as a powerful antiresorptive agent. Accordingly, antiresorptive agent-related ONJ (ARONJ) has been advocated, the incidence of which is continuing to increase in Japan as a super-aging society. Importantly, the jawbone is more susceptible to infection compared with bones in other parts of the body, due to the unique anatomical and physiological characteristics; for example, the jawbone with a high remodeling rate is stimulated by teeth during mastication. The risk factors of ARONJ include dental infection, poor occlusal or oral hygiene status, and bone-invasive dental treatment, such as tooth extraction, dental implants, and dentures. Proper collaboration between doctors and dentists is of utmost importance to understand the current status of ARONJ and prevent developing ARONJ. It is also important to ensure that the patients treated with BPs or denosumab can receive appropriate dental treatment. More recently, angiogenesis inhibitors were reported to cause ONJ; thus, medication-related ONJ (MRONJ) has been advocated. This article overviews the concept of MRONJ by focusing on antiresorptive agents and the status of BRONJ in Japan.


Assuntos
Osteonecrose da Arcada Osseodentária Associada a Difosfonatos/patologia , Conservadores da Densidade Óssea/efeitos adversos , Osso e Ossos/patologia , Animais , Osteonecrose da Arcada Osseodentária Associada a Difosfonatos/prevenção & controle , Conservadores da Densidade Óssea/química , Difosfonatos/efeitos adversos , Difosfonatos/química , Humanos , Modelos Biológicos
16.
Oral Dis ; 25(4): 1116-1135, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30712276

RESUMO

OBJECTIVES: To determine the extent that zoledronate (ZOL) dose and duration is associated with bisphosphonate-related osteonecrosis of the jaw (BRONJ) prevalence in rice rats with generalized periodontitis (PD), characterize structural and tissue-level features of BRONJ-like lesions in this model, and examine the specific anti-resorptive role of ZOL in BRONJ. MATERIALS AND METHODS: Rice rats (n = 228) consumed high sucrose-casein diet to enhance generalized PD. Groups of rats received 0, 8, 20, 50 or 125 µg/kg IV ZOL/4 weeks encompassing osteoporosis and oncology ZOL doses. Rats from each dose group (n = 9-16) were necropsied after 12, 18, 24 and 30 weeks of treatment. BRONJ-like lesion prevalence and tissue-level features were assessed grossly, histopathologically and by MicroCT. ZOL bone turnover effects were assessed by femoral peripheral quantitative computed tomography, serum bone turnover marker ELISAs and osteoclast immunolabelling. RESULTS: Prevalence of BRONJ-like lesions was significantly associated with (a) ZOL treatment duration, but plateaued at the lowest oncologic dose, and (b) there was a similar dose-related plateau in the systemic anti-resorptive effect of ZOL. ZOL and BRONJ-like lesions also altered the structural and tissue-level features of the jaw. CONCLUSION: The relationship between BRONJ-like lesion prevalence and ZOL dose and duration varies depending on the co- or pre-existing oral risk factor. At clinically relevant doses of ZOL, BRONJ-like lesions are associated with anti-resorptive activity.


Assuntos
Osteonecrose da Arcada Osseodentária Associada a Difosfonatos/epidemiologia , Conservadores da Densidade Óssea/uso terapêutico , Duração da Terapia , Periodontite/tratamento farmacológico , Ácido Zoledrônico/uso terapêutico , Animais , Osteonecrose da Arcada Osseodentária Associada a Difosfonatos/patologia , Relação Dose-Resposta a Droga , Prevalência , Ratos , Sigmodontinae , Ácido Zoledrônico/efeitos adversos
17.
PLoS One ; 14(2): e0211928, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30735554

RESUMO

Osteonecrosis of the jaw induced by administration of bisphosphonates (BPs), BP-related osteonecrosis (BRONJ), typically develops after tooth extraction and is medically challenging. As BPs inhibit oral mucosal cell growth, we hypothesized that suppression of the wound healing-inhibiting effects could prevent BRONJ onset after tooth extraction. Since basic fibroblast growth factor (bFGF) promotes wound healing, but has a short half-life, we examined whether the initiation of BRONJ could be prevented by applying a bFGF-containing gelatin hydrogel over the extraction sockets of BRONJ model rats. Forty-three rats, received two intravenous injections of zoledronic acid 60 µg/kg, once per week for a period of 2 weeks, underwent extraction of a unilateral lower first molar. The rats here were randomly assigned to the bFGF group (n = 15 rats, gelatin hydrogel sheets with incorporated bFGF applied over the sockets); the phosphate-buffered saline (PBS) group (n = 14 rats, gelatin hydrogel sheets without bFGF applied over the sockets); or the control group (n = 14 rats, nothing applied over the sockets). One rat in the bFGF group was sacrificed immediately after tooth extraction. Twenty-one rats were sacrificed at 3 weeks, and the remaining 21 rats were sacrificed at 8 weeks after tooth extractions. The harvested mandibles were analyzed using micro-computed tomography and sections were evaluated qualitatively for mucosal disruption and osteonecrosis. The incidence of osteonecrosis at 8 weeks after tooth extraction was 0% in the bFGF group, 100% in the PBS group, and 85.7% in the control group. The frequency of complete coverage of the extraction socket by mucosal tissue was significantly greater in the bFGF group than in the other groups. These results suggest that application of bFGF in the extraction socket promoted socket healing, which prevented BRONJ development. The growth-stimulating effects of bFGF may have offset the inhibition of wound healing by BP.


Assuntos
Preparações de Ação Retardada/química , Fator 2 de Crescimento de Fibroblastos/farmacologia , Mucosa Bucal/efeitos dos fármacos , Extração Dentária/efeitos adversos , Cicatrização/efeitos dos fármacos , Animais , Osteonecrose da Arcada Osseodentária Associada a Difosfonatos/diagnóstico por imagem , Osteonecrose da Arcada Osseodentária Associada a Difosfonatos/tratamento farmacológico , Osteonecrose da Arcada Osseodentária Associada a Difosfonatos/etiologia , Osteonecrose da Arcada Osseodentária Associada a Difosfonatos/patologia , Feminino , Fator 2 de Crescimento de Fibroblastos/farmacocinética , Gelatina/química , Humanos , Hidrogéis/química , Mandíbula/diagnóstico por imagem , Mandíbula/efeitos dos fármacos , Mandíbula/patologia , Dente Molar/efeitos dos fármacos , Dente Molar/patologia , Dente Molar/cirurgia , Mucosa Bucal/diagnóstico por imagem , Mucosa Bucal/patologia , Ratos , Ratos Sprague-Dawley , Alvéolo Dental/diagnóstico por imagem , Alvéolo Dental/efeitos dos fármacos , Alvéolo Dental/patologia , Microtomografia por Raio-X , Ácido Zoledrônico/administração & dosagem
18.
Bone ; 122: 45-51, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30738857

RESUMO

INTRODUCTION: An acidic environment has been recognized to increase catabolic activities and inhibit osteoblastic deposition, and also exhibited in the pathogenesis of various bone diseases. The aim of the study was to investigate the role of systemic and local pH alteration in the pathogenesis of medication-related osteonecrosis of the jaw (MRONJ). MATERIAL AND METHODS: Initially, MRONJ was induced in 54 Sprague-Dawley rats via subcutaneous bisphosphonate injections, once a week for 8 weeks. A week prior to bisphosphonate termination, surgical intervention was performed and rats were divided into 3 groups-alkalotic, acidic and control group, wherein each received NaHCO3, NH4Cl and normal saline, respectively for 8 weeks. Upon sacrifice, blood was sent for arterial blood pH analysis and their mandibles were subjected to histomorphometric and µCT analyses. ONJ was histologically defined as necrotic bone persisting for eight weeks after surgical intervention. RESULTS: Each intervention exemplified its expected outcome wherein each group exhibited a borderline alkalotic (7.43 ±â€¯0.05) and acidic state (7.27 ±â€¯37), respectively (P < 0.05). Acidic group showed a higher occurrence of MRONJ (95%) compared to that of alkalotic group (60%) and control (76.9%). Histomorphometric and microstructural evaluation revealed that acidic group presented deteriorated bone architectures with significantly higher necrotic bone fraction, clusters of empty lacunae, N.Oc/B.Pm and lower B.Ar./T.Ar, BV/TV, Tb.Th (P < 0.05). Alkalotic group showed possible protective effects against ONJ versus acidic group, however these trends were not statistically significant. CONCLUSIONS: An acidic milieu aggravated ONJ development in an animal model. Further investigations are needed to elucidate the exact role of acid-base balance in MRONJ pathogenesis and possible benefits of alkali supplementation for the prevention.


Assuntos
Osteonecrose da Arcada Osseodentária Associada a Difosfonatos/etiologia , Animais , Osteonecrose da Arcada Osseodentária Associada a Difosfonatos/diagnóstico por imagem , Osteonecrose da Arcada Osseodentária Associada a Difosfonatos/patologia , Osso e Ossos/diagnóstico por imagem , Osso e Ossos/patologia , Concentração de Íons de Hidrogênio , Masculino , Ratos Sprague-Dawley , Microtomografia por Raio-X
19.
J Craniomaxillofac Surg ; 47(2): 349-356, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30595476

RESUMO

PURPOSE: The mechanisms underlying the pathophysiology of medication-related osteonecrosis of the jaw (MRONJ) development have not yet been fully elucidated. MRONJ is described as a multi-factorial process in which bacterial infection seems to play an important role. The purpose of the present study was to investigate the influence of a primary installed infectious disease in the development of MRONJ after dental extraction. MATERIALS AND METHODS: Twenty-six rats underwent pulpal exposure of one upper and one lower first molar to induce periapical lesions. Thereafter, animals received zoledronate during a 4-week period. The day after the last injection, the four first molars from each quadrant were extracted. Eight weeks later, animals were sacrificed for macroscopic, radiological, and histological assessment. RESULTS: The incidence of MRONJ was highest in mandibular infected teeth (47.4%), while the histological evaluation showed the highest incidence of osteonecrosis (88.2%) and the largest mean value for extent of the necrotic bone area (1.22 ± 0.71 mm2). Radiological findings confirmed the clinical and histological results. Statistical analysis showed that the combination of both factors, mandibular localization and periapical infection, significantly increased the incidence of MRONJ after extraction, considering clinical (p = 0.0074), radiological (p = 0.026), and histological (p = 0.0022) outcomes. CONCLUSION: These findings support the potential implication of inflammatory/infectious dental pathology in initiating the osteonecrotic process before dental extraction. The possible partial role of the infectious process in MRONJ development emphasizes the importance of maintaining good oral health and dental care for preventing infectious pathology in the management of these patients.


Assuntos
Infecções Bacterianas/complicações , Osteonecrose da Arcada Osseodentária Associada a Difosfonatos/etiologia , Extração Dentária , Processo Alveolar/diagnóstico por imagem , Processo Alveolar/patologia , Animais , Osteonecrose da Arcada Osseodentária Associada a Difosfonatos/diagnóstico por imagem , Osteonecrose da Arcada Osseodentária Associada a Difosfonatos/patologia , Conservadores da Densidade Óssea/efeitos adversos , Masculino , Ratos , Ratos Wistar , Extração Dentária/efeitos adversos , Extração Dentária/métodos , Microtomografia por Raio-X , Ácido Zoledrônico/efeitos adversos
20.
J Vet Intern Med ; 33(2): 862-867, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30663796

RESUMO

A 12-year-old, neutered female, domestic medium hair cat was evaluated for a nonhealing, oral mucosal ulceration. The cat had a history of idiopathic hypercalcemia that had been treated with a bisphosphonate for 41 months. Oral examination identified exposed maxillary bone adjacent to a previous extraction site. Histopathology of the exposed bone and associated mucosa was most consistent with medication-related osteonecrosis of the jaw. Treatment involved both medical and surgical interventions. Oral mucosal healing occurred after 6 months of treatment.


Assuntos
Alendronato/efeitos adversos , Osteonecrose da Arcada Osseodentária Associada a Difosfonatos/veterinária , Doenças do Gato/induzido quimicamente , Difosfonatos/efeitos adversos , Alendronato/uso terapêutico , Animais , Osteonecrose da Arcada Osseodentária Associada a Difosfonatos/patologia , Osteonecrose da Arcada Osseodentária Associada a Difosfonatos/terapia , Doenças do Gato/tratamento farmacológico , Gatos , Difosfonatos/uso terapêutico , Feminino , Hipercalcemia/tratamento farmacológico , Hipercalcemia/veterinária , Úlceras Orais/etiologia , Úlceras Orais/veterinária
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