Preventive and therapeutic effects of relaxin on bisphosphonate related osteonecrosis of the jaw: an experimental study in rats / Efeitos preventivos e terapêuticos da relaxina na osteonecrose da mandíbula relacionada a bisfosfonatos: um estudo experimental em ratos

Objective: Bisphosphonate-related osteonecrosis of the jaw (BRONJ) is a challenging complication of chronic bisphosphonate (BP) use. The hormone relaxin is able to induce the multistep differentiation process of human osteoclastogenesis, exhibits antifibrotic and anti-inflammatory actions, and promotes vasodilatation, wound healing, and angiogenesis. The present study aimed to evaluate the effects of relaxin in the prevention and management of BRONJ. Material and Methods: Thirty-six male Sprague Dawley rats were randomly divided into four groups. Rats in group 1 (n = 10) received relaxin and BP simultaneously for 12 weeks. Rats in group 2 (n = 10) received injections of BP for 12 weeks, followed by relaxin for another 12 weeks. Rats in group 3 (n = 10) received only BP injections, and those in group 4 (control, n = 6) received only saline. Necrosis and inflammation in the rats' mandibles were evaluated as indicators of BRONJ. Results: Necrosis and inflammation were not detected in group 1 (BP + relaxin). In group 3 (BP only), incidence rates of necrosis and inflammation were 90% and 60%, respectively. Conclusions: Our findings suggest that relaxin may be potently effective in preventing BRONJ and have some benefit in the treatment of existing BRONJ (AU)

Objetivo: A osteonecrose da mandíbula relacionada ao bisfosfonato (BRONJ) é uma desafiadora complicação do uso crônico de bisfosfonato (BP). O hormônio relaxina é capaz de induzir o processo múltiplo de diferenciação da osteoclastogênese humana, exibe ações anti-fibróticas e anti-inflamatórias e promove vasodilatação, cicatrização de feridas e angiogênese. O presente estudo teve como objetivo avaliar os efeitos da relaxina na prevenção e tratamento do BRONJ. Material e Métodos: Trinta e seis ratos Sprague Dawley machos foram divididos aleatoriamente em quatro grupos. Os ratos do grupo 1 (n = 10) receberam relaxina e BP simultaneamente por 12 semanas. Os ratos do grupo 2 (n = 10) receberam injeções de BP por 12 semanas, seguidos de relaxina por mais 12 semanas. Os ratos do grupo 3 (n = 10) receberam apenas injeções de BP e os do grupo 4 (controle, n = 6) receberam apenas solução salina. Necrose e inflamação nas mandíbulas dos ratos foram avaliadas como indicadores de BRONJ. Resultados: Necrose e inflamação não foram detectadas no grupo 1 (BP + relaxina). No grupo 3 (somente BP), as taxas de incidência de necrose e inflamação foram de 90% e 60%, respectivamente. Conclusões: Nossos resultados sugerem que a relaxina pode ser potentemente eficaz na prevenção do BRONJ e ter algum benefício no tratamento do BRONJ existente.(AU)

Dental management of patients receiving bisphosphonate therapy – A review

Bisphosphonates, synthetic (Non-biodegradable) analogues of pyrophosphate, were initially used in industry as water softening agents in irrigation systems and lateron discovered as bone loss inhibitors. Bisphosphonates inhibit bone resorption by being selectively taken up and adsorbed to mineral surfaces in bone, where they interfere with the action of the bone-resorbing osteoclasts. Thus, they have been proposed in the management of periodontal diseases by inhibiting the osteoclastic bone resorption and hence are used as a host modulating factor for prevention of bone loss. The other indications being Osteoporosis , Paget’s disease, Malignant hypercalcemia , Bone metastasis, Multiple myeloma etc. Gastro intestinal intolerance, Renal and hepato-toxicity, Hypocalcaemia, Osteonecrosis of jaws seen especially after invasive dental treatment (called as Bisphosphonate related osteonecrosis of jaw, BRONJ) are the main side effects of bisphosphonate therapy. To overcome such effects during dental management of patients, the recommendations focus on conservative surgical procedures, proper sterile technique, appropriate use of oral disinfectants and the principles of effective antibiotic therapy. The dentist should retain in his/her file the acknowledgment and consent for the treatment.

Clinical diagnosis and treatment on bisphosphonate-related osteonecrosis of the jaw / 口腔疾病防治

@#Bisphosphonate-related osteonecrosis of the jaw (BRONJ) is a class of disease due to complications of long-term use of bisphosphonates drugs such as zoledronic acid, phosphoric acid, etc. It is mainly manifested in the mouth as a result of tooth extraction or appearing spontaneously mandibular long-term healing wounds, sequestrum exposure, local soft tissue swelling with pain and pus, etc. The X-ray showed irregular bone destruction and bone sclerosis as the lesions progress. At present, the diagnosis and treatment of the disease has not reached agreement. In this paper, clinical diagnosis and treatment on BRONJ in recent years were reviewed.

A Case of Pentastomiasis at the Left Maxilla Bone in a Patient with Thyroid Cancer

Pentastomiasis, a zoonotic parasite infection, is typically found in the respiratory tract and viscera of the host, including humans. Here, we report for the first time an extremely rare case of intraosseous pentastomiasis in the human maxilla suffering from medication related osteonecrosis of the jaw (MRONJ). A 55-year-old male had continuously visited the hospital for MRONJ which had primarily developed after bisphosphonate and anti-neoplastic administration for previous bone metastasis of medullary thyroid cancer. Pain, bone exposure, and pus discharge in the right mandible and left maxilla were seen. Osteolysis with maxillary cortical bone perforation at the left buccal vestibule, palate, nasal cavity, and maxillary sinus was observed by radiologic images. A biopsy was done at the left maxilla and through pathological evaluation, a parasite with features of pentastome was revealed within the necrotic bone tissue. Further history taking and laboratory evaluation was done. The parasite was suspected to be infected through maxillary open wounds caused by MRONJ. Awareness of intraosseous pentastomiasis should be emphasized not to be missed behind the MRONJ. Proper evaluation and interpretation for past medical history may lead to correct differential diagnosis and therapeutic intervention for parasite infections.

Effect of low-level laser therapy on bisphosphonate-treated osteoblasts / 대한악안면성형재건외과학회지

BACKGROUND: This study investigates the effect of alendronate-treated osteoblasts, as well as the effect of low-level laser therapy (LLLT) on the alendronate-treated osteoblasts. Bisphosphonate decreases the osteoblastic activity. Various treatment modalities are used to enhance the bisphosphonate-treated osteoblasts; however, there were no cell culture studies conducted using a low-level laser. METHODS: Human fetal osteoblastic (hFOB 1.19) cells were treated with 50 μM alendronate. Then, they were irradiated with a 1.2 J/cm² low-level Ga-Al-As laser (λ = 808 ± 3 nm, 80 mW, and 80 mA; spot size, 1 cm²; NDLux, Seoul, Korea). The cell survivability was measured with the MTT assay. The three cytokines of osteoblasts, receptor activator of nuclear factor κB ligand (RANKL), osteoprotegerin (OPG), and macrophage colony-stimulating factor (M-CSF) were analyzed. RESULTS: In the cells treated with alendronate at concentrations of 50 μM and higher, cell survivability significantly decreased after 48 h (p < 0.05). After the applications of low-level laser on alendronate-treated cells, cell survivability significantly increased at 72 h (p < 0.05). The expressions of OPG, RANKL, and M-CSF have decreased via the alendronate. The RANKL and M-CSF expressions have increased, but the OPG was not significantly affected by the LLLT. CONCLUSIONS: The LLLT does not affect the OPG expression in the hFOB cell line, but it may increase the RANKL and M-CSF expressions, thereby resulting in positive effects on osteoclastogenesis and bone remodeling.

Bisphosphonate-related osteonecrosis of the jaw in metastatic breast cancer patients: a review of 25 cases / 대한악안면성형재건외과학회지

BACKGROUND: Intravenous bisphosphonates have been used in metastatic breast cancer patients to reduce pathologic bone fracture and bone pain. However, necrosis of the jaw has been reported in those who received intravenous bisphosphonates. Bisphosphonate-related osteonecrosis of the jaw (BRONJ) is caused by dental extraction, dental implant surgery, and denture wearing; however, it occurs spontaneously. The purpose of this study was to report BRONJ in metastatic breast cancer patients. METHODS: Consecutive 25 female patients were referred from the Department of Oncology from 2008 to 2014 for jaw bone discomfort. Staging of breast cancer, history of bisphosphonate infusion, etiology of BRONJ, and treatment results were reviewed. Average age of the patients was 55.4 years old (38-74). Twelve maxillae and 16 mandibles were involved. Conservative treatments such as irrigation, antibiotic medication, analgesics, and oral gargle were applied for all patients for the initial treatment. Patients who had sequestrum underwent debridement and primary closure. RESULTS: The etiologies of BRONJ were dental extraction (19 cases), dental implant (2 cases), and endodontic treatment (1 case). However, three patients did not have any risk factors to cause BRONJ. Three patients died of progression of metastasis during follow-up periods. Surgical debridement was performed in 21 patients with success in 18 patients. Three patients showed recurred bone exposure and infection after operation. CONCLUSIONS: Prevention of the BRONJ is critical in metastatic breast cancer patients. Conservative treatment to reduce pain, discomfort, and infection is recommended for the initial therapy. However, if there is a sequestrum, surgical debridement and primary closure is the key to treat the BRONJ.

Regenerated Bisphosphonate Related Osteonecrosis of the Jaws: Clinical Data of Eleven Cases.

Aims: Bisphosphonate-related osteonecrosis of the jaw (BRONJ) is defined as the persistence of exposed necrotic bone in the oral cavity for 8 weeks or more in patients with current or previous history of BP use, despite adequate treatment, and no local evidence of malignancy or prior radiotherapy in the maxillofacial region. Complete resolution of symptoms and partial clinical achievement should be the primary goals in the management of BRONJ. The objective of the present study was to describe the clinical data and treatment of 11 patients with completely regenerated BRONJ. Methodology: This retrospective study included 11 patients who experienced oral complications after intravenous bisphosphonate therapy. The diagnostic procedure involved clinical and radiological examinations. The patients were treated by irrigation with oral rinses, nonsteroidal anti-inflammatory drugs, long-term antibiotic therapy to resolve the infection, and non-aggressive surgical debridement of soft or hard tissues and sequestrectomy. Results: Complete healing, defined as the absence of any mucosal breaches and exposed necrotic bone, signs of inflammation and infection, and clinical complaints, was achieved in all patients. Conclusion: Dental professionals should be aware of this potentially serious complication in oral surgery patients receiving long-term treatment with BPs. Although the management of patients with BRONJ is quite challenging since no ideal treatment protocol has been established thus far, discontinuity of bisphosphonate therapy combined with surgical debridement to obtain clear and bleeding margins along with long-term antibiotic therapy administration is the treatment of choice for osteonecrotic lesions of the jaws.

O efeito do ácido zoledrônico na microestrutura óssea analisado pela micro-CT em mandíbulas de ratos wistar / Zoledronic acid effect on the bone microarchitecture of the jaw of rats by Micro-CT

Os bisfosfonatos são medicamentos amplamente e efetivamente utilizados para o tratamento de doenças osteolíticas. Entretanto, na cavidade oral, é de particular relevância, pois possuem como efeito adverso a osteonecrose dos maxilares induzida pelo uso de bisfosfonatos. Sua etiopatogenia ainda não é bem estabelecida, os métodos de detecção são insatisfatórios e as terapias recomendadas são por vezes, medidas paliativas e ineficazes. Pouco ainda é sabido sobre o efeito do Ácido Zoledrônico na microestrutura óssea, portanto, propusemo-nos a realizar um estudo em modelo animal que analisasse o trabeculado ósseo da mandíbula através da Micro-CT. Foram utilizados 24 ratos machos (Rattus novergicus, albinus, Wistar), com 12 semanas de vida, divididos em 2 grupos: grupo controle (cloreto de sódio 0,9%) e grupo ácido zoledrônico (ácido zoledrônico 0,6mg/kg). As substâncias foram administradas via intraperitoneal a cada 28 dias em um total de 5 doses. Após 150 dias do início do experimento, foi realizada a eutanásia dos animais e então as amostras foram preparadas e escaneadas (Skyscan 1174) para análise da microestrutura óssea através da Micro- CT. O teste t-student demonstrou diferença estatisticamente significativa (p<0,05) em todos os fatores: volume ósseo, densidade óssea, fator de padrão trabecular, índice de modelo estrutural, espessura trabecular, separação trabecular, porosidade total exceção de número de trabéculas e volume tecidual, demonstrando que há alterações significativas na estrutura trabecular pelo uso de bisfosfonatos. O grupo medicado com ácido zoledrônico comparado ao grupo controle demonstrou trabéculas mais espessas, menos separadas e com menores ligações...

Bisphosphonates are widely and effectively drugs used for the treatment of osteolytic disorders. However, in the oral cavity, this situation is of particular relevance as it can lead to bisphosphonate related osteonecrosis of the jaws. Its etiopathogenesis is still not established, detection methods are unsatisfactory and recommended therapies are sometimes palliative and often ineffective. Little is known about the effect of zoledronic acid on the quality of trabecular bone, therefore, we proposed to conduct a study in an animal model to examine the trabecular bone of the jaw through the Micro-CT. 24 male rats were used (Rattus norvegicus, Albinus, Wistar), with 12 weeks old, divided into 2 groups: control group (sodium chloride 0.9%) and group with zoledronic acid (zoledronic acid 0.6 mg / kg). The substances were administered intraperitoneally every 28 days for a total of 5 doses. After 150 days from the beginning of the experiment, the animals were sacrificed and then the samples were prepared and scanned (Skyscan 1174) for analysis of the bone microstructure through Micro-CT. The "t-student" test demonstrated statistically significant differences (p<0.05) in all factors: bone volume, osseous density, trabecular pattern, structure model index, trabecular thickness, trabecular separation, total porosity except trabecular number and tissue volume, demonstrating that there are significant changes in the trabecular structure of the bisphosphonates. Zoledronic Acid compared to control group shows thicker, less separate and lower connected trabeculae...

Comparative Study on Surgical and Conservative Management of Bisphosphonate-related Osteonecrosis of the Jaw (BRONJ) in Disease Stage 2

0.05).CONCLUSION: The results of the present study suggests that surgical intervention is good choice against the conservative treatment, after proper drug holidays period, while further investigation is needed for a definite solution to BRONJ.

A Case of Intractable Bisphosphonate-Related Osteonecrosis of the Jaw Treated with Teriparatide / 대한골다공증학회지

Bisphosphonates are the most widely used medications for treating high bone turnover osteoporosis, Paget's disease of bone, multiple myeloma and metastatic carcinomas, etc. However, a destructive complication of bisphosphonate-related osteonecrosis of the jaw (BRONJ) can occur. The treatments of BRONJ are challenging and the currently recommended managements for BRONJ are still controversial. Our case demonstrated that teriparatide can be a treatment of choice for intractable BRONJ, which had not been cured for 2 years even with the proper surgical treatment and withdrawal of bisphosphonates.

Bisphosphonates : Can These Be The Bone Eaters.

Bisphosphonates are a group of synthetic analogs of inorganic pyrophosphate ( an endogenous regulator of bone mineralization) Bisphosphonates are a family of drugs used to prevent and treat osteoporosis, multiple myeloma, Paget’s disease (bone cancers), and bone metastasis from other cancers. These drugs can bond to bone surfaces and prevent osteoclasts (cells that breakdown bone) from doing their job.

Clinical study of correlation between C-terminal cross-linking telopeptide of type I collagen and risk assessment, severity of disease, healing after early surgical intervention in patients with bisphophonate-related osteonecrosis of the jaws

INTRODUCTION: The utility of the C-terminal cross-linking telopeptide test (CTX) as a method for staging Bisphosphonate-related osteonecrosis of the jaws (BRONJ) and its healing process was examined. MATERIALS AND METHODS: A total 19 patients who were diagnosed with BRONJ underwent a fasted morning CTX test, were enrolled in this study. The serum CTX values ranged from 50 to 630 pg/mL (mean 60). The risk assessment was rated according to the CTX values of the individual patient (minimal risk, > or =150 pg/mL, moderate, 100 to 150 pg/mL, high, < or =100 pg/mL). The BRONJ scores were then calculated according to the number of BRONJ lesions and their stage. The operation was done as soon as possible, regardless of BORNJ stage. RESULTS: The mean duration of bisphosphonate therapy was 4.1 years. Of the 19 patients, 15, 2 ans 2 received alendronate, risedronate and zoledronate, respecively. Of the 19 patients who underwent a sequestrectomy, saucerization and smoothing, 15 healed after the initial surgery, 1 patient healed after one more surgical procedure, 3 patients did not heal completely but showed improvement in symptoms. Therefore, 17 out of the 19 patients healed completely with complete mucosal coverage and the elimination of pain. The risk assessment using the CTX value and disease severity were not correlated (r=-0.264, P=0.275). In addition, the risk assessment using CTX value and healing after surgery were not correlated (r=-0.147, P=0.547). CONCLUSION: The serum CTX should be considered carefully by clinicians as part of overall management. Early surgical intervention is of benefit in the treatment of stage II BRONJ.

Dental Considerations of the Bisphosphonate-related Osteonecrosis of the Jaw / 대한골다공증학회지

Bisphosphonate-related osteonecrosis of the jaw (BRONJ) is a disease entity which is rare, but is a serious side effect of bisphosphonate therapy. Several professional associations have published position papers on BRONJ; in 2009, the Korean position statement was reported as a collaborative effect between the Korean Endocrine Society, Korean Society of Bone Metabolism, Korean Society of Osteoporosis, and Korean Association of Oral and Maxillofacial Surgeons. Diagnostic criteria and treatment strategies for BRONJ are now being established through a thorough investigation and cooperation amongst numerous specialties. Still obscure, it is suggested that the pathogenesis of BRONJ is due to the inhibition of farnesyl pyrophosphate synthase of the osteoclastic mevalonate pathway, thus disturbing the cytoskeletal motility for the fusion of mononuclear cells into a multinucleated giant cell or the establishment of a ruffled border. Eventually, such changes will be followed by inactivation and apoptosis of osteoclasts, leading to decreased bone resorption. The incidence of BRONJ is known to be as low as 0.01~0.001% of the entire population, but BRONJ is as high as 1 in 300 in the case of dental intervention of patients on bisphosphonate therapy. It is important for clinicians to remember in requesting a dental consultation for a patient on bisphosphonate therapy that oral cavity has a special environment for wound healing. Routine minor trauma caused by foreignbodies, such as hard food, is compensated by an appropriate wound healing mechanism involving rapid bone turnover due to the rich vascular supply of the oral mucosa. Bisphosphonate will disturb this normal wound healing as a consequence of decreased bone turnover. It should also be kept in mind that the disturbed wound healing is further complicated by the presence of normal microflora in the oral cavity and by the unique anatomic condition of the thin oral mucosa covering the the mandible, most mobile skeleton in the head and neck area. The potency of the bisphosphonates (intravenous bisphosphonate), local factors, such as local dental intervention (especially dental extraction), and systemic factors, such as patient age (old age), have statistical significance for all BRONJ risk factors. Although the recognition of BRONJ by clinicians has been inadequate until now, the growing body of evidence is unveiling the detailed aspects of BRONJ. Continued investigation and extensive cooperation of related specialties will elucidate the nature of the disease, thus enhancing the quality of life of patients on bisphosphonate therapy.

Clinical Study of Bisphosphonate-Induced Osteonecrosis of Mandibular and Maxillary Bone

Bisphosphonates are compounds widely used in the treatment of various metabolic and malignant bone disease. Recently, an association between bisphosphonate use and a rare dental condition termed 'osteonecrosis of the jaw(ONJ)' has been reported. Bisphosphonate-related osteonecrosis of the jaw(BRONJ) is rare, but serious, side effect of bisphosphonate therapy in affected patients. It is characterized by poor wound healing and spontaneous intra-oral soft tissue break down, which lead to exposure of necrotic maxillary and mandibular bone. We reviewed 11 patients of BRONJ visited Ajou University Hospital Dental clinic from May 2007 to November 2008. The management of the patients included cessation of bisphosphonate therapy and various surgical restorative procedures and conservative care there after. Aggressive debridement is contraindicated. A new complication of bisphosphonate therapy administration, osteonecrosis of jaws, seems to be developing. The improved results after cessation of the medication should make clinicians reconsider the merits of the rampant use of bisphosphonates, while further investigation is needed to completely elucidate this complication.

Features of Histopathologic and radiographic findings in bisphosphonate-related osteonecrosis of jaw-Clinical review

Bisphosphonates (BPs) are a class of agent used to treat patient with osteoporosis or malignant bone metastases. BPs can be categorized into 2 groups: nitrogen-containing and non-nitrogen containing. Nitrogen-containing BPs are considered to have more toxicity. Despite their clinical benefits, bisphosphonate-related osteonecrosis of jaw(BRONJ) is a significant complication to patients receveing these drugs. Since the first description of BRONJ in 2003 by Marx, the number of reports on BRONJ has been rapidly increasing. BRONJ is considered as an emerging problem in oral & maxillofacial surgery. Generally, osteonecrosis in the maxilla is rare, however BRONJ is found both in the maxilla and the mandible. This is an important feature of BRONJ compared to common infectious osteomyelitis of the jaw. Growing number of case reports, suggest that bisphosphonate therapy may cause exposed, necrotic bone. BRONJ has simillar features compared to IORN (infected osteoradionecrosis). BRONJ has meaningful features established through the interestigation on histopathologic and radiographic findings. These features have an impact on treatment plan and prognosis. This presentation contemplates on features of histopathologic and radiographic findings in bisphosphonate-related osteonecrosis of the jaw.