• Journal of the korean academy of Pediatric Dentistry
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• v.27 no.2
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• pp.309-317
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• 2000

Bisphosphonates inhibit bone resorption in vivo and in vitro. Currently proposed mechanism of action of bisphosphonates involves both direct effect on osteoclasts and indirect effect through the mediation of osteoblasts. Recent understanding of molecular mechanism of osteoclastogenesis indicates that osteoclast differentiation is quite tightly regulated by signaling molecules from differentiating osteoblasts. Therefore this investigation was designed to elucidate the effect of bisphosphonate on osteoblast differentation. For this purpose, in vitro effects of etidronate and alendronate on the expression of Cbfa1 a master control gene of osteoblast differentiation, several bone marker genes, and formation of calcified nodules were evaluated. To evaluate the effect of bisphosphonate on calcified nodule formation, osteoblasts isolated from rat calvaria were cultured in a-MEM containing $10^{-4},\;10^{-5},\;10^{-6}M$ of etidronate or $10^{-6},\;10^{-7},\;10^{-8}M$ of alendronate for 15 days, and then stained by alizarin red to determine mineralization. To evaluate the effect of bisphosphonate on osteoblast differentiation, osteoblast cells were cultured in a-MEM containing $10^{-4},\;10^{-5},\;10^{-6}M$ of etidronate or $10^{-6}$ M of alendronate for 8 days. And then total RNA was extracted and northern blot analysis was done to examine the expression of Cbfa1, type I collagen, alkaline phosphatase, osteopontin and osteocalcin. The results were as follows: 1. Etidronate suppressed the calcification of bone nodule in dose dependent manner, while alendronate didn't. 2. The expression of Cbfa1 was decreased dose dependently by etidronate, but increased by alendronate. 3. Etidronate suppressed the expression of type I collagen, osteopontin and osteocalcin in dose dependent manner however alendronate promote the expression of osteoblast marker gene. 4. The expression of alkaline phosphatase was not affected either etidronate nor alendronate. These results suggest that etidronate suppressed the expression of Cbfa1 in dose dependent manner, and consequently the expression of osteoblast marker genes, such as type I collagen, osteopontin and osteocalcin were also suppressed in similar manner. And finally this decreased expression of osteoblastic marker gene prevent calcined bone nodule formation.

• Journal of the Korean Association of Oral and Maxillofacial Surgeons
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• v.43 no.1
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• pp.16-22
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• 2017

Objectives: Bisphosphonate is the primary cause of bisphosphonate-related osteonecrosis of the jaw (BRONJ). Bisphosphonates are eliminated from the human body by the kidneys. It is anticipated that bisphosphonate levels in the body will increase if the kidney is in a weak state or if there is systemic disease that affects kidney function. The aim of this study was to analyze the relevance of renal function in the severity of BRONJ. Materials and Methods: Ninety-three patients diagnosed with BRONJ in Pusan National University Dental Hospital from January 2012 to December 2014 were included in this study. All patients underwent a clinical exam, radiographs, and serologic lab test, including urine analysis. The patient's medical history was also taken, including the type of bisphosphonate drug, the duration of administration and drug holiday, route of administration, and other systemic diseases. In accordance with the guidelines of the 2009 position paper of American Association of Oral and Maxillofacial Surgeons, the BRONJ stage was divided into 4 groups, from stage 0 to 3, according to the severity of disease. IBM SPSS Statistics version 21.0 (IBM Co., USA) was used to perform regression analysis with a 0.05% significance level. Results: BRONJ stage and renal factor (estimated glomerular filtration rate) showed a moderate statistically significant correlation. In the group with higher BRONJ stage, the creatinine level was higher, but the increase was not statistically significant. Other factors showed no significant correlation with BRONJ stage. There was a high statistically significant correlation between BRONJ stage and 'responder group' and 'non-responder group,' but there was no significant difference with the 'worsened group.' In addition, the age of the patients was a relative factor with BRONJ stage. Conclusion: With older age and lower renal function, BRONJ is more severe, and there may be a decrease in patient response to treatment.

• Maxillofacial Plastic and Reconstructive Surgery
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• v.32 no.1
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• pp.16-22
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• 2010

Objective: Bisphosphonate related osteonecrosis of the jaw (BRONJ) is reported in patients taken bisphosphonate for a long time, however, the mechanism of osteonecrosis in BRONJ was not clarified yet. This study was designed to investigate the effect of short administraion zoledronate on the healing pattern of periosteum and sinus membrane after iliac bone graft into maxillary sinus. Methods: In this study, 18 Newzeland rabbits were used. The animals were divided into 2 group. In the experimental group, rabbits were treated with weekly peritoneal injection (0.06 mg/kg/week) of zoledronate for three times. In the control group, rabbits were treated with saline solution injection instead of zoledronate. Periosteum and sinus membrane were harvested from one rabbit of the experimental group and one of the control group in the fourth week. The autogeneous bone was harvested from ilium and grafted into maxillary sinus. The rabbits were sacrificed at 1, 2, 4 and 8 weeks after bone graft. The healing pattern of periosteum and sinus membrane were evaluated histologically. Results: Inflammatory reaction in the periosteum was less conspicuous and healing process appeared earlier in experimental group compared with control group at 1, 2, 4 weeks. There were no differences of microscopic findings of sinus membrane between both groups at any weeks. Conclusion: Short-term use of zoledronate decreased the inflammatory reaction and enhanced healing process in the periosteum. These findings suggest the possibility that zoledronte suppress the function of macrophages.

• Journal of the Korean Association of Oral and Maxillofacial Surgeons
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• v.42 no.4
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• pp.193-204
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• 2016

Objectives: This study examined the statistical relevance of whether the systemic predisposing factors affect the prognosis of surgical treatment of bisphosphonate-related osteonecrosis of the jaw (BRONJ). All cases had undergone bone biopsies to determine the characteristics of the mechanisms of BRONJ by optical microscopy. Materials and Methods: The data included 54 BRONJ cases who underwent surgery and in whom bone biopsies were performed. The results of surgery were evaluated and the results were classified into 3 categories: normal recovery, delayed recovery, and recurrence after surgery. The medical history, such as diabetes mellitus, medication of steroids, malignancies on other sites was investigated for an evaluation of the systemic predisposing factors in relation to the prognosis. The three factors involved with the medication of bisphosphonate (BP) were the medication route, medication period, and drug holiday of BP before surgery. The serum C-terminal cross-linking telopeptide (CTX) value and presence of microorganism colony in bone biopsy specimens were also checked. Statistical analysis was then carried out to determine the relationship between these factors and the results of surgery. Results: The group of patients suffering from diabetes and on steroids tended to show poorer results after surgery. Parenteral medication of BP made the patients have a poorer prognosis after surgery than oral medication. In contrast, the medication period and drug holiday of BP before surgery did not have significance with the results of surgery nor did the serum CTX value and presence of microorganism colony. Necrotic bone specimens in this study typically showed disappearing new bone formation around the osteocytic lacunae and destroyed Howship's lacunae. Conclusion: Although many variables exist, this study could in part, predict the prognosis of surgical treatment of BRONJ by taking the patient's medical history.

• Journal of Korean Dental Science
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• v.7 no.1
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• pp.38-42
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• 2014

Bisphosphonate-related osteonecrosis of the jaw (BRONJ) is defined as exposed necrotic bone without evidence of healing for at least 8 weeks in the maxillofacial area in a patient with history of bisphosphonate use. Obtaining complete coverage of the hard tissue by soft tissue in BRONJ patients is especially important. Therefore, managing the mucosa is one of the key factors in a successful outcome, but this is especially hard to achieve in BRONJ patients. Various applications of buccal fat pad in oral reconstruction-including the closure of surgical defects following tumor excision, repair of surgical defects following the excision of leukoplakia and submucous fibrosis, closure of primary and secondary palatal clefts, coverage of maxillary and mandibular bone grafts, and lining of sinus surface of maxillary sinus bone graft in sinus lift procedures for maxillary augmentation-have been studied. Eliminating all potential sites of infection and post-operative infection control is crucial in BRONJ. We present a case using the buccal fat pad pedicle for a stage 3 BRONJ defect. Uneventful total epithelialization of the buccal fat pad regardless of size was noted. In summary, the buccal fat pad has versatile application and various recipient sites for surgical utilization. It is an easy technique, with promising overall success rates. With careful selection and handling, buccal fat graft can resolve problems with soft tissue coverage in stage 2 or 3 BRONJ patients.

• Journal of Dental Rehabilitation and Applied Science
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• v.27 no.4
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• pp.449-454
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• 2011

Recently, jawbone osteonecrosis has been largely reported as a potential adverse effect of bisphosphonate (BP)administration. Currently available published incidence data for BRONJ are based on retrospective studies and estimates of cumulative incidence range from 0.8 to 12%. The mandible is more commonly affected than the maxilla (2:1 ratio), and 60-70% of cases are preceded by a dental surgical procedure. The signs and symptoms that may occur before the appearance of clinical evident osteonecrosis include changes in the health of periodontal tissues, non-healing mucosal ulcers, loose teeth and unexplained soft-tissue infection. Tooth extraction as a precipitating event is a common observation. The significant benefits that bisphosphonates offer to patients clearly surpass the risk of potential side effects; however, any patient for whom prolonged bisphosphonate therapy is indicated, should be provided with preventive dental care in order to minimize the risk of developing this severe condition.

• Journal of the Korean Association of Oral and Maxillofacial Surgeons
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• v.42 no.5
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• pp.271-277
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• 2016

Objectives: The objective of this study was to retrospectively investigate the association of diseases having an influence on inhibition of angiogenesis such as hypertension, diabetes mellitus type II, hypercholesterolemia, and rheumatoid arthritis (RA) with the development of osteonecrosis of the jaws. Materials and Methods: The 135 patients were allocated into 4 groups of bisphosphonate-related osteonecrosis of the jaw (BRONJ) group (1A); non-BRONJ group (1B); osteonecrosis of the jaw (ONJ) group (2A); and control group (2B), according to histologic results and use of bisphosphonate. This retrospective study was conducted with patients who were treated in one institute from 2012 to 2013. Fisher's exact test and logistic regression analysis were used to analyze the odds ratios of diseases having an influence on inhibition of angiogenesis for development of ONJ. Results: The effects of diabetes and hypertension were not statistically significant on development of ONJ. When not considering bisphosphonate use, RA exhibited a high odds ratio of 3.23 (P=0.094), while hyperlipidemia showed an odds ratio of 2.10 (P=0.144) for development of ONJ. More than one disease that had an influence on inhibition of angiogenesis showed a statistically significant odds ratio of 2.54 (P=0.012) for development of ONJ. Conclusion: Patients without diseases having an influence on inhibition of angiogenesis were at less risk for developing ONJ.

• Journal of the Korean Association of Oral and Maxillofacial Surgeons
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• v.41 no.6
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• pp.327-331
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• 2015

Bisphosphonate-related osteonecrosis of the jaw (BRONJ) occurs mainly in female patients. In males the occurrence rate is low, which seems to be related to the low incidence of osteoporosis in men. Unfortunately, BRONJ tends to be ignored in general dental clinics in male patients with a history of osteoporosis treatment. BRONJ occurred in a male patient due to the clinician's lack of interest in the patient's history. In this case, the male patient was on bisphosphonate therapy because of a orchiectomy, and a dental treatment was performed without consideration of his medical history, resulting in BRONJ. We performed careful examinations and treatment with antibiotics and surgical operations. The postoperative healing was successful. In light of this particular case, we concluded that careful listening to the patient's history is very important.

• Journal of the Korean Association of Oral and Maxillofacial Surgeons
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• v.36 no.4
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• pp.291-302
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• 2010

Bisphosphonate-related osteonecrosis of the jaw (BRONJ) is a side effect of Bisphosphonates (BPs) use. These days, oral bisphosphonates are normally prescribed to treat osteoporosis. Intravenous BPs are used extensively to treat osteolytic bone lesions related to multiplemyeloma and bone metastasis of solid cancers, breast cancer or prostate cancer. As the prescription of BPs is universalized and the number of people treated with BPs is increasing, an accurate understanding and proper management of BRONJ are required. The aim of this study was to improve the clinicians' understanding of BRONJ by reviewing the literature. To achieve this, this paper introduces case reports as well as the current concept of BRONJ based on the 2009 updates by American Association of Oral and Maxillofacial (AAOMS) including the definition, epidemiology, etiology, diagnosis, treatment and prevention of BRONJ.

• Bulletin of the Korean Chemical Society
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• v.31 no.9
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• pp.2561-2564
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• 2010

The accurate determination of bisphosphonate levels in bone and biological fluids is important in both clinical and pharmacological/toxicological studies; however, the quantitative analysis of the bisphosphonate is difficult because its concentration is quite low in most of biological sample. A novel fluorescent chemosensor (FCS)-based measurement method of bisphosphaonate levels using Naphta-diDPA-$2Zn^{2+}$ (NadDPA-$2Zn^{2+}$, DPA = dipycolylamine), an excellent FCS previously used for detecting PPi, was developed. By the FCS method, the concentration of bisphosphonates having no fluorophores can be determined analyzed with sufficient sensitivity. The results of this study indicate that the FCS-based measurement can be a useful method to analyze bisphosphonates in biological samples.