• Maxillofacial Plastic and Reconstructive Surgery
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• v.38
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• pp.48.1-48.8
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• 2016

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 $50{\mu}M$ alendronate. Then, they were irradiated with a $1.2J/cm^2$ low-level Ga-Al-As laser (${\lambda}=808{\pm}3nm$, 80 mW, and 80 mA; spot size, $1 cm^2$; NDLux, Seoul, Korea). The cell survivability was measured with the MTT assay. The three cytokines of osteoblasts, receptor activator of nuclear factor ${\kappa}B$ ligand (RANKL), osteoprotegerin (OPG), and macrophage colony-stimulating factor (M-CSF) were analyzed. Results: In the cells treated with alendronate at concentrations of $50{\mu}M$ 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.

• Journal of Periodontal and Implant Science
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• v.31 no.1
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• pp.179-193
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• 2001

previous studies have demonstrated an increase in bone mass and density with use of bisphosphonate in osteoporosis. This agent acts as an inhibitor of osteoclastic activity and results in increase of net osteoblastic activity. The purpose of the present study was to examine the effect of the bisphosphonate on osteoblastic activity of the human periodontal ligament cells in vitro. Periodontal ligament cells were primarily obtained from extracted healthy third molars. Cells of 4th to 6th passage were cultured in Dulbecco's modified Eagle's medium containing alendronate sodium or etidronate disodium at the concentration of $10^{-12}{\sim}10^{-6}mol/L$ in 5% $Co_2$ incubator at $37^{\circ}C$. Cell count and MTT assay for cellular activity were done at 2 to 7 days of culture. Alkaline phosphatase activity at 4 to 7 days of culture and formation of mineralized nodules at 28 days of culture with addition of $50{\mu}g/m{\ell}$ ascorbic acid, 10 nM${\beta}-glycerophosphate$, $10^{-7}M$ dexamethasone were evaluated. 1. Alendronate sodium Compared to the control, the proliferation of periodontal ligament cells was generally increased and the cellular activity was maintained at 2 days of culture and generally decreased at 7 days of culture. Alkaline phosphatase activity of periodontal ligament cells was inceased and the formation of mineralized nodules by periodontal ligament cells was enhanced compared to the control. 2. Etidronate disodium The proliferation of periodontal ligament cells was increased at 2 days of culture and decreased or maintained at 7 days of culture. Compared to the control, the cellular activity of periodontal ligament cells was generally decreased. Alkaline phosphatase activity of peridontal ligament cells was increased and the formation of mineralized nodules by periodontal ligament cells was enhanced compared to the control. These results suggest that alendronate sodium and etidronate disodium may have a potential effect on osteoblastic lineage of periodontal ligament cells, distinct from their inhibitory action on osteoclasts and could contribute to enhance periodontal regeneration and alveolar bone regeneration.

• Asian-Australasian Journal of Animal Sciences
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• v.5 no.2
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• pp.303-308
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• 1992

Three female sheep were daily administered a pyrophosphate analogue, disodium 1-hydroxyethylidene-1, 1-bisphosphonate (HEBP) at the level of 4 mg/kg body weight. HEBP largely suppressed bone resorption, which was indicated by the reduction in plasma free hydroxyproline concentration and in calcium mobilization rate during the intravenous infusion of disodium ethylenediaminetetraacetate (EDTA). Contrary to the suppression of bone resorption, plasma total-calcium, magnesium and phosphorus concentrations were not changed by HEBP administration. These results suggest that bone mineral crystals play a meaningless role on calcium, magnesium and phosphorus homeostasis in ruminants if they are fed adequate amounts of these minerals. Plasma magnesium and phosphorus concentrations were not significantly changed after feeding. However, plasma total-calcium was decreased after feeding in both periods and the reduction seemed to be remarkable in the HEBP-treated period. Infusion of EDTA more remarkably reduced plasma ionized calcium concentration in the HEBP-treated that in the untreated period and the recovery of ionized calcium was retarded by HEBP administration. These results suggest that calcium release from bone is necessary for maintenance of plasma calcium when animals rapidly lose calcium.

• Nuclear Engineering and Technology
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• v.55 no.2
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• pp.669-673
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• 2023

Introduction: The crucial step in preclinical process of radiopharmaceutical production is internal dosimetry evaluation by different ways to realize radiobiological dose-response relationships and to extract the results for clinical use. Till now several bone-seeking radiopharmaceuticals have been developed for bone metastasis. Interesting features of bisphosphonates attracted attentions to them in the field of radiopharmaceutical therapy and studies on new generation of them have been doing too. Materials and methods: In this study, we used ZNA as representative of the third generation. The radiopharmaceutical ¹⁸⁸Re-ZNA was produced and its radiochemical purity was investigated. Then, the biological distribution of the produced radiopharmaceutical at 1, 2, 4 and 24 h after injection on different organs of mice were investigated. Finally, the absorbed dose of organs in the human body was assessed using the RADAR method. Results: The results show 96% radiochemical purity of the ¹⁸⁸Re-ZNA radiopharmaceutical. The amount of %ID/g in bone is 1.131% after 1 h and in 24 h it has a significant amount compared to other organs, that is 0.516%. Also dosimetric results show that the highest absorption dose is related to bone and the amount of this dose is 0.050 mGy/MBq. Conclusion: Considering the possibility of producing the ¹⁸⁸Re-ZNA radiopharmaceutical, as well as the proper distribution of this radiopharmaceutical in target and non-target organs and increasing the absorbed dose in bone, it can be concluded that this radiopharmaceutical can be useful in the "radiopharmaceutical therapy" in metastases.

• Journal of Oral Medicine and Pain
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• v.47 no.1
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• pp.1-9
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• 2022

Medication-related osteonecrosis of the jaw (MRONJ) is a serious side effect of antiresorptive agents and bone-modifying agents. It is of the utmost importance to know the management of the MRONJ to improve the patient's quality of life. This study comprehensively reviews the current definitions of MRONJs, and antiresorptive medications, clinical manifestation and staging, risk factors, treatment strategies, and prevention methods of MRONJ. The disease is defined as an exposure of bone and osteonecrosis of the jaw in the oral cavity for at least 8 weeks in patients taking antiresorptive drugs or antiangiogenic agents and with no history of radiotherapy treatment of the jaws. Many articles have reported risk factors associated with MRONJ such as systemic diseases, antiresorptive medication, oral infection, and poor oral hygiene. Osteonecrosis and antiresorptive medications including bisphosphonate and denosumab have been strongly associated, but the pathology of MRONJ is only limited. Hence, an effective and appropriate management and treatment for MRONJ is still to be defined. The objectives of MRONJ treatment are to minimize osteonecrosis and relieve symptoms, and many treatments are suggested from conservative treatment to marginal resection, but this remains controversial. Appropriate treatment of MRONJ remained difficult, although many studies are being covered.

• The Journal of Korean Academy of Prosthodontics
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• v.53 no.1
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• pp.39-45
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• 2015

Loss of continuity of the mandible destroys the balance and symmetry of mandibular function, leading to altered mandibular movements and deviation of the residual fragment towards the resected side. Apart from deviation, other dysfunctions include difficulty in swallowing, speech, mandibular movements, mastication, and respiration are accompanied. In general, surgical reconstruction is considered first then proceeds to the prosthetic restorations. However, patients with systemic disease such as BRONJ (Bisphosphonate related osteonecrosis of the Jaw), surgical reconstruction may be limited. Thus, the prosthetic restoration remains as the only resort. Numerous prosthetic methods are employed to minimize deviation and to improve masticatory efficiency, function and esthetics. If a removable partial denture is the selected treatment modality, maximum stability of the partial denture base may be accomplished with a functional impression procedure by means of eliminating lateral and horizontal forces caused by the functional movements of the lips, cheeks and tongue. Also, Twin occlusion is used to obtain a favorable occlusal relationship and check support for esthetics. The purpose of this case report is to demonstrate how neutral zone impression technique and twin occlusion scheme were applied to restore a hemi-mandiblectomy patient with BRONJ syndrome to achieve satisfactory results in functional and esthetic aspects.

• The Journal of the Korean dental association
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• v.53 no.2
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• pp.120-131
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• 2015

Objective: The purpose of this study is to compare the surgical treatment with conservative treatment and to evaluate the effectiveness of drug-holiday in bisphosphonate related osteonecrosis of the jaw (BRONJ) patients who were diagnosed as stage 2. Patients and Method: From January 2012 to October 2014, seventy-two patients who visit to Pusan National University of Dental Hospital were diagnosed as stage 2 of BRONJ. All the patients had taken computed tomography(CT) and panoramic radiography. The surgical treatment including sequestrectomy of necrotic bone and curettage of soft tissue around the sequestrum were performed to fifty patients. Twenty-two patients underwent conservative treatment such as antibiotics medications, mouth rinsing and follow up checking for every two weeks. Prognosis of treatment was classified into 3 groups - response, unresponse, and worsens - according to clinical, radiographic symptoms. P-value less than 0.05 were regarded as significant. Results: In surgery group, forty-five patients (90%) were healed without recurrence or any complication and five patients (10%) showed the wound dehiscence or infection. In conservative treatment group, fifteen patients (68.2%) were healed without any complication, four patients (18.2%) did not show improvement and three(4.2%) patients$^{\circ}{\emptyset}$ symptoms increased. P-value among groups was 0.014. Evaluation of preoperative drug-holiday in surgery group did not show the effectiveness(p=0.478). Conclusion: Statistically, the prognosis of patients with stage 2 BRONJ treated with surgery was significantly better than conservative treatment. There was no statistical difference for the preoperative drug-holiday.

• International Journal of Oral Biology
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• v.36 no.1
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• pp.37-42
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• 2011

The working mechanism of bisphosphonate on bone cells is unclear despite its powerful inhibitory activity on bone resorption. The differentiation and activation of osteoclasts are essential for bone resorption and are controlled by the stimulatory RANKL and inhibitory OPG molecules. Teeth exhibit a range of movement patterns during their eruption to establish their form and function, which inevitably accompanies peripheral bone resorption. Hence, the mandible, which contains the teeth during their eruption processes, is a good model for revealing the inhibitory mechanism of bisphosphonate upon bone resorption. In the present study, RANKL and OPG expression were examined immunohistochemically in the mandible of rats with developing teeth after alendronate administration (2.5 mg/kg). The preeruptive mandibular first molars at postnatal days 3 to 10 showed the developing stages from bell to crown. No morphological changes in tooth formation were observed after alendronate administration. The number of osteoclasts in the alveolar bone around the developing teeth decreased markedly at postnatal days 3, 7 and 10 compared with the control group. RANKL induced strong positive immunohistochemical reactions in the dental follicles and stromal cells around the mandibular first molar. In particular, many osteoclasts with strongly positive reactions to RANKL appeared above the developing mandibular first molars at postnatal days 3 and 10. Immunohistochemical reactions with RANKL after alendronate administration were weaker than the control groups. However, the immunohistochemical reactivity to OPG was stronger after alendronate administration, at postnatal days 3 and 10. These results suggest that alendronate may decrease bone resorption by regulating the RANKL/OPG pathway in the process of osteoclast formation, resulting in a delay in tooth eruption.

• Journal of the Korean Association of Oral and Maxillofacial Surgeons
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• v.37 no.1
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• pp.1-8
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• 2011

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, ${\geq}$ 150 pg/mL, moderate, 100 to 150 pg/mL, high, ${\leq}$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.

• Journal of Oral Medicine and Pain
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• v.34 no.3
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• pp.295-301
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• 2009

Recently, bisphosphonate-associated osteonecrosis of the jaw(BONJ) is added to the list of diseases of the oromaxillofacial region. BONJ is defined as exposed bone in the jaw that does not heal within 8 weeks after identification, in a patient who has been received to bisphosphonates and has not taken radiation therapy to the craniofacial region. Bisphosphonates binded to bone mineral are concentrated in highly active remodeling site, reside in the skeleton for a long time, and do a role as powerful inhibitors of bone resorption. As the patients receiving bisphosphonates therapy grow in number, the patients of BONJ would go on increasing in Korea. We would like to present two patients who were suspected to BONJ, describe the outline of BONJ, and mention importance of our understanding about BONJ. BONJ is rare disease, but once it develops, its prognosis is very poor. Our adequate understanding of BONJ is necessary to prevent it and cope with it properly.