• Journal of Periodontal and Implant Science
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• v.39 no.1
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• pp.1-8
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• 2009

Purpose: Bisphosphonates are drugs used to suppress osteoclastic activity and to treat osteoporosis, Paget's disease of bone and bone metastasis. The purpose of this report is to review the literatures on bisphosphonates use that could affect bone healing and cause osteonecrosis of the jaws. Materials and methods: Medline research was carried out to find relevant articles on bisphosphonates and osteonecrosis of the jaw. Results: Oral administration of bisphosphonates is reported to decrease the risk of adverse bone outcomes. On the contrary, IV bisphosphonates is known to significantly increase the risk. Prevention of the osteonecrosis of the jaw is primary concern before usage. If the adverse bone reaction takes place, proper management and treatments are required to alleviate pain of patients and prevent further progression of necrosis. Conclusion: Case reports of bisphosphonates induced osteonecrosis of the jaw are increasing. Dentists and physicians should be aware of the higher frequency of osteonecrosis of the jaw in patients receiving IV bisphosphonates and be prepared to prevent and cope with adverse bone reaction.

• Korean Journal of Clinical Pharmacy
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• v.24 no.2
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• pp.98-105
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• 2014

Purpose: The aim of this study was to compare retrospectively the efficacy of anti-osteoporotic agents (RAL-Raloxifene 60 mg, ALD-weekly alendronate 70 mg, RSD-weekly risedronate 35 mg, AVD3-weekly alendronate 70 mg/vitamin $D_3$ 2800IU, IBD-quarterly IV ibandronate 3 mg/3 ml, ZLD-yearly IV zoledronate 5 mg/100 ml) in postmenopausal patients with osteoporosis or osteopenia. Method: This study retrospectively reviewed medical record and compared the lumbar spine BMD percentage changes of each medicine group one year later from the baseline. 209 patients (27, 50, 60, 30, 35, and 7 patients in RAL, ALD, RSD, AVD3, IBD, and ZLD groups, respectively) are within the inclusion criteria for the study. Results: From baseline to month 12, lumbar spine BMD increased significantly larger with bisphosphonate groups, compared to SERM (p < 0.05). In all bisphosphonate groups, the lumbar spine BMD were increased significantly from baseline. Of the bisphosphonates, the changes from baseline in BMD of IV bisphosphonates were more larger than those of oral bisphosphonates, and yearly, quarterly bisphosphonates yielded significantly greater BMD gains, compared with weekly bisphosphonate groups (p<0.05). In addition, patients receiving 70 mg weekly alendronate+vitamin D3 had greater gains in BMD than alendronate Single preparation (p<0.05). Conclusion: Bisphosphonates yielded significantly greater BMD gains than SERM. Of the bisphosphonates, the changes from baseline in BMD of yearly, quarterly IV bisphosphonates yielded significantly greater BMD gains, compared with weekly oral bisphosphonate groups. In addition, vitamin D3 plays an significant role in BMD gains.

• BMB Reports
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• v.52 no.9
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• pp.572-576
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• 2019

Bisphosphonates are the mainstay of therapy worldwide for osteoporosis. However, bisphosphonates also have limitations. The objective of this study was to determine the role of miR-101-3p/Rap1b signal pathway in osteoclast differentiation after treatment with bisphosphonates. Our results revealed that miR-101-3p was an important regulator in bisphosphonates treated-osteoclasts. When miR-101-3p was down-regulated in bone marrow-derived macrophage-like cells (BMMs), the development of mature osteoclasts was promoted, and vice versa. However, alendronate decreased multinucleated cell number regardless of whether miR-101-3p was knocked down or over-expressed. TRAP activity assay confirmed the above results. Luciferase assay indicated that miR-101-3p was a negative regulator of Rap1b. Western blot analysis revealed that protein expression level of Rap1b in BMMs transfected with OV-miR-101-3p was lower than that in BMMs transfected with an empty vector. Rap1b overexpression increased TRAP-positive multinucleated cells, while Rap1b inhibition decreased the cell numbers. In vivo data showed that miR-101-3p inhibited osteoclast differentiation in ovariectomized mice while overexpressed of Rap1b blocked the differentiation. Taken together, our data demonstrate that miR-101-3p/Rap1b signal pathway plays a key role in osteoclast differentiation after treatment with bisphosphonates.

• Journal of the Korean Association of Oral and Maxillofacial Surgeons
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• v.42 no.6
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• pp.365-369
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• 2016

Objectives: To determine the prevalence and oral characteristics of cancer patients treated with bisphosphonates in the oncology and maxillofacial prosthesis departments of the General Hospital of Mexico between 2011 and 2013. Materials and Methods: This cross-sectional study included patients who received prior treatment with bisphosphonates; an intraoral examination was performed by 2 standardized examiners. Results: The prevalence of bisphosphonate-related necrosis in 75 patients was 2.6%; the most common malignancy was breast cancer (84.0%), followed by prostate cancer (16.0%). Exostosis was present in 9.3% of patients and the mean Decayed, Missing, Filled Teeth index was 4.64; 44.0% of the study group had a Community Periodontal Index value between 2 and 2.9 (mean, 0.60). Conclusion: A detailed intraoral assessment must be performed before initiating treatment with bisphosphonates to identify risk factors for osteonecrosis.

• Maxillofacial Plastic and Reconstructive Surgery
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• v.37
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• pp.18.1-18.7
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• 2015

Background: The aim of this study is to develop a rat model of bisphosphonates-related osteonecrosis of the jaw (BRONJ) that would be verified with clinical, radiological and histological examination, and to confirm the influence of concurrent bisphosphonates and steroids use upon the occurrence and aggravation of BRONJ. Methods: Twenty seven rats were divided into 3 groups; Saline group (I), Zoledronate group (II), Zoledronate and Dexamethasone group (III). Rats got weekly intraperitoneal injection for 4 times and extraction of left maxillary and mandibular 1st, 2nd molars were followed. Consecutive injections were performed, and blood sampling for measurements of C-terminal crosslinked telopeptide of type I collagen and tartrate-resistant acid phosphate 5b rats were performed at the time of 2, 4 and 8 weeks. And then, rats were sacrificed and evaluated clinically, radiologically and histologically. Results: 12/18 (66.6 %) of experimental group were diagnosed as BRONJ. There was no significant difference in incidence between zoledronate alone group (ll) and concurrent use of zoledronate and dexamethasone group (lll). Conclusions: Concurrent use of bisphosphonates and steroids increase incidence of BRONJ compared to saline group (l). Zoledronate alone group (ll) and concurrent use of zoledronate and dexamethasone group (lll) shows same incidence of BRONJ. Based on this study, the rat treated with bisphosphonates and steroids can be considered a novel, reliable and reproducible model to understand pathology of BRONJ.

• Biomolecules & Therapeutics
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• v.24 no.1
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• pp.94-98
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• 2016

The objective of the present study was to elucidate the effect of bisphosphonates, anti-osteoporosis agents, on glucose uptake in retinal capillary endothelial cells under normal and high glucose conditions. The change of glucose uptake by pre-treatment of bisphosphonates at the inner blood-retinal barrier (iBRB) was determined by measuring cellular uptake of $[^3H]3$-O-methyl glucose (3-OMG) using a conditionally immortalized rat retinal capillary endothelial cell line (TR-iBRB cells) under normal and high glucose conditions. $[^3H]3$-OMG uptake was inhibited by simultaneous treatment of unlabeled D-glucose and 3-OMG as well as glucose transport inhibitor, cytochalasin B. On the other hand, simultaneous treatment of alendronate or pamidronate had no significant inhibitory effect on $[^3H]3$-OMG uptake by TR-iBRB cells. Under high glucose condition of TR-iBRB cells, $[^3H]3$-OMG uptake was increased at 48 h. However, $[^3H]3$-OMG uptake was decreased significantly by pre-treatment of alendronate or pamidronate compared with the values for normal and high glucose conditions. Moreover, geranylgeraniol (GGOH), a mevalonate pathway intermediate, increased the uptake of $[^3H]3$-OMG reduced by bisphosphonates pre-treatment. But, pre-treatment of histamine did not show significant inhibition of $[^3H]3$-OMG uptake. The glucose uptake may be down regulated by inhibiting the mevalonate pathway with pre-treatment of bisphosphonates in TR-iBRB cells at high glucose condition.

• Biomolecules & Therapeutics
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• v.16 no.2
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• pp.141-146
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• 2008

Imbalance in calcium and phosphorous metabolism due to aging or menopause leads to osteoporosis. In contrast to patients with normal blood pressure, hypertensive patients have a higher loss of calcium in the urine with its attendant risk of osteoporosis. The high blood pressure is associated with the risk of bone loss and abnormalities in calcium metabolism leading to calcium loss. So we retrospectively investigated the changes of bone mineral density (BMD) which drugs can have clinical influences over osteoporosis treatments of patients with calcium-antagonists as common antihypertensive drugs and with bisphosphonates which causes a most effective inhibition of osteoclasts resorption. As a result over 70 years of age group and within bisphosphonates group, alendronate 70 mg once-weekly group showed significant increase of BMD in lumbar area. Combination group of cilnidipine and $maxmarvil^{(R)}$ showed very significant decrease of BMD. In conclusion, it is desirable that combination therapy with calcium-antagonists is used carefully in the treatment of osteoporosis with high blood pressure.

• Journal of the Korean Association of Oral and Maxillofacial Surgeons
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• v.43 no.2
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• pp.120-124
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• 2017

Osteonecrosis of the jaw (ONJ) is commonly described as an adverse effect of the use of bisphosphonates. A few cases of ONJ associated with tyrosine kinase inhibitors (sunitinib, imatinib) have been reported in the literature and usually they occurred in patients simultaneously treated with bisphosphonates. We report an atypical case of ONJ related only to imatinib. A 72-year-old male patient was treated with imatinib for metastases from gastrointestinal stromal tumors (GISTs). The patient developed ONJ after 22 months of imatinib only therapy. During his whole life, the patient had never been treated with bisphosphonates or radiotherapy. Microscope examination of the tissues confirmed the clinical diagnosis of diffuse osteonecrosis and showed absence of neoplastic cells. Thus, secondary localisations from GISTs were ruled out. Osteonecrosis of the lower jaw appeared 22 months after initial and exclusive therapy with imatinib. Therefore, imatinib monotherapy can induce ONJ in patients that have never been treated with bisphosphonates or radiotherapy.

• Journal of the Korean Association of Oral and Maxillofacial Surgeons
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• v.37 no.1
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• pp.54-61
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• 2011

Introduction: Bisphosphonates is used widely for the treatment of the Paget's disease, multiple myeloma, bone metastases of malignant tumors with the prevention of pain and their pathological fracture. However, it was recently suggested that bisphosphonates related osteonecrosis of the jaw (BRONJ) is a side effect of bisphosphonate use. Materials and Methods: Twenty-four individuals, who were referred to the Department of Oral and Maxillofacial surgery, Dankook University Dental Hospital, were selected from those who had exposed bone associated with bisphosphonates from January, 2005 to December, 2009 according to the criteria of American Association of Oral and Maxillofacial Surgeons (AAOMS) for BRONJ. The patients group consisted of 7 males and 17 females between the age of 46 to 78 years (average 61.8 years). Each patient had panoramic imaging, computed tomography (CT), whole body bone scanning performed for a diagnosis and biopsy sampling from the necrotizing tissue. C-terminal cross-linking telopeptide of type I collagen (CTX) level of patients who had undergone surgical intervention was measured 7 days before surgery. Results: The main cause of bone exposure was post-extraction (15), chronic periodontitis (4), persistent irritation of the denture (3). Twenty people had undergone BRONJ treatment for two to eight months except for 4 people who had to maintain the bisphosphonates treatment to prevent a metastasis and bone trabecular pain with medical treatment. When the bisphosphonate treatment was suspended at least for 3 months and followed up according to the AAOMS protocols, the exposed necrotizing bones were found to be covered by soft tissue. Conclusion: Prevention therapy, interruption of bisphophonates for at least 3 months and cooperation with the physician for conservative treatment are the essential for treating BRONJ patient with high risk factors. The CTX level of BRONJ patients should be checked before undergoing surgical intervention. Surgical treatments should be delayed in the case of a CTX level <150 pg/mL.

• Journal of the Korean Association of Oral and Maxillofacial Surgeons
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• v.35 no.2
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• pp.106-111
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• 2009

Bisphosphonates have been approved for Paget's disease, cancer-related hypercalcemia, bone involvement in multiple myeloma or solid tumors and osteoporosis. Although, underlying pathophysiological mechanisms remain unclear, it seems that bisphosphonates inhibit osteoclast precursor cells, modulate migratory and adhesive characteristics and induce apoptosis of osteoclasts. Furthermore impacts on angiogenesis, microenvironment and signal transduction between osteoclasts and osteoblasts. In this report, we present a case of oral bisphosphonates induced osteonecrosis of the mandible in a 84-year-old patient who received for two years. Two tapered screw vent implants(Zimmer, USA) were placed in the area of first and second molar. Two weeks later after crowns restored, some inflammatory signs and symptoms were observed on the second molar area. Sequestrum was formed and the sequestrum was removed with the implant. Frequent follow-up checks and oral hygiene maintenances were done and the first molar implant was restored. There is insufficient evidence suggests that duration of oral bisphosphonate therapy correlates with the development and severity of osteonecrosis. Therefore, dentists should not overlook the possibility of development of bisphosphonate induced osteonecrosis in patients who have taken oral forms of medication for less than three years.