A Review Into the Effects of Pamidronic Acid and Zoledronic Acid on the Oral Mucosa in Medication-Related Osteonecrosis of the Jaw.

Medication-related osteonecrosis of the jaw (MRONJ) is a growing problem without an effective treatment, presenting as necrotic bone sections exposed via lesions in the overlying soft tissue. There is currently a lack of clarity on how the factors involved in MRONJ development and progression contribute to disease prognosis and outcomes. Bisphosphonates (BPs), the most common cause of MRONJ, affect bone remodeling, angiogenesis, infection, inflammation and soft tissue toxicity, all of which contribute to MRONJ development. This article reviews the cellular mechanisms through which BPs contribute to MRONJ pathology, with a focus on the effects on cells of the oral mucosa. BPs have been shown to reduce cell viability, reduce proliferation, and increase apoptosis in oral keratinocytes and fibroblasts. BPs have also been demonstrated to reduce epithelial thickness and prevent epithelial formation in three-dimensional tissue engineered models of the oral mucosa. This combination of factors demonstrates how BPs lead to the reduced wound healing seen in MRONJ and begins to uncover the mechanisms through which these effects occur. The evidence presented here supports identification of targets which can be used to develop novel treatment strategies to promote soft tissue wound healing and restore mucosal coverage of exposed bone in MRONJ.

A case of tooth fracture occurred upon medicating bisphosphonate for an elderly person: Preservation therapy and responses for Stage 0 of bisphosphonate-related osteonecrosis of jaw.

This case report aimed to report the progress of preservation therapy and response of symptoms and signs for Stage 0 of bisphosphonate-related osteonecrosis of jaw (BRONJ). A 68-year-old female was recognized having a tooth at the left upper first molar fracture upon medicating bisphosphonate (BP) in 2007. At that time, the extraction of the tooth was an absolute contraindication. Therefore, we performed preservation therapy. We observed the symptoms and signs every month. After 5 months, swelling and redness in the entire first molar tooth were seen and fistula formed partly. Bone exposure was not seen. We administrated antibiotics immediately. As a result, symptoms disappeared. On April 10, 2009, the patient visited us as she felt a sense of incongruity in the lower left first and second molar teeth. Clinically, there were no symptoms of pain. However, we observed the radiolucent finding in about 5 mm diameter at apical position by X-ray photography; we considered a possibility of Stage 0 for BRONJ. We immediately administered medicine for 5 days and the symptoms disappeared. At present, no inflammation with signs and symptoms at the upper left first molar and lower left first, second molar parts is shown. We performed preservation therapy for tooth fracture case medicating of BP. Immediate responses for inflammation and symptoms of the Stage 0 of BRONJ have led to success. Hence, dentists should perform regular clinical observation, and enough education to the patient for BRONJ is necessary.

Wound healing protein profiles in the postoperative exudate of bisphosphonate-related osteonecrosis of mandible.

Recurrent bacterial infections in cases of bisphosphonate-related osteonecrosis of jaw (BRONJ) frequently occur. Therefore, BRONJ are usually treated by radical saucerization followed by intensive antibiotic medications without bisphosphonate therapy. The postoperative exudate (POE) from BRONJ lesions may directly indicate the inflammatory status of osteomyelitis in patients, but so far, the POE has rarely been examined for its expression of various cytokines and wound healing proteins. A total of 27 cases of BRONJ, which involved the mandible, were selected and their individual POE collected 6 h, 1 day, and 2 days after surgical intervention was analyzed by immunoprecipitation high performance liquid chromatography (IP-HPLC). The different protein expressions in the BRONJ POE were compared with findings from ten cases of chronic mandibular osteomyelitis (CMO) exudate as the control group. For the protein expressions for inflammation, osteogenesis, and angiogenesis, in the 6 h POE sample, the BRONJ exudate exhibited more expression of IL-10, IL-28, OPG, and osteocalcin, but less expression of TNFα and LL-37 than the control. In the 1 day POE sample, the BRONJ exudate showed more expression of TNFα, IL-6, 8, 12, 28, α1-antitrypsin, VEGF-A, and VEGF-C, but less expression of CD68, lysozyme, bFGF, RANKL, bFGF, and ALP than the control. In the 2 day POE sample, the BRONJ exudate consistently showed more expression of LL-37, ß-defensin-1, and VEGF-A than the control. The present BRONJ POE revealed the rapid progress of bony wound healing through increased molecular signaling for inflammation, angiogenesis, and osteogenesis compared to the control. Therefore, it was suggested that the POE obtained from the postoperative bony lesions should be collected and analyzed by the IP-HPLC method to predict the prognosis of seriously complicated inflammatory bony diseases such as BRONJ.

The observational study of delayed wound healing after tooth extraction in patients receiving oral bisphosphonate therapy.

INTRODUCTION: In this study, we investigated whether such a discontinuation of oral bisphosphonate (BP) for 3 months might influence the incidence of BP-related osteonecrosis of the jaw (BRONJ) and wound healing after tooth extraction in patients receiving oral BP therapy. MATERIAL AND METHODS: There were a total of 434 teeth in 201 patients (18 males and 183 females). The patients were divided into two groups depending on whether or not they underwent a 3-month discontinuation of BP therapy (BP- and BP+) before tooth extraction. In this observational study investigated delayed wound healing after tooth extraction in patients receiving oral BP therapy. RESULTS: In all cases of the BP- group, there were no BRONJ although there was delayed wound healing in two cases. However, in one case of the BP+ group, oral BP was continued because it was deemed high risk to discontinue treatment by the patient's physician. In this case, an intraoral fistula was still present with bone exposure at 120 weeks after extraction (BRONJ stage 1). CONCLUSION: This study supports the idea of a drug holiday and encourages further clinical research on this topic of tooth extraction in patients receiving oral BP therapy.

The effect of alendronates administration duration on the healing of extraction socket in rats: pilot study / 대한치과보철학회지

PURPOSE: The purpose of this study was to investigate the effect of different administration duration of alendronate on initial wound healing and new bone formation of extraction socket in rats. MATERIALS AND METHODS: Fifteen male Sprague-Dawley rats (body weight 130-140 g, 4 weeks old, male) were divided into control group (no alendronate administration) and experimental group (alendronate administration). Experimental group was subdivided into 1 week administrated group, 2 week administrated group, 4 week administrated group and 6 week administrated group according to duration of administration. For the experimental groups, during the designated time period (at the time of extraction, 1 week before extraction, 3 week before extraction and 5 week before extraction) till 1 week after extraction, rats were subcutaneously injected with Alendronate at the dose of 1.0 mg/Kg three times a week. Each specimen from 6 week experimental group and control group were used for microarray analysis, and other specimens were used for histological analysis. The rate of new bone formation within the extraction site and bone loss activity was analyzed using TRAP staining. Statistical analysis was performed using Kruskal Wallis test. (alpha=.05) RESULTS: After one week from the time of extraction, the rate of new bone formation within extraction site for the control group (16.77% +/- 1.36%) compared to the 4 week experimental group (14.99% +/- 6.26%) was lower. However, no statistically significant difference was found. Increase in the number of inactive lacuna (empty lacuna) and decrease in the number of TRAP positive cell were identified with increased duration of administration. There was no significant difference. CONCLUSION: The results of this study showed as the duration of Alendronate administration increased the rate of new bone formation decreased with loss of bone activity and reduced number of osteoclast.