Copyright © 2017 Mutaz B. Habal, MD. Unauthorized reproduction of this article is prohibited. Comparison of the Effects of Local and Systemic Zoledronic Acid Application on Mandibular Distraction Osteogenesis Serkan Dundar, DDS, PhD,  Gokhan Artas, MD, y Izzet Acikan, DDS, z Ferhan Yaman, DDS, PhD, z Mustafa Kirtay, DDS, PhD, § Muhammed Fatih Ozupek, DDS, PhD, § Fatih Asutay, DDS, PhD, jj and Mustafa Kom, DVM, PhD ô Abstract: Bisphosphonates are antibone resorptive drugs that are used to prevent bone tissue resorption in several skeletal diseases. The aim of this study was to examine the effects of systemic and local applications of zoledronic acid (ZA) on newly regenerated bone in a model of experimental distraction osteogenesis (DO). To do this mandibular DO was applied to 30 adult female Sprague Dawley rats, which were randomly divided into 3 groups: control, DO only, systemic zoledronic acid (SZA), and local zoledronic acid (LZA). In the LZA group, the gap between the bone fragments was filled with a gelatin sponge soaked in 2 mg of ZA and 0.1 mL of sterile saline. In the SZA group, a single dose of 0.1 mg/kg ZA was administered systemically. After the surgery, there was a 5-day latent waiting period and 10-day distraction phase. Following a 28-day consolidation period, the rats were euthanized and their mandibles were collected. The distracted bone area was seen to be filled with newly regenerated bone tissue in all 3 groups, both histologically and histomorphometrically. In addition, amounts of new bone formation, osteoblast cella, osteoclast (OC) cells, osteopon- tin, and vascular endothelial growth factor in the SZA and LZA groups were found to be higher when compared with the controls. Further- more, in the SZA group, new bone formation, osteoblast, OC, osteo- pontin, and vascular endothelial growth factor were detected in significant amounts compared with the LZA group. Osteoclast num- bers did not differ in a statistically significant manner in the SZA group with respect to the LZA group. Based on the results of this study, systemic and local applications of ZA could increase the formation of new bone in patients of DO, and systemic application is a more effective method compared with local application. Key Words: Distraction osteogenesis, histomorphometry, new bone formation immunohistochemistry, zoledronic acid D istraction osteogenesis (DO) is a technique widely used for treating mandibular and maxillar bone deformities or deficiencies in dentistry. This technique is a physiological process that generates new bone tissue formation using progressively separated bone fragments and an external distraction device. The principal advantage of DO is that bone tissue formation occurs along with the adaptation of the surrounding soft tissues. 1,2 While the application of DO is a favorable method in the treatment of bone and soft tissue deficiencies, deformities, and abnormalities of the maxillofacial region, there are some drawbacks due to the long- term consolidation periods required, and to the process of bone tissue resorption. 3,4 In recent years, several techniques have been researched to improve the maturation of the newly regenerated bone tissue, including electronic and ultrasonic stimulation, growth fac- tors, hormones, calcium sulfate, and bisphosphonates (BPs). For instance, the authors showed that BP was an effective material for the acceleration of bone formation in DO procedures. 2,3,5–8 As carbon-substituted pyrophosphate-originated drugs, BPs are used to prevent and treat increased bone resorption in several skeletal diseases, including Paget disease, osteoporosis, and meta- static bone disease. 3,8 Throughout the bone repair mechanism, BPs have been shown to have an antiosteoclastic effect, and thus, a relatively proosteoblastic effect. Various theories have been suggested, but the exact mechanism of interaction between BPs and bone tissue has not yet been fully explained. Previous findings have shown that BPs directly restrict the activation of osteoclast (OC) cells, which could induce mineralized bone formation via the osteoblast (OB) cells, and thus, decrease bone loss. 5,9,10 Zoledronic acid (ZA) is the most potent BP currently in clinical use. Several adverse effects ofBPs-ZA, such as osteonecrosis, especially in the jaw bone tissue, as well as bleeding, inflammation, ulceration, nausea, and abdominal pain in the upper gastrointestinal tract, were reported in the literature when using these drugs in humans. 11,12 Therefore, we thought that the local application of ZA is a safer method than the systemic application. For this reason, the aim of this study was to compare the effects of local and systemic applications of ZA on the improvement of new bone formation in a DO model of the rat mandible. METHODS Experimental Animals The experimental design and study protocol were approved by the Animal Ethics Committee at Dicle University in Diyarbakir, Turkey, and the rats were obtained from the Sabahattin Payzin Experimental Research Center at the same university. In total, 30 female Sprague Dawley rats, aged 4 to 6 months, were used. Their average body weights were 280 to 300 g on the first day of the experiment. The animals were kept in temperature-controlled cages, exposed to a 12/ 12-hour light/dark cycle, and had ad libitum access to food and water. First, the rats were divided randomly into 3 groups, as listed below: Control group: No treatment was administered, but DO was applied to the rat mandibles. Local zoledronic acid (LZA) group: The bone gap between the bone fragments was filled with a gelatin sponge soaked in 2 mg of ZA in 0.1 mL of sterile saline, according to the procedure followed in a previous study. 8 Systemic zoledronic acid (SZA) group: A single dose of 0.1 mg/ kg of ZA was administered systematically, according to the pro- cedure followed in a previous study. 8,9 Device Design To construct the distractor used in applying DO, an orthodontic jackscrew embedded in acrylic resin was used, as previously From the  Department of Periodontology, Faculty of Dentistry; y Department of Medical Pathology, Faculty of Medicine, Firat University, Elazig; z Department of Oral and Maxillofacial Surgery, Faculty of Dentistry, Dicle University, Diyarbakir; § Department of Oral and Maxillofacial Surgery, Faculty of Dentistry, Inonu University, Malatya; jj Department of Oral and Maxillofacial Surgery, Faculty of Dentistry, Afyon Kocatepe University, Afyon Karahisar; and ô Department of Surgery, Faculty of Veterinary Medicine, Firat University, Elazig, Turkey. Received August 30, 2016. Accepted for publication December 28, 2016. Address correspondence and reprint requests to Dr Serkan Dundar, DDS, PhD, Firat University, Faculty of Dentistry, Department of Period- ontology, Elazig, Turkey 23119; E-mail: dtserkandundar@gmail.com; sdundar@firat.edu.tr The authors report no conflicts of interest. Copyright # 2017 by Mutaz B. Habal, MD ISSN: 1049-2275 DOI: 10.1097/SCS.0000000000003629 BRIEF CLINICAL STUDIES The Journal of Craniofacial Surgery  Volume 00, Number 00, Month 2017 1