Bisphosphonates and osteonecrosis of the jaw: moving from the bedside to the bench.

Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, Ind. 46202, USA.
Cells Tissues Organs (Impact Factor: 2.14). 09/2008; 189(1-4):289-94. DOI: 10.1159/000151371
Source: PubMed

ABSTRACT Osteonecrosis of the jaw (ONJ) has received significant attention as a potential side effect of bisphosphonate treatment. The limited understanding of the underlying pathophysiology of the condition emphasizes the need to transition ONJ research from the bedside to the bench, supplementing ongoing clinical research with animal/basic science studies. The goal of this review is to briefly highlight the most commonly proposed mechanisms for ONJ and then summarize our laboratory's recent efforts to begin transitioning ONJ research to an animal model. Remodeling suppression, disrupted angiogenesis and infection have all been proposed to connect bisphosphonates to ONJ, although most supportive data for each of these are either indirect or nonexistent. Our laboratory has begun studying the dog as a potential model of ONJ. We have shown regions of necrotic bone matrix within the mandible of dogs treated with oral or intravenous bisphosphonate. We hypothesize these regions are the result of remodeling suppression, and if combined with additional factors such as dental intervention or infection, would result in manifestation of exposed oral lesions, the clinical definition of ONJ. Although these findings suggest the dog may be a viable animal model to study ONJ, many questions remain unanswered. No matter what animal model is found to mimic the clinical presentation of ONJ, once established it will allow significant progress toward understanding the specific role of bisphosphonates in the pathophysiology of ONJ and if/how the entity of ONJ can best be treated and prevented.

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    ABSTRACT: Background Bisphosphonates are powerful drugs used for the management of osteoporosis and metastatic bone disease to avoid skeletal-related complications. Side effects are rare but potentially serious such as the bisphosphonate-related osteonecrosis of the jaws (BRONJ). BRONJ impairs the quality of life and can even lead to pathologic fractures of the mandible. Management of BRONJ is difficult per se. If complicated with pathologic mandibular fractures in advanced stages, the treatment options are controversially discussed. This review delineates the epidemiology and pathogenesis of BRONJ to put the various modalities for the treatment of pathologic mandible fractures into perspective. Methods Various case reports and case series in the literature were reviewed. Cases were reviewed of patients suffering from pathologic fracture due to bisphosphonate-related osteonecrosis of the jaw treated in the Department of Oral and Maxillofacial Surgery (Ludwig-Maximilians-University of Munich) from 2003 to 2010. Of 140 patients suffering from BRONJ, four were identified with pathologic fracture of the mandible. Results Management of pathologic mandibular fractures in patients suffering from BRONJ is an unsolved issue. At present there is a paucity of information to establish reliable therapy guidelines. The published strategies range from conservative treatment to major bone resections with or without internal or external fixation and with or without autogenous reconstruction. There is no evidence for the superiority of a single therapeutic mode, however. Conclusion Further understanding of BRONJ is mandatory to establish a sound rationale for the treatment of associated mandibular fractures.
    Craniomaxillofacial Trauma and Reconstruction 09/2013; 6(3):147-154. DOI:10.1055/s-0033-1343776
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    ABSTRACT: Antiresorptive medications are essential in treating diseases of pathologic osteoclastic bone resorption, including bone cancer and osteoporosis. Bisphosphonates (BPs) are the most commonly used antiresorptives in clinical practice. Although inhibition of bone resorption is important in regulating unwanted malignant and metabolic osteolysis, BP treatment is associated with potential side effects, including osteonecrosis of the jaws (ONJ). Recently, non-BP antiresorptive medications targeting osteoclastic function and differentiation, such as denosumab, have entered the clinical arena. Denosumab treatment results in a similar rate of ONJ as BPs. Animal models of ONJ, using high-dose BP treatment in combination with tooth extraction or dental disease, provide valuable tools and insight in exploring ONJ pathophysiology. However, the ability of other antiresorptives to induce ONJ-like lesions in animal models has not been explored. Such studies would be beneficial in providing support for the role of osteoclast inhibition in ONJ pathogenesis versus a direct BP effect on oral tissues. Here, we tested the ability of the receptor activator of NF-κB ligand (RANKL) inhibitors RANK-Fc (composed of the extracellular domain of RANK fused to the fragment crystallizable [Fc] portion of immunoglobulin G [IgG]) and OPG-Fc (composed of the RANKL-binding domains of osteoprotegerin [OPG] linked to the Fc portion of IgG) to induce ONJ in mice in the presence of periapical disease, but in the absence of dental extractions. We demonstrate radiographic evidence of ONJ in RANK-Fc–treated and OPG-Fc–treated mice, including inhibition of bone loss, increased bone density, lamina dura thickening, and periosteal bone deposition. These findings closely resembled the radiographic appearance of an ONJ patient on denosumab treatment. Histologic examination revealed that RANK-Fc treatment and OPG-Fc treatment resulted in absence of osteoclasts, periosteal bone formation, empty osteocytic lacunae, osteonecrosis, and bone exposure. In conclusion, we have successfully induced ONJ in mice with periapical disease, using potent osteoclast inhibitors other than BPs. Our findings, coupled with ONJ animal models using high-dose BPs, suggest that osteoclast inhibition is pivotal to the pathogenesis of ONJ. © 2014 American Society for Bone and Mineral Research.
    Journal of bone and mineral research: the official journal of the American Society for Bone and Mineral Research 04/2014; 29(4). DOI:10.1002/jbmr.2097 · 6.59 Impact Factor
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    ABSTRACT: Bisphosphonates have a widespread indication for osteoporosis and are also applied in cancer patients with skeletal-related conditions. Bisphosphonate-associated osteonecrosis of the jaw (BONJ) is a feared side effect which is hard to treat and often affects patient s quality of life in an extensive manner. Adalimumab (Humira(R)), a fully human recombinant antibody specific for tumor necrosis factor- alpha, is approved for treatment in patients with Inflammatory Bowel Disease like ulcerative colitis or Crohn's disease. In March 2013, a 36-year-old female presented with right-sided perimandibular swelling, recurrent facial pain and exposed necrotic bone after previous extraction of tooth 47. She had the medical history of Crohn's disease for more than one decade with chronic active enterocolitis, fistula disease as well as previous oral manifestation and was currently treated with Adalimumab since September 2008. Due to steroid-induced osteoporosis, diagnosed in 2004, she received oral Bisphosphonates (Risedronate) from 2004 until 2007 followed by two infusions of Zoledronic acid in 2008 and 2009. This patient with a medical history of Crohn's disease and gastrointestinal remission under Adalimumab therapy presented with osteonecrosis of the jaw after suspended oral and intravenous Bisphosphonate therapy implicating that the biologic therapy with an anti-TNF-alpha antibody might promote the manifestation of osteonecrosis and compromise oral healing capacity.
    BMC Gastroenterology 01/2014; 14(1):6. DOI:10.1186/1471-230X-14-6 · 2.11 Impact Factor

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