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


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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Available from: Matthew R Allen, Feb 19, 2014
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    • "This process can aggravate to bone sequestration going along with acute osteomyelitis resulting in spreading and increased mobility of additional teeth [9]. Presumably, BRONJ is associated with infection and therefore immune-modulating drugs, as applied in patients with Crohn’s disease or rheumatoid arthritis, might be an important risk factor in the development of necrotic lesions in the jaw [10,11]. We already know that not only Bisphosphonates but also Denosumab or other biologicals are under suspicion to promote or even cause necrotic lesions in the jaw [12,13]. "
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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.
    Full-text · Article · Jan 2014 · BMC Gastroenterology
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    • "Prior exposure of jaw bone to bisphosphonate also supports progression of BJON since high bisphosphonate concentration causes direct toxicity to osteocytes, osteoblasts and osteogenic precursors (Idris et al., 2008, Stefanik et al., 2008, Stefanik et al., 2006). Therefore, focal loss of osteocytes and canaliculi network (Allen & Burr, 2008, Hansen et al., 2006) can promote accumulation of regions of dead osteocytes and non-viable bone over time (Allen, 2009a). "
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    ABSTRACT: Bisphosphonates commonly used to treat osteoporosis, Paget's disease, multiple myeloma, hypercalcemia of malignancy and osteolytic lesions of cancer metastasis have been associated with bisphosphonate-associated jaw osteonecrosis (BJON). The underlying pathogenesis of BJON is unclear, but disproportionate bisphosphonate concentration in the jaw has been proposed as one potential etiological factor. This study tested the hypothesis that skeletal biodistribution of intravenous bisphosphonate is anatomic site-dependent in a rat model system. Fluorescently labeled pamidronate was injected intravenously in athymic rats of equal weights followed by in vivo whole body fluorimetry, ex vivo optical imaging of oral, axial, and appendicular bones and ethylenediaminetetraacetic acid bone decalcification to assess hydroxyapatite-bound bisphosphonate. Bisphosphonate uptake and bisphosphonate released per unit calcium were similar in oral and appendicular bones but lower than those in axial bones. Hydroxyapatite-bound bisphosphonate liberated by sequential acid decalcification was the highest in oral, relative to axial and appendicular bones (P < 0.05). This study demonstrates regional differences in uptake and release of bisphosphonate from oral, axial, and appendicular bones of immune deficient rats.
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