Osteonecrosis of the jaws in patients treated with bisphosphonates – histomorphologic analysis in comparison with infected osteoradionecrosis Torsten Hansen 1 *, Martin Kunkel 2 *, Achim Weber 1 , C. James Kirkpatrick 1 1 Institute of Pathology, Johannes Gutenberg University, Mainz; 2 Clinic of Maxillofacial Surgery, Johannes Gutenberg University, Mainz, Germany BACKGROUND: Patients treated with bisphosphonates because of bone metastases have been shown to develop osteonecrosis of the jaws. In the present study, we exam- ined the histologic findings of these cases. As similarities between this disorder and infected osteoradionecrosis (IORN) are described, both lesions were compared. METHODS: We investigated eight patients with bisphos- phonate treatment and osteonecrosis (four female, four male; median age: 65.6 years; cancer: multiple myeloma in five patients, breast cancer in three patients; mandibular involvement in five patients, maxillar involvement in three cases), and 10 patients suffering from IORN (all male; median age: 61.3 years; cancer: squamous cell carcinoma in nine patients, adenoid cystic carcinoma in one patient; mandibular involvement in all cases). Multicentric and bilateral involvement was common in the bisphosphonate group. Histologically, the bone revealed diffuse and patchy areas of necrosis in the bisphosphonate group, while in IORN osteonecrosis was larger and not diffusely distri- buted. RESULTS: In all cases, we found Actinomyces attached to the necrotic bone tissue. In five of eight bisphosphonates cases, and in six of 10 IORN cases, numerous osteoclasts could be detected close to vital bone exhibiting signs of bone resorption. Pseudoepitheliomatous hyperplasia (PH) was revealed in five of eight bisphosphonate patients, and in seven of 10 IORN patients. CONCLUSION: We conclude that Actinomyces is involved in the chronic, non-healing inflammatory processes as a characteristic feature of both diseases. Together with the associated presence of increased osteoclast numbers, we suggest that both factors may be involved in osteolytic mechanisms. J Oral Pathol Med (2006) 35: 155–60 Keywords: Actinomyces; bisphosphonate; infected osteoradio- necrosis; osteoclast; osteonecrosis; pseudoepitheliomatous hyper- plasia Introduction Patients sustaining osseous metastatic spread not only suffer substantial pain but also may develop pathologic fractures with devastating consequences. As it is known that the mechanisms of osteolysis associated with metastatic destruction of bone are essentially mediated by osteoclasts, inhibition of osteoclastic activity by biphosphonates has become a major target in the drug treatment of these patients. Bisphosphonates bind avidly to the mineralized bone tissue at the sites of osteoclast lacunae, and are then internalized by the osteoclasts. They inhibit both osteoclastic activity and osteoclast recruitment and, moreover, diminish the lifespan of these cells. The efficacy of bisphosphonates has been established in numerous studies. Based upon the guide- lines by the American Society of Clinical Oncology, bisphosphonates are standard treatment in severe hypercalcemia associated with malignancy and bone metastases, mainly in patients suffering from multiple myeloma and breast cancer (1–4). Recently, a conspicuous number of jaw osteonecrosis was reported for patients undergoing bisphosphonate treatment, especially with the nitrogen containing bis- phosphonates pamidronate and zoledronate (4–8). Most authors favor the view that bisphosphonates induce obliteration of the regional blood vessels and thus lead to avascular bone necrosis (4–6) but there is also evidence of an inhibitory effect of bisphosphonates on the keratinocyte cell cycle, which might promote a mucosal breakdown as a second line of pathogenesis (9). The clinical symptoms and lesions are rather similar to the lesions seen in patients with osteoradionecrosis. Necrotic bone is exposed to the oral cavity. The lesions are often painless; however, the patients may suffer from pain because of surrounding inflammatory soft tissue Correspondence: Dr. T. Hansen, Institute of Pathology, Johannes Gutenberg-University of Mainz, Langenbeckstr. 1, D-55101 Mainz, Germany. Tel: ++49-6131-177301. Fax: ++49-6131-176604. E-mail: torstenhansen@gmx.de *Both authors contributed equally to this work and thus share first authorship. Accepted for publication June 6, 2005 J Oral Pathol Med (2006) 35: 155–60 ª Blackwell Munksgaard 2006 Æ All rights reserved www.blackwellmunksgaard.com/jopm