Materials and methods

The authors conducted a retrospective analysis of patients who had undergone tooth extraction between April 2006 and June 2009 at the Department of Oral and Maxillofacial Surgery, Kyoto University Hospital. Patients were identified using administrative data, and dental and medical records were reviewed from January 2010 to August 2010. This study protocol was approved by the Ethics Committee of Kyoto University Graduate School and Faculty of Medicine.

Inclusion was restricted to patients aged 20 years or older. ONJ in this study was diagnosed by the presence of exposed bone in the maxillofacial region that had persisted for more than 8 weeks, in reference to diagnostic criteria formulated by the American Association of Oral and Maxillofacial Surgeons. Diagnoses were determined independently by two oral and maxillofacial surgeons. Among patients undergoing tooth extraction at the authors’ institution, the following were excluded: tooth extraction in patients with metastatic tumours to the oral region; signs of osteomyelitis or exposed bone in the maxillofacial region before extraction; any history of craniofacial radiation therapy; and patients for whom panoramic radiographs before extraction were not available. Cases with diagnostic disagreement were discussed. Finally, ONJ cases with diagnostic disagreement were regarded as non-ONJ cases and analysed with the non-ONJ patients. The kappa value for inter-observer agreement was 0.86 (95% confidence interval (CI); 0.82–0.89).

For each chart reviewed, the following information was collected: demographics; medical history; test results; and potential risk factors associated with ONJ, namely the use of steroids, chemotherapy (including anticancer agents, immunosuppressive agents and thalidomide), current smoking status, current alcohol intake, diabetes, and details of BP treatment (indication, type, dose, duration). Recommended regimens for oral BP administration in the treatment of osteoporosis in Japan are etidronate sodium, 200 mg per day (Didronel ^® ); alendronate sodium, 5 mg per day or 35 mg per week (Fosamac ^® or Bonalon ^® ); and risedronate sodium, 2.5 mg per day or 17.5 mg per week (Actonel ^® or Benet ^® ), while those for intravenous administration in the treatment of osteolytic bone metastases of malignant cancer, multiple myeloma, or hypercalcemia of malignancy are incadronate, 10 mg per time (Bisphonal ^® ); pamidronate, 30–45 mg for hypercalcemia of malignancy, or 90 mg every 4 weeks for osteolytic bone metastases of malignant cancer (Aredia ^® ); and zoledronic acid, 4 mg every 4 weeks (Zometa ^® ). Intravenous BP has not been approved for osteoporosis in Japan.

For patients treated with BP in the hospital, these medications were entered into the electronic medical record system to obtain the type and duration of BP administration, and the number of patients to whom they were administered, to estimate the incidence of BIONJ. For patients treated with BP in other hospitals, the authors reviewed the record of their first examination at the authors’ hospital, at which the type and duration of BP administration as obtained from the referring physician by letter is recorded.

Using the patient’s panoramic radiograph before tooth extraction, an experienced examiner calculated the DMF index and severity of alveolar bone loss. The DMF index, which comprises the number of decayed (D), missing (M), and filled (F) teeth, has been established as a key measurement of caries experience in dental epidemiology. The severity of alveolar bone loss was measured to examine periodontal status as a percentage of missing bone at the mesial and distal surfaces of each tooth present. Severity was estimated from ( a − b )/ a × 100 (%) using the panoramic radiograph (where a is the distance from radiographic apex to cement–enamel junction (mm) and b is the distance from radiographic apex to interproximal alveolar bone crest (mm)). If the location of the cemento-enamel junction was obscured by interproximal fillings, the cervical margin of these fillings was chosen as standard. If the cervical margin of these fillings was obscured, bone loss height was characterized as unmeasurable. Each tooth surface was assigned a score corresponding to a bone loss of 0–24%, 25–49%, 50–74%, and 75–100%, respectively. These measurements were averaged to yield a single mean bone loss score for each patient, with a higher score indicating more severe periodontal disease.

Results

3240 patients underwent tooth extraction at the authors’ institute. After exclusion of 8 patients with a history of craniofacial radiation therapy and 16 without a panoramic radiograph, 3216 (99.2%) eligible patients were entered into the analysis. Patient characteristics are summarized in Table 1 . 126 patients (3.9%) had received BP; among the 103 women (81.7%), 86 (83.5%) were treated with oral BP and 17 (16.5%) with intravenous BP, while among the 23 men, 13 (56.5%) received oral and 10 (43.5%) received intravenous BP. Seven patients were diagnosed with both osteoporosis and breast cancer, all of whom had been treated with oral BP. The total number of patients without BP administration was 3090 (96.0%), of whom 51.8% were women. Median age was lower (39.0 years) than that of patients administered BP (66.0 years).