Bisphosphonates and Osteonecrosis of the Jaws: Incidence in a Homogeneous Series of Patients with Newly Diagnosed Multiple Myeloma Treated with Zoledronic Acid.

Osteonecrosis of the jaws (ONJ) is a rare complication that has been described as osteoradionecrosis in patients who had previously undergone radiotherapy for head and neck cancer or similar disorders. It has been recently reported that the incidence of ONJ has significantly increased since the wide application of bisphosphonates as specific therapy of cancer related bone disease. No consensus on diagnostic criteria does presently exist, the pathogenesis of this complication is unknown and the relative contribution of repeated trauma from dental procedures, poor oral hygiene, concomitant chemotherapy, and cancer bone involvement has not been clarified yet. All the same, no data have so far been presented concerning the incidence of ONJ in a homogeneous series of patients with respect to disease status and treatment received. For this purpose, we have retrospectively evaluated the occurrence of ONJ in patients with symptomatic newly diagnosed multiple myeloma enrolled in the “Bologna 2002” clinical trial. According to treatment protocol, all patients received four months of combined thalidomide (100mg/d for two weeks and 200mg/d thereafter) and dexamethasone (40mg/d on d 1–4, 9–12, 17–20/28d on odd cycles and on d 1–4 on even cycles) followed by cyclophosphamide 7g/m2 + G-CSF and PBSC collection, and two courses of Melphalan 200mg/mq and PBSC transplantation. Zoledronic acid was administered at 4mg/28 d throughout the whole study period and afterwards until disease progression. Out of 225 patients analyzed so far (median follow-up = 26 months), ONJ was diagnosed in 6 cases (2.7%), median time from start of treatment and occurrence of dental symptoms was 23 months (range 13–32 months). All the patients underwent dental extraction and/or oral/maxillofacial surgery that resulted in areas of non-healing bone with persistent purulent discharge. Bone biopsies confirmed bone necrosis and inflammation; in 1 case, however, a concomitant infiltration of monoclonal plasma cells was detected in the site of necrosis. In conclusion, results of this retrospective analysis indicate that the occurrence of ONJ among newly diagnosed MM patients receiving long-term (median: 2 years) zoledronic acid treatment was approximately 3%. Surgery can significantly impact patients outcome, so that, according to currently available recommendations on ONJ, dental procedures should be avoided. In addition, the role played by disease itself in the pathogenesis of this complication should not be overlooked.