Evolution of Bisphosphonates RELATED Osteonecrosis of the Jaw (BRONJ) IN PATIENTS with MULTIPLE MYELOMA (MM) and WALDENSTROM'S Macroglobulinemia (WM): A Retrospective STUDY.

Bisphosphonate (BSFs) are an effective drug which have been mainly used in oncology for the treatment of solid tumour with bone metastasis, as well as for haematologic disease such as multiple myeloma (MM) and Waldenstrom's Macroglobulinemia (WM), but also prescribed in non neoplastic disease such osteoporosis and Paget's disease. As rare complications related to prolonged treatment with BSFs, an osteonecrosis of the jaw (BRONJ) in neoplastic and non neoplastic diseases is reported with an incidence between 2 and 15% as described in different casitics. The aim of this retrospective multicentric study is to describe the clinical aspects and the evolution of the osteo-necrotic lesions in a long term group of MM patients treated with BSFs.

We studied retrospectively 55 patients (pts) with MM or WM who developed BRONJ followed from January 2003 to January 2009 in different haematological departments. Median age was 72 years (range 56-95), male 16/ 39 female. Immunoglobulin isotype was: 25 pts IgG-κ; 6 pts IgG-α, 12 pts IgA-κ; 3 pts IgA-γ, 5 pts IgM-κ (WM), 3 pts MM light chain κ and 1 pt MM light chain γ. All patients have been treated with BSFs for bone lesions and/or factures: Pamidronate was used in 1 pt (1,8 %), Zolendronic acid in 36 pts (65,5 %), Pamidronate followed by zolendronate in 18 pts (32,7 %). The average dose of Pamidronate was 2.022 mg (range 90-6.750 mg) and of zoledronate was 84 mg (range 4-256 mg). Anatomic localisation of the BRONJ was: mandible 29 pts (52,7%); maxilla 22 pts (40%); mandible/maxilla 4 cases (7,3 %). The most common trigger for BRONJ was dentoalveolar surgery, including extractions (43 cases-78,4%), dental implant placement (3 patients-5,4%), periodontal disease (5 cases-9 %), and in 3 patients with dental prothesis (5,4%); only 1 patient (1,8%) developed BRONJ spontaneously.

All patients stopped bsf therapy after BRONJ diagnosis.

After a median observation of 26 months (range 1-110 months) no death for BRONJ complication was reported. All patients were treated with conservative treatment such as antibiotic therapy. In 18 patients (32,7%) antibiotic therapy was the only treatment used. Six patients (10,9%) received antibiotic associated with surgical debridement of necrotic bone. Sixteen patients (29%) were treated with antibiotic therapy in combination with ozonotherapy and curettage; twelve patients (21, 8%) required sequestrectomy in association with antibiotic and oxygen/hyperbaric therapy. Three patients (5, 4%) refused any therapy.

Among the evaluable patients (53) complete response (CR) was observed in 20 cases (37.75%); partial response (PR) in 21 patients (39.6%) with improving as secondary infection and pain; the clinical finding was unchanged (SD) in 9 patients (16,3%) and 3 patients (5,4%) developed a worsening of the osteonecrosis (PD).

In the unvariate analysis association of surgical treatment with antibiotic therapy, is more effective to eradicate the necrotic bone than antibiotic treatment alone (p=<0.053). O₂Iperbaric/Ozonotherapy is a very active treatment, because 44.4% of patient obtain complete resolution of ONJ in comparison to 30.8% of patients who didn't performed this procedure (p=<0.0007). A Multivariate analysis was performed to evaluate differences between variables, but no significant association was found. According to our retrospective study, we confirm that the incidence of this complication is between 2% and 15%, and the cumulative dosage of BSFs is important to induce ONJ. Because the most common trigger for BRONJ was dental extractions, it's an universally recognized indication before BSFs' treatment to implement control of periodontal disease, achieving optimal periodontal health. BRONJ is a late complication of the use of BSFs which interfere on quality of life of patients but not on survival because none death was observed.

Petrucci:Ortho Biothec, Jannsen Cilag: Honoraria; Celgene: Honoraria.