The Incidence of Osteonecrosis of the Jaw (ONJ) in Patients with Multiple Myeloma Who Receive Biphosphonates Depends on the Type of Biphosphonate.
Authors: Dimopoulos Meletios A. , Kastritis Efstathios , Moulopoulos Lia A. , Melakopoulos Ioannis , Anagnostopoulos Athanasios , Gika Dimitra , Bozas George , Koutsoukou Vassiliki , Bamias Aristotelis 
Published: April 2020

Abstract
Purpose: Biphosphonates have been approved for the treatment of bone lesions in patients with multiple myeloma. Although these agents are usually well tolerated, osteonecrosis of the jaw (ONJ) has been recently associated with the use of pamidronate and zoledronic acid. Nevertheless, the true incidence of this complication is not clearly defined. Therefore, we studied the incidence, characteristics and risk factors for the development of ONJ among patients with multiple myeloma treated with biphosphonates in our institution.
Patients and Methods: One hundred and thirty-seven patients who received biphosphonates (zoledronic acid: 50 pts, pamidronate: 29 patients, bondronate: 2 pts, pamidronate and zoledronic acid: 50 pts, zoledronic acid and bondronate: 5 pts) since January 1995 and had a minimum exposure of 6 months to the drug were included in this analysis. Since the first reports, which associated ONJ with biphosphonate treatment, we prospectively evaluated this complication (first patient diagnosed in July 2003): all patients complaining of symptoms suggestive of ONJ were referred to a maxillofascial surgeon who confirmed the diagnosis and managed the patients for this complication. The medical records of all patients who were included in the analysis were reviewed in order to exclude symptoms and signs of ONJ, which might have not been formally diagnosed. From this retrospective review, no patient with a highly probable diagnosis of ONJ was identified.
Results: Ten patients (6.7%) developed ONJ. The median number of treatment cycles and time of exposure to biphosphonates were 26 infusions and 42 months for patients with ONJ compared to19 infusions (p=0.2) and 27 months (p=0.05) for patients with no ONJ. The cumulative hazard of ONJ increased with time to exposure from 0% for exposure 6–12 months to 13% (95% CI: 3–23) for exposure of 5 years. The use of thalidomide was not associated with the development of ONJ. No case of ONJ was observed among patients treated with pamidronate or pamidronate and ibandronate. In patients who received sequential pamidronate and zoledronic acid, all cases of ONJ occurred during the use of zoledronic acid. The cumulative hazard was significantly higher with zoledronic acid compared to pamidronate alone or sequential administration of pamidronate and zoledronic acid (p=0.022). Among the 10 patients, who developed ONJ, 7 had had dental extraction prior to the development of the complication, 2 had dentures and only one had not had either. In spite of the discontinuation of biphosphonate treatment, only one patient experienced improvement of osteonecrosis, in 7 cases it remained stable and in 2 cases osteonecrosis progressed.
Conclusions: The use of biphosphonates in patients with multiple myeloma seems to be associated with the development of ONJ. Our cohort study is the first one which provides a fairly accurate estimate of the incidence of documented ONJ after treatment with biphosphonates. Length of exposure and the type of biphosphonate used appear to be the most important risk factor for this complication. The risk of developing osteonecrosis appears to be higher with zoledronic acid than with pamidronate and may be precipitated by dental extraction.