Osteonecrosis of the Jaw in Myeloma Patients Receiving Pamidronate or Zoledronate.
Authors: Kut Victoria , Mehta J. , Tariman J. , Olsson A. , Singhal S. 
Published: April 2020

Abstract
Background: Pamidronate (P) and zoledronate (Z) are bisphosphonates (BPs) that reduce the risk of skeletal events in patients with multiple myeloma (MM). Although published comparative data and the drug label are confined to patients with bone lesions, the drugs are widely used in patients without bone lesions and often in those with smoldering myeloma. Systematic safety data are available only for short-term administration (up to 2 years) but the drugs are commonly administered for prolonged periods of time. Recently, reports of osteonecrosis (ON) of the jaw (mandible and/or maxilla) have appeared with the chronic use of BPs predominantly P and Z. ON has been identified in association with BP therapy in patients with MM, other malignancies, and non-cancerous conditions.
Methods: We reviewed the medical and dental records of MM patients with confirmed, clinically obvious ON seen at our MM program between March 2001 and June 2004. Several clinical and pathological characteristics were evaluated.
Results: Seven patients with ON of the jaw were identified amongst approximately 600 MM patients seen at our institution during this time period. An additional case, identified very recently on clinical grounds, is being investigated. There were 6 men and 1 woman, with a median age of 60 years (range, 56–64). All 7 patients were on P or Z at the time of diagnosis, and the median duration of prior BP therapy was 43 months (range, 4–75). All had received corticosteroids previously, and 3 had received thalidomide. Two had received local radiation to the jaw previously, and 2 had a history of dental extraction more than 3 years prior to this diagnosis. ON involved the mandible in 5, the maxilla in 1, and both in 1. Symptoms included local pain and discomfort. Therapy was variable, and the multiple approaches used included systemic analgesics (n=7), surgical debridement (n=6; repeatedly in 3), gingivoplasty (n=1), teeth extraction (n=2), prolonged antibiotic therapy (n=2), and hyperbaric oxygen therapy (n=2). Some symptom control was achieved in all patients, but all continued to have persistent problems at the time of last contact (n=6) or death from progressive myeloma (n=1). The limited data suggested that surgical intervention controlled symptoms for a short while but was invariably followed by worse symptoms.
Conclusions: We conclude that jaw ON is a newly identified serious complication of pamidronate and zoledronate therapy that is difficult to manage. Possible contribution of other agents such as corticosteroids and thalidomide to its causation remains to be determined. The prevalence rate of 1.5% in our patient population is very likely an underestimate because only symptomatic patients have been identified. A multi-pronged approach is necessary to identify the extent of this problem in MM patients, and broaden our understanding of it. Amongst the steps to be taken are: (1) careful assessment of the need for continued P or Z therapy in patients who have received the drugs for 2 years, (2) jaw imaging in patients with any local symptoms, (3) discontinuation of BP therapy in patients developing ON, (4) reporting details of cases with ON to FDAs MedWatch Program, and (5) avoidance of P/Z in patients with plasma cell dyscrasias where the utility of these drugs has not been established (e.g. smoldering myeloma). An additional step that may be useful as a prospective clinical investigation would be to perform detailed imaging studies of the jaw in all MM patients who have received P and/or Z for 3 years or more.