Bisphosphonate-Related Osteonecrosis of Jaw in the Adjuvant Breast Cancer Setting: Risks and Perspective

Bisphosphonate-related osteonecrosis of jaw (BONJ) is a rare adverse effect of antiresorptive treatments (primarily zoledronic acid and more recently denusomab) to my knowledge first described 10 years ago. The definition of BONJ includes the presence of necrotic bone for more than 6 weeks in an area of the oral cavity normally covered by mucosa, prior or current bisphosphonate use, and no prior history of radiation to the head and neck. The risks of BONJ increase with more frequent scheduling (ie, monthly) and prolonged durations of administration (ie, 2 years) of intravenous bisphosphonates, and the major risk factor for BONJ is dental extractions or procedures that expose bone during antiresorptive therapy. Principally, this led to the recommendation that, before initiating bisphosphonates, a dental evaluation and, if needed, dental work be completed before starting these drugs. Small nonrandomized cohort studies suggest that the incidence of BONJ is decreased with dental screening before initiating intravenous (IV) bisphosphonates. There is no evidence that routine dental health maintenance increases the risks of BONJ, and patients should be encouraged to have routine care during treatment with these drugs. The precise mechanism(s) of BONJ or why it is confined to the jaw, predisposing risk factors other than dental extractions, optimal treatments, and more importantly, the shortand long-term outcomes and health-related quality of life of patients who develop BONJ are largely unknown. Some, but not all, recent studies suggest that genetic polymorphisms in genes related to bone metabolism, collagen, or aromatase may predispose patients to BONJ. As is true of other rare but serious complications of cancer treatment, health professionals tend to overestimate or underestimate the risks, depending on their specialty (eg, dentists or medical oncologists), general knowledge of BONJ, and anecdotal experience. In addition, recent small studies in patients seen in either dental or cancer clinics suggest that awareness and education about BONJ is lacking. Rathbone et al, on behalf of the Adjuvant Zoledronic Acid to Reduce Recurrence (AZURE) trial investigators, have made an important contribution by providing the incidence and outcomes of BONJ in a prospective randomized controlled trial of zoledronic acid in more than 3,000 women with localized breast cancer receiving adjuvant systemic therapy and assessing the oral health-related quality of life in a small subset of them. Several aspects of the trial are noteworthy. The trial opened in 2003, which is the same year that BONJ was first described. In 2004, the protocol and consent was amended to exclude women with active dental issues or recent jaw surgery, consent was reaffirmed for all prior trial enrollees, educational materials were provided to all trial participants and investigators, and suspected cases of BONJ were reported as serious adverse events in real time to the trial coordinating center. These then triggered requests for additional information, and the final case determinations were adjudicated by the study team, which included an oral surgeon. Thus to the extent possible, investigators and trial participants were made aware of the potential of BONJ. However, we do not know whether a standard approach to case ascertainment of BONJ was performed at every clinic visit for all women enrolled onto the trial. For example, in recently closed Cancer and Leukemia Group B (CALGB) trial 70604 (ClinicalTrials.gov trial number NCT00869206) trial participants were queried about dental problems, visits, and procedures they had had in the past 1 to 12 months, and the information was recorded in the monthly case report form. Without such a standard approach to case ascertainment, the potential bias of underor over-reporting suspected cases of BONJ is possible. The schedule of zoledronic acid in the AZURE trial was intensive, with one 4-mg dose administered every 3 to 4 weeks for 5 to 6 months, followed by one dose every 3 to 6 months for 46 months, or a total of 19 doses in 5 years. This schedule approximates the 24 once-permonth zoledronic acid doses typically used to treat women with breast cancer and skeletal metastases. It is interesting to note that, in the Austrian Breast Cancer Study Group (ABCSG) trial-12, in which more than 1,800 premenopausal women received goselerin and were randomly assigned to either tamoxifen or anastrozole with or without zoledronic acid, treatment with zoledronic acid reduced the risk of local recurrence, bone metastases, and distant metastases (overall hazard ratio, 0.68; 95% CI, 0.51 to 0.91; P .009). The schedule of zoledronic acid in the ABCSG trial was one 4-mg dose every 6 months for 3 years or a total of 6 doses, and there were no reports of BONJ (median follow-up, 62 months). In the AZURE trial, the overall cumulative incidence of BONJ at 108 months was 2.1% (95% CI, 0.9% to 3.3%) and, extrapolating from Figure 1 of the article, was about 1.1% at 36 months. This is JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 31 NUMBER 21 JULY 2