Osteonecrosis of the Jaw Linked to Adjuvant Zoledronic Acid

Laurie Barclay, MD

July 01, 2013

Adjuvant zoledronic acid (Zometa, Novartis) used for bone strengthening in women with breast cancer was associated with a 2.1% rate of osteonecrosis of the jaw (ONJ), in a randomized controlled trial published online June 24 in the Journal of Clinical Oncology.

The study authors consider this rate of ONJ to be "encouragingly low," but an expert writing in an accompanying editorial say this rate is "not acceptable," because zoledronate did not improve disease-free survival or overall survival in the study population as a whole.

These latest findings on ONJ come from an analysis of the Adjuvant Zoledronic Acid to Reduce Recurrence (AZURE) trial, which was negative overall in that zoledronic acid (also known as zoledronate) did not reduce breast-cancer recurrence in the total study population, although a significant reduction was seen in a subset of postmenopausal women.

The AZURE trial involved 3360 women with stage II or III breast cancer randomized to receive standard adjuvant systemic therapy alone or with intensive zoledronate therapy (4 mg for 19 doses over 5 years). The investigators reported all potential cases of ONJ as serious adverse events (AEs), and these were reviewed centrally.

The current study focused on reports of osteonecrosis of the jaw and also on oral health, explain the authors, headed by Emma Rathbone, MD, from Weston Park Hospital, Sheffield, United Kingdom.

After completion of 5 years of study treatment, 486 participants were asked to complete the Oral Health Impact Profile-14 (OHIP-14) as a measure of oral quality of life (QOL). The investigators used multivariable linear regression to calculate mean scores and to identify independent prognostic factors.

Osteonecrosis and Oral-Health Findings

Median follow-up was 73.9 months (interquartile range, 60.7 – 84.2 months). Of 33 reports of possible ONJ during follow-up, all in patients treated with zoledronate, 26 were confirmed to be consistent with the diagnosis of ONJ. In the zoledronate group, cumulative incidence of ONJ was 2.1% (95% CI, 0.9% – 3.3%).

Among the 26 women with ONJ, 35% were said to be "completely recovered," 19% "improving," 12% "recovered with sequela," and in 31% ONJ was "present and unchanged" after treatment.

Based on 362 completed OHIP-14 questionnaires (74% response rate), participants given or not given zoledronate did not differ significantly in prevalence or severity of effects on oral QOL. Among 45 patients who reported 55 dental AEs, 84% were in the zoledronate group. Only 2 of these events were grade 3 (1 episode of jaw pain and 1 of loose teeth), and no grade 4 events were reported.

"Although the cumulative incidence of confirmed ONJ is encouragingly low at 2.1% after a median follow-up of 73.9 months and less than that associated with zoledronic-acid use in the setting of metastatic bone disease, it is higher than that observed in other trials of adjuvant zoledronate that have used a less intense schedule and fewer infusions (6 to 10 infusions) over 3 to 5 years," the study authors write. "There was also an apparent additional increase in reported dental-specific AEs, including jaw pain and dental infections, in the zoledronate arm."

Study Limitations and Clinical Implications

Limitations of this study include open-label design, which could have affected AE reporting; evaluation of oral QOL at a single time point at completion of 5 years of study; and reliance on retrospective patient evaluation of QOL at only 2 time points.

"Our data provide reassurance to clinicians and patients that zoledronate does not seem to significantly affect oral QOL," note the study authors. "The relationship between reporting of a dental AE during the study and worse oral QOL scores strongly suggests that the OHIP-14 is sensitive to oral-health events in patients with early breast cancer. The knowledge that there seems to be no demonstrable adverse impact on quality of life is encouraging, given the widespread use of zoledronate and the recent results in the adjuvant setting indicating that bisphosphonates may improve both disease-free survival (DFS) and overall survival (OS) in certain disease settings."

The problem of ONJ is not unique to zoledronate, as it has been reported with variable frequency in patients receiving intravenous or oral bisphosphonates, and it has also been reported with denosumab (Xgeva, Amgen), which is a RANK-ligand inhibitor.

The cumulative incidence of ONJ in patients receiving intravenous bisphosphonate as adjuvant cancer treatment ranges from 0.8% to 12%, according to an updated position paper from the American Association of Oral and Maxillofacial Surgeons. Significant potential risk factors include treatment potency and duration as well as dentoalveolar surgery.

In February 2004, on the basis of an awareness of these risk factors, the AZURE study protocol was amended to exclude patients with significant active dental problems or recent jaw surgery. All patients received dental-hygiene advice, and investigators received guidance on ONJ diagnosis, prevention, and treatment of ONJ based on emerging clinical guidelines. Exclusion of patients with risk factors for ONJ might have resulted in underestimation of ONJ prevalence, whereas increased vigilance by clinicians might have increased reports of possible ONJ, the authors comment.

"It seems unlikely that a bone-targeted agent will become available in the foreseeable future that is not associated with the development of ONJ," the study authors write. "We need to understand the potential genetic, oral-health, and treatment risk factors; incidence; and resolution of this uncommon problem somewhat better than we do at the present time."

In an accompanying editorial, Charles L. Shapiro, MD, from Wexner Medical Center and Comprehensive Cancer Center, Ohio State University, in Columbus, elaborates on unanswered questions regarding bisphosphonate-related ONJ (BONJ). These include specific underlying mechanism(s), why it is confined to the jaw, predisposing risk factors other than dental extractions, optimal treatments, outcomes, and health-related QOL.

 
The 2% total cumulative incidence of ONJ, although low, is clearly not acceptable. Dr. Charles Shapiro
 

Dr. Shapiro describes the AZURE findings as "an important contribution" but points out an additional study limitation — namely, the lack of clarity regarding whether a standard approach to case ascertainment of ONJ was performed at every clinic visit. If not, there could be potential bias of under- or overreporting suspected cases of ONJ, he points out.

Furthermore, he notes that precise definitions were not given for descriptors regarding ONJ outcomes, nor were the details of specific treatments for ONJ.

"Overall, the AZURE trial results showed that IV zoledronic acid on an intensive schedule did not improve disease-free survival or overall survival, and therefore the 2% total cumulative incidence of ONJ, although low, is clearly not acceptable," Dr. Shapiro writes. "Whether there is a subpopulation of women with early-stage breast cancer as has been proposed — premenopausal receiving ovarian suppression or postmenopausal women — in which the therapeutic ratio favors using adjuvant zoledronic acid or clodronate vis-à-vis ONJ and other adverse effects remains to be verified in subsequent trials."

Novartis supported the study. Dr. Rathbone has reported no relevant financial relationships. Disclosures for the coauthors are listed in the article. Dr. Shapiro has reported no relevant financial relationships.

J Clin Oncol . Published online June 24, 2013. Abstract Editorial

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