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Osteonecrosis of the Jaw Associated With Zoledronic Acid Treatment for Bone Metastases in Patients With Cancer
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Among patients with solid tumors, multiple myeloma, and other malignancies treated with zoledronic acid for metastatic bone disease, the 3-year cumulative incidence of osteonecrosis of the jaw was 2.8%, with rates of 0.8% at 1 year and 2% at 2 years. The rate was highest in patients with multiple myeloma (4.3%) and lowest in patients with breast cancer (2.4%). Additional factors associated with higher rates of osteonecrosis of the jaw included higher zoledronic acid exposure, fewer teeth, dentures, prior oral surgery, and current smoking.
- The study highlights the need to conduct baseline dental assessment and to monitor dental health during the course of zoledronic acid treatment. Appropriate dosing intervals should be defined for this population.
abstract
This abstract is available on the publisher's site.
Access this abstract nowImportance
Osteonecrosis of the jaw (ONJ) affects patients with cancer and metastatic bone disease (MBD) treated with bone-modifying agents (BMAs), yet the true incidence is unknown.
Objective
To define the cumulative incidence of ONJ at 3 years in patients receiving zoledronic acid for MBD from any malignant neoplasm.
Design, Setting, and Participants
This multicenter, prospective observational cohort study (SWOG Cancer Research Network S0702) included patients with MBD with either limited or no prior exposure to BMAs and a clinical care plan that included use of zoledronic acid within 30 days of registration. Medical, dental, and patient-reported outcome forms were submitted at baseline and every 6 months. Follow-up was 3 years. Osteonecrosis of the jaw was defined using established criteria. Data were collected from January 30, 2009, to December 13, 2013, and analyzed from August 24, 2018, to August 6, 2020.
Interventions/Exposures
Cancer treatments, BMAs, and dental care were administered as clinically indicated.
Main Outcomes and Measures
Cumulative incidence of confirmed ONJ, defined as an area of exposed bone in the maxillofacial region present for more than 8 weeks with no concurrent radiotherapy to the craniofacial region. Risk factors for ONJ were also examined.
Results
The SWOG S0702 trial enrolled 3491 evaluable patients (1806 women [51.7%]; median age, 63.1 [range, 2.24-93.9] years), of whom 1120 had breast cancer; 580, myeloma; 702, prostate cancer; 666, lung cancer; and 423, other neoplasm. A baseline dental examination was performed in 2263 patients (64.8%). Overall, 90 patients developed confirmed ONJ, with cumulative incidence of 0.8% (95% CI, 0.5%-1.1%) at year 1, 2.0% (95% CI, 1.5%-2.5%) at year 2, and 2.8% (95% CI, 2.3%-3.5%) at year 3; 3-year cumulative incidence was highest in patients with myeloma (4.3%; 95% CI, 2.8%-6.4%). Patients with planned zoledronic acid dosing intervals of less than 5 weeks were more likely to experience ONJ than patients with planned dosing intervals of 5 weeks or more (hazard ratio [HR], 4.65; 95% CI, 1.46-14.81; P = .009). A higher rate of ONJ was associated with fewer total number of teeth (HR, 0.51; 95% CI, 0.31-0.83; P = .006), the presence of dentures (HR, 1.83; 95% CI, 1.10-3.03; P = .02), and current smoking (HR, 2.12; 95% CI, 1.12-4.02; P = .02).
Conclusions and Relevance
As the findings show, the cumulative incidence of ONJ after 3 years was 2.8% in patients receiving zoledronic acid for MBD. Cancer type, oral health, and frequency of dosing were associated with the risk of ONJ. These data provide information to guide stratification of risk for developing ONJ in patients with MBD receiving zoledronic acid.
Additional Info
Disclosure statements are available on the authors' profiles:
Association of Osteonecrosis of the Jaw With Zoledronic Acid Treatment for Bone Metastases in Patients With Cancer
JAMA Oncol 2020 Dec 17;[EPub Ahead of Print], CH Van Poznak, JM Unger, AK Darke, C Moinpour, RA Bagramian, MM Schubert, LK Hansen, JD Floyd, SR Dakhil, DL Lew, JL Wade, MJ Fisch, NL Henry, DL Hershman, J GralowFrom MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
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Oncology
Osteonecrosis of the jaw (ONJ) is a known and serious complication of bone-modifying agents (BMAs) such as zoledronic acid (ZA) and denosumab. These drugs reduce skeletal-related events in patients with osseous metastases and are widely used in practice. Data on the overall incidence of ONJ and quantitation of causative factors have been lacking. Moreover, it is not clear when to hold or discontinue BMAs.
This study from SWOG investigators published in JAMA Oncology is a large, observational trial that sheds much-needed light on the ONJ situation. Patients enrolled had adequate racial, ethnic, and insurance variability to represent the real world of oncology patient care. About two-thirds of patients had a baseline dental exam as recommended, and patients with a variety of disease types were enrolled, including those with breast cancer, multiple myeloma, prostate cancer, and lung cancer, the most common cancers to exhibit osseous metastases.
The ONJ rate in this study was 2.8% at 3 years and occurred in a linear fashion, approximately 1% per year. The incidence was lowest for breast cancer and highest for multiple myeloma. Interestingly, pre-existing dental disease predicted ONJ, including patients who had prior oral surgery or fewer than normal number of teeth and any type of dentures. Additionally, in patients receiving ZA <5 weeks between doses had a much higher incidence than those with >5-week intervals between doses, with a hazard ratio of 4.65. Current smoking also raised the risk of ONJ.
How can we use the information from this study in our practices? We can start by improving our history taking of oral surgery, tooth extraction, or denture use in patients as known risk factors, a simple intervention that may alter the therapeutic strategy. Obtaining a dental exam prior to the initiation of BMAs may also be very useful to treat any ongoing oral conditions. Since ZA may give similar benefits in reducing skeletal-related events at 3-month dosing intervals, high-risk patients could begin at this schedule. Patients at somewhat lower risk could switch to every 3-month dosing after a year of monthly infusions.
The risk–benefit ratio favors the use of BMAs in patients with osseous metastases. However, the relatively uncommon complication of ONJ could be reduced substantially by careful attention to pre-existing risk factors, holding the drug during oral cavity surgery and improving oral health in general.