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Original Investigation
December 17, 2020

Association of Osteonecrosis of the Jaw With Zoledronic Acid Treatment for Bone Metastases in Patients With Cancer

Author Affiliations
  • 1Department of Internal Medicine, University of Michigan, Ann Arbor
  • 2SWOG Cancer Research Network Statistics and Data Management Center, Fred Hutchinson Cancer Center, Seattle, Washington
  • 3Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington
  • 4School of Dentistry, University of Michigan, Ann Arbor
  • 5University of Washington School of Dentistry, Seattle
  • 6Clinical Program Specialists, Legacy Good Samaritan Hospital, Portland, Oregon
  • 7Heartland NCORP (National Cancer Institute Community Oncology Research Program)/Cancer Care Specialists of Illinois, Swansea
  • 8Wichita NCORP/Cancer Center of Kansas, Wichita
  • 9Cancer Care Specialists of Illinois, Decatur
  • 10Department of General Oncology, Division of Cancer Medicine, MD Anderson Cancer Center, Houston, Texas
  • 11Columbia University Medical Center, New York, New York
  • 12University of Washington, Seattle, Cancer Care Alliance, Seattle
JAMA Oncol. Published online December 17, 2020. doi:10.1001/jamaoncol.2020.6353
Key Points

Question  What is the incidence of osteonecrosis of the jaw (ONJ) in patients treated with zoledronic acid for bone metastases from any cancer?

Findings  In this cohort study of 3491 participants initiating zoledronic acid treatment for bone metastases, the cumulative incidence of ONJ was 0.8% at year 1, 2.0% at year 2, and 2.8% at year 3, with the highest incidence observed in multiple myeloma and the lowest in breast cancer. More frequent dosing of zoledronic acid and poor oral health were associated with higher rates of ONJ.

Meaning  These findings suggest that cancer type, oral health, and frequency of dosing are associated with the risk of ONJ, which should help to guide stratification of risk for developing ONJ in patients receiving zoledronic acid.

Abstract

Importance  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.

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    1 Comment for this article
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    Suggest deeper review of oral and maxillofacial surgery literature
    Kim Goldman, OMS | University
    Although the prospective nature of this study is commendable, and the recommendation to establish baseline dental health before beginning therapy is excellent and already well circulated in the OMS literature as well as in basic dental training. There is little new information here and the suggestion that dosing zoledronic acid less frequently will alter the eventual development of MRONJ does not appear to be founded UNLESS such less frequent dosing is also associated with shorter treatment period (?) and lower total dose. A preponderance of clinical evidence reveals that the length of treatment (> 4 years vs < 4 years) and the route of treatment (IV > PO/IM) most influence the development of MRONJ. Research additionally suggests that total dosing affects the speed at which MRONJ might develop.
    CONFLICT OF INTEREST: None Reported
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