Journal of the National Cancer Institute Advance Access originally published online on June 27, 2007
JNCI Journal of the National Cancer Institute 2007 99(13):1016-1024; doi:10.1093/jnci/djm025
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Intravenous Bisphosphonate Therapy and Inflammatory Conditions or Surgery of the Jaw: A Population-Based Analysis
Affiliations of authors: Departments of Preventive Medicine and Community Health (GSW, YFK, JLF, JSG) and Internal Medicine (YFK, JLF, JSG), and Sealy Center on Aging (GSW, YFK, JLF, JSG), University of Texas Medical Branch, Galveston, TX
Correspondence to: Gregg Wilkinson, PhD, Department of Preventive Medicine and Community Health, University of Texas Medical Branch, 301 University Blvd, Galveston, TX 77555-1153 (e-mail: gswilkin{at}utmb.edu).
Background: Recent reports have identified an association between osteonecrosis of the jaw or facial bones and treatment with nitrogen-containing intravenous bisphosphonates. We investigated this association by use of data from the Surveillance, Epidemiology, and End Results (SEER) program linked to Medicare claims.
Methods: We identified 16073 cancer patients who were diagnosed between January 1, 1986, and December 31, 2002, and were treated intravenously with the bisphosphonates pamidronate and/or zoledronic acid between January 1, 1995, and December 31, 2003. We matched 28698 bisphosphonate nonusers, at a 2:1 ratio, to 14349 bisphosphonate users on month and year of the first bisphosphonate administration received by users, cancer type, age, sex, risk factors for osteonecrosis (diabetes, alcoholism, cigarette smoking, obesity, hyperlipemia, pancreatitis, or chemotherapy with L-asparaginase), bone metastasis, and SEER program geographic region. Patients were followed until the study's end on December 31, 2003; loss of coverage from Medicare Parts A and B; or one of the following outcomes: a diagnosis of inflammatory conditions or osteomyelitis of the jaw, surgery on the facial bones, or death, whichever occurred first.
Results: Use of intravenous bisphosphonates was associated with an increased risk of jaw or facial bone surgery (hazard ratio [HR] = 3.15, 95% confidence interval [CI] = 1.86 to 5.32) and an increased risk of being diagnosed with inflammatory conditions or osteomyelitis of the jaw (HR = 11.48, 95% CI = 6.49 to 20.33), compared with nonuse. The absolute risk at 6 years for any jaw toxicity was 5.48 events per 100 patients using intravenous bisphosphonates and 0.30 events per 100 patients not using such drugs. The risk of each outcome increased as cumulative dose increased (e.g., for 4–8 infusions, HR for operations on the jaw and facial bones = 3.63, 95% CI = 0.77 to 17.08; for more than 21 infusions, HR = 9.18, 95% CI = 1.74 to 48.53).
Conclusion: Users of intravenous bisphosphonates had an increased risk of inflammatory conditions, osteomyelitis, and surgical procedures of the jaw and facial bones. The increased risk may reflect an increased risk for osteonecrosis of the jaw.
| CONTEXT AND CAVEATS Prior knowledge Associations between osteonecrosis of the jaw or facial bones and treatment with intravenous bisphosphonates have been reported from small studies. Study design Population-based cohort study of data from the Surveillance, Epidemiology, and End Results program linked to Medicare claims. Contribution In a large study of 14 349 bisphosphonate users and 28 698 nonusers, use of bisphosphonates, compared with its nonuse, was associated with substantially increased risks of jaw or facial surgery or of being diagnosed with inflammatory conditions or osteomyelitis of the jaw. Implications Increased risks of jaw complications among bisphosphonate users may reflect an increased risk for osteonecrosis of the jaw. Increasing oral hygiene and avoiding tooth extractions may lead to a decrease in the incidence of jaw complications. Given the increasing use of intravenous bisphosphonate therapy for treating osteoporosis, these patients should be followed carefully for adverse bone events involving facial bones. Limitations Because there is no disease code for facial or jaw osteonecrosis or aseptic necrosis of the jaw, the authors used surrogates, which could introduce some misclassification. Reliance on Medicare claims data required that patients and physicians be aware of their condition or that patients had undergone treatment by a clinician who billed Medicare; underreporting could have occurred if patients had unreported disease or were treated by a dentist who could not charge Medicare.
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Manuscript received December 14, 2006; revised April 26, 2007; accepted May 22, 2007.
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J Natl Cancer Inst 2008 100: 155.
J Natl Cancer Inst 2007 99: 986-987.
J Natl Cancer Inst 2007 99: 981.
J Natl Cancer Inst 2007 99: 981.
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