Intravenous bisphosphonate therapy and inflammatory conditions or surgery of the jaw: a population-based analysis

J Natl Cancer Inst. 2007 Jul 4;99(13):1016-24. doi: 10.1093/jnci/djm025. Epub 2007 Jun 27.


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 16,073 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 28,698 bisphosphonate nonusers, at a 2:1 ratio, to 14,349 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Aged
  • Aged, 80 and over
  • Bone and Bones / pathology
  • Diphosphonates / adverse effects*
  • Diphosphonates / therapeutic use*
  • Female
  • Humans
  • Inflammation / epidemiology*
  • Jaw Diseases / chemically induced*
  • Jaw Diseases / epidemiology
  • Jaw Diseases / immunology*
  • Jaw Diseases / surgery
  • Male
  • Medicare
  • Middle Aged
  • Neoplasms / complications
  • Neoplasms / drug therapy*
  • Neoplasms / epidemiology
  • Neoplasms / immunology*
  • Osteonecrosis / pathology
  • SEER Program
  • United States


  • Diphosphonates