Population-based analysis of link between IV bisphosphonates and inflammatory conditions or surgery of the jaw
Date Published 28/06/2007
Reporter initials Yuet
Reporter surname Wan
Reporter affiliation Hospital Pharmacist
Source J Nat Cancer Inst published early online June 27, 2007
Abstract This American administrative claims based analysis examined the link between osteonecrosis of the jaw or facial bones and treatment with IV bisphosphonates. Data were obtained from the Surveillance, Epidemiology, and End Results (SEER) programme linked to Medicare claims for 16,073 cancer patients treated with pamidronate and/or zoledronic acid. They were matched to 28,698 bisphosphonate non-users and to 14,349 bisphosphonate users on month and year of the first bisphosphonate administration, cancer type, age, sex, risk factors for osteonecrosis (diabetes, alcoholism, cigarette smoking, obesity, hyperlipidaemia, pancreatitis, or chemotherapy with L-asparaginase), bone metastasis, and SEER programme geographical region. Patients were followed until the study's end, loss of coverage from Medicare, or one of the following outcomes: diagnosis of inflammatory conditions or osteomyelitis of the jaw, surgery on the facial bones, or death, whichever occurred first.
Compared with non-use, use of IV bisphosphonates was associated with an increased risk of:
• Jaw or facial bone surgery (hazard ratio [HR] = 3.15, 95% CI, 1.86 to 5.32)
• Diagnosis of inflammatory conditions or osteomyelitis of the jaw (11.48; 6.49 to 20.33).
In addition, the absolute risk at 6 years for any jaw toxicity was 5.48 events per 100 patients using IV bisphosphonates vs 0.30 events per 100 patients not using such drugs. Furthermore, 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; 0.77 to 17.08; and for more than 21 infusions, 9.18; 1.74 to 48.53).
The study concluded “users of IV 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.”
An accompanying editorial notes some of the shortcomings of the study:
• It is unclear what percentage of inflammatory conditions of the jaw actually represents osteonecrosis.
• Cancer patients on chemotherapy may experience exacerbation of, or new odontogenic infections as a result of, neutropenia and immunosuppression.
• A review of the medical records of the patients identified with inflammatory conditions of the jaw was not carried out to validate the presence of osteonecrosis.
• Risk of detection bias as clinicians are likely to have assessed patients on bisphosphonates more closely for jaw osteonecrosis than those not on treatment, due to increasing awareness of this potential oral complication.
• There may have been underreporting of jaw conditions consistent with osteonecrosis of the jaws since the first cases of bisphosphonate-related osteonecrosis of the jaws were reported in 2003, and the study ended in 2003. Since then, there has been a large rise in the number of cases reported due to increased awareness among oncologists and the dental community.
In spite of these shortcomings, the editorial acknowledges that this study does add to the growing body of evidence of the link between use of IV bisphosphonates and jaw osteonecrosis. Though the association had been called into question, it suggests that the sheer number of cases reported, as well as the mode of action of these drugs, lend support to the view that there is a real and probable causal relationship. It notes that studies are under way to define patient risk factors, identify biomarkers and radiographic findings that may predict osteonecrosis of the jaw. It concludes “the morbidity of skeletal-related events in patients with cancer compared with the morbidity of patients who develop osteonecrosis of the jaws (of various severities) must be carefully weighed before making decisions to continue or discontinue bisphosphonate use.”
Reporter initials Yuet
Reporter surname Wan
Reporter affiliation Hospital Pharmacist
Source J Nat Cancer Inst published early online June 27, 2007
Abstract This American administrative claims based analysis examined the link between osteonecrosis of the jaw or facial bones and treatment with IV bisphosphonates. Data were obtained from the Surveillance, Epidemiology, and End Results (SEER) programme linked to Medicare claims for 16,073 cancer patients treated with pamidronate and/or zoledronic acid. They were matched to 28,698 bisphosphonate non-users and to 14,349 bisphosphonate users on month and year of the first bisphosphonate administration, cancer type, age, sex, risk factors for osteonecrosis (diabetes, alcoholism, cigarette smoking, obesity, hyperlipidaemia, pancreatitis, or chemotherapy with L-asparaginase), bone metastasis, and SEER programme geographical region. Patients were followed until the study's end, loss of coverage from Medicare, or one of the following outcomes: diagnosis of inflammatory conditions or osteomyelitis of the jaw, surgery on the facial bones, or death, whichever occurred first.
Compared with non-use, use of IV bisphosphonates was associated with an increased risk of:
• Jaw or facial bone surgery (hazard ratio [HR] = 3.15, 95% CI, 1.86 to 5.32)
• Diagnosis of inflammatory conditions or osteomyelitis of the jaw (11.48; 6.49 to 20.33).
In addition, the absolute risk at 6 years for any jaw toxicity was 5.48 events per 100 patients using IV bisphosphonates vs 0.30 events per 100 patients not using such drugs. Furthermore, 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; 0.77 to 17.08; and for more than 21 infusions, 9.18; 1.74 to 48.53).
The study concluded “users of IV 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.”
An accompanying editorial notes some of the shortcomings of the study:
• It is unclear what percentage of inflammatory conditions of the jaw actually represents osteonecrosis.
• Cancer patients on chemotherapy may experience exacerbation of, or new odontogenic infections as a result of, neutropenia and immunosuppression.
• A review of the medical records of the patients identified with inflammatory conditions of the jaw was not carried out to validate the presence of osteonecrosis.
• Risk of detection bias as clinicians are likely to have assessed patients on bisphosphonates more closely for jaw osteonecrosis than those not on treatment, due to increasing awareness of this potential oral complication.
• There may have been underreporting of jaw conditions consistent with osteonecrosis of the jaws since the first cases of bisphosphonate-related osteonecrosis of the jaws were reported in 2003, and the study ended in 2003. Since then, there has been a large rise in the number of cases reported due to increased awareness among oncologists and the dental community.
In spite of these shortcomings, the editorial acknowledges that this study does add to the growing body of evidence of the link between use of IV bisphosphonates and jaw osteonecrosis. Though the association had been called into question, it suggests that the sheer number of cases reported, as well as the mode of action of these drugs, lend support to the view that there is a real and probable causal relationship. It notes that studies are under way to define patient risk factors, identify biomarkers and radiographic findings that may predict osteonecrosis of the jaw. It concludes “the morbidity of skeletal-related events in patients with cancer compared with the morbidity of patients who develop osteonecrosis of the jaws (of various severities) must be carefully weighed before making decisions to continue or discontinue bisphosphonate use.”
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