Journal of the National Cancer Institute Advance Access originally published online on January 8, 2008
JNCI Journal of the National Cancer Institute 2008 100(2):155; doi:10.1093/jnci/djm261
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© The Author 2008. Published by Oxford University Press.
CORRESPONDENCE |
Re: Intravenous Bisphosphonate Therapy and Inflammatory Conditions or Surgery of the Jaw: A Population-Based Analysis
Affiliations of authors: Departments of Medicine (MK) and Oral Medicine (SE) and Diabetes Center (MK), Hadassah Hospital and Hebrew University Medical School, Jerusalem, Israel
Correspondence to: Mogher Khamaisi, MD, PhD, Department of Medicine, Hadassah Hospital, PO Box 12000, Jerusalem 91240, Israel (e-mail: murir{at}hadassah.org.il).
Wilkinson et al. (1) recently reported in the Journal that users of intravenous bisphosphonates had an increased risk of inflammatory conditions, osteomyelitis, and surgical procedures of the jaw and facial bones. The inflammatory condition investigated in this paper was bisphosphonate-related osteonecrosis of the jaws, which was first described in 2003 (2).
A negative association was found between various risk factors, including diabetes, and bisphosphonate-related osteonecrosis of the jaws. That is, the development of inflammatory disease or osteomyelitis of the jaw after exposure to intravenously administered bisphosphonate was not affected by the presence of other risk factors.
In contrast, we found (3) a clear association between diabetes and bisphosphonate-related osteonecrosis of the jaws. In our study, 18 (58%) of the 31 patients with bisphosphonate-related osteonecrosis had diabetes mellitus or impaired fasting glucose, a rate much higher than the 14% incidence in the general population (3). Furthermore, the proportion of diabetes mellitus in a control group of oncologic patients without osteonecrosis was 12% (P < .001).
The negative association between diabetes and bisphosphonate-related osteonecrosis of the jaws that was observed by Wilkinson et al. raises the question of what may account for the discrepancy between their study and our study. The study designs were different. Whereas the study of Wilkinson et al. (1) was a population-based cohort study, our study was a clinical comparative study that focused on diabetes mellitus. However, we wonder whether fundamental elements in the design of the study of Wilkinson et al. (1) contributed to a structured bias. Risk factors were assessed by developing a risk factor index for osteonecrosis. This index was a summary of the occurrence among study subjects of the following conditions: diabetes, alcoholism, cigarette smoking, obesity, hyperlipidemia, pancreatitis, and chemotherapy with L-asparaginase. The results refer to a combination of risk factors. Thus, the question of whether diabetes alone is a risk factor is left unanswered. We would appreciate it if the authors would reanalyze their data by focusing on diabetes as a risk factor for bisphosphonate-related osteonecrosis of the jaws.
In fact, the authors provided no information about the patients with diabetes. We do not know the duration of the diabetes, the presence of complications, or the treatments received. In addition, it is not clear whether the patients had type 2 diabetes before bisphosphonate therapy or steroid-induced diabetes after being given steroids, presumably as a component of chemotherapy protocols. Microvascular disease is a common complication of diabetes and may result in impaired bone nutrition through the loss of full function of the nutrient vessels in the bone. However, the authors make no mention of evidence in their patients of microangiopathy, such as the presence of nephropathy, retinopathy, or peripheral vascular insufficiency.
Moreover, this analysis is an associational analysis between a qualitative parameter (diagnosis of diabetes) and bisphosphonate-related osteonecrosis of the jaws. A quantitative analysis would be more persuasive as to the potential importance of diabetes as a risk factor. In such an analysis, the glycemic control of the patient could be weighted as a component in the analysis rather than just using the background diagnosis of diabetes.
The authors acknowledge that this negative association does not indicate causality. We believe that a controlled study with an animal model that mimics the risk factors of diabetes mellitus and osteonecrosis would provide information about the importance of diabetes as a risk factor for osteonecrosis of the jaws.
REFERENCES
1. Wilkinson GS, Kuo YF, Freeman JL, Goodwin JS. Intravenous bisphosphonate therapy and inflammatory conditions or surgery of the jaw: a population-based analysis. J Natl Cancer Inst. (2007) 99:1016–1024.
2. Marx RE. Pamidronate (Aredia) and zoledronate (Zometa) induced avascular necrosis of the jaws: a growing epidemic. J Oral Maxillofac Surg. (2003) 61:1115–1117.[CrossRef][Web of Science][Medline]
3. Khamaisi M, Regev E, Yarom N, et al. Possible association between diabetes and bisphosphonate-related jaw osteonecrosis. J Clin Endocrinol Metab. (2007) 92:1172–1175.
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J Natl Cancer Inst 2008 100: 227.
J Natl Cancer Inst 2008 100: 155-156.
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