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Editorial |
Section of Endocrinology, Diabetes, and Metabolism The University of Chicago Pritzker School of Medicine Chicago, Illinois 60637
Address all correspondence and requests for reprints to: Dr. Murray J. Favus, University of Chicago, 5841 South Maryland Avenue, MC 1027, Chicago, Illinois 60637. E-mail: mfavus{at}medicine.bsd.uchicago.edu.
The widespread use of bisphosphonates has dramatically reduced the frequency of pathological fractures and bone pain in a variety of malignant and nonmalignant diseases including skeletal metastases from solid tumors, multiple myeloma, and other marrow malignancies and in benign conditions such as Paget’s disease of bone. In addition, bisphosphonates are now first-line treatments in osteoporosis because of their efficacy in reducing fractures and fracture risk and the low incidence of serious adverse events. The perception of safety from serious adverse events has changed with the recent association of osteonecrosis of the jaw (ONJ) and bisphosphonate therapy (1, 2). ONJ is a condition of subacute onset in which localized bone necrosis of the mandibular or maxillary alveolar ridge appears, usually after an oral surgical procedure such as tooth extraction, root canal, or placement of implants (3, 4). The hallmark of ONJ is failure of the surgical site to heal accompanied by localized jaw pain and the appearance of exposed necrotic bone. Infection is involved in almost all the well-documented cases (5). ONJ may persist without healing for months and may reach a steady-state without progression or resolution.
Although physicians have been particularly concerned about the potential appearance of ONJ during oral bisphosphonate therapy for osteoporosis, it is now very clear that the vast majority of ONJ cases reported are in patients with myeloma or solid malignant tumors treated with large doses of iv bisphosphonates, particularly zoledronic acid and pamidronate (2). Only 4–5% of ONJ cases have occurred in patients taking oral bisphosphonates for osteoporosis. With the low frequency of ONJ in osteoporosis, progress in understanding the pathogenesis of ONJ, identification of potential risk factors, and development of management and prevention strategies must come from what we learn from the larger numbers of affected cancer patients.
For now, we may assume that the higher frequency of ONJ in cancer patients is due to the use of higher doses of long-acting bisphosphonates via iv delivery (incidence is about one per 100 in cancer patients vs. one per 100,000 cases in osteoporosis) (2). However, there may be significant differences in the pathogenesis of ONJ between cancer patients and those with osteoporosis. For example, in patients with head and neck cancer, a portion of the mandible may have been within the field of radiation, which is known to cause osteonecrosis in the absence of bisphosphonates; and the chemotherapy protocol may have included glucocorticoids (6). Both chemotherapy and glucocorticoids may cause osteonecrosis by damaging vascular endothelial cells and the bone microcirculation with the resultant thrombosis of nutrient end arteries.
In this issue of the journal, Khamaisi et al. (7) describe a higher incidence of diabetes mellitus in a group of patients with malignancy and ONJ compared with a retrospective group of cancer patients without ONJ. The authors suggest that diabetes may be a potential risk factor in the development of ONJ during iv bisphosphonate therapy in patients with malignancy. This novel observation suggests that diabetes increases the risk of bisphosphonate-induced ONJ, perhaps through an effect of poor glucose control on bone or the microvasculature. The authors provide minimal information about the patients with diabetes. We do not know the duration of the diabetes, presence of complications, or treatments used. It appears that for many of the patients, the diabetes is rather recent and of a mild nature. Indeed, only 14 of 31 cases were known to have type 2 diabetes before bisphosphonate therapy, and 12 patients may have had steroid-induced diabetes, given presumably as a component of chemotherapy protocols.
Microvascular disease is a common complication of diabetes and may have impaired bone nutrition through loss of full function of the nutrient vessels in bone. However, the authors make no mention of evidence for microangiopathy in their patients such as the presence of nephropathy, retinopathy, or peripheral vascular insufficiency. Although infections of the gingivae and mandibular bone are more common in diabetes, the authors did not specifically mention the frequency of such infections or indicate the dental health status of those who developed ONJ. Therefore, even if vascular complications were present in the study population, it is not clear whether microvascular angiopathy of diabetes involves mandibular or maxillary bone. Studies of the mandible in diabetes have not yielded clear evidence of pathology of the microvasculature even in the setting of gingival disease and alveolar ridge bone loss.
Diabetes may have increased the risk of ONJ through other mechanisms, such as sensitizing or predisposing alveolar bone to necrosis by bisphosphonates by altering the microcirculation. However, experimental models of diabetes show alveolar bone destruction in poorly controlled diabetes may occur in the absence of microangiopathy (8) and osteoclastic bone resorption of necrosed bone is impaired in experimental diabetes and bone infection (9). Therefore, bone necrosis along the mandibular and maxillary alveolar ridges may occur in diabetes independent of microvascular disease.
The mechanisms through which bisphosphonates cause ONJ are not known. Bisphosphonates directly suppress osteoclastic bone resorption and enhance bone matrix mineralization (10). However, the mechanisms whereby bisphosphonates may cause ONJ may involve the microvasculature of bone. A number of bisphosphonates, including the widely used zoledronic acid, inhibit endothelial cell proliferation both in cell culture, in vivo in experimental animal models, and in vitro in human blood vessels (11, 12, 13) in part through suppression of vascular endothelial growth factor expression and inhibition of proliferation and migration of endothelial cells. As a result, vascular networks do not arise from existing capillaries. Therefore, the lack of repair of the microvasculature during wound healing could compromise nutrient flow to mandibular alveolar bone and thereby predispose to osteonecrosis.
A strategy to minimize the risk of developing ONJ during bisphosphonate therapy is sorely needed and could be used in both cancer patients receiving high-dose iv bisphosphonates and in osteoporosis patients treated with oral bisphosphonates. Advances in our understanding of ONJ will likely come from studies of cancer patients, because there are larger numbers of affected cancer patients who develop ONJ. Studies of pathophysiology and testing preventative measures should be encouraged in the bisphosphonate-treated cancer population. Successful interventions could then be applied to the large population of osteoporosis patients who have benefited greatly from oral bisphosphonates and who have a remote risk for developing ONJ.
Discontinuing bisphosphonate therapy before an oral surgical procedure has been suggested as a way to decrease the risk of ONJ. However, this requires knowledge of the in vivo half-life of bisphosphonate action on angiogenesis if indeed inhibition of angiogenesis is involved in the process. If bisphosphonates cause ONJ through a direct action on bone cells and/or the bone matrix, then patients on long-term oral or iv bisphosphonates would require a period of 1–2 yr or more free of bisphosphonates before the actions of the drugs disappear.
Whether bisphosphonates in the presence or absence of diabetes predispose to ONJ through a vascular mechanism remains speculative, but potential shared actions of diabetes and bisphosphonates on the microcirculation suggest a plausible pathophysiology for the development of ONJ that could be tested experimentally. The ultimate tests will require measurements of microvascular competency in human mandibular bone in vivo during bisphosphonate therapy. In the meantime, the very rare appearance of ONJ in osteoporosis patients taking oral bisphosphonates suggests that maintenance of optimal dental hygiene to minimize oral surgical interventions would be prudent until new strategies emerge from advances in clinical research.
Footnotes
Abbreviation: ONJ, Osteonecrosis of the jaw.
Received January 13, 2007.
Accepted January 15, 2007.
References
This article has been cited by other articles:
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  A. A. KHAN, G. K.B. SANDOR, E. DORE, A. D. MORRISON, M. ALSAHLI, F. AMIN, E. PETERS, D. A. HANLEY, S. R. CHAUDRY, B. LENTLE, et al. Bisphosphonate Associated Osteonecrosis of the Jaw J Rheumatol, March 1, 2009; 36(3): 478 - 490. [Abstract] [Full Text] [PDF]
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 A. Khan Bisphosphonate-associated osteonecrosis of the jaw Can Fam Physician, July 1, 2008; 54(7): 1019 - 1021. [Full Text] [PDF]
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