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Bisphosphonate-associated ONJ: at the interface of dentistry and medicine
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Bisphosphonate-associated osteonecrosis of the jaw presents in patients as exposed, non-healing bone in the oral cavity. It has generated a huge amount of attention despite its considerably rare occurrence. The first report of its occurrence was in 2003 and 2004 via a series of case reports with more comprehensive reviews that have followed.
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The American Society for Bone and Mineral Research established a task force on Bisphosphonate-Associated Osteonecrosis of the Jaw (ONJ) last year and recently released a summary report of their findings. Several key issues were addressed. First, a case definition was given where a confirmed case of ONJ was described as “an area of exposed bone in the maxillofacial region that did not heal within eight weeks after identification by a health care provider, in a patient who was receiving or had been exposed to a bisphosphonate and had not had radiation therapy to the craniofacial region.”
Next, the committee assessed what is known and unknown about ONJ. Although ONJ has been identified in a population of bisphosphonate users, it has not yet been definitively linked to bisphosphonate use. The evidence in the literature regarding ONJ is scant and mostly associated with case reports. As such, there is a clear need for widespread reporting of cases according to the definition described above.
The incidence of ONJ is clearly different in the population of patients who are administered IV bisphosphonates for the treatment of malignancy vs. patients treated for Paget’s disease or osteoporosis. In IV bisphosphonate patients, the incidence is suggested to be anywhere from 1% to 10% of the population and may be linked to duration and dose. The incidence in osteoporosis patients is much lower with estimates of 1 in 100,000 patient-treatment years. This represents a very low risk for this population; however, the reporting is not yet consistent due to the previous lack of a case definition.
It is still too early to know how widespread the condition is and the predisposing factors. Proposed risk factors for ONJ include the use of IV bisphosphonates; cancer and anti-cancer therapy; dental procedures that expose bone such as extractions, surgery and intraoral trauma; duration of exposure to bisphosphonate treatment; glucocorticoid use, co-morbid conditions such as malignancy; alcohol and/or tobacco abuse; and pre-existing dental or periodontal disease.
Diagnostic and imaging techniques with which to better characterize and diagnose ONJ are under intensive investigation. For an established case, there is little need for imaging technologies because the clinical presentation dictates the diagnosis. A real benefit would come from imaging technologies that could identify patients at risk and/or patients in the early stages before non-healing exposed bone is present. Traditional radiography is inconsistent in the presentation of ONJ with some areas presenting as radiopaque and others as radiolucent. Still, the use of conventional radiographs is considered the first line of action in a suspected patient. Magnetic resonance imaging may prove to be beneficial in the diagnosis of ONJ patients but insufficient data exist to support any of the imaging modalities.
Patient treatment
Clinical management of ONJ patients can be particularly challenging, and some patients are relegated to living with exposed bone. A key component to treating these patients is to maintain adequate communication between the patient, dentist and physician. Prior to initiation of bisphosphonate therapy, patients should be informed of the benefits and risks of bisphosphonates. It is strongly recommended that for patients with cancer who will be initiating bisphosphonate treatment that they have a dental examination and establish a baseline of oral health prior to IV bisphosphonate administration. As the risk for ONJ in the osteoporosis population appears very low, the guidelines for these patients are to inform them of the risk for ONJ and to encourage them to maintain adequate oral health. The duration of exposure for oral bisphosphonates may also be associated with increased likelihood of ONJ, so patients who have been on a bisphosphonate for periods of more than three years may be more likely to experience compromised healing in the oral cavity. However, there is still minimal evidence to support significant alterations in standard dental procedures in patients on oral bisphosphonates. In patients who have been on long-term bisphosphonate therapy, conservative approaches to their dental care may be prudent with non-surgical therapies preferred. However, with informed consent there is no contraindication to procedures such as extractions, dental implants, periodontal or endodontic surgery.
Patients with cancer
In contrast, in the IV bisphosphonate cancer patients, if possible, all oral surgical procedures should be performed before the initiation of the bisphosphonates. Once the IV bisphosphonate therapy has been initiated, elective oral surgical procedures should be avoided and non-surgical approaches should be favored. The use of IV bisphosphonates for the treatment of osteoporosis is fairly recent, so evidence for their impact on ONJ is lacking. At least one source suggests that serum CTX markers be used to determine the patient’s risk for ONJ, and many dentists are requesting such serum markers be analyzed on their patients as part of their treatment planning for possible surgery cases. Although an apparently rational suggestion, there does not appear to be scientific evidence to support this at this time.
Many health care providers are considering taking their patients off a bisphosphonate for a window of time during which dental work is performed. Again, little evidence exists to support this. Such a drug holiday may not significantly impact the course of the patient’s osteoporosis due to the accumulation of bisphosphonates in the skeleton, but this is a decision that should be made on a case-by -case basis and in consultation with the patient and appropriate health care providers.
In the event of a confirmed case of ONJ, a qualified dental specialist should be managing the oral health care. The case should be reported to the appropriate agencies (pharmaceutical manufacturer and the FDA). An infection-free environment should be encouraged with the use of oral anti-microbial rinse (0.12% chlorhexidine digluconate) antibiotics and meticulous oral hygiene.
Pain, which is variable, should be managed appropriately. Surgical treatment should be limited to conservative approaches to remove bony sequestrate and sharp edges. Some patients may require jaw segmentation and assisted feeding. Recent published case reports support the use of PTH and platelet poor plasma in the treatment of ONJ. The rationale would be to increase remodeling in the case of PTH in hopes of turning over the necrotic bone, and to provide growth factors topically to assist the healing in the case of the platelet poor plasma.
There is clearly a need for more research in this area. Studies are necessary to verify a causative role of bisphosphonates and elucidate their pathophysiologic mechanisms. If it is solely associated with their antiresorptive actions, then other agents with antiresorptive actions should surface with similar pathology. However, the sequestration of bisphosphonates in the bone matrix may place these agents in a unique position to impact wound healing in a local and persistent manner. Distinctive aspects of the oral cavity such as the microflora, vascularity and cortical/trabecular bone ratio may function in the predisposition to ONJ. These are all questions that need to be addressed before we can effectively prevent and treat this uncommon condition. Conditions like this highlight the need for effective interactions between the medical, dental, pharmaceutical, and skeletal biology communities.
For more information:
- Laurie K. McCauley, DDO, PhD, William K. and Mary Anne Najjar Professor and Chair in the Department of Periodontics and Oral Medicine at the University of Michigan School of Dentistry
- Ruggiero SL, Mehrotra B, Rosenberg TJ, Engroff SL. Osteonecrosis of the jaws associated with the use of bisphosphonates: a review of 63 cases. J Oral Maxillofac Surg. 2004;62:527-534.
- Marx RE. Pamidronate (Aredia) and Zolendronate (Zometa) induced avascular necrosis of the jaws: a growing epidemic. J Oral Maxillofac Surg. 2003;61:1115-1118.
- Woo S-B, Hellsstein JW, Kalmar JR. Systematic review: bisphosphonates and osteonecrosis of the jaws. Ann Intern Med. 2006;144:753-761.
- Khosla S, Burr D, Cauley J, et al. Bisphosphonate-associated osteonecrosis of the jaw: Report of a task force of the American Society for Bone and Mineral Research. J Bone and Miner. Res. In press: online. 2007.
- Marx RE. Oral & intravenous bisphosphonate-induced osteonecrosis of the jaws: history, etiology, prevention, and treatment. Quintesscene Books, 2007.
- Adornato MC, Morcos I, Rozanski J. The treatment of bisphosphonate-associated osteonecrosis of the jaws with bone resection and autologous platelet-derived growth factors. J Ameri. Dent Assoc, 138:971-977.
- Harper RP, Fung E. Resolution of bisphosphonate-associated osteonecrosis of the mandible: possible application for intermittent low-dose parathyroid hormone [rhPTH(1-34)]. J Oral Maxillofac Surg. 2007;65:573-580.