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Osteonecrosis of the jaw and bisphosphonate use: How big a risk?
Patients with cancer who receive high intravenous doses are at highest risk.
Until recently, osteonecrosis of the jaw had appeared in medical literature as no more than a curiosity, with little information on its cause or prevalence. With the initiation of widespread use of bisphosphonates, however, the prevalence and subsequent reports of this complication rose dramatically.
There is now a growing body of research on the connections between these very effective drugs and this particularly devastating complication. For this in-depth look at the condition and its link to osteonecrosis of the jaw, Endocrine Today interviewed several leading researchers in the field.
Osteonecrosis of the jaw (ONJ) can be painful and can lead to further infection of the jaw bone and other areas. A recent task force convened by the American Society of Bone and Mineral Research (ASBMR) produced the following case definition for ONJ: the presence of exposed bone in the maxillofacial region that does not heal within eight weeks after identification by a health care provider. The diagnosis, thus, is fairly straightforward, involving clinical presentation and the observation of exposed bone.
ONJ had been described in the past, but John R. Kalmar, DMD, PhD, a professor of oral pathology at Ohio State University in Columbus, said that “it had been so infrequent as to be a sort of curiosity of medical history.” It was only after bisphosphonates were put into widespread use that the case reports of ONJ began to flood in.
Since the association was first observed and reported several years ago, a number of attempts have been made to characterize the incidence of the complication. In order to do so, two groups of bisphosphonate users must be delineated: those taking the drugs as a treatment for various forms of cancer and the much larger population of people taking bisphosphonates as a treatment for osteoporosis or Paget’s disease.
 Elizabeth Shane |
Bisphosphonates have proven effective as part of the treatment for malignancy, reducing the risk for skeletal complications and cancer-induced bone pain. The incidence of ONJ in this group, although uncertain, is relatively high, however, compared to patients with osteoporosis. Various estimates place it somewhere between less than 1% to 10% of patients.
Importantly, patients given bisphosphonates for malignancy receive significantly higher doses – infused intravenously – compared with patients treated for osteoporosis. The two FDA-approved drugs for this indication are pamidronate (Aredia, Novartis), 90 mg infused over at least two hours every three to four weeks; and zoledronic acid (Zometa, Novartis), 4 mg infused over at least 15 minutes every three to four weeks.
Among patients treated for osteoporosis, the numbers are very different, although many researchers stress that the incidence rate is not clear. As of the publication of the ASBMR’s report on ONJ, only 64 cases of bisphosphonate-associated ONJ had been reported in patients taking the medications orally; of those, 57 patients had osteoporosis and seven had Paget’s disease.
Based upon several case series and international studies conducted in Australia, Germany and Greece, various estimates of the incidence have been made. Elizabeth Shane, MD, professor of medicine in the division of endocrinology at Columbia University Medical Center in New York, said the data suggest the prevalence “is on the order of 1 in 100,000 to 1 in 250,000” patient-treatment-years. She noted that one survey from Australia found the prevalence to be approximately 10 times higher than that, but that there are questions about the methods used in that study that suggest the incidence is most likely overestimated.
Management of ONJ
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Photo courtesy of the Mayo Clinic |
Once a patient does present with ONJ, what methods of treatment are preferred? Again, it clearly depends on the patient’s health and history. For patients with cancer, most clinicians agree that stopping the drug is simply not a good option.
“If a patient has ONJ and they also have, say, multiple myeloma, they should definitely not stop the drug,” Kalmar said.
“The bony exposure(s) should be treated as conservatively as possible: Use oral antimicrobial rinses, smooth or file off the rough edges of exposed bone, and basically just let it be. This isn’t great for quality of life, but with cancer patients you’re still going to choose increased survival and take the medication.”
He noted that if the exposed area becomes secondarily infected, systemic antibiotics might be required as well.
For patients with osteoporosis who develop ONJ, however, there is still debate about the appropriate action. It is not yet known if stopping the drugs may help heal the ONJ, but the long half-lives of bisphosphonates shed some doubt on that hypothesis.
Sundeep Khosla, MD, professor of medicine and an endocrinologist at the Mayo Clinic in Rochester, Minn., said that his personal approach would be to stop the bisphosphonate if possible. “We know there is an association, and unless there is a compelling reason where you absolutely cannot stop the drug – and generally with a patient with osteoporosis that is not the case – I think there is a potential rationale for stopping the drug and seeing if that resolves the situation,” he said.
Furthermore, Khosla noted, while the antiremodeling effects of bisphosphonates do last long after a patient ceases taking the drug, other effects, such as those on angiogenesis, may wane sooner and may play a role in ONJ development. Khosla co-chaired the ASBMR task force on bisphosphonate-associated ONJ along with Shane.
Moving forward
With the knowledge base on ONJ still clearly in its infancy, determining directions for research is crucial. The two most important areas of research currently are examining the condition’s pathogenesis and achieving a firmer grasp on ONJ’s true incidence.
Very little is currently understood about the pathogenesis and why bisphosphonates may be a contributing factor to development of ONJ.
“There has been virtually no research, all the literature is case reports, so I don’t think one can really speak to mechanisms at this point,” said Laurie K. McCauley, DDS, PhD, professor and chair of the department of periodontics and oral medicine at the University of Michigan School of Dentistry in Ann Arbor; she also participated in the ASBMR task force on ONJ.
McCauley said that one hypothesis is that because bisphosphonates are sequestered in the bone, during wound healing they can be released and compromise that healing. “There are also some reports in the literature about bisphosphonates being antiangiogenic, and that could possibly be a contribution,” she said.
According to Shane, more research, particularly in animal models, is needed in order to fully understand the pathogenesis of ONJ. “That’s probably where we are going to get the most information right now,” she said.
“We need more research in order to fully understand the pathogenesis, especially animal models. I think that’s probably where we are going to get the most information right now,” Shane said.
The extremely low prevalence of ONJ among patients with osteoporosis will hinder research into mechanisms as well as incidence. “I think it is going to be very difficult to do clinical trials with osteoporosis patients because the incidence of ONJ is apparently very low,” McCauley said.
“Clearly, there is a need for reliable epidemiologic studies in both cancer patients and in osteoporosis patients to determine what the exact incidence is.” She noted that some such studies are ongoing.
Predicting risk of ONJ
Another area of research is that of predicting risk for ONJ. Of course, understanding the mechanisms underlying the condition would help with risk prediction. Barring that, however, there are some who think that currently available methods could be used to predict who is at risk or who might soon develop ONJ. One such method may be the monitoring of various serum bone turnover markers such as serum CTX.
“It is important to see what other risk factors beyond malignancy might predispose a patient to bisphosphonate-associated ONJ,” Khosla said. “There is a lot of discussion about whether monitoring bone turnover markers is useful, and right now there is no evidence one way or the other. It’s another issue that needs to be examined.”
Shane said that these markers generally are not very useful in individual patients. “To say that you could, with certainty, pinpoint someone with low bone turnover based on currently available bone turnover markers is probably not true. It may well be that when appropriate studies are done that this will turn out to be true, but right now there are insufficient data to support that,” she said.
Appropriate action
For clinicians who treat patients with osteoporosis, what action should be taken now? With ONJ receiving significant press about its association to bisphosphonates, some doctors worry that their patients are simply stopping the drugs without consult. “You have to weigh this risk against the risks associated with osteoporosis,” Kalmar said.
“Osteoporosis is associated with increased morbidity and mortality – people die of hip fractures. The problem is that people get so frightened by things in the lay press that they make decisions on their own. And right now, we believe the risk for oral bisphosphonates is extremely low,” he said.
Research should look into any potential benefits of giving so-called drug holidays, especially in the time period surrounding surgical dental procedures, he said. “If we do that, do we then reestablish the normal metabolic processes in the bone and maybe reduce the risk of ONJ?”
Khosla agreed that the public attention is an issue. “This is something I discuss with my patients, but it really hasn’t substantially changed my approach to treating patients that need these drugs.”
Risk-benefit analysis
With the risk of ONJ for oral bisphosphonate users apparently falling somewhere in the 1 in 100,000 patient-treatment-years range, the risk-benefit analysis is an easy one, Shane said. “The risk of having a fracture in the next five years [for elderly individuals with osteoporosis] could be, say, 20% to 25%. This is swayed enormously toward the benefit side of taking these drugs.
“I think the vast majority of older people with low bone density, previous history of fracture or other risk factors for fracture are much safer to be on a bisphosphonate than not. We need these drugs right now. We don’t have any other simple ways to reduce the risk of fracture.”
ONJ is clearly a serious complication, but the current knowledge base surrounding this condition and its association with drugs proven to be very effective in the treatment of several different diseases appears to be too tenuous to drastically change prescribing practices.
As ongoing research sheds further light on the mechanisms underlying ONJ, recommendations may become more specific. As this process continues, Kalmar said, physicians may be able to reduce its incidence “back to the level of a medical curiosity.” – by Dave Levitan
Do patients with osteoporosis need a thorough dental exam before starting bisphosphonate therapy?
For more information:
- Khosla S, Burr D, Cauley J, et al. Bisphosphonate-associated osteonecrosis of the jaw: report of a task force of the American Society of Bone and Mineral Research. J Bone Miner Res. Published online July 30,2007;10.1359/jbmr.0707ONJ.
- Mavrokokki A, Cheng A, Stein B, et al. The nature and incidence of bisphosphonate associated osteonecrosis of the jaws in Australia. J Oral Maxillofac Surg. 2007;65:415-423.
- Ruggiero SL, Mehrotra B, Rosenberg TJ, et al. Osteonecrosis of the jaws associated with the use of bisphosphonates: a review of 63 cases. J Oral Maxillofac Surg. 2004;62:527-534.
- Shane E, Goldring S, Christakos S, et al. Osteonecrosis of the jaw: more research needed. J Bone Miner Res. 2006;21:1503-1505.
- Woo SB, Hellstein JW, Kalmar JR. Systematic review: bisphosphonates and osteonecrosis of the jaws. Ann Intern Med. 2006;144:753-761.