A Time for Perspective on Bisphosphonates

Article Outline

• How Do Bisphosphonates Work to Effect the Jaws?
• Do Micro-Organisms Play Any Significant Role?
• What If Any Are the Essential Co-Factors?
• Why the Jaws?
• Why Are Only Limited Areas of the Jaw Involved While the Whole Jaw Is Exposed to Bisphosphonates?
• Why Do Some ONJ Patients Experience Such Severe Pain?
• What Is the Eventual Outcome?
• Take Home Messages
• Copyright

Communication on the use of bisphosphonates has become skewed toward the risk of osteonecrosis of the jaws (ONJ). While this is an important clinical problem, it should not be allowed to deny patients the important benefits of these drugs or prevent researchers from investigating the potential benefits yet to be gained from bisphosphonates.

While I currently manage many patients with ONJ, many hundreds of patients at my institution receive oral or parenteral bisphosphonates without noted adverse effect. Bisphosphonates have done enormous good in fending off hypercalcemia in malignancy, decreasing bone pain, and decreasing the risk of often catastrophic pathologic fracture of the femoral neck or spine. In oral and maxillofacial surgery, bisphosphonates may show promise in the treatment of giant cell lesions among other pathologic conditions. Bisphosphonates may also offer potential roles in support of maxillofacial reconstructive surgery. Areas such as distraction osteogenesis, bone grafting, free tissue transfer, craniofacial development, and implantology have active and exciting research endeavors in process (or conceptualized) involving the use of bisphosphonates.

Nonetheless, we face the troubling problem of ONJ, made more difficult by the limited information available as well as its sometimes confusing dissemination. While much has been learned regarding the effects of bisphosphonates on the jaws in the past 3 years, it is time for some perspective on this issue. Unknown factors still exist that preclude truly evidence-based treatment. Surgeons are often left to experiential and empirical approaches to diagnosis and management of ONJ.

In this environment, oral and maxillofacial surgeons are asked to be the experts:

They filed in—some smiling, some angry, some resigned. Spouses and a few health care professionals filled the remaining seats in the quiet auditorium. The placid nurse coordinator, the flowers, the coffee and pastries set a perversely cheerful tone. The myeloma support group had come to hear an oral and maxillofacial surgeon. No one clapped after he was introduced.

To illustrate this problem, I ask you to think of what we do not know about ONJ.

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How Do Bisphosphonates Work to Effect the Jaws? 

The underlying mechanism of bisphosphonates’ effect on the jaws may be due to a single essential factor or it may be multifactorial. Antiangiogenesis, induced apoptosis of osteoclasts, altered enzymatic function of osteoclasts, incorporation of the bisphosphonate molecule into the hydroxyapatite matrix, resulting changes in bone microarchitecture, and interaction of bisphosphonates with periodontal structures are known findings. Is one of these the essential component affecting the jaws? This remains unknown.

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Do Micro-Organisms Play Any Significant Role? 

Micro-organisms such as actinomycosis are noted in ONJ. Are any of them important or essential to the disease process? Is oral cavity immunity a factor in pathogenesis? Does pre-existing oral infection play a role? Perhaps the most common site of ONJ is the internal oblique ridge, a site known for traumatic injury and poor blood supply, but not particularly as a nidus for pathologic microorganisms. As pointed out in the third molar studies appearing in JOMS, if periodontal pathogens were the key issue, one would expect the angle of the mandible and the maxillary tuberosity to be the most frequent sites of ONJ. They are not.

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What If Any Are the Essential Co-Factors? 

Nearly half of patients with ONJ have myeloma. In this startling, discomfiting session with a myeloma support group, I asked the approximately 40 patients present whether they were currently experiencing jaw pain. In addition to the handful of patients who had already seen oral and maxillofacial surgeons for ONJ, a majority of those present indicated they were currently experiencing jaw pain. However, osteonecrosis and bone pain are classic possible findings in myeloma, preceding the use of bisphosphonates.

Are smoking, diabetes, atherosclerosis, chemotherapy, steroid use, whole body radiation, bone marrow transplant, among others, essential co-factors?

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Why the Jaws? 

For the first few patients with this condition, I waited for the other shoe to drop. The infected hip or the necrotic tibial head (as presents in sickle cell osteonecrosis) has yet to present. While the pathologic fractures of malignancy (especially in the myeloma patient) have occurred, these patients seem to respond in large part uneventfully to treatment.

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Why Are Only Limited Areas of the Jaw Involved While the Whole Jaw Is Exposed to Bisphosphonates? 

With but a few exceptions, ONJ has been limited to one or two sites in the jaws. Unaffected sites seem to remain truly unaffected (Fig 1).

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• FIGURE 1. 

  Three years after exposed bone in the left ramus and angle region, ONJ remains confined to a single site.

• Leon A. Assael. Editorial. J Oral Maxillofac Surg 2006.

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Why Do Some ONJ Patients Experience Such Severe Pain? 

The most vexing aspect of management has not been treating the exposed bone or acute infections. The greatest problem is pain management for those patients who present with chronic pain, perhaps related to chronic tissue hypoxia.

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What Is the Eventual Outcome? 

With more than 3 years experience with bisphosphonate-related ONJ, it remains uncertain whether any of these patients have had their last episode of pain, swelling, or bone expsosure. While the residual systemic effect of bisphosphonates has been studied, the lasting effect on the jaws, after therapy is discontinued, remains uncertain.

Clearly, bisphosphonate dose matters, as well as specific chemistry of agents and route of administration. It is likely that all bisphosphonates will be noted to have important clinical effects on the jaws and that the effects will vary based upon the pharmacologic details of their utilization.

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Take Home Messages 

In presenting to the myeloma support group, I left them with some take home messages I leave with you now:

Take Home Message #1

Take Home Message #2

Take Home Message #3

Take Home Message #4

Take Home Message #5

Take Home Message #6

Take Home Message #7

What can you (the patient) do?

Take Home Message #8

What can your doctor do?

The lectern was sloppy with sweat. My talk seemed too complicated, too pessimistic, too uncertain. I was sure they had not grasped it. But I had made my points and awaited their questions. There were none.

Finally a frail hand went up. “What should I say to my doctor?” he asked. “Communicate,” I replied. There was applause.