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Select Excerpts from the Interview
Track 2
DR LOVE: Can you talk about the history of bisphosphonate-related
osteonecrosis of the jaw (ONJ)?
DR MARX: We began to notice, in late 1999 and early 2000, a number of
people who had exposed mandibular and maxillary bone and then developed
secondary infections. We also noticed a peculiarity in that if we performed
surgical debridement, after which we would expect healing and the bone to be
covered, it didn’t happen. In fact, it made the situation worse.
We accumulated a critical number of patients and then assessed retrospectively what those individuals had in common, which was that they were receiving pamidronate or zoledronic acid. It dawned on us that the problem was related to the use of bisphosphonates.
Initially, they were all patients with either metastatic breast cancer or multiple myeloma. We published a medical alert in the Journal of Oral and Maxillofacial Surgery in September 2003 (Marx 2003). About five to six months later, my colleague from New York, Dr Salvatore Ruggiero, published 63 additional cases (Ruggiero 2004). That seemed to spur Novartis to convene a panel of experts. We had several meetings and generated a position paper (Ruggiero 2006).
Track 3
DR LOVE: What do we know about the pathophysiology of ONJ?
DR MARX: The pathophysiology
is directly related to
dose and time of exposure
to the bisphosphonate. The
intravenous bisphosphonates,
zoledronic acid and pamidronate,
are absorbed directly
into the mineral matrix of
the bone, and they inhibit
the enzyme farnesyl synthase,
which is required by the
osteoclasts for basic survival.
It all has to do with osteoclast
downregulation and
apoptosis (5.1).
What is unique about the mandible and maxilla is the presence of teeth or the wearing of dentures. Studies have shown that the bone in tooth-bearing areas of the jaw remodels 10 times faster than any other adult bone.
Therefore, vulnerability of the bone around the teeth is 10 times greater. Then you add the ubiquity of dental disease, like decay and periodontal disease, and you add increased inflammation and turnover.
If you use zoledronic acid or pamidronate, which affect the osteoclasts that are involved with bone turnover, the bone cannot turn over. Osteocytes live for 150 to 180 days. They die of a terminal lifespan, and they’re not renewed or replaced. When the osteoclast resorbs bone, we know it releases insulin-like growth factors 1 and 2 and bone morphogenetic protein. This, in turn, stimulates and causes a differentiation of stem cells into osteoblasts and reforms the bone.
DR LOVE: What happens to the mucosa that covers the jawbone?
DR MARX: The overlying mucosa or gum tissue has blood supply that is
dependent on the underlying bone. So when the bone dies off, the overlying
mucosa essentially undergoes a necrosis too, and the bone becomes exposed.
The most common place for ONJ to occur is the lower jaw in the molar area.
That has to do with bite-force characteristics. When you bite down on food
or during the swallowing process, you put pressure on your teeth. The greatest
pressure is on the lower jaw in the molar area.
This is what makes the jaw vulnerable to anything that affects the osteoclasts, including intravenous and oral bisphosphonates. The bone has to adjust to this bite pressure, so it resorbs and renews itself on a more rapid basis to accommodate the forces of the chewing and swallowing cycles.
Approximately 30 percent of the cases occur spontaneously in people who do not have an underlying dental pathogenesis. On the other side of that coin are the people who have inflammation from dental decay, abscessed teeth or periodontal disease, which increase the rate of bone turnover. Therefore, you have a higher percentage of people developing bone exposures who have those underlying dental problems.
Track 4
DR LOVE: What are the typical clinical presentations?
DR MARX: The most common presentation is exposed bone. Most definitions
include the presence of exposed bone in the oral cavity that fails to heal over
eight weeks and is not associated with local radiation therapy (5.2, 5.3). The
onset is asymptomatic in about one third of the patients. Because the exposed
bone is necrotic, it’s deenervated and not necessarily painful. Two thirds
experience pain because of secondary infection.
Fortunately, we’ve been able to control the pain in 90 percent of individuals with relatively simple antibiotics. The bacteria associated with this are almost always anaerobes, which are sensitive to penicillin. The best therapy is penicillin VK 500 mg four times a day, which can be taken in the long term without toxicity. For patients not allergic to penicillin, it is the drug of choice.
The pain, if you’re taking penicillin regularly, is subdued within a week. It’s a quick response.
Very few patients don’t respond. If they don’t respond to penicillin by itself, our backup is to combine it with metronidazole. For short periods, we double the antibiotic therapy. For the patient with a penicillin allergy, out of empirical trial and error, we have found levofloxacin to be the best alternative to penicillin.
Track 6
DR LOVE: What’s the typical clinical course of ONJ?
DR MARX: It usually takes about eight to 12 doses of zoledronic acid to reach
the risk range. With pamidronate it’s a little bit slower — about 10 to 14 doses
are required before people develop exposed bone.
As it is pertinent to the oral surgeon, an invasive dental procedure that has a risk of not healing and of developing exposed bone can parlay itself into losing, literally, half of the jaw. When people develop exposed bone, they tend to be confused about it.
We educate patients by telling them that it’s likely to be permanent and that discontinuing the drug will not necessarily resolve it. The good news is that the exposed bone, by itself, is not painful, and we can control their pain with simple antibiotics and an antiseptic mouthwash called Peridex® (chlorhexidine gluconate).
Most people respond to that. They live with exposed bone, and they function normally. The risk for fracture is low, simply because the jaw has an overbuilding of strength. Unless part of it is surgically removed, it is not at much of a risk for fracture.
DR LOVE: How large are these lesions?
DR MARX: Some involve either the whole jaw or half the jaw. Some of them
are large — seven, eight or 10 centimeters.
DR LOVE: Over a period of a few years, how often would a patient require
antibiotics?
DR MARX: Some patients require ongoing antibiotic therapy. That’s one of
the values of penicillin therapy, which can be used continuously with few
secondary problems. Some patients can be treated intermittently. We have
them take the antibiotic when they have exacerbations of pain. It squelches the
pain, and then they go on for a pain-free period and only restart the antibiotic
should the pain return.
Tracks 7-9
DR LOVE: For patients who receive more than eight or 12 courses of a
bisphosphonate, what’s the incidence of ONJ?
DR MARX: The incidence is unknown. We have studies that report as little
as 0.8 percent to as much as a 12 percent incidence. I believe the reality is
probably somewhere in between, about a six to eight percent incidence, which
is not based on any hard data.
The good news here is that it’s controllable. Ninety percent of our patients — and we’ve recorded 143 patients so far — are living with exposed bone, eating relatively normally, pain free and functioning as they did prior to the bone exposure.
DR LOVE: I’ve heard oncologists say, “I’m not going to use a bisphosphonate
if the patient has just one or two bone metastases” because of their concern
about ONJ. Does that make sense to you?
DR MARX: I don’t believe it makes sense. The message for the medical oncologists
is — and I say this to the patients: “The bisphosphonates have been
beneficial for you. Prior to the bisphosphonates, patients with your diagnosis
suffered fractures, bone resorption, hypercalcemia, and a number of other
complications that often led to severe disability and even death. These drugs
have been good for patients like you.
With some education of medical oncologists and dentists, we can prevent most of this. If patients do develop it, we may not be able to cure it, but we can manage it. You can lead a normal life and still reap the benefits from this drug.”
DR LOVE: Are there any preventive measures?
DR MARX: The message I want to impart to the oncologists is, when you
identify patients with metastatic disease who require a bisphosphonate, refer
them right away to a dentist who is familiar with ONJ. They should probably
start with an oral and maxillofacial surgeon who can direct the care and a
dentist who is familiar with this entity.
The medical oncologist should, if possible, defer the bisphosphonate for about two months (5.4), which is physiologically feasible according to cancer kinetics. The dentist needs to begin one fundamental task: Take care of the mouth to avoid future dental extractions or dental implants. They need to get the mouth in optimum health.
I tell the dentist or oral surgeon, “Give everybody a thorough examination. Take out any teeth that are abscessed, not restorable or have failing root canals. Do all of the invasive work while the bone is capable of healing through a remodeling process. Then begin preventive dentistry. Crowns, bridges, dentures and fillings are feasible anytime during bisphosphonate exposure because they are not invasive.”
DR LOVE: What about performing this type of work while patients are
on chemotherapy?
DR MARX: That is not too much of a problem, but chemotherapy does affect
healing. The mouth is gifted with a blood supply and an immune response
that generally handle that well.
DR LOVE: Are these recommendations your individual thoughts, or do they
represent the oral surgery community in general?
DR MARX: They represent the oral surgery community in general. My parent
organization, the American Association of Oral and Maxillofacial Surgeons,
has published a position paper that includes most of this (AAOMS 2006; [5.4]).
Eight other specialties of dentistry have their own position papers that mimic
what I’ve said.
Tracks 10-11
DR LOVE: What is the impact on the risk of ONJ of changing the dosing
interval of the intravenous bisphosphonates to six months?
DR MARX: That is unstudied. What we have is an extrapolation from the oral
bisphosphonates. We don’t see individuals develop problems with alendronate
until they’re on it for three years. This is proof that the bisphosphonates
cause the problem, not chemotherapy, because we have 35 cases due to oral
bisphosphonates alone — 32 with alendronate, three with risedronate and
none with ibandronate.
We found that you don’t have a risk for osteonecrosis of the jaw until you’ve been on an oral bisphosphonate for three years, and most cases occur with five years or more of therapy. So it’s related to dose accumulation.
The big difference between intravenous and oral bisphosphonates is that if you undergo a six-month drug holiday from alendronate, the bone heals or lends itself to a minor, office-based surgical debridement, indicating that the osteoclasts are able to repopulate. Stopping an intravenous bisphosphonate (zoledronic acid or pamidronate) — and this is another message to the medical oncologists — does not benefit oral exposed bone to any great degree. So if the benefits are still there for the cancer patient, don’t hesitate to continue the medication.
DR LOVE: If a patient with metastatic bone disease develops ONJ, you’re
saying to continue the bisphosphonate?
DR MARX: If the medical oncologist feels that it’s still benefiting the patient
from a cancer perspective, yes, continue on. We can manage the oral exposed
bone. You can’t manage the runaway cancer. So if it’s still benefiting the
cancer, go ahead and continue the medication. There’s no absolute reason to
stop it.
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