Tumors that have invaded the bones cause the bone to wear away, leaving small holes, called osteolytic lesions. This process of bone erosion is called resorption and leaves bones weak and fragile. Tumors can also stimulate abnormal bone formation, resulting in areas of bone build-up called osteosclerotic lesions, which can be painful. These areas of build-up are weak and unstable and can easily break or collapse. Both of these processes put patients with cancer that has spread to the bone or multiple myeloma at risk for fractures, a faster spread of bone metastases, spinal cord compression (when the bone in the spine compresses the spinal cord) and hypercalcemia (increased levels of calcium in the blood caused by bone breakdown, which can cause severe problems). A class of medications called bisphosphonates has the ability to interfere with these processes.
Bisphosphonates are a group of medications that slow the bone destroying activity that occurs with bone metastases (cancer that has spread to the bone) or Multiple Myeloma (cancer of plasma cells, which invade and destroy bone). Bisphosphonates work by slowing the wearing away (also called resorption) of bone and the abnormal build-up of unstable bone. These problems can lead to what doctors call “skeletal related events”. These events include the previously listed fractures, increased bone metastases, spinal cord compression and hypercalcemia. Bisphosphonates are used to help improve bone strength in many diseases associated with bone resorption, including cancer and osteoporosis.
Currently approved bisphosphonates include:
Osteonecrosis is exposed bone of the maxilla (upper jaw bone) or mandible (lower jaw bone). These bones are normally covered by gum tissue. In the case of osteonecrosis of the jaw (ONJ), this tissue is gone and the bone is exposed. Typical symptoms associated with ONJ are: pain, swelling or infection of the gums, loosening of the teeth, exposed bone (often at the site of a previous tooth extraction). Some patients may report numbness or tingling in the jaw or a “heavy” feeling jaw. ONJ may have no symptoms for weeks or months and may only be recognized by the presence of exposed bone.
ONJ has been associated with the use of bisphosphonates. It was first reported in 2002 and exact incidence is unknown, but it is thought to be rare. The exact cause is also not known, but certain risk factors have been found. The most important risk factors are dental issues while receiving bisphosphonates. The manufacturer of the first drugs in this class had 875 cases of ONJ reported to them; this after some 2.9 million patients had received the drugs. Of these 875 patients, 50% had a dental issue prior to diagnosis, including: tooth extractions (82% of cases), dental procedures, abscesses, and trauma. The majority of patients reported to have ONJ had either multiple myeloma or metastatic breast cancer, but this is most likely because these patients are the most common recipients and have been receiving bisphosphonate therapy for the longest (starting as early as 1991). Patients with metastatic prostate and thyroid cancers have more recently been treated with this therapy, and a few cases have been reported in patients with these cancers.
ONJ should not be confused with osteoradionecrosis of the jaw, which is caused by radiation therapy and is treated differently than ONJ.
An expert panel met in June 2004 to develop the following treatment recommendations for ONJ. Patients with suspected ONJ should have panoramic and/or intra-oral x-rays performed to rule out other dental problems (impacted teeth, cysts, bone changes). These patients should be seen and evaluated by an oral maxillofacial surgeon or dental oncologist familiar with ONJ. If infection is suspected, cultures can provide confirmation for appropriate treatment. Non-surgical approaches are preferred, as surgery on these bones does not heal well and may worsen the problem. Debridement (the surgical removal of foreign material and/or dead, damaged, or infected tissue) of the bone should only be done to reduce sharp edges that may irritate surrounding tissues. An appliance can be used to cover and protect the exposed bone.
Antibiotics, either continuously or intermittently, are thought to be beneficial. This therapy can prevent infection of surrounding tissue and the bone itself (osteomyelitis). Penicillin based antibiotics are preferred, unless the patient is allergic, in conjunction with antifungals or antivirals, if these infections are suspected. Oral rinses with chlorhexidine (Peridex®) should be used 3-4 times a day, indefinitely. Dentures can be worn, but may require some resizing or cushioning to prevent further injury.
There is some controversy regarding the stopping of bisphosphonates in patients with ONJ and there are no clear-cut recommendations. These medications clearly benefit patients at high risk of the previously discussed skeletal related events and, unfortunately, no other class of drugs has this benefit. The patient and physician must weigh the patient's risk with the benefit derived from these medications. An interesting point is that bisphosphonates have a “half life” of 10 years. The half life is the time it takes for one half of the original dose of a medication to leave the body. Some experts say, given the length of the half life, there is no sense in stopping the drug. Further research into appropriate management is ongoing.
What experts have learned is that most cases were associated with some type of dental event, and if these are avoided, ONJ may be as well. Any patient who is going to start receiving bisphosphonates should be seen by an oral maxillofacial surgeon or dental oncologist familiar with ONJ. If there are any dental concerns (requiring dental surgeries, extractions, root canals, or removal of abscessed teeth), therapy with bisphosphonates should be delayed (if possible) until they are addressed and several weeks have passed, to allow for healing. Dental exams should include cleaning, examining of denture fit, and patient education regarding oral care while on bisphosphonates.
Patients receiving bisphosphonates should have regularly scheduled oral assessments, perhaps as often as every 3-4 months. They should maintain good oral hygiene and have routine dental cleanings (with care to avoid injury to tissues). If invasive dental procedures are absolutely necessary, some have suggested that temporarily stopping bisphosphonates may result in improved healing. Given the long half-life of these medications, this is uncertain.
ONJ is a relatively newly recognized concern for patients receiving bisphosphonates. It is thought to be quite rare, but is probably underreported given the lack of understanding regarding this problem. Stay tuned, as research is ongoing into the best treatments and preventative strategies for ONJ.
Expert Panel Recommendations for the Prevention, Diagnosis, and Treatment of Osteonecrosis of the Jaws: June 2004. Available at: http://www.ada.org/prof/resources/topics/topics_osteonecrosis_whitepaper.pdf
Presentation at the 2005 Greenspan meeting, Osteonecrosis of the Jaw and Bisphosphonate Therapy, given by June Eilers, November 5, 2005 .
Marx, R. et al. Bisphosphonate-induced exposed bone (osteonecrosis/osteopetrosis) of the jaws: risk factors, recognition, prevention and treatment. (2005) Journal of Oral Maxilofacial Surgery; 63:1567-1575.
Pires, FR et al. Oral avascular bone necrosis associated with chemotherapy and biphosphonate therapy. (2005) Oral Diseases; 11:365-369