Medication Related Osteonecrosis of the Jaw
Cancer and Bone Invasion
Tumors that have affected and grown into the bones (called invasion) can cause the bone to wear away, leaving small holes called osteolytic lesions. When the bone wears away, it is called resorption and it leaves bones weak and fragile. Tumors can also cause 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 osteolytic and osteosclerotic lesions put patients with multiple myeloma or a cancer that has spread to the bone at risk for many issues. These include: Fractures, a faster spread of bone metastases (spreading of cancer to the bone), spinal cord compression (when the bone in the spine compresses the spinal cord), and hypercalcemia (high levels of calcium in the blood caused by bone breakdown).
A few medications are able to prevent or slow these complications, including denosumab and a class of medications called bisphosphonates. Both bisphosphonates and denosumab are associated with the adverse effect of osteonecrosis of the jaw (ONJ).
Medications Associated with ONJ
Bisphosphonates are a group of medications that slow the breakdown of bone that happens with bone metastases or multiple myeloma (cancer of plasma cells, which invade and destroy bone). Bisphosphonates slow down how quickly the bone wears away (called resorption) and decreases the abnormal build-up of unstable bone. These problems can lead to "skeletal related events.” These events include those listed above: 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:
- Alendronate (Fosamax®).
- Etidronate (Didronel®).
- Ibandronate (Boniva®) – currently used only for osteoporosis.
- Pamidronate (Aredia®) (given intravenously).
- Risedronate (Actonel®).
- Tiludronate (Skelid®).
- Zoledronic acid (Zometa®) (given intravenously).
Another medication used to slow or prevent bone breakdown and bone complications is denosumab (Xgeva®). Denosumab is a type of monoclonal antibody, which is a medicine designed to target a specific protein or cell – in this case, the target is a protein called RANKL, which is necessary for bone breakdown and is overproduced in bone metastases. By targeting RANKL, denosumab inhibits bone breakdown. In addition, a class of medications called anti-angiogenesis inhibitors, which work by interfering with a tumor's blood supply, are a known cause of ONJ. These medications are used in many cancer treatment regimens.
What is Osteonecrosis of the Jaw?
Osteonecrosis is exposed (uncovered) 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), the bone is exposed, either through an opening in the gum tissue or with the gum tissue missing entirely. Typical symptoms associated with ONJ are: pain, swelling, or infection of the gums, loosening of the teeth, and 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 of the jaw. ONJ may have no symptoms for weeks or months and may only be found by the presence of exposed bone.
The exact cause of ONJ is not known, but possible causes include: dental work, infection, inflammation, and the slowdown of angiogenesis (making of new blood vessels). Originally, the cause was thought to be related to dental work while taking the medications listed above. However, further research found that this dental work was often done because of underlying dental disease, such as inflammation of the gum tissue or infection. Anti-angiogenic medications slow down blood supply, which can lead to bone damage. Research has found that bisphosphonates also have some effect on angiogenesis. ONJ is rare, but as patients with bone metastases are living longer and being treated with medications associated with ONJ for many years, it is important to be aware of this complication.
ONJ should not be confused with osteoradionecrosis of the jaw, which is caused by radiation therapy and is treated differently than ONJ.
Prevention is the Key
What experts have learned is that most cases of ONJ 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 a medication associated with ONJ 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 the medication should be delayed (if possible). The patient should not start the medication until the dental concerns 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 these medications.
Patients receiving bisphosphonates should have regularly-scheduled oral assessments, perhaps as often as every 3-4 months. They should have good oral hygiene and have routine dental cleanings (with care to avoid injury to tissues).
If invasive dental procedures are absolutely necessary, it has been suggested that temporarily stopping the at-risk medications may lead to improved healing. However, there is no evidence that this helps prevent ONJ in oncology patients. These medications remain in the body for many months after the last dose, meaning you would need several months or more off the medication to make stopping the therapy worthwhile. These medications clearly benefit patients at high risk of bone complications and, unfortunately, no other class of medications have this benefit. The patient and provider must weigh the patient's risk with the benefit when considering these medications. Further research is ongoing.
How do we treat 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. Primary goals of treatment of ONJ are to reduce pain, treat or prevent infection, and slow down progression.
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. An appliance can be used to cover and protect the exposed bone. Antibiotics may be given. The area may be tested to determine what bacteria is present to guide the choice of which antibiotic to use.
Non-surgical approaches are often preferred, as surgery on these bones may not heal well and may worsen the problem. However, in more advanced cases, surgical removal of the involved bone can improve quality of life, reduce pain, prevent this area from spreading, and help promote soft tissue healing. When used, surgery may include the surgical removal of foreign material and/or dead, damaged, or infected tissue or bone and in some cases, reconstruction of the bone.
ONJ is a relatively newly recognized concern for patients receiving certain medications. It is thought to be quite rare, but is probably underreported given the lack of understanding regarding this problem. As a patient, follow recommendations for prevention and report any signs of ONJ to your healthcare team.
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
Berenson JR et al. Medication-related osteonecrosis of the jaw in patients with cancer. UptoDate. 2015. Available at: www.uptodate.com/contencts/medication-related-osteonecrosis-of-the-jaw-in-patients-with-cancer.
Ruggiero, Salvatore L., et al. "American Association of Oral and Maxillofacial Surgeons position paper on medication-related osteonecrosis of the jaw—2014 update." Journal of Oral and Maxillofacial Surgery 72.10 (2014): 1938-1956.
Eid, Ahmed, and Jennifer Atlas. "The role of bisphosphonates in medical oncology and their association with jaw bone necrosis." Oral and maxillofacial surgery clinics of North America 26.2 (2014): 231-237.
American Dental Association. Osteoporosis Medications and Medication-Related Osteonecrosis of the Jaw. Feb 8, 2018. Found at: https://www.ada.org/en/member-center/oral-health-topics/osteoporosis-medications