Osteonecrosis of the Jaw With Cancer

Possible Side Effect of Bisphosphonates, Denosumab, and More

Osteonecrosis of the jaw is a complication that may occur in people with cancer receiving osteoporosis drugs or angiogenesis inhibitors. It has been seen with breast cancer, lung cancer, multiple myeloma, prostate cancer, and other cancers.

The diagnosis is made by seeing exposed alveolar bone, often with the help of imaging tests. Treatments can include mouth rinses, antibiotics, surgical debridement, or removal of the damaged bone.

It's important to look in-depth at both the benefits and risks of medications that may lead to osteonecrosis. You and your healthcare provider must balance a reduced risk of fractures (and often extended life) against the significant impact that osteonecrosis of the jaw can have on the quality of life.

This will become even more important in the future as these medications have now been approved for early-stage breast cancer as well, and preventive activities appear to reduce risk.

osteonecrosis of the jaw may cause pain in cancer patients
Pornpak Khunaton / iStockphoto

Basics

Osteonecrosis literally means "bone death." With the progression of osteonecrosis of the jaw, the gums disappear, exposing the jaw bone. Since the gums provide the blood supply to the bone, when the gums aren't present, the bone begins to die.

Some of the medications change the microenvironment of bone so that cancer cells don't "stick" as easily. This can result in improvements in bone metastases or prevent the spread of cancer to bone in the first place. They may also improve the osteoporosis so common with some cancer treatments by their actions on cells called osteoclasts. It is this same action, however, that can prevent repair of the jaw bone in response to dental injury or trauma.

Incidence

The first case of medication-related osteonecrosis of the jaw (MRONJ) was reported in the early 2000s in association with bisphosphonate medications. The condition has subsequently been reported with other osteoporosis medications and other cancer drugs.

The exact incidence and prevalence of osteonecrosis of the jaw is uncertain, and varies with many factors (see below). Overall, roughly 2% of people treated with bisphosphonates for cancer will develop the condition.

Signs, Symptoms, and Complications

Early on, osteonecrosis of the jaw may not have any symptoms. When they occur, potential signs and symptoms include:

  • Pain that may feel like a toothache, jaw pain, or sinus pain
  • A heavy feeling in the jaw
  • Swelling, redness, or drainage
  • Decreased sensation or numbness of the lower lip
  • Bad breath (halitosis)
  • Loose teeth
  • A decreased ability to open the mouth (lockjaw or trismus)
  • Visible exposure of the jaw bone (either the mandible or maxilla): Medication-induced osteonecrosis in the lower jaw bone (mandible) is more common than in the upper jaw bone (maxilla) due to less blood supply.

Complications

The first signs or symptoms of osteoporosis of the jaw may be related to complications of the condition, such as:

  • Pathologic fracture: A pathologic fracture is a fracture that occurs due to a bone that is weakened for some reason, such as necrosis, tumor, or infection. In this case, the weakened and fractured bone is in the jaw.
  • Infection: Signs of infection may include redness, swelling, drainage (often pus-like), fever and/or chills, and general flu-like symptoms.
  • Fistulas: A fistula is an abnormal connection between two body parts. It may develop between the mouth and skin surrounding the mouth (oral-cutaneous fistula).
  • Chronic sinus infection (maxillary sinuses): In people who do not have teeth or who have oral implants, chronic sinusitis and pathological fractures are more common.

Causes and Risk Factors

There are likely different underlying mechanisms involved in osteonecrosis of the jaw (ONJ) depending on the specific drug category. The most common culprit, bisphosphonates, bind to osteoclasts, which are specialized cells involved in bone turnover and repair. This can lead to a decreased ability to heal.

ONJ of the jaw commonly develops after dental procedures. In this case, a combination of dental injury and reduced ability of the bone to heal itself appears to be involved.

Other drugs that have recently been associated with osteonecrosis of the jaw are angiogenesis inhibitors. Angiogenesis is the process by which new blood vessels are made to either repair tissue injury or allow a cancer to grow. This can lead to less blood supply to the jaw, and subsequently osteonecrosis (also referred to as avascular necrosis).

Risk Factors

The most important risks for the development of osteonecrosis of the jaw include a combination of three factors:

  • Dental risk factors
  • Cancer, its treatments, and other medical conditions
  • The type of medication

Dental Risk Factors

Roughly half of the people who develop ONJ with cancer have had some type of dental procedure performed while on one of the medications associated with the condition. Risk factors include:

  • Recent dental surgery: This may include tooth extractions (removal), surgery for periodontal disease, dental implants
  • Dentures: People who wear dentures are at greater risk than those who have a fixed partial denture.
  • Trauma (injuries to the head and mouth)
  • Gum disease (periodontitis)
  • Lack of regular dental care

The strongest association has been noted with dental extractions and dental implants. In one study looking at people with multiple myeloma who developed osteonecrosis of the jaw (9 of 155 participants), 6 of the 9 people reported a recent dental extraction.

Cancer, Treatments, and Other Medical Conditions

People who have cancers that may be treated with medications associated with osteonecrosis of the jaw are at higher risk. This is particularly true for people who have multiple myeloma (due to its behavior in bone), lung cancer, and breast and prostate cancers (both commonly spread to bone and may also be treated with medications that raise osteoporosis risk).

The risk is also higher in people with cancer who are treated with chemotherapy (immunosuppression), have low hemoglobin levels (anemia), or are receiving more than one medication that is associated with osteonecrosis of the jaw.

People who are receiving radiation therapy to the head and neck in combination with bisphosphonates have a significant risk of developing the condition (osteoradionecrosis), and it tends to occur earlier than those treated with only one of the treatments alone.

Other medical conditions associated with a higher risk include:

  • Diabetes
  • Kidney disease treated with dialysis
  • High blood pressure
  • High cholesterol

Smoking does not appear to increase the risk, and the risk of ONJ actually appears lower in current smokers.

It also appears that some people have a genetic predisposition to develop osteonecrosis of the jaw.

Type, Dose, and Route of Administration of Medication

The medications associated with ONJ are discussed below. It's important to note that the dose of the medication, whether it is given orally or intravenously (IV), and how long they are used are very important considerations. When these medications are used for osteoporosis in people without cancer, the risk is very low. In contrast, with cancer the medications are frequently given at much higher doses and by injection rather than orally.

Medications

Medications to treat bone loss are important for maintaining the quality of life for many people with cancer, but are also the most common cause of osteonecrosis of the jaw. These may be prescribed for a number of different reasons, including:

  • Bone metastases: Bisphosphonates and denosumab are "bone modifying drugs" that can be used for cancers that spread to bone. Bone metastases can greatly reduce quality of life. They can also lead to complications such as pain (which can be severe), pathologic fractures, malignant spinal cord compression, and hypercalcemia (an elevated calcium level in the blood). Roughly 70% of people with metastatic breast cancer will have bone metastases, and these medications can significantly increase survival. While bone metastases can occur with many types of cancer, they are also common with prostate cancer, kidney cancer, lung cancer, and lymphomas.
  • For bone involvement with multiple myeloma: Multiple myeloma may both inhibit the cells that form bone (osteoblasts) and stimulate the cells that break down bone (osteoclasts) resulting in bones that have a "moth-eaten" appearance. Bone complications are very common with the disease, and bone pain is often the first symptom. Either bisphosphonates or denosumab can reduce complications of bone involvement.
  • For early-stage breast cancers that are estrogen receptor positive (bisphosphonates for early stage breast cancer): In postmenopausal women (or premenopausal women treated with ovarian suppression therapy), bisphosphonates combined with an aromatase inhibitor reduced the risk of recurrence and bone recurrence by 35%. These drugs appear to alter the microenvironment of the bone such that cancer cells that make their way to the bone do not "stick."
  • To counteract medications used to treat cancer. Both anti-estrogen therapy (aromatase inhibitors) for breast cancer and anti-androgen therapy for prostate cancer can lead to osteoporosis.

It's important to thoroughly understand the benefits of these medications when weighing the risk of osteonecrosis of the jaw.

Bisphosphonates

Many people are familiar with bisphosphonates as medications used to treat osteoporosis. With osteoporosis, these drugs are usually taken orally. With cancer, however, bisphosphonates are often given intravenously and at a potency that is 100 times to 1000 times higher than the medications given to treat osteoporosis.

Bisphosphonates used to treat cancer include:

  • Zometa (zoledronic acid): In the U.S.
  • Bonefos (clodronic acid): In Canada and Europe
  • Aredia (pamidronate)

In contrast, bisphosphonates used primarily for osteoporosis include Actonel (risedronate), Boniva (ibandronate), and Fosamax (alendronate).

Studies looking at osteonecrosis of the jaw in people receiving oncology doses of bisphosphonates or denosumab have found a prevalence of 1% to 15%. In contrast, the prevalence of osteonecrosis of the jaw in people who receive lower doses of these medications to treat osteoporosis is estimated to be 0.001% to 0.01%.

Due to the method by which bisphosphonates bind in cells, their effects can last up to 10 years after treatment is finished. This may be beneficial when it comes to reducing fracture risk, but also means that the negative effects of the drug may persist a long time after the drug is discontinued.

Denosumab

Denosumab is a different type of medication that may also be used to treat bone metastases in people with cancer or osteoporosis. The medication decreases bone resorption by interfering with the formation and survival of osteoclasts.

There are two brand name drugs containing denosumab, with the difference being the indication:

  • Xgeva (denosumab) is used for cancer
  • Prolia (denosumab) is used for osteoporosis in the U.S.

While denosumab has been studied less in the setting of bone metastases than bisphosphonates, it appears to be similarly effective in reducing complications such as fractures. Like bisphosphonates, it appears to have anti-tumor activity as well.

In contrast to bisphosphonates, the medication doesn't bind permanently with bone and therefore the effects of the drug do not last as long. Most of these effects (good or bad) are gone after six months.

Similar to bisphosphonates, the risk of osteonecrosis of the jaw varies depending on the use of the drug. When used for people with cancer, the risk ranged from 1% to 2%, while the risk in people using the medication for osteoporosis was 0.01% to 0.03%.

Bisphosphonates vs. Denosumab

While Zometa (and Bonefos in Canada and Europe) and Xgeva have benefits as well as risks for people with cancer, there are a few differences.

When osteonecrosis of the jaw occurs with bisphosphonates, it tends to occur after 48 months of use (IV) or 33 months (with oral preparations). With Xgeva, osteonecrosis tends to occur early on after the medication is started.

Until recently, studies suggested that the benefits and risks of denosumab were similar to bisphosphonates (Zometa). That said, a 2020 study suggested that Xgeva was associated with a significantly higher risk of osteoporosis of the jaw than Zometa. In this study the incidence of osteonecrosis of the jaw with Xgeva was between 0.5% and 2.1% after one year of treatment, 1.1% to 3.0% after two years, and 1.3% to 3.2% after three years. With Zometa, the incidence of ONJ was 0.4% to 1.6% after one year, 0.8% to 2.1% after two years, and 1.0% to 2.3% after three years of using the medication.

Other Cancer-Related Medications

The research is very young, but a number of other cancer treatments have recently been linked to osteonecrosis of the jaw. Since the findings are early, the exact incidence is unknown.

In some situations, even if osteonecrosis of the jaw occurs, the benefits of the drug may far outweigh this potential risk. It's important to be aware of these associations, however, especially for people who will be treated with a bisphosphonate or denosumab as part of their cancer treatment. This is especially true if both drugs are combined with other risk factors, such as radiation to the head and neck.

Angiogenesis inhibitors are medications that interfere with a cancer’s ability to develop recruit new blood vessels and grow (angiogenesis). The same mechanism, however, can interfere with the formation of blood vessels as a normal part of healing (for example, healing after a tooth is removed). Examples of angiogenesis inhibitors used for cancer in which ONJ has been reported include:

  • Avastin (bevacizumab)
  • Sutent (sunitinib)
  • Afinitor (everolimus)
  • Torisel (temsirolimus)
  • Cometriq (cabozantinib)
  • Nexavar (sorafenib)
  • Inlyta (axitinib)
  • Sprycell (dasatinib)
  • Votrient (pazopanib)
  • Zatrop (ziv-afibercept)

Other targeted therapies that have been associated (very uncommonly) with ONJ include:

Other medications used with cancer where ONJ has been reported include corticosteroids and methotrexate.

Unlike bone modifying drugs, these medications don't persist in bones for an extended period of time.

Risk Related to Cancer Type and Stage

A review looking at types of cancers found that the highest risk of developing osteonecrosis of the jaw was with kidney cancer. This could be due to the combination of a bisphosphonate and an angiogenesis inhibitor for treatment.

A 2016 review of studies looked at the prevalence of osteonecrosis of the jaw in three types of cancer among people who were treated with bisphosphonates. The overall prevalence (number of people currently living with the condition) was 2.09% in people with breast cancer, 3.8% among people with prostate cancer, and 5.16% among people with multiple myeloma.

In contrast to the risk associated with bisphosphonates for bone metastases from breast cancer, the use of these drugs for early-stage breast cancer may not carry the same degree of risk. In one review, osteonecrosis of the jaw occurred in less than 0.5% of the women who were using the drug to reduce the risk of bone metastases occurring in the first place (adjuvant use).

People who are receiving radiation therapy to the head and neck in combination with bisphosphonates have a significant risk of developing the condition (osteoradionecrosis), and it tends to occur earlier than those treated with only one of the treatments alone.

Risk and Dental Care

For those who will be using these drugs for their cancer, the importance of good dental care was pointed out in another study. Looking at patients with advanced cancer who were treated with Zometa of Xgeva over a period of three years, 8.4% developed osteonecrosis of the jaw, with the risk strongly related to the number of infusions and how long they were continued. For people who had excellent preventive dentistry visits, however, the risk was much lower.

Diagnosis and Staging

The diagnosis of osteonecrosis begins with a careful review of medications, as well as dental health. On physical exam, you or your doctor may see exposed alveolar bone. It's important to note, however, that in the early stages there may be no symptoms.

Imaging

Panoramic or plain X-rays may show areas of jaw bone destruction or even pathologic fractures.

Computerized tomography (CT) or magnetic resonance imaging (MRI) are most often done to further understand the extent of the disease. According to some researchers, MRI is the better method to find early changes related to osteonecrosis in the jaw, but can also give false positives (it may look like the disease is present when it is actually not).

Biopsy

A biopsy is not usually needed but may be recommended at times to make sure changes are due to osteonecrosis.

Differential Diagnosis

Conditions that may mimic osteonecrosis of the jaw include:

  • Benign bone conditions in the jaw
  • Bone metastasis to the jaw from the primary cancer
  • Osteomyelitis: An infection in the bone

Staging

Staging is very important in order to determine the best treatments for osteonecrosis of the jaw (OSJ), and the American Association of Oral and Maxillofacial Surgeons has designed a system breaking the condition down into four stages.

Stage "At Risk": This stage is present when there is no evidence of bone damage in someone who has been treated with oral or IV medications associated with OSJ, but nonspecific changes may be present.

Stage 1: No symptoms but exposed bone is present. No signs of infection

Stage 2: Exposed bone (or a fistula) with evidence of infection such as redness and pain.

Stage 3: Exposed bone or a fistula that has signs of infection and is painful. This stage may also include discharge, damaged bone that extends beyond the alveolar bone, a pathologic fracture, a fistula outside of the mouth (such as oral-nasal fistula), or involvement of the maxillary sinus.

Treatment

The treatment of osteonecrosis of the jaw will depend on the stage, how much pain is present, and patient preferences. Proper care usually means working with several specialists who communicate with each other over the best options (multidisciplinary care). Your team may include your oncologist, your dentist, and a maxillofacial surgeon. You are a very important part of that team, and making sure your questions are answered and your preferences are well understood is critical.

Discontinuing the Medication

In some cases, discontinuing the medication may be helpful. This decision may be challenging if the offending drug is controlling the cancer, and will take careful discussion between the person coping with the condition, their dentist, and their oncologist.

While it's known that bisphosphonates remain in the body for an extended period of time, stopping these drugs may be helpful. One study found that people who continued to receive bisphosphonates after they developed ONJ had much slower healing than those who stopped the medication.

Antimicrobial Mouth Rinses

Mouth rinses, for example, with chlorhexidine 0.12% solution. are recommended for all stages of the condition (stages 1 through 3).

Antibiotics

When the condition has progressed to stage 2 or stage 3, oral or intravenous antibiotics are usually needed to clear up the associated infection. In some cases, an anti-fungal medication (topical or oral) may be needed as well.

Pain Control

For stage 2 and stage 3 disease, pain control is usually needed, and the best options should be carefully discussed with your doctor.

Supportive Care

Good dental care is important for everyone. This may include reducing the time that dentures are worn to minimize their contact with exposed bone, and much more.

Surgery

With stage 3 ONJ, surgery may be needed if the osteonecrosis is not responding to treatment and permanent bone damage is present. In general, the most conservative approach is considered best. Debridement, essentially scraping out dead bone, may be all that is needed. In some cases, removal of the bone (osteotomy) may be required. If a fracture is present or if the damage is extensive, grafting and reconstruction may be needed.

Other Potential Treatment Options

The medication Forteo (teriparatide) has shown some benefit in isolated cases. A number of different treatment options have been or are being studied to help people cope with osteonecrosis of the jaw, either alone or in combination with other treatments. Some of these include hyperbaric oxygen, application of platelet-derived growth factor, low-level laser therapy, ozone therapy, leukocyte-platelet rich fibrin, and bone marrow stem cell transplantation to the region.

Prevention

An ounce of prevention is truly worth a pound of cure when it comes to osteonecrosis of the jaw.

Regular Dental Health Maintenance Is Critical

If you are considering using Zometa or Xgeva, it's important to see your dentist before you begin. Ideally, you can arrange for your dentist and your oncologist to work together to discuss the treatment.

A Memorial Sloan Kettering study supports the impact of routine dental care. People with cancer on bone loss medications were divided into two groups, with one having a premedication dental evaluation. Among the group that had this dental care prior to starting the medication, the incidence of osteonecrosis was 0.9%. In contrast, the incidence was 10.5% in the group that did not have premedication dental care.

Another review of studies found that receiving dental care every three months reduced the incidence of osteonecrosis of the jaw in people with advanced cancer receiving bisphosphonates.

In women with early stage breast cancer treated with bisphosphonates, build up of plaque on the teeth (dental calculus) and gingivitis were both associated with a doubling of the risk of osteoporosis of the jaw.

In addition to regular dental visits, seeing your dentist at the first sign of any problems is important.

Continuing with excellent oral health and regular dental care while using these medications is critical. Some dental procedures are actually strongly recommended, as these might help prevent more involved dental surgeries in the future. This includes procedures such as crowns, bridges, and removable partial and complete dentures.

Antibiotics May Be Helpful

When it comes to dental treatment, the least invasive options are usually safest. For example, a root canal will likely be suggested over removing a tooth. Antibiotics before and after a dental procedure (along with antimicrobial rinses) may help prevent osteonecrosis of the jaw.

One study suggested that people with multiple myeloma may benefit from antibiotics before dental surgery, as 90% of the people in the study developed a bacterial infection (Actinomycosis).

Some Dental Treatments Should Be Avoided

Procedures such as extractions, periodontal surgery, and orthodontics should ideally be avoided. In some cases, dental implants may be considered, but only with a team including your dental specialist and oncologist who can discuss potential risks.

Be Your Own Advocate

Simply being aware of the risk of osteonecrosis of the jaw and taking steps to reduce your risk can be priceless. According to a 2019 study, the majority of people being treated with these medications were unaware of the risk.

A Word From Verywell

Osteonecrosis of the jaw is a condition that can significantly reduce the quality of life. At the same time, the medications that can lead to the condition may extend life with cancer, and reduce complications that can likewise negatively impact your life. Each person is different. In order to make the best choices for you as an individual, it's important to discuss the risks and benefits of any treatment, as well as your personal preferences and needs.

If you develop osteonecrosis, make sure to consult a dental specialist who is very familiar with treating osteonecrosis and will be aware of the latest research. As a patient, you have every right to ask questions such as how many patients with the condition a specialist has treated. As with any occupation, experience can make a difference.

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