Bisphosphonates for Early-Stage Breast Cancer: Benefits & Risks

How can osteoporosis drugs Zometa or Bonefos help?

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While osteoporosis medications have been used for people with metastatic breast cancer with bone metastases, the new 2017 guidelines from the American Society of Clinical Oncology recommend the use the bisphosphonate drug Zometa for some women with early-stage breast cancer as well. What exactly are bisphosphonates and how do they work? Can they really lower the chance that your breast cancer will spread to your bones and improve survival?

How can you know if these medications may be right for you?

Breast Cancer and Risk of Recurrence

Early stage breast cancer is very treatable, and survival rates have improved with the addition of adjuvant chemotherapy and hormonal therapy for those who are candidates for these treatments. Yet even with early-stage breast cancer (stage I, stage II, and stage III), recurrence is all too common.

The risk of recurrence varies with a number of factors incuding the stage of your cancer, your age, treatments you receive, and other factors. We don't know why cancer sometimes recurs many years or decades later, though theories about why breast cancer recurs include the idea that there is a hierarchy of cancer cells, and that cancer stem cells (the generals) may lie dormant in the bone marrow until the condition is right to begin growing again.

Breast cancer recurrences can be of three types:

  • Local recurrence, in which a tumor recurs in the breast near the site of the original tumor.
  • Regional recurrence, in which the cancer recurs nearby in lymph nodes or nearby structures.
  • Distant recurrence, in which the cancer returns in a distant region of the body such as the bones, liver, lungs, or brain. Of these, the bones are the most common site of metastases.

It is the distant recurrences—metastatic breast cancer (stage 4 breast cancer)—which are responsible for 90 percent of breast cancer-related deaths.

Who Is at Risk of Bone Metastases From Breast Cancer?

Nearly anyone who has had breast cancer could be at risk of developing bone metastases, but there are settings in which the likelihood is greater.

Bone metastases are more common in people with estrogen receptor-positive breast cancer. Estrogen receptor positive tumors are also more likely to be associated with a late recurrence, for example, many years or decades after the original cancer was found and treated. Other factors which increase the risk that breast cancer will recur include lymph node-positive disease.

Around 70 percent of women with metastatic breast cancer (stage 4 breast cancer) will have bone metastases.

The Role of Bisphosphonates in Breast Cancer

Bisphosphonates were first used in the 1990s when they were approved for the treatment of osteoporosis. Since that time they have also been approved for the treatment of bone metastases from breast cancer (and other cancers) as well as hypercalcemia associated with cancer.

Several potential ways in which bisphosphonates may be helpful for people with breast cancer include:

  • In women with breast cancer that has spread to bones (breast cancer with bone metastases), bisphosphonates such as Zometa reduce the risk of complications such as bone fractures. Since bone fractures are a  significant cause of pain and disability, these medications can significantly improve the quality of life for women with stage 4 disease.
  • Aromatase inhibitors, the hormonal therapy for breast cancer often used in postmenopausal women, can result in bone loss leading to osteoporosis. This bone loss can lead to fractures on its own, but can further increase complications when bone metastases are also present.
  • In studies, the use of Zometa in metastatic breast cancer improved survival.
  • Most recently, the use of bisphosphonates in estrogen receptor-positive early stage breast cancer was associated with a lower risk of developing bone metastases in the first place as well as a higher survival rate (see below).

Benefits of Bisphosphonates as Adjuvant Treatment for Early-Stage Breast Cancer 

In studies looking at breast cancer metastatic to bone, it was found that bisphosphonates not only lowered the risk of fractures due to metastases but appeared to prevent the spread of cancer to bones in the first place.

While we aren't entirely certain how they work, these drugs appear to influence the microenvironment of bone in a way in which breast cancer cells are less likely to take up residence.

Since bone metastases are a significant cause of mortality with breast cancer, a reduction in the risk of these metastases could possibly improve survival for women with early-stage disease.

Subsequent studies confirmed that these theories were correct. When given after surgery and chemotherapy and along with hormonal therapy the use of bisphosphonates for early-stage breast cancer in women who are postmenopausal was found to reduce the risk of developing bone metastases by one-third as well as reducing the risk of death by one-sixth. While these numbers look impressive, the actual reduction in overall risk is smaller when looking at the big picture, with bisphosphonates providing a roughly 1 to 2 percent overall reduction in the risk of death in women who are candidates for the drug.

In addition to reducing the risk of metastases and improving survival, bisphosphonates can serve yet another role. Aromatase inhibitors, the type of adjuvant hormonal treatment recommended for women who are menopausal (or premenopausal women after ovarian suppression therapy) can lead to bone loss and osteoporosis. This is of even greater concern now that these medications are recommended for a longer duration or after treatment with tamoxifen. Zometa was found to reduce the risk of osteoporosis associated with aromatase inhibitors. Drugs classified as aromatase inhibitors include Aromasin (exemestane), Arimidex (anastrozole), and Femara (letrozole).

Bisphosphonate Guidelines in Early Stage Breast Cancer

Current guidelines recommend the use of one of two different medications in this setting:

  • Zometa (zoledronic acid): Zometa is an intravenous form of bisphosphonate. The dose recommended as adjuvant therapy for early-stage breast cancer is 4 mg IV every six months for three to five years.
  • Bonefos (clodronate): Bonefos is an oral bisphosphonate that may be used as an alternative to Zometa if needed. The dose for adjuvant therapy is 1600 mg tablet taken once daily for two to three years. Bonefos is not FDA approved in the United States.

The dose of Zometa used for early-stage breast cancer is different (less frequent) than that used for metastatic breast cancer.

Who Can Use Zometa or Bonefos for Breast Cancer Treatment?

Zometa (or Bonefos) are recommended for the adjuvant treatment of estrogen receptor-positive intraductal breast cancer. It should only be used in women who are postmenopausal at the time of diagnosis or who are premenopausal but have received ovarian suppression therapy.

Many women who were treated for early-stage breast cancer prior to this recommendation may wonder whether or not they should begin the drug now. The answer is that it depends, and there are many factors to take into consideration. The studies were done with women who began bisphosphonates after finishing surgery and chemotherapy, and we don't have any good data on reduction in metastases or survival benefit in people who begin these drugs later on.

We do know that bisphosphonates can reduce bone loss in people with osteopenia and osteoporosis, and aromatase inhibitors are associated with significant bone loss in some people. Some physicians recommend bisphosphonates for osteopenia if further bone loss is expected (although different doses may be used) or if a person has significant risk factors for a fracture. You may wish to talk to your oncologist about doing a  bone density test before you make your decision. If you already have or are at risk for osteoporosis, there may be a clear benefit to using these medications.

Risks and Side Effects of Bisphosphonates

The most common side effect of Zometa is a flu-like syndrome lasting for a few days after the infusion.

Side effects of oral Bonefos can also include heartburn, indigestion, and esophageal inflammation. Oral medications should be taken with water and people are instructed to remain upright for 30 to 60 minutes to reduce the risk of esophageal irritation.

Less common side effects of bisphosphonates either used orally or intravenously include a low blood calcium level (hypocalcemia), muscle, joint, and/or bone pain (this may occur at any time during the use of the medication), and impaired kidney function. People who have impaired kidney function before their diagnosis may not be able to use the medication. Other uncommon potential side effects include atypical femur fractures and atrial fibrillation.

An uncommon but serious and challenging adverse effect of bisphosphates is osteonecrosis of the jaw. Osteonecrosis refers to the destruction of bone and may occur in either the mandible or maxilla. Symptoms often begin with jaw pain or the loss of a tooth. In studies looking at the use of Zometa as adjuvant therapy for breast cancer, osteonecrosis of the jaw occurred in roughly 2 percent of women taking Zometa.

Risk factors for developing osteonecrosis include gum disease, poor dental hygiene, or the use of dental appliances. Studies have been looking into ways to reduce the risk. In one study, instituting dental examinations every three months and using antibiotic prophylaxis prior to dental procedures was associated with a lower risk of the condition. When osteonecrosis of the jaw occurs, it can be challenging to treat. Most often a combination of antibiotics, surgery, mouth rinses, and hyperbaric oxygen therapy are used.

While osteonecrosis of the jaw may occur with any bisphosphonate, it is much more commonly seen (94 percent of the time) with intravenous bisphosphonates.

Before Taking Zometa or Bonefos 

Before starting Zometa or Bonefos it's recommended that you have a thorough dental examination specifically looking for any evidence of gum disease. If you need any dental work done, such as a tooth extraction, it's also recommended that you complete these dental procedures prior to starting bisphosphonates.

Bisphosphonates and Metastatic Breast Cancer

Bisphosphonates and another type of medication, denosumab (Xgeva or Prolia) are referred to as bone-modifying drugs. These drugs are very effective in reducing the risk of fractures related to bone metastases from breast cancer. It's now recommended that either bisphosphonates or denosumab be started when bone metastases are first diagnosed. When used for bone metastases, the dose of Zometa is higher and given as a 4 mg infusion either every 12 weeks or every three to four weeks.

Bottom Line on Adjuvant Bisphosphonates for Early Stage Breast Cancer

Bisphosphonates (Zometa) were added to the 2017 clinical practice guidelines for the adjuvant treatment of early-stage estrogen receptor-positive breast cancer in postmenopausal women. Not only may these drugs reduce the risk of treatment-associated osteoporosis, but appear to reduce the risk of developing bone metastasis and may improve survival.

These drugs are started after completing surgery and chemotherapy and at the same time that hormonal therapy is initiated.

Bone metastases with breast cancer not only mean that the cancer is no longer curable but cause significant pain and disability. Complications of bone metastases include fractures, spinal cord compression, and an elevated blood calcium level, all of which reduce quality of life and reduce survival.

Bisphosphonates, like all medications, may have side effects. Zometa often causes a flu-like syndrome for a day or two after the infusion and Bonefos can lead to irritation of the esophagus. Some people also develop impaired kidney function or a low blood calcium level. An uncommon but serious side effects is osteonecrosis of the job, a condition thought to affect one in 50 women who use the drug in this way. Good dental hygiene and a dental evaluation prior to beginning treatment may reduce risk.

For women who were treated for early-stage breast cancer in the past but who would otherwise have been a candidate for adjuvant treatment, there are currently no recommendations in place. Talk with your oncologist about her thoughts and what she considers to be the advantages and disadvantages of the treatment. Knowing your bone density and looking at risks, either for recurrence or from side effects from treatment may help guide your decision. As with all of your care, being your own advocate in your cancer care makes a difference.

Sources:

Beth-Tasdogan, N., Mayer, B., Hussein, H., and O. Zolk. Interventions for Managing Medication-Related Osteonecrosis of the Jaw. Cochrane Database of Systematic Reviews. 2017. 10:CD012432.

Coleman, R. Impact of Bone-Targeted Treatments on Skeletal Morbidity and Survival in Breast Cancer. Oncology (Williston Park). 2016. 30(8):695-702.

Dhesy-Thind, S., Fletcher, G., Blanchette, P. et al. Use of Adjuvant Bisphosphonates and Other Bone-Modifying Agents in Breast Cancer: A CancerCare Ontario and American Society of Clinical Oncology Clinical Practice Guideline. Journal of Clinical Oncology. 2017. 35(18):2062-2081.

Hadii, P., Coleman, R., Wilson, C. et al. Adjuvant Bisphosphonates in Early Breast Cancer: Consensus Guidance for Clinical Practice From a European Panel. Annals of Oncology. 2016. 27(3):379-90.

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