Bisphosphonates for Early-Stage Breast Cancer

Bisphosphonates, a class of drugs well-known to prevent and treat osteoporosis, are also used in cancer treatment. Generally, they are used for cancer-related bone pain and hypercalcemia. In breast cancer specifically, bisphosphonates are primarily used to reduce the risk of fracture and osteoporosis in postmenopausal women. But research suggests that these drugs may offer the additional benefit of preventing recurrence of metastatic breast cancer in bone.

There is even evidence that bisphosphonates may improve survival times in premenopausal and postmenopausal women with early-stage breast cancer. However, not all women will benefit from treatment.

Of the available bisphosphonates agents, only two are specifically used to protect bones in women with breast cancer:

• Bonefos (clodronic acid), taken by mouth
• Zometa (zoledronic acid), delivered by injection

Despite differences in availability, Bonefos and Zometa are both endorsed for use in breast cancer in a joint guideline issued by the American Society of Clinical Oncologists (ASCO) and Cancer Care Ontario (CCO).

How They Work

As a drug class, bisphosphonates are able to slow or prevent osteoporosis by triggering cell death in osteoclasts. These are naturally occurring cells responsible for breaking down bone so that osteoblasts can rebuild them. By reducing the number of osteoclasts, bisphosphonate can significantly slow bone loss in postmenopausal women prone to osteoporosis.

Within the context of breast cancer, Bonefos and Zometa are used in adjuvant therapy for women with estrogen receptor-positive breast cancer (a type of breast cancer whose growth is influenced by estrogen). Adjuvant therapies are used to prevent cancer from recurring.

Postmenopausal Women

Bonefos and Zometa are important for postmenopausal women with breast cancer whose risk of osteoporosis is high. Beyond the age-associated risk of osteoporosis, which increases in women after the age of 50, chemotherapy and radiation therapy can accelerate bone loss. Even aromatase inhibitors used in adjuvant therapy can contribute to this loss.

In addition to their bone-protective effects, Bonefos and Zometa appear to have anti-tumor properties. Although the exact mechanism of action is unknown, test tube studies have shown that bisphosphonates prevent the adhesion of cancer cells to normal cells and may induce cell death in certain types of breast cancer.

Most of the evidence supporting their use is based on human clinical trials. Among them:

• A 2011 study published in Breast Cancer reported that Zometa used in adjuvant therapy, with either tamoxifen or Arimidex (anastrozole), increased survival times by roughly 20 percent to 30 percent compared to tamoxifen or Arimidex alone.
• A 2018 study in the Journal of Clinical Oncology concluded that Bonefos and Zometa improved survival times by 30 percent. Moreover, switching from one drug to the next appeared to be effective if bone metastasis suddenly progressed.
• A 2015 review of studies in the Lancet reported that Bonefos and Zometa reduced the risk of bone metastasis recurrence by 28 percent and breast cancer mortality by 18 percent.

In all of the listed studies, the benefits were constrained to postmenopausal women. In the Lancet study especially, the benefits to premenopausal women were considered "of only borderline significance."

Premenopausal Women

That is not to suggest that Bonefos and Zometa are of no benefit to premenopausal women. Although studies are conflicting, a few have suggested that the long-term use of bisphosphonates may be beneficial to women with breast cancer irrespective of menstrual status. This suggests that the duration of treatment may play as important a role as the drug itself.

Of these, a 2018 study from the University of Washington concluded that the long-term use of bisphosphonates (average 11.8 years) reduced the risk of bone metastasis recurrence and breast cancer recurrence by roughly 35 percent in both premenopausal and postmenopausal women. If anything, premenopausal women fared slightly better (although the number of premenopausal women in the study was relatively small).

Moreover, the long-term use of bisphosphonates reduced the risk of breast cancer deaths by some 60 percent.

As with other studies investigating the use of bisphosphonates in breast cancer, the benefits appear constrained to early-stage (stages 0 to stage 3a) malignancies. Women with advanced cancer generally fare less well.

Who Can Take Them

In June 2017, ASCO and CCO jointly recommended that Bonefos and Zometa be considered for use in adjuvant therapy in postmenopausal women with breast cancer. (In the United States, the recommendation is limited by the fact that only Zometa is currently FDA-approved.)

Bonefos and Zometa are recommended for the adjuvant treatment of early-stage, estrogen receptor-positive breast cancer. Research is ongoing as to whether the drugs may be useful in women with estrogen receptor-negative breast cancer.

To establish your receptor status, a sample of cancer cells would need to be obtained by biopsy or surgery.

Dosage

Zometa is considered the first-line option in the United States given its market availability. According to the ASCO/CCO guidelines, the drugs would be dosed as follows:

• Zometa is delivered in a 4-milligram (mg) intravenous (IV) infusion every six months for three to five years for women with early-stage breast cancer.
• Bonefos is delivered in 1,600-mg oral tablet taken once daily with or without food for two to three years.

Research is ongoing to determine the benefits and risks of long-term bisphosphonate use.

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Side Effects

Side effects are common with Zometa. Those occurring in over 10 percent of users include:

• Nausea
• Fatigue
• Constipation
• Coughing
• Fever
• Bone pain
• Shortness of breath
• Anxiety
• Confusion
• Agitation
• Oral thrush
• Urinary tract infection

Flu-like symptoms lasting for several days after the IV infusion are also common.

Side effects of Bonefos (occurring in at least 1 percent of users) include heartburn, indigestion, diarrhea, nausea, loss of appetite, stomach pain, and vomiting.

Drug allergy to bisphosphonates is rare but may include rash, itching, and shortness of breath. Anaphylaxis, a serious, whole-body allergy, has rarely been reported with either Zometa or Bonefos.

Kidney Failure

Bisphosphonates are cleared by the body via the kidneys. Long-term used can potentially impair kidney function and lead to kidney failure and dialysis. While people with underlying kidney disease are at greatest risk, kidney failure has been known to occur in people with normal baseline kidney function.

Research suggests that people with reduced kidney function, defined as a glomerular filtration rate of under 60 mL/min or serum creatinine of less than 45 mg/dL, should be given a lower bisphosphonate dose.

Irrespective of baseline kidney function, routine monitoring is strongly recommended to avoid serious and sometimes irreversible kidney injury. In rare cases, kidney failure occurred after just one IV infusion of Zometa.

The risk is almost entirely related to injectable bisphosphonates. Oral bisphosphonate may cause impairment, but rarely enough to require a dose adjustment or treatment termination.

Osteonecrosis of the Jaw

An uncommon but serious side effect of bisphosphate use is osteonecrosis of the jaw (ONJ). This refers to the destruction of bone in either the mandible (lower jaw) or maxilla (upper jaw). Serious cases may require the surgical removal of damaged bone and marrow.

ONJ may affect up to 2 percent of bisphosphonate users. The vast majority develop after an invasive dental procedure, such as tooth extraction. Advanced breast cancer, poor oral health, and the concurrent use of chemotherapy or corticosteroids may also contribute to the risk.

ONJ is far more common with injectable bisphosphonates like Zometa than with oral ones.

Interactions

Bisphosphonates can interact with certain drugs, particularly those that influence calcium blood levels. Among them:

• Aminoglycoside antibiotics, like streptomycin and neomycin, should be used with caution when taking bisphosphonates, as they can further decrease calcium levels.
• Loop diuretics like Lasix (furosemide) and Demadex (torsemide) can also cause a severe drop in calcium levels, known as hypocalcemia.
• Nephrotoxic drugs (drugs toxic to the kidney) may add to the toxic effect bisphosphonates can sometimes have on the kidney. The list of drugs is extensive.

To avoid interactions, speak with your oncologist about the safety of your current medications, both pharmaceutical, non-pharmaceutical, and traditional.

Contraindications

The only absolute contraindication for the use of Zometa or Bonefos is a known allergy to any component of the drug.

With that being said, the use of bisphosphonates in people with severe kidney impairment is not recommended. People who are severely impaired should only be treated if the benefits are seen to outweigh the risks. Even so, the short-term consequences may be extremely high.

Bisphosphonates should also be used with extreme caution during pregnancy. Animal studies reveal evidence of fetal harm associated with Zometa, mainly related to bone malformations. While bisphosphonates are not outright contraindicated in pregnancy, they should only be used after careful consultation with an experienced clinician.