How and Why Are Zoledronic Acid, Pamidronate, and Denosumab Used as Breast Cancer Medications?

When caught early, breast cancer is only found in the breast. But in some cases, it can spread (metastasize) outside of the breast to other areas of the body, including your bones. These are known as bone metastases. Bones are the most common places that breast cancer spreads to, and this spreading happens in about 70% of people with advanced (metastatic) breast cancer. 

Bone metastases can wreak havoc on bones and be painful. Thankfully, there are medications that can help prevent bone loss and also help treat bone metastases from breast cancer.

There are three medications that are recommended to be used to prevent bone loss and fractures and/or treat bone metastases in breast cancer. Collectively, they’re known as bone-modifying agents, or bone density medications. They include zoledronic acid (Zometa), pamidronate (Aredia), and denosumab (Xgeva). They work by slowing or stopping bone breakdown (gradual destruction). 

In this article, we’ll compare how these medications work, the important roles they play in the treatment of breast cancer, and possible side effects that can happen.

How do zoledronic acid (Zometa), pamidronate (Aredia), and denosumab (Xgeva) differ?

Bone-modifying agents — zoledronic acid, pamidronate, and denosumab — work in different ways to help strengthen bones. They can help prevent bone loss, bone metastases, and potential complications of bone metastases called skeletal-related events (SREs). 

SREs may include hypercalcemia (high calcium levels), spinal cord compression (pressure on the spine), bone fractures, or the need for radiation or surgery to treat a fracture. These fractures can be caused by the cancer itself or by certain cancer treatments.

Why are these medications used in breast cancer?

Bone-modifying agents are used in breast cancer to help delay the progression (worsening) of bone metastases. These medications can also help relieve painful symptoms of bone metastases and improve bone density. 

These medications are divided into different categories based on how they work. Zoledronic acid and pamidronate are in a class of medications called bisphosphonates. Denosumab is a type of medication known as a RANK ligand (RANKL) inhibitor. 

Bisphosphonates like zoledronic acid and pamidronate have been found to be given safely for up to about 2 years in people with breast cancer. In some cases, they’re used indefinitely as long as they’re tolerated. In people with metastatic breast cancer who have bone metastases, bisphosphonates are associated with fewer SREs, fewer fractures, and a reduced need for radiation or surgery to treat bone pain. 

A different study compared the effects of denosumab and zoledronic acid in people with metastatic breast cancer with bone metastases. This study showed that denosumab significantly delayed the time to the first SRE by about 18% compared with zoledronic acid. 

Overall, these medications can be helpful in controlling symptoms of bone metastases and preventing additional bone loss for people with breast cancer. This is why bone-modifying agents are often used for people with certain types of breast cancer. 

Current treatment guidelines don’t reveal a preference for the use of one bone-modifying agent over the other, but zoledronic acid and denosumab are more commonly used in the U.S.

How do they work?

In order to understand how bone-modifying agents work, it’s helpful to know how bones normally grow and change.

Bones can change over time mostly because of two different types of cells: osteoblasts and osteoclasts. Osteoblasts make new bones, and osteoclasts dissolve, or “eat away,” old bones.

These two types of cells keep bones strong and maintain a balance of forming new bone and breaking down old bone. This process is known as bone remodeling. Breast cancer cells can stop or speed up this process and, when this happens too much, bone can be dissolved. This leads to bones weakening and breaking easier than normal.

Bisphosphonates — like zoledronic acid and pamidronate —work by targeting osteoclasts. Bisphosphonates are taken up, or engulfed, by the osteoclasts in the bone and disrupt them, which lessens bone breakdown. 

Zoledronic acid (Zometa) is given as an intravenous (IV) infusion into the vein. It’s usually given at a dose of 4 mg once every 4 weeks or once every 3 months, but doses can vary based on the type of cancer and other health conditions you may have. The dose may also be reduced if you have certain kidney problems.

Pamidronate (Aredia) is given as an intravenous (IV) infusion into the vein over 2 hours. It’s usually given at a dose of 90 mg every 3 to 4 weeks in breast cancer, but doses can vary.

Denosumab is a monoclonal antibody that inhibits (blocks) RANKL. RANKL is a protein that’s important in overall bone metabolism, and it helps make osteoclasts active. By blocking RANKL, denosumab can help control bone breakdown and therefore lower the severity of bone loss. This helps to maintain bone mass and strengthen bone. 

Denosumab is given as a subcutaneous injection in the upper arm, upper thigh, or abdomen. Denosumab (Xgeva) is usually given at a dose of 120 mg once every 4 weeks, but doses can vary depending on what type of cancer you have and your other health conditions. Your healthcare provider will determine the best dose and frequency for you.

What other cancer types can they be used for?

Bone-modifying agents are also used in other types of solid tumors that can cause bone metastases. A tumor is an abnormal mass of tissue, and a solid tumor means it doesn’t contain any cysts or liquid parts. 

Virtually any type of cancer can cause bone metastases, but the solid tumors most likely to cause them are breast cancer, prostate cancer, lung cancer, and thyroid cancer. Bone-modifying agents may be used in any of these types of cancer to treat bone metastases.

Bone-modifying agents are also a main part of treatment for people with multiple myeloma. Multiple myeloma is a type of cancer that affects plasma cells in the blood. More than 80% of people with multiple myeloma suffer from changes or damaged bones caused by their cancer. Denosumab, pamidronate, and zoledronic acid can be used to help prevent SREs associated with multiple myeloma.

Are there any other medications that can be used?

Other medications that can be used for bone loss caused by breast cancer include oral bisphosphonates, which are taken as a pill by mouth. This includes medications like ibandronate (Boniva). It’s important to note that ibandronate is only used as off-label for metastatic breast cancer, meaning it hasn’t been FDA-approved for this use. Ibandronate may be an option if you cannot receive or tolerate medications into the vein or under the skin.

There are some other formulations (versions) of denosumab and zoledronic acid that can be used to treat other situations associated with bone loss. Endocrine (hormone) therapy used in the treatment of hormone-sensitive breast cancer can also raise the risk of bone loss and osteoporosis. These medications include aromatase inhibitors (AIs) like anastrozole (Arimidex), letrozole (Femara), and exemestane (Aromasin).

If you’re taking an AI, your healthcare provider may also recommend starting a bone-modifying agent like zoledronic acid or denosumab to help prevent bone loss. In this case, denosumab is given at a lower dose of 60 mg injected once every 6 months under the skin. This brand name formulation of denosumab is called Prolia. 

You can read more about denosumab (Prolia) and its use in breast cancer here.

What bone-related complications does breast cancer cause?

Breast cancer can spread to any bone in the body, but it most commonly spreads to the pelvis, ribs, spine, or long bones of the arms and legs. 

Bone metastases can cause bone loss (osteoporosis), bone fractures, bone pain, and compression (or squeezing) of the spinal cord. Spinal cord compression is a life-threatening complication of bone metastases. Bone loss and bone metastases symptoms can include:

• Sudden severe pain and the inability to move — a sign of a fracture

• Neck or back pain

• General numbness or weakness

• Difficulty passing urine or stool

Another problem that can happen with too much bone breakdown is the release of extra calcium from the bones into the bloodstream. This is called hypercalcemia, and these high levels of calcium in the blood can cause problems in the body. Common symptoms can include fatigue, dehydration, nausea, and loss of appetite.

What side effects are associated with Zometa, Aredia, and Xgeva?

All bone-modifying agents can affect your calcium levels. They most commonly cause a lower amount of calcium in your blood, also known as hypocalcemia. Your healthcare provider may recommend that you start a calcium and vitamin D supplement for healthy bone support while on this type of treatment. 

Other side effects of denosumab can include:

• Fatigue

• Muscle weakness

• Lower levels of phosphorus in the blood

• Nausea

• Low levels of calcium in the blood

Other side effects of zoledronic acid and pamidronate can include:

• Bone pain

• Worsened kidney function

• Nausea and/or vomiting

• Fever

• Fatigue

• Anemia

• Constipation

• Difficulty breathing

These medications can also affect your teeth and jaws. Bone tissue death of the jaw, also known as osteonecrosis of the jaw (ONJ), is a rare but very serious side effect. You should take care of your teeth and see a dentist before starting any of these medications. You should also need to let your healthcare provider know if you’re planning to have any dental procedures while on treatment with any of these medications.

How much do they cost?

Zoledronic acid, pamidronate, and denosumab are generally not available as a prescription at a pharmacy. These medications are administered by a healthcare provider, which usually means that they can be expensive.

These medications are likely to be covered under your medical benefit if you have insurance. You may find the cost paid by an insurance company, government, or nonprofit organization. If you are uninsured or need help with your copay, the manufacturer of the medication may also offer assistance.

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Written by:

Sonja Jacobsen, PharmD, BCPS, BCOP

Sonja Jacobsen, PharmD, BCPS, BCOP,  is a clinical oncology pharmacy specialist currently practicing in Seattle. She has been practicing as a pharmacist since 2015 and is licensed to practice in Washington state and North Carolina.

Edited by:

Joshua Murdock, PharmD, BCBBS

Joshua Murdock, PharmD, BCBBS, is a licensed pharmacist in Arizona, Colorado, and Rhode Island. He has worked in the pharmacy industry for more than 10 years and currently serves as a pharmacy editor for GoodRx.

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