Bone-Modifying Drugs for Cancer With Bone Metastases

Bisphosphonates and Denosumab for Bone Metastases and Adjuvant Therapy

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Cancer that has spread to bones (bone metastases) are very common and can cause a great deal of pain and disability related to fractures and other complications. In recent years medications called bone-modifying agents have been recommended for many cancers to treat bone metastases as soon as they are diagnosed. In this setting, these drugs not only reduce the risk of fractures but may, in some cases, improve survival.

As a secondary benefit, both categories of bone-modifying drugs have anti-cancer properties. What do you need to know about drugs such as Zometa and denosumab if you're living with metastatic cancer?

Bone Metastases vs. Bone Cancer

When people hear about cancer in the bones, it can be very confusing. Most of the time when people talk about "bone cancer" they are referring to bone metastases; cancers that began in another region of the body and spread to the bones. While these people may use the term "bone cancer," cancers which spread to bones are not considered bone cancer. For example, a breast cancer which has spread to bones is not called bone cancer but rather "breast cancer metastatic to bones'" or breast cancer with bone metastases. Primary bone cancer is much less common than bone metastases. Under the microscope, bone cancer would show cancerous bone cells. In contrast, with bone metastases the cancer cells in the bone are the same tissue as the original cancer; cancerous breast cells in the case of breast cancer, cancerous lung cells in the bone (with lung cancer) and so on.

With primary bone cancer, there is usually a single tumor in one bone. With bone metastases, there is often evidence of cancer in different areas of a bone or in several different bones.

Cancers Which May Spread to Bone 

There are many cancers which can spread to bone the most common being breast cancer, lung cancer, prostate cancer, and multiple myeloma.

Other cancers which may spread to bone include kidney cancer, stomach cancer, bladder cancer, uterine cancer, thyroid cancer, and colorectal cancers.

Bone metastases occur in roughly 70 percent of women with metastatic breast cancer (bones are the most common site of metastases), and bone metastases from breast cancer are a significant cause of pain and disability for these women (and men). For many of these people, bone metastases are the first sign that the cancer has recurred after years or even decades of remission. Some of the hormonal treatments used for breast cancer (such as aromatase inhibitors) can lead to bone loss, further compounding the problem. The most common bones to which breast cancer spreads are the spine, the ribs, the pelvis, and the bones of the upper legs and arms.

Bone metastases from lung cancer are also common, affecting roughly 30 to 40 percent of people with advanced lung cancer. The bones most commonly affected are the spine, pelvis, and upper leg and arm bones. Lung cancer is fairly unique in that metastases may occur to the bones in the hands and feet. Among people with bone metastases from lung cancer, 22 to 59 percent will experience a "skeletal-related event" such as a fracture.

Bone metastases are also common in advanced prostate cancer. As with women with breast cancer, hormonal treatments with androgen deprivation therapy can also weaken bones. Four out of five men with metastatic prostate cancer will have metastases to bone. Common site of metastases are the hips, spine, and pelvic bones.

Bone metastases from multiple myeloma are also common. On an x-ray, the bones take on a moth-eaten appearance. When multiple myeloma invades bones the cancer cells both inhibit the bone making cells (osteoblasts) and stimulate the bone cells which break down bone (osteoclasts). Multiple myeloma is usually found in larger bones such as the spine, the skull, the pelvis, the ribs, and the larger bones of the legs.

Types of Bone Metastases

There are two primary types of bone metastases: osteolytic and osteoblastic. With osteolytic metastases, the tumor causes the breakdown (lysis) of bone. Osteolytic metastases are seen with multiple myeloma as well as solid tumors such as breast cancer. Osteoblastic metastases result in increased bone production and are most commonly seen with prostate cancer. Most cancers have both types of bone metastases although 80 to 85 percent of metastases with breast cancer are osteolytic. Fractures are more likely to occur in bones with osteolytic metastases than osteoblastic metastases. 

Complications From Bone Metastases

Bone metastases can greatly reduce your quality of life with cancer, yet newer treatments are making a difference for many people. Not only do bone metastases mean a cancer has spread and is no longer curable, but can lead to several complications.

Pain from bone metastases can be very severe and often requires treatment with narcotic pain relievers along with anti-inflammatory medications.

Bone metastases also increase the chance of a fracture in the areas of bone which are weakened by a tumor. When a fracture occurs in bones with metastatic cancer they are referred to as a pathologic fracture. Pathologic fractures may occur with very mild injuries. In addition to predisposing to fractures, bone metastases can make it difficult for fractured bones to heal.

When metastases occur to the lower spine, an emergency condition called spinal cord compression may occur. Cancer in the vertebrae can cause them to collapse and compress the nerves traveling from the spinal cord to the lower half of the body. Symptoms include back pain that radiates down the leg, weakness, and numbness of the legs, and loss of bowel and/or bladder control. Emergent treatment with radiation or surgery can stabilize the spine to avoid permanent disability.

Hypercalcemia of malignancy or a high calcium level in the blood may occur due to the release of calcium from destroyed sections of bone into the bloodstream. It's thought that 10 to 15 percent of people with advanced cancer will suffer from this condition (which has other causes as well in addition to bone metastases). 

Loss of mobility due to fractures not only reduces quality of life but can put you at risk of other problems. The risk of blood clots in people with cancer is already increased, and immobility raises the risk of developing deep vein thromboses or pulmonary emboli

Treatments for Bone Metastases

There are currently many different options available for treating bone metastases. Some of the general treatments used for metastatic cancer may also reduce bone metastases. These treatments may include chemotherapy, targeted therapies, monoclonal antibodies, and immunotherapy drugs. There are also treatments which address bone metastases specifically. These include:

  • Radiation therapy: Radiation therapy is a local therapy and can significantly reduce both pain and the likelihood of a fracture occurring. 
  • Radiopharmaceuticals: Radiopharmaceutics are drugs in which a particle of radiation is attached to another chemical which can then be injected into the bloodstream. Examples include Strontium-89 and Radium-223. Since these particles of radiation are carried through the bloodstream to all of the bones in the body, they may be particularly effective for people with many or widespread metastases.
  • Surgery: Surgery may be needed to stabilize a fracture or stabilize damaged bones to prevent a fracture.
  • Stereotactic body radiotherapy (SBRT) and proton beam therapy: For a single or only a few metastases (oligometastatic disease), eradication of the metastases with treatments such as stereotactic body radiotherapy or proton therapy may be done with a curative attempt, but this is very uncommon.
  • Bone-modifying agents: These will be discussed below.

Medications for Bone Metastases (Bone-Modifying Agents)

There are two primary classes of drugs used to treat bone metastases. These include bisphosphates (such as Zometa) and denosumab. Bone-modifying agents are recommended for anyone with breast cancer metastatic to bone, and is frequently used with other solid tumors (such as lung cancer) as well. Other treatments (such as radiation therapy) are usually needed along with medications to control pain.

Bone-modifying agents can help people with cancer in several ways.

  • They can strengthen bones affected by metastases to reduce both pain and the risk of fractures 
  • Many of the treatments used for breast cancer and prostate cancer, can increase the risk of osteoporosis, and along with bone metastases predispose people to fractures. This is especially important as people are now living longer with cancer.
  • Due to their effects on the microenvironment of bones, bone-modifying agents may reduce the risk of bone metastases occurring in the first place (with breast cancer and possibly prostate cancer thus far). The risk of bone metastases was lowered by up to one third, while the mortlity rate dropped by one-sixth.
  • In recent studies looking at bone-modifying agents with lung cancer, it appears that these drugs may improve both progression-free and overall survival.

Bisphosphonates (Zometa)

Bisphosphonates are medications which were first used to treat osteoporosis and later noted to help with bone metastases. When used for cancers which have spread to bones they can do double duty. Not only can they reduce bone loss but they have anti-cancer effects as well. They work by suppressing the breakdown of bone to improve bone density.

Bisphosphonates most commonly used for bone metastases include:

  • Zometa (zoledronic acid): Zometa is an intravenous medication used for bone metastases from many different cancers.
  • Aredia (pamidronate): Aredia is an intravenous bisphosphonate. It is approved for breast cancer and multiple myeloma.

The most common side effects of Zometa and Aredia are a mild flu-like syndrome for the first few days after the infusion. Other less common side effects of bisphosphonates given intravenously may include kidney damage, low calcium levels, muscle, joint, and/or bone pain (which can arise any time after treatment), unusual fractures of the femur, and atrial fibrillation. Bisphosphonates may not be recommended for people with kidney disease.

An uncommon but serious adverse event associated with Zometa use (and other bisphosphonates) is osteonecrosis of the jaw. This condition is characterized by the progressive breakdown in an area of bone in either the mandible or maxilla and can be challenging to It's not known exactly how often the condition occurs, but a risk of roughly 2 percent was found in women who were treated with Zometa as adjuvant therapy for early-stage breast cancer. Osteonecrosis may occur with any drugs in the category of bisphosphonates but 94 percent of cases are found with intravenous bisphosphonate drugs and it is very uncommon with oral drugs.

Osteonecrosis of the jaw is more likely if people suffer from gum disease, have poor dental hygiene, or undergo dental procedures such as tooth extraction. There is some evidence that scheduling dental examination every three months and using preventive antibiotics for procedures such as tooth extraction may reduce risk.  Treatment options include a combination of surgery, rinses, antibiotics, and hyperbaric oxygen treatments.

Bisphosphonates are also approved for postmenopausal women with early-stage breast cancer. In clinical trials, Zometa was found to reduce the risk of developing bone metastases by one-third and the risk of death by one-sixth.

Denosumab (Xgeva and Prolia)

Xgeva and Prolia (denosumab) is a monoclonal antibody (man-made antibody) which can reduce complications (such as fractures) associated with bone metastases. There are two formulations of this drug which have somewhat different indications with cancer. They are given by injection every four weeks.

Denosumab works by binding with and inactivating a receptor on a protein (RANKL) that regulates bone remodeling. There are two main types of cells in the bones: osteoblasts which cause bone growth, and osteoclasts which break down bone. Denosumab inhibits osteoclasts and increases bone density.

In a 2016 review of studies, denosumab was evaluated in three separate clinical trials looking at its role in breast cancer, prostate cancer, and a third study with people who had multiple myeloma or solid tumors other than breast or prostate cancer. With breast cancer and prostate cancer, denosumab was superior to Zometa in reducing the risk of fractures related to bone metastases. With multiple myeloma and other solid tumors (such denosumab was roughly equivalent in effectiveness to Zometa.

With lung cancer, a 2015 study found that compared with Zometa, denosumab reduced the risk of a fracture occurring by 17 percent. It also appears to delay the development of bone metastases, reduce skeletal tumor growth, and improved survival time by a little over a month.

Denosumab was also found to reduce the risk of treatment-related osteoporosis in breast cancer and prostate cancer (related to the use of aromatase inhibitors in breast cancer and androgen deprivation therapy in prostate cancer),

Side effects of denosumab are similar to bisphosphonates but these drugs are more likely to result in a low calcium level with long-term use. For this reason, taking a supplement of calcium and vitamin D is often recommended. Unlike bisphosphonates, denosumab may be used in people with impaired kidney function. As with bisphosphonates, there is a small risk of osteonecrosis of the jaw with these drugs.

Guidelines for Bone-Modifying Agents With Bone Metastases

Studies on bone-modifying agents have led to guidelines being in place for some cancers.

For metastatic breast cancer, with bone metastases, the American Society of Clinical Oncology guidelines from 2017 recommend women be treated with one of the following drugs as soon as bone metastases are detected:

  • Xgeva or Prolia 120 mg subcutaneously every 4 weeks
  • Aredia 90 mg IV every 3 to 4 weeks
  • Zometa 4 mg IV every 12 weeks or every 3 to 4 weeks

For prostate cancer,  2017 clinical practice guidelines also recommended that bone-modifying agents be started at the time of diagnosis of bone metastases. Options include either:

  • Xgeva/Prolia (denosumab) 120 mg subcutaneously every 4 weeks
  • Zometa 4 mg IV every 12 weeks or every 3 to 4 weeks

All other solid tumors with bone metastases may be treated with one of the following:

  • Zometa 4 mg IV every 3 to 4 weeks
  • Denosumab 120 mg subcutaneously every 4 weeks

Before Beginning Treatment

Before beginning treatment with either denosumab or bisphosphonates, it's recommended that people have a thorough dental exam looking for evidence of gum disease and that any dental work that is required should be done prior to starting these drugs.

Bottom Line on Bone-Modifying Medications for Bone Metastases From Solid Tumors

Bone metastases are challenging for many people with metastatic cancer and can reduce quality of life and survival. Bone-modifying agents are a relatively new approach and are now recommended early on after a diagnosis of bone metastases for many cancers. 

Bisphosphonates such as Aredia and Zometa can reduce the risk of fractures, and subsequently a cause of pain and immobility. Denusomab is effective in reducing fractures as well and may be somewhat superior to bisphosphonates for breast and prostate cancers. Both classes of medications carry an uncommon risk of osteonecrosis of the jaw, and a careful dental exam looking for signs of gum disease is recommended before starting these drugs.

In addition to reducing fracture risk, these medications can help correct bone loss due to hormonal therapies used for breast and prostate cancers. Both IV bisphosphonates and denosumab appear to have significant anti-cancer activity, increasing the benefits for people who choose to use these drugs. In fact, in addition to people with metastatic breast cancer, Zometa is now recommended for early stage breast cancer as an adjuvant therapy to reduce the chance that breast cancer will spread to bones in the first place.

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.

Gravalos, C., Rodriquez, C., Sabino, A. et al. SEOM Clinical Guideline for Bone Metastases From Solid Tumours (2016). Clinical and Translational Oncology. 2016. 18(12):1243-1253.

Gul, G., Sendur, M., Aksoy, S., Sever, A., and K. Altundaq. A Comprehensive Review of Denosumab for Bone Metastasis in Patients With Solid Tumors. Current Medical Research and Opinion. 2016. 32(1):133-45.

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