Medications to Treat Cancer That Has Spread to Bones

Cancer that has spread to bones ( bone metastasis) is 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 embolism.

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 guideline 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.

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An Overview of Bone Metastases

Bone metastases are common in people who've had cancer, especially that of the breast, lung, or prostate. They occur when cells from the original tumor break off and take up residence in the bone. Metastases are very painful and are different from tumors that originate in the bone. For example, breast cancer that moves to the bones is not bone cancer, but rather breast cancer metastatic to bone.

Common Sites

Each type of cancer has a tendency to spread to certain bones in the body more often than others, but this can vary. Metastases have occurred to nearly every bone in the body.

	Breast Cancer	Prostate Cancer	Lung Cancer
Spine	✓	✓	✓
Ribs	✓	✓
Pelvis	✓		✓
Long bones of arms, legs	✓		✓
Hips		✓

It's not uncommon for bone metastases to occur in a few different bones at the same time, such as the spine and the pelvis. Metastases may also occur in other regions of the body (such as the liver, lungs, or brain) at the same time as the bones.

Symptoms and Complications

Bone metastases can lead to many different symptoms and complications, some of which may lead to the discovery that cancer has recurred. Many of them may require treatment above and beyond what's needed to battle the tumor(s).

• Difficult-to-manage pain
• Fractures and fracture risk
• Spinal cord compression
• Loss of mobility
• Hypercalcemia

All of these concerns can significantly reduce your quality of life. Reporting new symptoms to your doctor and getting prompt diagnosis and treatment can help you get ahead of their progression and preserve your quality of life.

Hypercalcemia

In hypercalcemia, bones release calcium into the blood as they're broken down by cancer. While calcium is something your body needs, having too much leads to several problems. Symptoms include:

• Constipation
• Fatigue
• Extreme thirst
• Muscle weakness

In severe cases, untreated hypercalcemia can lead to:

• Kidney failure
• Coma
• Death

Get treatment right away if you have symptoms that suggest hypercalcemia.

Causes

Experts don't yet understand why cancer spreads to bones. The bones are rich with blood vessels, but so are the liver and lungs—areas to which cancer spreads less frequently than bone. Metastases are the cause of death in 90 percent of fatal breast cancer cases, so this area is being actively investigated.

One theory is that cancer may lie dormant in bone marrow since the bones that cancer most commonly spreads to are those that are rich in bone marrow. This may explain why cancer can hide in the body for years, or even decades, and then recur.

Diagnosis

Bone metastases from breast cancer may be diagnosed in a number of different ways. Sometimes metastases are seen when an X-ray is done for a fracture that occurred with minimal trauma due to the weakening of a bone (what's known as a pathological fracture).

Other times, they're diagnosed incidentally when a test such as a positron emission tomography (PET) scan is done for another reason.

Tests done specifically to look for bone metastases include:

• Bone scans
• PET scans
• Computed tomography (CT) scans
• Single-photon emission computerized tomography (SPECT) scans
• Whole-body magnetic resonance imgaing.

The types of scans your doctor orders will depend on a variety of factors, and some scans may be done in combination to reach a diagnosis. There's no consensus that one test or combination of tests is best in all cases.

Treatment

Addressing bone issues and bone metastases are important no matter what stage of cancer a person has. Cancer treatments such as hormonal therapies can lead to bone loss. In fact, medications used for bone metastases  (bisphosphonates) are now being considered even for those with early-stage breast cancer as a way to strengthen bones and possibly prevent bone metastases from occurring in the first place.

A number of different treatments are available for bone metastases. The option that is best for you depends on a number of factors, such as the number and location of bones affected, the presence of other metastases, and your general health.

General cancer treatments such as chemotherapy, hormonal therapies, and targeted medications are often used, as are treatments designed specifically to slow the spread of cancer to bones. They frequently result in the successful management of cancer for quite some time.

Radiation Therapy

Radiation therapy is a common choice. It can help both to decrease pain and reduce the risk of fractures, often being the most effective treatment for alleviating pain. Radiation is a "local treatment," which means that it works better for isolated areas of metastases than those that are widespread. Even so, when combined with immunotherapy drugs, some people experience what's referred to as the abscopal effect, in which radiation appears to prime the immune system. This results in a decrease in the tumor at sites distant from where the radiation was given.

In the past, radiation was often given over several sessions, but a 2019 study suggests that a single dose is not only easier from a quality-of-life standpoint (fewer visits), but may more effectively reduce pain and reduce the risk of cancer recurring at the site—and with no greater side effects. In this approach, a single dose (either 12 Gy or 16 Gy, depending on the size of the metastasis) given by a specialized type of radiation called sterotactic body radiotherapy (SBRT)  was even more effective than 10 sessions delivering a total of 30 Gy of radiation.

Radiopharmaceuticals

Radiopharmaceuticals are medications that include a particle of radiation attached to another chemical, which is injected into the bloodstream. The radiation is thus delivered directly to the bone metastases. Examples of these drugs include Strontium-89 and Radium-223.

Radiopharmaceuticals may be particularly helpful for those who have multiple or extensive bone metastases that would be difficult to treat with local therapies such as radiation therapy. These medications have relatively few side effects and can be very effective in controlling bone pain.

Bone-Modifying Agents

Bone-modifying agents are drugs that can be used orally or by injection to reduce bone metastases. These include:

• Bisphosphonates: First approved for osteoporosis, these drugs were later then found to be effective in treating and preventing bone metastases. They also appear to have strong anti-tumor effects and help prevent bone loss due to hormonal therapies (such as aromatase inhibitors). An example is Zometa (zoledronic acid). These medications are being considered for treating early-stage breast cancer in women on ovarian suppression therapy. Bisphosphonates do carry a rare side effect of osteonecrosis of the jaw.
• Xgeva (denosumab): Denosumab is an antibody that has been found to be effective in reducing complications such as fractures for people with bone metastases. It also appears to have anti-cancer properties. It is given as a subcuticular injection once every four weeks.

Treatment for Complications

While the following will not address the metastasized cancer itself, they can help patients with issues that stem from such disease.

• Pain control: Metastases to bones can be very painful, but you have a lot of options for pain relief. Finding the right medications and balancing the side effects with effectiveness can be challenging. If you're struggling to find that balance, you may want to work with a palliative care physician or pain specialist. They use numerous therapies in addition to medications, including nerve blocks.
• Fractures and fracture risk: Surgery is used most often to stabilize fractures or areas of bone at risk for fractures. (It may also be done to remove tumors putting significant pressure on the spinal cord.) When fractures are in the long bones of the arms or legs, a rod is usually placed to provide support for a weakened bone. Vertebroplasty or "cement" may be used for spinal fractures or weakened areas where fractures are likely to occur.
• Hypercalcemia: First-line treatment includes IV rehydration and bisphosphonates. Sometimes other medications, such as calcitonin, gallium nitrate, or mithramycin may be used. If hypercalcemia is severe, dialysis is another option.

Prognosis

The prognosis for bone metastases depends on what type of cancer it is.

For example, the average overall survival for metastatic breast cancer with bone metastases is 18 to 24 months (and thought to be increasing), with around 20 percent of people surviving beyond five years. In bone metastases from lung cancer, the median survival time is just six months.

It's important to note that the prognosis is better for people with only bone metastases and, thanks to treatment, there are some long-term survivors.

A Word From Very well

While bone metastases confirm that your cancer has spread and can be painful, there are some excellent treatment options available, with more treatments currently being evaluated in clinical trials . After you have adjusted to this diagnosis, work with your healthcare team to find the best regimen to control your disease and ease symptoms. Take it one day at a time.

this is only for your information, kindly take the advice of your doctor for medicines, exercises and so on.   
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