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Xgeva, Zometa, and Other Bone-Protecting Drugs

Chapter Four

In this chapter, we’ll consider the drugs Xgeva and Zometa. Recent phase-3 comparison clinical trials indicate that Xgeva appears to work better than Zometa for most patients to protect bones and reduce skeletal-related events (SREs). If a doctor recommends these drugs, a patient would receive one or the other (usually Xgeva). Neither drug has been shown to improve survival in HRPC patients (although this is currently being studied), but they can have a large impact on improving quality of life.

We’ll also briefly discuss other drugs approved to reduce bone pain from metastatic disease. Those drugs, radiopharmaceutical (IV drugs that give off radiation to specific metastatic bone sites), include samarium and strontium. A newer radiopharmaceutical, Alpharadin, may soon replace samarium and strontium for most patients (see chapter nine).

Question: What is an SRE?

Answer: Problems associated with cancer going into the bone are collectively referred to as skeletal-related events (SREs). There are several SREs caused by metastatic prostate cancer:

Bone fractures These are known as “pathologic bone fractures” of the spine (vertebral area) or non-spine areas (such as hip, leg, or wrist). The most common sites for bone fractures are the hip and upper legs, the spine, wrist, and ribs.

Spinal cord compression If prostate cancer gets into the backbone or spinal cord, it can create pressure and cause nerve damage. The nerves of the spinal cord control all sorts of body operations, so damage to the cord can cause problems such as pain, numbness, muscle weakness, and even bladder control issues.

Radiation to the bone or an IV drug needed to get to the bones When cancer penetrates the bone and causes pain, some patients need radiation delivered to that same site to reduce the bone pain and to potentially stop the tumor site from doing more damage. This is known as spot radiation. Other patients may require radioisotopes (radiopharmaceuticals), drugs given that find those tumor sites, reduce the pain, and potentially stop more damage to the tumor site.

Surgery to the bone If the bones become weak, damaged, or broken, they often need some type of surgery to repair the problem bone site.

Hypercalcemia Another SRE is a high blood level of calcium (hypercalcemia) that can occur with bone loss. However, Xgeva and Zometa do a very good job of preventing this problem. In fact, these drugs are now used in several non–cancer-related emergency situations, including in children when a blood level of calcium becomes high enough that it creates a life-threatening condition.

XGEVA

Also known as Denosumab

How is it taken? injection

Approval status FDA approved

Company Amgen

Advantages It is an injection usually given once every month, or less often in some cases, with a low rate of side effects. It may be usable at any time in men with HRPC to improve bone health and reduce the risk of skeletal-related events (SREs). In a phase-3 study, it beat Zometa in terms of preventing SREs and, perhaps, at reducing the risk of metastatic bone disease.

The catch Calcium (at least 500 mg or more) and vitamin D (at least 400 IU or more) supplements are strongly recommended for patients getting Xgeva. The precise amount to take depends on how much calcium you get from food and the results of a vitamin D blood test. Discuss these supplements with your doctor to determine the right amount for your situation. There seems to be a rare increased risk of osteonecrosis of the jaw (ONJ), similar or even slightly greater to what has been observed with Zometa, and a higher risk of causing low blood calcium (hypocalcemia). Approximately 80 percent of patients with ONJ had a previous tooth removal, were using a dental appliance, or had poor oral hygiene.

What else do I need to know? Xgeva is an antibody that is injected monthly or less frequently. It basically blocks a signal that allows bone loss to occur and prevents SREs. Ask your doctor if it is available and can be used after or instead of Zometa.

ZOMETA

Also known as Zoledronic acid

How is it taken? IV

Approval status FDA approved

Company Novartis

Information www.us.zometa.com

Zometa belongs to a class of drugs called bisphosphonates that are generally prescribed for bone health. It is not an FDA-approved treatment for cancer, but it is an FDA-approved treatment for preventing or delaying problems associated with hormone-reducing drugs or from cancer itself, such as bone loss. Both Zometa and Xgeva can be used for patients with metastatic prostate cancer to prevent or delay a skeletal-related event (SRE). Some of these SREs can be serious enough to change the way your cancer is treated overall, causing serious delays in treatment, changes in the treatment itself, or cessation of the treatment to alleviate the bone pain.

Zometa significantly reduces the risk of all the earlier mentioned SREs to some degree, but has been most effective at reducing the risk of bone fractures, making it a popular osteoporosis drug in both cancer situations and general medicine. It also has been shown to have an impact on reducing bone pain long-term.

Dosage Given intravenously (IV) in the oncology or urology office, clinic, or hospital to prevent bone loss and skeletal problems associated with HRPC. Total amount given per visit is generally 4 mg. It is used every 3 to 4 weeks in many cases, but can be used once every few months or even once a year in some rare cases. Your physician will decide the frequency of the IV infusions of this drug based on your situation.

Advantages This drug improves quality of life. It takes only 15 to 30 minutes to administer and prevents bone loss from hormone therapy (ADT). It may also prevent or delay harm to the bone that can be caused by prostate cancer that has become metastatic. The earlier Zometa is used in HRPC, the more it can do to prevent these problems.

The catch Calcium and vitamin D supplements should be used daily while on and off this medication (their dosages should be determined by a doctor). If your doctor encourages you to do some weight lifting because you have minimal or no bone disease, you should consider that as well to improve your bone health. Many men and women do not get the full bone health benefit because they do not undertake the lifestyle and dietary supplement changes that can improve the positive impact of the drug itself (see the side effects chapter for more information on bone health).

What else do I need to know? Although there are lots of osteoporosis drugs on the market, Zometa was the first one the FDA approved for metastatic HRPC. However, this does not mean that other osteoporosis-prevention pills are not an option for some patients to prevent bone loss.

Speaking just in terms of bisphosphonate or other osteoporosis pills available to prevent bone loss in men and women, there are medications that can be taken once a day, once a week (alendronate and risedronate, for example), twice a month (risedronate), or just once a month (ibandronate and risedronate, for example). All of them require that you take the medication on an empty stomach, sitting or standing, with a full glass of water at least 30 minutes before you eat anything. All of them have the ability to irritate your esophagus, which is why you need the glass of water to get the pill all the way down into the stomach. These pills do not absorb well with food in the stomach; hence the recommendation to take them on an empty stomach. The good news about the pills is that they allow flexibility and, unlike the IV bisphosphonates, do not require an office visit. However, for people who have issues swallowing pills and esophageal (throat) problems (such as Barrett’s esophagus), or simply for most patients with HRPC and bone metastasis, these oral drugs are not as effective as Xgeva or Zometa. Remember, none of these other bone loss pills are FDA approved for HRPC metastatic prostate cancer to reduce skeletal-related events.

Zoledronic acid (Zometa) is the most powerful bisphosphonate medication, which is probably why it is often used for HRPC. However, this powerful drug comes with powerful side effects, so always weigh the risk-to-benefit options with your doctor.

Question: What should I know about the common and not-so-common side effects of Xgeva and Zometa?

Answer: Most of the side effects of these drugs are mild and rare. For example, the most common side effect is a short-duration fever soon after the treatment. Other side effects include gastrointestinal problems (constipation), anemia, nausea, fatigue, and loss of appetite. A collection of flu-like symptoms can also occur (fever; chills; weakness; and muscle, bone, and joint aches) after the drugs are given.

If you have a kidney problem or an irregular heartbeat, Xgeva or Zometa can make it worse in some rare cases. A complete review of your current and recent medications with your doctor is important before you receive Xgeva or Zometa to prevent or reduce the risk of any side effects. It is very important that your doctor know if you have been taking any over-the-counter or prescription drug that can affect (reduce) your kidney function, such as aspirin, non-steroidal anti-inflammatories (ibuprofen, naproxen, or celecoxib), diuretics, and angiotensin-converting enzyme (ACE) inhibitors for blood pressure. Your doctor needs to know if you have been taking any prescription aminoglycoside medications (used to treat some infections), because the combination of these drugs can reduce your blood calcium to abnormally low levels (hypocalcemia), causing all sorts of health issues. Some examples of aminoglycosides include gentamycin sulfate, streptomycin sulfate, and tobramycin sulfate. Kidney function and blood levels of certain compounds (creatinine and calcium, in particular) will also be monitored over time by your doctor.

Also, if you have any dental problems or dental procedures planned for the near future, please talk to your doctor about them. Xgeva and Zometa are getting some attention for a rare side effect known as osteonecrosis of the jaw (ONJ). This problem occurs when an upper or lower area of the teeth or jaw becomes infected, and this infection becomes difficult to cure while you are on these drugs. One way to reduce the risk of this problem is to get dental clearance or a clean bill of health from a dentist before you start Xgeva or Zometa. Also, ask your doctor if your bone imaging test indicates that you might be at higher risk for ONJ.

The majority of cases of ONJ are in patients who have been treated for a longer duration, and commonly ONJ patients reported a previous dental procedure. If you develop any of the following symptoms, be sure to check with your physician right away:

• Mouth or facial pain that resembles a toothache

• Chronic sinusitis (inflammation of the sinuses)

• Foul-smelling drainage in the jaw area

• Numbness in either the upper or lower jaw area

• An exposed bony area inside mouth when looking in mirror

Although it has received a good deal of media attention, it is worth repeating that this side effect is very rare.

Question: How do Xgeva or Zometa work to promote better bone health?

Answer: Although it doesn’t appear so on an X-ray, bone is dynamic and constantly changing, breaking down and building up every second of the day. There are two types of cells that bone relies on to build healthy new bone. The osteoblasts help to build new bone and act to simply “fill in potholes on the road,” so to speak. In contrast, the osteoclasts create the potholes, for good and bad reasons. In healthy bones, osteoclasts function to break down bone so that osteoblasts can put healthy bone back in areas of the bone that need repair. Xgeva and Zometa simply work by blocking or inhibiting the ability of osteoclasts to function. In this way, the skeleton stops losing any more bone and may even build a little new bone.

Prostate cancer can increase the action of the osteoclasts, causing more bone breakdown, but it especially increases the tendency of the osteoblasts to build abnormally weak bone. This is why prostate cancer has been known for years as a cancer that causes osteoblastic bone disease. By reducing the ability of the osteoclasts to do an abnormal amount of damage, Xgeva and Zometa are effective at reducing bone loss and SREs in prostate cancer patients.

Question: Why does prostate cancer tend to travel to the bones more as compared to most other body sites?

Answer: Bone releases or produces a large number of compounds to which prostate cancer is attracted, more so than most other locations in the body. There is research ongoing to attempt to discover everything related to bones that prostate cancer finds attractive to determine whether production of these compounds can be shut off in order to fight the cancer. It is plausible that Xgeva and Zometa and other osteoporosis drugs may work partly by shutting off the production of some of these compounds.

Question: When prostate cancer goes into the bone, is this the same thing as “bone cancer” or “cancer of the bones”?

Answer: No. Cancer that starts in the bone is very different. Cancer that starts in the prostate and eventually goes into the bone can be associated with minimal to major problems. There can be a single tumor at one bone site or many tumors located in many bone sites from head to toe. The impacts of cancer that goes to the bones vary in each person.

Question: When during the course of HRPC is it best to start Xgeva or another bone-protecting drug?

Answer: Research has demonstrated that the earlier these drugs are taken in the course of HRPC, the better the results. In fact, it is best to start the drugs before there is any cancer-related bone pain, but they still work well at most time periods. It is not usual for men to have received them or another bone-health drug before being diagnosed with HRPC. Some men are given Xgeva or Zometa the moment they start on hormone therapy for any stage of cancer. You will discuss treatment intervals with your physician. More treatments can equate to more benefit, but also can increase the risk of rarer side effects. For this reason, some experts suggest limited treatment with Xgeva or Zometa as opposed to continuous use. There are clinical trials considering treatment frequency, so be aware that the timing and length of treatment need to be a matter of ongoing discussion.

Question: Do these drugs help with other types of cancer?

Answer: Yes. These drugs have also been shown to be a benefit in breast, kidney, and lung cancers and multiple myeloma (cancer of the immune cells of the bone marrow). These are also exactly the same drugs used currently by some post-menopausal women to prevent bone loss from osteoporosis. As you can see, these drugs have fairly diverse applications in the area of bone health.

Radiopharmaceutical Drugs

SAMARIUM-153	STRONTIUM-89
Also known as Quadramet	Also known as Metastron
How is it taken? IV	How is it taken? IV
Approval status FDA approved	Approval status FDA approved
Company EUSA-Pharma Inc.	Company Amersham Healthcare and AstraZeneca

Advantages Radiopharmaceutical drugs (radioactive IV drugs) are given several times over a period of weeks to months, in general. They are used to treat pain when cancer has gone into the bones. Once the drug is given, it goes through the body seeking cancerous areas and emits energy particles that kill some of the cells. Many individuals get some pain relief in the first week. Only one of these drugs can be given. They are never given in combination. In conjunction with chemotherapy, each may provide a survival benefit.

The catch The side effects from these drugs result from radiation that goes into the bone and can cause blood cell production (of white blood cells and platelets) to be reduced. Less commonly, diarrhea can occur. The half-life of the drug samarium is much shorter than that of strontium; it seems to cause fewer bone marrow side effects because it emits radiation for a shorter time. Therefore, samarium has become more popular lately among some men with HRPC.

What else do I need to know? A newer radiopharmaceutical, Alpharadin (radium-223), involves alpha radiation, which generally travels a shorter distance compared to beta radiation drugs (such as samarium and strontium), so the benefit-to-risk ratio may be better for patients (see chapter nine). Regardless, all of these medications work well and are probably underused in HRPC patients with bone pain.

Other Non-Bisphosphonate Bone Health Drugs

As a final thought in this area, we should mention other bone-health drugs that are not in the bisphosphonate drug class. There are several available, including:

• Calcitriol (pills) should not be used by most patients. It was combined with chemotherapy in a recent trial of men with HRPC. It did not improve their condition and may have even made it a little worse.

• Estrogen (see also the secondary hormonal treatments chapter), a partially effective secondary hormonal therapy, has cardiovascular side-effect issues, so it is not a popular osteoporosis drug for HRPC.

• Parathyroid hormone (PTH or Forteo, an injection) is an effective FDA-approved osteoporosis drug for men and women, but it is not being used in cancer patients because of a lack of research in this area.

• Strontium ranelate (pills, not FDA approved) is an effective drug used around the world, but it has not been tested enough in cancer patients. The same is true for strontium dietary supplements.

• Raloxifene (Evista, a pill) is FDA approved for osteoporosis, but not in HRPC because of a lack of research and also because it increases the risk of blood clots.

• Toremifene (pill) is not FDA approved for prostate cancer and may increase the risk of blood clots.

The bottom line is that when it comes to HRPC, the only FDA-approved drugs to reduce SREs are Xgeva or Zometa.

Notes