Zometa (zoledronic acid)

What Is Zometa?

Zometa® (zoledronic acid) is a medication known as a bisphosphonate that prevents bone damage in multiple myeloma patients. Our body closely controls cells that build bone (osteoblasts) and cells that break down bone (osteoclasts). For myeloma patients, signals sent by myeloma cells can disturb cell control by stimulating osteoclasts, leading to excess bone breakdown. Myeloma patients may experience various bone problems, including weak bones, lytic lesions (destruction of an area of bone), and fractures or breaks in the bone. 

Experts from the International Myeloma Working Group recommend Zometa as the preferred targeted treatment in patients with newly diagnosed myeloma, whether or not they are diagnosed with bone disease.¹

In addition to preventing bone damage, research suggests that Zometa may also have an antimyeloma effect. In the Myeloma IX trial of studying bisphosphonate and thalidomide-based therapy in 1,970 patients, Zometa improved progression-free survival by about two months and reduced mortality by about 5.5 months compared to clodronic acid.^2,3

Who Is a Candidate for Zometa? 

Zometa may be recommended for myeloma patients, even if you do not have current bone disease. Zometa is the preferred bone-targeted treatment in patients with newly diagnosed myeloma, except in certain circumstances, such as patients with impaired kidney function.⁴  If you have kidney impairment, your doctor may offer another medication, such as Xgeva® (denosumab). 

Hypocalcemia or low calcium levels in your blood must be corrected before starting treatment with Zometa. Your doctor will do a blood test to measure your calcium levels before starting treatment. Depending on the results, your doctor may recommend taking calcium and vitamin D supplements. Calcium and vitamin D are often given as pills to take at home.  

You may not be eligible to take Zometa if you are pregnant because Zometa can cause harm to a developing unborn baby.

There are other reasons you may not be a candidate for Zometa. Please see the package insert for more information and discuss Zometa with your doctor.

How Is Zometa Given?

Zometa is administered monthly by an IV infusion. The standard dose is 4 mg infused during 15–45 minutes. Toxicities associated with Zometa are related to dosage, frequency of administration, and duration of infusion. Therefore, your doctor may recommend to reduce your dose and/or frequency of administration, and/or increase the duration of infusion.

What Are Potential Side Effects and Concerns with Taking Zometa?

The kidney toxicity-related concern with the use of Zometa is an increase in serum creatinine. Reports of both increased serum creatinine and occasionally more severe kidney damage called acutetubular necrosis (ATN) have raised questions if Zometa must be used more cautiously to minimize the potential for kidney-related problems.

Your serum creatinine level should be checked before each dose of Zometa, especially if there is concern about kidney function, such as with Bence-Jones myeloma, diabetes, long-standing high blood pressure, and in elderly or frail patients. 

If you had normal renal (kidney) function at the outset, and your serum creatinine value increases by 0.5 mg/dL, or if you had abnormal renal function at the outset, and your serum creatinine value increases by 1.0 mg/dL, your doctor should hold the next dose of Zometa until your serum creatinine value returns to within 10% of the baseline. 

If you experienced a mild elevation in serum creatinine value, which then returns to within 10% of the baseline, your doctor may consider adjustments to your treatment schedule, such as increasing the time of infusion from 15 minutes to 30 minutes or more, using a larger volume of diluting fluids, or delaying the administration of the next dose. Ask your doctor which option is most appropriate for your individual case.

The Z-MARK clinical trial, conducted from 2007 through 2012 at 67 centers in the U.S., evaluated the effectiveness and safety of a dosing method for Zometa in preventing skeletal complications in121 patients with advanced  myeloma who were on an IV bisphosphonate for about 1–2 years. Participants received the standard dose or a reduced dose of Zometa every 4 weeks or every 12 weeks for up to 96 weeks. Participants in the “every 12 weeks” group who experienced a skeletal-related event (SRE) were switched to the “every 4 weeks” group.

Study results published in 2016 showed that “the use of Zometa every 12 weeks compared with every 4 weeks did not result in an increased risk of skeletal events over 2 years.” 

Updated ASCO Guidelines and Zometa

The updated ASCO guidelines state that “for patients without active myeloma who are receiving maintenance therapy, receiving bisphosphonates every 3 months, rather than monthly, is an option.” The guidelines note that “there are insufficient data to recommend a specific duration of bisphosphonate therapy” beyond 2 years. Monthly treatment is to be resumed “upon relapse with new-onset SREs.”

Other Potential Side Effects with Zometa

Be sure to discuss with your doctor the possible side effects of Zometa, including the following:

Osteonecrosis of the jaw

Osteonecrosis of the jaw (ONJ) is a problem that occurs in 3%–4% of patients with myeloma or other cancers who have been treated with either bisphosphonates or Xgeva. Often preceded by inflammation or an infection in the mouth, ONJ produces pain, swelling, and bone damage around the tooth sockets in the jaws. 

Bone tissue may die or deteriorate, resulting in:

• Loose teeth
• Sharp edges of exposed bone
• Bone spurs
• Small fragments of bone or dead tissue breaking loose

Symptoms may not be obvious at first, or may include pain, swelling, numbness, a “heavy jaw” feeling, or loosening of a tooth.

• Before treatment with any bone-modifying agent (BMA), such as Zometa, all myeloma patients should undergo a dental evaluation, preferably by an oral surgeon or dental oncologist familiar with ONJ. Careful monitoring and follow-up are required.
• Prevention can help avoid or reduce the complications of ONJ. Here are three things you can do to help prevent ONJ:
  • Tell your dentist if you are receiving treatment with a BMA. 
  • Maintain excellent oral hygiene.
  • Visit your dentist regularly.
• If an infection is present, antibiotics are the recommended treatment. The choice of antibiotic depends upon the type of infection. An oral rinse may be appropriate.
• If required, proceed with preventive dental care before starting treatment with a BMA.
• Management without surgery is recommended as a first step. Minor dental work to reduce sharp edges or remove injured tissue may be required. A protective mouth guard may be helpful.
• If possible, avoid tooth extraction and any elective jaw surgery. If dental surgery is required, BMA therapy should be interrupted. Current data indicate poor healing with continued BMA therapy in surgical situations.
• If problems persist or if healing is slow, you and your doctor may consider stopping bisphosphonate therapy for 2 to 4 months to facilitate recovery.
• Dentures can be worn, but they may need adjustment. Dental implants are not recommended. Use of hyperbaric oxygen does not appear to be helpful.

Kidney dysfunction

All bisphosphonates are potentially toxic to the kidneys. Because the myeloma itself can affect kidney function (through damage caused by myeloma light chain protein and/or by elevated blood calcium), kidney-related side effects are a concern.

Before you begin treatment with a BMA such as Zometa, ask your doctor if the BMA in combination with other medications you are receiving may be more likely to negatively affect your kidney function. Other medications include myeloma therapies as well as nonsteroidal anti-inflammatory drugs (NSAIDs).

Fever

Fever (or pyrexia) is a temperature of 100.4°F (38°C) or higher. Fever may occur as an infusion-related reaction (IRR) associated with bisphosphonate use such as Zometa. The fever is usually mild; each treatment center has its own definition for “mild” temperature. You may experience a fever during your IV infusion or during the hours after, and the fever may last for several hours. Typically, fever occurs with the first or second infusion, and less frequently (if at all) with subsequent infusions. Patients who have severe recurrent fevers may not be able to tolerate IV bisphosphonates. As with other possible side effects, promptly report your fever to your doctor.

Vein irritation

With IV infusions of bisphosphonates, mild phlebitis (vein irritation) can occur at the infusion site. The phlebitis is usually mild, and patients typically recover within 1 to 2 days. To avoid any leakage of medication around the vein, your healthcare team should carefully monitor your veins during each infusion.

At the end of the bisphosphonate infusion, a short infusion of saline is recommended to clear the Zometa from the area and reduce the chance of phlebitis.

General aches and pains

These effects sometimes occur briefly, along with fever, with infused bisphosphonates. Back pain has been reported in patients who are receiving therapy with Xgeva. Ask your doctor if receiving medication before your infusions may be beneficial for you.

Combining Zometa with Myeloma Therapies

In general, BMAs can be safely combined with most myeloma therapies. Your doctor may decide not to give these therapies on or close to the same day as you receive an intravenous treatment for myeloma. Talk to your doctor to be sure that the BMA you are receiving is not being combined with another drug that can harm your kidneys.

Insurance coverage

In the U.S., the Centers for Medicare & Medicaid Services (CMS), a federal agency that administers the Medicare program, rei burse for bisphosphonate therapy. Most other insurance programs in the U.S. also reimburse for bisphosphonate therapy. Xgeva is significantly more expensive than generic Aredia or Zometa, so unless there are medical reasons why a patient cannot receive bisphosphonate therapy (e.g., kidney disease), there may be insurance issues with receiving reimbursement for Xgeva. If you experience any problems with insurance coverage or reimbursement, speak with your healthcare team.

Since hospitals and clinics set up contracts for one product versus another, it’s important to double-check which agent, from which source, is being given to you. Some patients may experience a new side effect or be intolerant of the solution into which the active ingredients are added. If this happens to you, be sure to find out what drug you received and which company manufactured it, and report your side effects to your doctor.

For a complete list of side effects, please see the Zometa package insert or check out the additional resources below.

Additional Information

The European Public Assessment Report on Zometa

FDA Package Insert: Zometa

Denosumab versus zoledronic acid in bone disease treatment of newly diagnosed multiple myeloma: an international, double-blind, double-dummy, randomized, controlled, phase 3 study