What is zoledronic acid used for. How is zoledronic acid administered. What are the common side effects of zoledronic acid. How can patients manage side effects of zoledronic acid. What precautions should be taken when using zoledronic acid.

Understanding Zoledronic Acid: A Powerful Bisphosphonate

Zoledronic acid, available under the brand names Zometa® and Reclast®, is a potent medication classified as a bisphosphonate. This drug plays a crucial role in managing bone-related complications associated with certain cancers and other bone disorders. Its primary function is to slow down the destruction of bone tissue caused by cancer cells, making it an invaluable tool in oncology and bone health management.

How Does Zoledronic Acid Work?

Zoledronic acid works by inhibiting the activity of osteoclasts, the cells responsible for breaking down bone tissue. By doing so, it helps maintain bone density and strength, particularly in patients whose bones are under attack from cancer cells. This mechanism of action is particularly beneficial in cases of bone metastasis and multiple myeloma.

Indications for Zoledronic Acid Use

• Bone metastases from breast, prostate, and lung cancers
• Multiple myeloma
• Osteoporosis
• Paget’s disease of bone

Administration and Dosage of Zoledronic Acid

The administration of zoledronic acid is a carefully controlled process that requires medical supervision. Understanding how this medication is given can help patients prepare for their treatment sessions and manage their expectations.

Route of Administration

Zoledronic acid is administered intravenously (IV), meaning it is delivered directly into a vein. This method ensures that the medication reaches the bloodstream quickly and efficiently, maximizing its effectiveness in protecting bone health.

Dosage Considerations

The dosage and frequency of zoledronic acid treatments are not one-size-fits-all. Healthcare providers determine the appropriate regimen based on several factors:

• The specific condition being treated
• The patient’s overall health status
• Kidney function
• Response to previous treatments

Typically, treatments are given at regular intervals, which could range from monthly to yearly, depending on the medical indication.

Supplementary Medications

To enhance the effectiveness of zoledronic acid and support overall bone health, healthcare providers often prescribe calcium and vitamin D supplements. These supplements play a crucial role in bone metabolism and can help mitigate some of the potential side effects of bisphosphonate therapy.

Monitoring During Zoledronic Acid Treatment

Close medical supervision is essential during zoledronic acid treatment to ensure safety and efficacy. Regular monitoring allows healthcare providers to adjust the treatment plan as needed and address any emerging concerns promptly.

Laboratory Tests

Patients undergoing zoledronic acid treatment will have regular lab work to monitor various aspects of their health:

• Electrolyte levels: To ensure proper balance of minerals in the body
• Creatinine levels: As an indicator of kidney function
• Calcium levels: To prevent hypocalcemia, a potential side effect

Kidney Function Monitoring

Special attention is paid to kidney function throughout the course of treatment. Zoledronic acid can potentially affect the kidneys, so creatinine levels are closely watched. If any significant changes are observed, the healthcare provider may adjust the dosage or consider alternative treatments.

Managing Side Effects of Zoledronic Acid

While zoledronic acid is an effective treatment for bone-related conditions, it can cause various side effects. Understanding these potential effects and knowing how to manage them can significantly improve the treatment experience for patients.

Nausea and Vomiting

Gastrointestinal disturbances are common side effects of many medications, including zoledronic acid. To manage nausea and vomiting:

• Take anti-nausea medications as prescribed by your doctor
• Avoid heavy, greasy, spicy, or acidic foods
• Try eating small, frequent meals rather than large ones
• Stay hydrated with clear fluids

If nausea persists or leads to severe vomiting, contact your healthcare provider immediately.

Anemia and Fatigue

Zoledronic acid can sometimes lead to a decrease in red blood cell count, resulting in anemia and fatigue. To manage these symptoms:

• Get plenty of rest
• Maintain a balanced diet rich in iron
• Consider gentle exercise, as approved by your doctor
• Report any severe fatigue or shortness of breath to your healthcare team

Bone, Joint, and Muscle Pain

Some patients experience musculoskeletal pain after receiving zoledronic acid. This can range from mild discomfort to severe pain. Management strategies include:

• Over-the-counter pain relievers, as approved by your doctor
• Gentle stretching exercises
• Application of heat or cold packs
• Physical therapy, if recommended by your healthcare provider

Rare but Serious Side Effects: What to Watch For

While most side effects of zoledronic acid are manageable, there are some rare but serious complications that patients and healthcare providers need to be aware of. Recognizing these potential issues early can lead to prompt intervention and better outcomes.

Osteonecrosis of the Jaw (ONJ)

Osteonecrosis of the jaw is a rare but significant side effect associated with bisphosphonate therapy, including zoledronic acid. ONJ is characterized by the death of bone tissue in the jaw, which can lead to serious complications. Symptoms to watch for include:

• Pain or swelling in the jaw
• Loosening of teeth
• Exposed bone in the mouth
• Numbness or tingling in the jaw
• Slow healing of the gums, especially after dental procedures

To reduce the risk of ONJ, patients should:

• Maintain excellent oral hygiene
• Have a comprehensive dental exam before starting zoledronic acid treatment
• Inform their dentist about their zoledronic acid treatment
• Avoid invasive dental procedures during treatment, if possible

Atypical Femur Fractures

Long-term use of bisphosphonates, including zoledronic acid, has been associated with a rare type of thigh bone (femur) fracture. These fractures can occur with minimal or no trauma to the area. Patients should be aware of the following symptoms:

• Dull, aching pain in the groin, hip, or thigh
• Difficulty walking or standing for long periods
• Sudden, severe pain in the thigh or hip area

If these symptoms occur, patients should contact their healthcare provider immediately for evaluation.

Special Precautions and Considerations

Certain patient groups require special attention when considering zoledronic acid treatment. Understanding these considerations can help ensure safe and effective use of the medication.

Kidney Function

Patients with pre-existing kidney issues or those at risk for kidney problems require careful monitoring during zoledronic acid treatment. Your healthcare provider may adjust the dosage or frequency of treatment based on your kidney function. It’s crucial to stay well-hydrated and report any changes in urination patterns to your doctor.

Pregnancy and Breastfeeding

Zoledronic acid is not recommended for use during pregnancy or while breastfeeding. The medication can potentially harm the developing fetus or infant. Women of childbearing age should use effective contraception during treatment and discuss family planning with their healthcare provider.

Dental Health

Due to the risk of ONJ, maintaining good oral hygiene is crucial for patients on zoledronic acid. Before starting treatment:

• Complete any necessary dental work
• Inform your dentist about your planned treatment
• Establish a regular dental check-up schedule

During treatment, avoid elective dental procedures if possible, and inform your oncology team of any dental issues that arise.

Long-Term Management and Follow-Up

Zoledronic acid treatment often requires long-term management and regular follow-up with healthcare providers. This ongoing care ensures that the treatment remains effective and that any potential complications are caught early.

Bone Density Monitoring

Regular bone density scans may be recommended to assess the effectiveness of the treatment and monitor for any changes in bone health. These scans can help guide decisions about continuing or modifying treatment.

Cancer Monitoring

For patients receiving zoledronic acid as part of their cancer treatment, regular check-ups and imaging studies will be necessary to monitor the progression of the disease and the effectiveness of the overall treatment plan.

Lifestyle Modifications

Patients on long-term zoledronic acid therapy should consider lifestyle modifications to support bone health:

• Regular weight-bearing exercise, as approved by your doctor
• A balanced diet rich in calcium and vitamin D
• Avoiding smoking and excessive alcohol consumption
• Fall prevention strategies, especially for older adults

By following these guidelines and maintaining open communication with their healthcare team, patients can maximize the benefits of zoledronic acid treatment while minimizing potential risks and complications.

Zoledronic Acid (Zometa®, Reclast®) | OncoLink

Author: Karen Arnold-Korzeniowski, BSN RN

Read more about our content writing process

Last Reviewed: August 5, 2021

Pronounced: ZOE-le-DRON-ik AS-id

Classification: bisphosphonate

About: Zoledronic Acid (Zometa®, Reclast®)

Zoledronic acid is a type of medication called a bisphosphonate, which is used to slow the destruction of bone caused by cancer cells. Cancer cells from some tumors (most commonly breast, prostate and lung cancers) can spread to the bone, which is called bone metastasis. Multiple myeloma is a type of cancer affecting plasma cells, which are found in the bone marrow, and thus directly involves bone. In both of these situations, the cancer cells cause breakdown or wearing away of normal bone. In turn, affected bones become more fragile; they may be painful and can even break due to the damage from the cancer cells.  

How to Take Zoledronic Acid

Zoledronic acid is administered intravenously (IV, into a vein). Your dose, and how often you receive it, will be determined by your provider. Your healthcare provider may prescribe you calcium and vitamin D supplements to promote bone health.

You will have lab work done to monitor your electrolytes during treatment. Your creatinine level (indicator of your kidney function) will be monitored closely to determine if the medication is affecting your kidneys. If it is, the dose may be altered or the medication stopped completely.

Possible Side Effects of Zoledronic Acid

There are a number of things you can do to manage the side effects of zoledronic acid. Talk to your care team about these recommendations. They can help you decide what will work best for you. These are some of the most common or important side effects:

Nausea and/or Vomiting

Talk to your doctor or nurse so they can prescribe medications to help you manage nausea and vomiting. In addition, dietary changes may help. Avoid things that may worsen the symptoms, such as heavy or greasy/fatty, spicy or acidic foods (lemons, tomatoes, oranges). Try antacids, (e.g. milk of magnesia, calcium tablets such as Tums), saltines, or ginger ale to lessen symptoms.

Call your doctor or nurse if you are unable to keep fluids down for more than 12 hours or if you feel lightheaded or dizzy at any time.

Low Red Blood Cell Count (Anemia)

Your red blood cells are responsible for carrying oxygen to the tissues in your body. When the red cell count is low, you may feel tired or weak. You should let your oncology care team know if you experience any shortness of breath, difficulty breathing or pain in your chest. If the count gets too low, you may receive a blood transfusion. 

Bone, Joint, and Muscle Pain

Zoledronic acid can cause bone, joint and/or muscle pain that can be severe. This can occur from 1 day to several months after starting the medication. Report these symptoms to your provider, who can advise you on strategies to relieve the pain. Pain in the hip, thigh, and groin can be caused by an atypical femur fracture. Notify your provider immediately of any new pain in this area. 

Fatigue

Fatigue is very common during cancer treatment and is an overwhelming feeling of exhaustion that is not usually relieved by rest. While on cancer treatment, and for a period after, you may need to adjust your schedule to manage fatigue. Plan times to rest during the day and conserve energy for more important activities. Exercise can help combat fatigue; a simple daily walk with a friend can help. Talk to your healthcare team for helpful tips on dealing with this side effect.

Breathing Difficulties

Bronchoconstriction is the constriction of the lung airways caused by muscle tightening. Patients who are sensitive to aspirin may have bronchoconstriction related to zoledronic acid. Notify your provider of any trouble breathing, tightness in the chest or wheezing. 

Less common but important side effects can include:

• Osteonecrosis of the Jaw: Osteonecrosis of the jaw (ONJ) is a rare side effect, however, it is important that you know about it and take steps to protect your dental health. The maxilla (upper jaw bone) and mandible (lower jaw bone) are normally covered by gum tissue. In the case of ONJ, this tissue disappears and the bone is exposed. Typical symptoms associated with ONJ are: pain, swelling or infection of the gums, loosening of the teeth, exposed bone (often at the site of a previous tooth extraction). Some patients may report numbness or tingling in the jaw or a “heavy” feeling jaw. ONJ may have no symptoms for weeks or months and may only be recognized by the presence of exposed bone. ONJ most often occurs soon after a dental procedure, though not always. Stop treatment with zoledronic acid at least 3 weeks prior to any dental procedures.
  • Prior to starting therapy, you should have a complete dental exam, cleaning, and removal of any teeth in poor health.
  • Dentures should be checked for proper fit.
  • Brush your teeth after meals and at bedtime with a soft brush. Floss gently once a day. If your gums bleed, talk with your healthcare team to see if you can continue to floss.
  • Check your teeth and gums in a mirror daily for any sores, swelling, loose teeth, pain or numbness, or other changes and report these to your dentist or oncology team immediately.
• Acute Reaction: The infusion can cause a reaction that occurs within 3 days of the infusion and may cause chills, fever and muscle aches. Prior to taking any medications, check with your healthcare provider as these can also be signs of infection. If you are able to take anti-inflammatory medications, such as ibuprofen (Motrin) and naproxen (Aleve), they may be helpful in treating these side effects. Reactions are most common during or shortly after the first infusion, but not after subsequent doses.
• Kidney problems: This medication can cause kidney problems, including an increased creatinine level, which your oncology care team may monitor for using blood tests. Notify your healthcare provider if you notice decreased urine output, blood in the urine, swelling in the ankles, or loss of appetite.
• Hypocalcemia: This medication can lower your calcium levels. Your healthcare team will monitor your calcium levels with blood tests. If you experience muscle cramps or confusion, contact your healthcare team.

Reproductive Concerns

Exposure of an unborn child to this medication could cause birth defects, so you should not become pregnant or father a child while on this medication. Effective birth control is necessary during treatment. Even if your menstrual cycle stops or you believe you are not producing sperm, you could still be fertile and conceive. You should consult with your healthcare team before breastfeeding while receiving this medication.

Zoledronate – StatPearls – NCBI Bookshelf

Continuing Education Activity

Zoledronate, also known as zoledronic acid, is an example of a class of drugs known as bisphosphonates. It is a bisphosphonate that is administered intravenously. This medication is used to treat many forms of metabolic bone disease. Zoledronate is broadly classified as an antiresorptive medication. Zoledronate is a commonly prescribed agent that is approved and indicated for both benign and malignant bone disorders. This activity outlines the indications, actions, and contraindications for zoledronate. This activity will highlight the mechanism of action, adverse event profile, and other key factors (e.g., off-label uses, dosing, monitoring) pertinent for members of a healthcare team to utilize in the treatment of patients on zoledronate.

Objectives:

• Outline the indications for the use of zoledronate.

• Review the mechanism of action of zoledronate.

• Describe adverse reactions associated with zoledronate.

• Summarize the contraindications and monitoring needed for zoledronate.

Access free multiple choice questions on this topic.

Indications

Zoledronate, also known as zoledronic acid, is an intravenous (IV) medication that belongs to a class of drugs known as bisphosphonates. It is an antiresorptive therapy used to treat various bone conditions, including both malignant and benign diseases.[1]

Food and drug administration (FDA) approved indications for this agent include the prevention and treatment of osteoporosis in postmenopausal females, osteoporosis in males, glucocorticoid-induced osteoporosis, Paget disease of bone, hypercalcemia of malignancy, multiple myeloma, and solid tumor bone metastases.[2][3][4][5][6][7][8]

Non-FDA-approved indications include adjuvant therapy in breast cancer, bone loss in postmenopausal patients related to aromatase inhibitor therapy, and bone loss related to androgen deprivation therapy. [9][10]

As zoledronate is administered intravenously, it can be used in patients with an intolerance or contraindication to oral bisphosphonates. It is the treatment of choice for Paget disease of bone and hypercalcemia of malignancy. Using zoledronate as initial therapy in preventing postmenopausal osteoporosis is also appropriate in patients with very high fracture risk.[2][11]

The American Association of Clinical Endocrinologists defined very high fracture risk in the 2020 postmenopausal osteoporosis guideline. A patient is said to be at a very high fracture risk if at least one of the following is present, including

1. Postmenopausal with a history of multiple fractures

2. The presence of a fracture within the preceding 12 months

3. Fracture(s) despite being on appropriate osteoporosis treatment

4. Fracture while on a drug known to cause skeletal harm

5. T-score less than -3.0

6. High fall risk, history of a fall resulting in an injury, or a very high risk of a fracture using a validated fracture risk algorithm[2]

Mechanism of Action

An integral step in new bone formation is the avid binding of inorganic pyrophosphate (PPi) to hydroxyapatite crystals found in bone. Nitrogen-containing bisphosphonates such as zoledronate are PPi analogs with a higher binding affinity. These bisphosphonates, therefore, preferentially bind to bone, especially at sites that are being actively remodeled. The bone-bound bisphosphonates are released during the process of bone breakdown by osteoclasts.

Once released, the bisphosphonate is then absorbed by osteoclasts. Within the osteoclasts, the bisphosphonate binds to and blocks the activity of farnesyl diphosphate synthase (FPPS). FPPS is an essential intracellular enzyme in the 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase pathway responsible for producing isoprenoid lipids, cholesterol, and other sterols. Inhibition of this pathway prevents the posttranslational modification of small proteins, including guanosine triphosphate binding proteins, which are needed for the activity and survival of osteoclasts.

Therefore, the administration of zoledronate increases osteoclast apoptosis, thus reducing bone resorption and loss. Osteoblastic activity and bone formation are not impacted by the use of zoledronate. Hence the use of this agent shifts bone metabolic activity in favor of bone formation, reducing bone loss. This ultimately leads to an increase in bone mass and bone density as bone formation exceeds resorption.[12]

Administration

Zoledronate is administered in the following manner:

Dose adjustments may be necessary for patients with renal dysfunction and are as follows:

Adverse Effects

Adverse effects associated with zoledronate include hypocalcemia, secondary hyperparathyroidism, musculoskeletal pain, acute phase response, renal injury, atypical femur fractures, osteonecrosis of the jaw, atrial fibrillation, and ocular inflammation.[17][18]

All bisphosphonates can cause hypocalcemia and secondary hyperparathyroidism; IV formulations such as zoledronate are more prone to cause these adverse effects. Normal serum calcium is largely maintained by a balance between osteoblast-mediated bone formation and osteoclast-mediated bone resorption. The mechanism behind hypocalcemia and secondary hyperparathyroidism from zoledronate use relates to its actions on the osteoclasts.

Zoledronate halts bone resorption and calcium release by osteoclasts, resulting in hypocalcemia. To conserve calcium, parathyroid hormone (PTH) levels increase and antagonize the actions of zoledronate by acting at the level of the kidneys. The increase in PTH and a decrease in both serum phosphorus and calcium are dose-dependent. In the kidneys, PTH stimulates the production of 1,25-dihydroxy vitamin D, and tubular reabsorption of calcium is increased. Over time bisphosphonate-induced hypocalcemia will typically abate.

However, symptomatic hypocalcemia can occur and would be seen within days of zoledronate administration. Risk factors for symptomatic hypocalcemia include renal failure, vitamin D deficiency, and preexisting hypoparathyroidism. To reduce this risk, supplementation with calcium and vitamin D with the use of zoledronate is recommended. Supplementation should begin at least two weeks before zoledronate administration.[17]

Musculoskeletal pain, including myalgias and arthralgia, has been reported after zoledronate therapy. This adverse effect has been said to occur at varying time points following treatment, ranging from days to years. The mechanism behind this effect is not understood.[17][18]

An acute phase response (APR) with arthralgias, myalgias, pyrexia, chills, and fatigue has been described – this is described as a post-infusion influenza-like illness. This adverse effect is most common following the first infusion, with the frequency and incidence of APR decreasing with subsequent infusions. Symptoms begin approximately 24 to 72 hours following the infusion and resolve within 72 hours.

APR is often self-limiting, though symptomatic treatment with non-steroidal anti-inflammatory drugs or acetaminophen is recommended. Recent data suggest that the coadministration of zoledronate with acetaminophen may reduce the risk of APR in half. The risk of APR may be influenced by the underlying indication for which treatment was initiated.[17][18]

APR is thought to be mediated by high levels of pro-inflammatory cytokines, including interleukin-6 and tumor necrosis factor-alpha. A study looking at patients receiving treatment for aromatase inhibitor-associated osteoporosis noted that APR was around 70%. A large study looking at APR after using zoledronate in women with post-menopausal osteoporosis revealed the incidence to be approximately 40%.[19][20]

The most common form of renal injury following zoledronate administration is acute tubular necrosis (ATN). Risk factors for the development of ATN have been described and include rapid infusions, shorter time intervals between infusions, and higher doses.[18]

Observational studies have demonstrated a risk between long-term zoledronate use and subtrochanteric or atypical femur fractures. These atypical fractures are located between the diaphysis and subtrochanteric region of the femur. These fractures occur with minimal to no trauma and can be bilateral. Symptoms include aching or dull pain in the thigh or groin. Certain comorbid conditions and medications have been associated with a further increase in the risk, including vitamin D deficiency, rheumatoid arthritis, and corticosteroid use. This risk can be decreased with the use of zoledronate holidays.[21][22]

Zoledronate-induced osteonecrosis of the jaw (ONJ) has been extensively described. This relationship seems to be influenced by both the dose and indication for which the medication is prescribed. Treatment of bone metastasis and multiple myeloma with zoledronate 4 mg IV every 3 to 4 weeks carries a higher risk when compared to the treatment of osteoporosis. Other factors, including head/neck radiation, dental disease, and dental procedures with bone manipulation, are also known to increase the risk of the development of ONJ.[17][18]

Atrial fibrillation has also been reported following zoledronate administration. The data regarding this complication is not as robust as other complications, but studies have shown that zoledronate may modestly increase the risk for atrial fibrillation.[23]

Ocular manifestations have been linked to zoledronate therapy. This includes conjunctivitis, scleritis, and uveitis. Overall these reactions appear to be uncommon but warrant prompt evaluation. Thus, patients receiving zoledronate and experiencing changes in vision, eye pain, or eye redness should be evaluated by an ophthalmologist.[17][18]

Contraindications

The contraindications to using zoledronate depend on the nature and type of disease being treated.

Hypocalcemia, acute kidney injury, or creatinine clearance (CrCl) less than or equal to 35 mL/minute are contraindications for use in benign bone disease.[24] In the treatment of hypercalcemia of malignancy, the use of zoledronate should be avoided in patients with serum creatinine greater than 4.5 mg/dL.[25] 

Minimal data exist regarding treating solid tumor bone metastasis patients with a CrCl of less than 30 mL/min. Therefore caution is necessary for this patient group.[26]

A history of allergic reaction to zoledronate is also a contraindication. This contraindication applies to all indications of zoledronate use.

Zoledronate is pregnancy category D and should be avoided during pregnancy, and caution is necessary for women of childbearing age.

Monitoring

The following labs should be checked before each infusion: renal function and clearance, vitamin d, calcium, magnesium, and phosphorus. Electrolyte imbalances and vitamin D deficiency should be corrected before treatment is initiated.[2]

In patients receiving treatment for osteoporosis, periodic monitoring of bone mineral density should be completed to check for treatment response and effectiveness.[2]

In patients receiving treatment for Paget disease of bone, alkaline phosphatase requires periodic monitoring.[5]

In patients receiving treatment for multiple myeloma, periodic monitoring for albuminuria is required. [7]

Toxicity

In the event of toxicity or overdose, there are no reversal agents approved by the FDA for this drug.

Enhancing Healthcare Team Outcomes

Zoledronate is a versatile medication that helps prevent morbidity and mortality in various conditions. It is used in different medical and surgical specialties. As it is an infused therapy, patients often receive this treatment in a healthcare facility. Interprofessional collaboration is vital to providing safe and effective care with this medication.

Counseling patients regarding potential side effects of zoledronate begins with the physician. Pharmacists play an integral role in checking for drug interactions. Nurses infuse this medication and monitor for adverse reactions. This approach requires collaboration from all healthcare team members and can help ensure our patients are given optimal treatment. 

The safety of patients receiving treatment with zoledronate relies on the prescriber’s knowledge of the contraindications, monitoring, and dose adjustments required when using this medication. For this medication, each indication has different parameters for each of these categories. Careful attention to these details is needed for each patient care team member. 

Healthcare costs and the appropriate utilization of healthcare resources are of utmost importance. When making decisions regarding patient care, one must ensure that when selecting a treatment option, all aspects of the patient are considered. Many treatment options for osteoporosis are available, and when zoledronate is selected as therapy, patients receive this medication in a healthcare facility intravenously.

This medication requires more invasive procedures for administration compared to its oral counterparts. Also, as it is administered under direct supervision in a healthcare facility, the total healthcare cost is higher than other options. These factors should not deter prescribers from utilizing this treatment option, but appropriate patient selection is required for this drug to have the most benefit. [Level 5] 

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Disclosure: Emma Greear declares no relevant financial relationships with ineligible companies.

Disclosure: Adegbenga Bankole declares no relevant financial relationships with ineligible companies.

Zoledronic acid for osteoporosis and low-energy fractures that complicate its course | Rodionova

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