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.

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:

• Treatment or prevention of osteoporosis in males or postmenopausal females 
  • 5 mg IV once yearly[2]

• Treatment or prevention of glucocorticoid-induced osteoporosis
  • 5 mg IV once yearly[4]

• Paget disease of bone 
  • 5 mg IV once, retreatment can be considered in the setting of disease relapse/recurrence[5]

• Hypercalcemia of malignancy 
  • 3 to 4 mg IV once[6]

• Multiple myeloma 
  • 4 mg IV every 3 to 4 weeks[7]

• Solid tumor bone metastasis
  • 4 mg IV every 3 to 4 weeks[13][14]

• Prevention of bone loss related to aromatase inhibitor therapy 
  • 5 mg IV once every two years[15]

• Prevention of bone loss related to androgen deprivation therapy 
  • 5 mg IV once every two years[15]

• Breast cancer adjuvant therapy 
  • 4 mg IV once every 6 months for three years or 4 mg IV once every 3 months for two years[16]

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

• Treatment or prevention of osteoporosis in males or postmenopausal females, treatment or prevention of glucocorticoid-induced osteoporosis, and Paget disease of bone
  • Avoid use in the following situations:
    • Patients with acute kidney injury 
    • Patients with a creatinine clearance (CrCl) less than or equal to 35 mL/minute[2]

• Hypercalcemia of malignancy
  • Avoid use in patients with serum creatinine greater than 4.5 mg/dL[6]

• Multiple myeloma and solid tumor bone metastasis
  • Dose reduction is required in patients with CrCl less than or equal to 60 mL/min, but dosing intervals are not impacted
    • CrCl 50 to 60 mL/min
      • The dose should be adjusted to 3.5 mg
    • CrCl 40 to 49 mL/min
      • The dose should be adjusted to 3.3 mg
    • CrCl 30 to 39 mL/min
      • The dose should be adjusted to 3 mg[7]

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]