Continuing Education Activity

Zoledronate, also known as zoledronic acid, is classified as a bisphosphonate and, more broadly, an antiresorptive medication. Zoledronate is approved by the US Food and Drug Administration (FDA) for various indications, including the prevention and treatment of osteoporosis in males and postmenopausal females, glucocorticoid-induced osteoporosis, Paget disease of bone, hypercalcemia of malignancy, multiple myeloma, and solid tumor bone metastases. Zoledronate is administered intravenously and is commonly prescribed and indicated to treat various metabolic bone disorders, including both malignant and benign diseases. As zoledronate is administered intravenously, it can be utilized in patients with an intolerance or contraindication to oral bisphosphonates.

This activity comprehensively reviews indications, mechanisms of action, pharmacokinetics, adverse drug reactions, monitoring strategies, drug-drug interactions, and clinical toxicology of zoledronate, highlighting the crucial roles of healthcare professionals in the comprehensive management of zoledronate therapy. This activity provides clinicians with the necessary expertise and tools for safe and proficient Zoledronate administration by elucidating distinct roles and facilitating collaborative practices within the interprofessional healthcare team. With this comprehensive knowledge regarding zoledronate, clinicians can elevate patient outcomes and establish elevated standards of care when prescribing the drug effectively to patients with bone disorders and other related conditions.

Objectives:

• Identify appropriate candidates for zoledronate therapy based on indications such as osteoporosis, hypercalcemia of malignancy, Paget disease of bone, or other metabolic bone disorders.

• Implement evidence-based protocols for zoledronate administration, dosing, and monitoring in accordance with established guidelines.

• Apply knowledge of zoledronate pharmacology to adjust dosage regimens appropriately in patients with renal dysfunction or other comorbidities.

• Collaborate with other healthcare professionals to optimize zoledronate therapy in complex patient cases, including monitoring for adverse reactions and addressing any potential drug interactions.

Indications

Zoledronate, also known as zoledronic acid, is an antiresorptive medication that belongs to a class of drugs known as bisphosphonates. Zoledronate is administered intravenously (IV) and is commonly prescribed and indicated to treat various metabolic bone disorders, including both malignant and benign diseases.[1] As zoledronate is administered via the IV route, it can be utilized in patients with an intolerance or contraindication to oral bisphosphonates.

FDA-Approved Indications

Zoledronate is approved by the US Food and Drug Administration (FDA) for various indications, including the prevention and treatment of osteoporosis in males and postmenopausal females, glucocorticoid-induced osteoporosis, Paget disease of bone, hypercalcemia of malignancy, multiple myeloma, and solid tumor bone metastases.[2][3][4][5][6][7] 

The Endocrine Society Clinical Practice guideline suggests considering IV bisphosphonates, such as zoledronate, based on the severity of hypercalcemia before initiating calcimimetic therapy. For adults with mild hypercalcemia and accompanying symptoms, starting treatment with calcimimetics is recommended. However, for adults experiencing moderate-to-severe hypercalcemia and related symptoms, initial therapy may involve the use of IV bisphosphonates such as zoledronate or Denosumab.[8]

The 2020 postmenopausal osteoporosis guideline from the American Association of Clinical Endocrinologists defines very high fracture risk. A patient is considered to have a very high fracture risk if they meet at least one of the following criteria:[9]

• Postmenopausal with a history of multiple fractures

• Presence of a fracture within the preceding 12 months

• Fracture(s) despite being on appropriate osteoporosis treatment

• Fracture while on a drug known to cause skeletal harm

• T-score less than -3.0

• 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

Off-Label Uses

Off-label uses of zoledronate include adjuvant therapy in breast cancer, bone loss in postmenopausal patients related to aromatase inhibitor therapy, and bone loss related to androgen deprivation therapy.[10][11] The American Society of Clinical Oncology-Cancer Care Ontario guidelines endorse zoledronate in breast cancer.[12] As per the American Urological Association guidelines, in advanced prostate cancer patients at a high risk of fractures due to bone loss, clinicians should advise preventive treatment using bisphosphonates or denosumab. Furthermore, clinicians might contemplate the use of zoledronate or Denosumab for patients with metastatic castration-resistant prostate cancer (mCRPC) having bony metastases, aiming to prevent skeletal adverse events.[13]

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. Osteoclasts release the bone-bound bisphosphonates during bone breakdown.

When released, the bisphosphonate is absorbed by osteoclasts. The bisphosphonate binds to and blocks the farnesyl diphosphate synthase activity within the osteoclasts. Farnesyl diphosphate synthase 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, administering zoledronate increases osteoclast apoptosis, reducing bone resorption and loss. The use of zoledronate does not impact osteoblastic activity and bone formation. Hence, zoledronate 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.[14]

Pharmacokinetics

Absorption: Zoledronate mean plasma concentrations peak immediately after administration.[15] Zoledronate exhibits a triphasic decline in plasma concentrations, showing rapid reduction from peak levels at the end of infusion to less than 1% of the maximum concentration (Cmax) after 24 hours. The drug displays early disposition phases and a prolonged terminal elimination phase with minimal plasma concentrations observed between days 2 and 28 after infusion, having a terminal elimination half-life of 146 hours. Dose-proportional pharmacokinetics is marked within the 2 to 16 mg dosage range, with low accumulation after repeat administration. 

Distribution: Zoledronate's protein binding in human plasma ranges from 28% to 53%. In vitro studies demonstrate that zoledronate exhibits the greatest affinity for binding to hydroxyapatite in mineralized bone, surpassing alendronate, ibandronate, or risedronate. This heightened binding affinity of zoledronate to mineralized bone explains its prolonged duration of action. Approximately 55% of the administered zoledronate is absorbed by bone, undergoing gradual release into the systemic circulation. The remaining 45% of the dosage is eliminated unchanged through urinary excretion.[16]

Metabolism: Zoledronate is not metabolized by human P450 enzymes.[17]

Elimination: The primary route of elimination for zoledronate is through the kidney.[18] Zoledronate's clearance is independent of the dose but correlates with the creatinine clearance (CrCl). The terminal elimination half-life is 146 hours, indicative of a triphasic elimination.

Administration

Available Dosage Forms, Strengths, and Adult Dosage

Zoledronate is available as an IV solution in strengths of 4 mg/5 mL and 5 mg/100 mL. The recommended adult dosages are as follows:

• Treatment or prevention of osteoporosis in males or postmenopausal females: 5 mg IV yearly.[9]

• Treatment or prevention of glucocorticoid-induced osteoporosis: 5 mg IV yearly[3]

• Paget disease of bone: 5 mg IV once, with retreatment considerations in disease relapse or recurrence cases.[4]

• Hypercalcemia of malignancy: 3 to 4 mg IV once.[5]

• Multiple myeloma: 4 mg IV every 3 to 4 weeks.[6]

• Solid tumor bone metastasis: 4 mg IV every 3 to 4 weeks.[19][20]

• Prevention of bone loss related to aromatase inhibitor therapy: 5 mg IV once every 2 years.[21]

• Prevention of bone loss related to androgen deprivation therapy: 5 mg IV once every 2 years.[21]

• Breast cancer adjuvant therapy: 4 mg IV once every 6 months for 3 years or 4 mg IV once every 3 months for 2 years.[12]

Specific Patient Populations

Hepatic impairment: No clinical studies assessed the impact of hepatic impairment on zoledronate's pharmacokinetics.

Renal impairment: Dosage adjustments may be necessary for patients with renal dysfunction, which are listed below.[22]

• 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 patients with acute kidney injury or those with a CrCl ≤35 mL/min.[9]

• Hypercalcemia of malignancy
  • Avoid use in patients with serum creatinine >4.5 mg/dL.[5]

• Multiple myeloma and solid tumor bone metastasis
  • Dose reduction is required in patients with CrCl ≤60 mL/min, without affecting dosing intervals.
  • The adjusted dosages are as follows:
    • CrCl of 50 to 60 mL/min is 3.5 mg.
    • CrCl of 40 to 49 mL/min is 3.3 mg.
    • CrCl of 30 to 39 mL/CrCl min is 3 mg.[6]

Pregnancy considerations: Zoledronate is categorized as a pregnancy category D drug and should be avoided during pregnancy, and caution is necessary for women of childbearing age. Zoledronate injection's safety profile during pregnancy lacks comprehensive data for assessing potential adverse effects on maternal and fetal health. When pregnancy is identified, it is advisable to discontinue zoledronate. Animal studies demonstrated increased fetal malformations, decreased fetal survival and weight, and maternal complications. The gradual release of bisphosphonates from bone matrices raises concern for potential fetal harm, particularly related to skeletal anomalies, if conception occurs after therapy.

Breastfeeding considerations: Insufficient clinical data exist regarding the presence of zoledronate in human milk or its impact on lactation or breastfed infants. When considering the use of zoledronate, it is important to weigh the benefits of breastfeeding for both the mother and child against the maternal need for zoledronate and any potential risks to the infant related to zoledronate or the mother's underlying condition. Due to the lack of data on zoledronic acid's use during breastfeeding, considering an alternative medication might be advisable, particularly when nursing a newborn or preterm infant.[23]

Pediatric patients: Zoledronate is not indicated for use in children. However, it is used off-label for primary and secondary osteoporosis, osteogenesis imperfecta, hypercalcemia of malignancy, and chemotherapy-related osteonecrosis.[16]

Older patients: Carefully monitoring renal function in older patients is crucial due to the higher prevalence of decreased renal function.

Adverse Effects

The commonly reported adverse reactions include pyrexia, headache, myalgia, pain in extremities, and arthralgia. Significant adverse effects associated with zoledronate include hypocalcemia, secondary hyperparathyroidism, acute phase response (APR), renal injury, atypical femur fractures, osteonecrosis of the jaw (ONJ), atrial fibrillation, and ocular inflammation.[24][25]

All bisphosphonates can cause hypocalcemia and secondary hyperparathyroidism; IV formulations such as zoledronate are more prone to cause these adverse effects. A balance between osteoblast-mediated bone formation and osteoclast-mediated bone resorption maintains normal serum calcium. 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 serum phosphorus and calcium are dose-dependent. In the kidneys, PTH stimulates the production of 1,25-dihydroxy vitamin D, and tubular calcium reabsorption is increased. Over time, bisphosphonate-induced hypocalcemia will typically decrease. 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. Calcium and vitamin D supplementation using zoledronate is recommended to reduce this risk. Supplementation should begin at least 2 weeks before zoledronate administration.[24]

Musculoskeletal pain, including myalgias and arthralgia, has been reported after zoledronate therapy. This adverse effect occurs at varying time points following treatment, ranging from days to years. The mechanism behind this effect is not understood. An 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 nonsteroidal anti-inflammatory (NSAIDs) or acetaminophen is recommended. The concomitant administration of zoledronate and acetaminophen may effectively reduce the incidence of APR by 50%. 

Research findings indicate that the combination of dexamethasone and acetaminophen can be notably effective in reducing APR, especially myalgia.[26] The risk of APR may be influenced by the underlying indication for which treatment was initiated.[24][25] APR is thought to be mediated by high levels of pro-inflammatory cytokines, including interleukin-6 and tumor necrosis factor-alpha. A study on 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%.[27][28]

Acute tubular necrosis is the most common form of renal injury following zoledronate administration. Risk factors for developing acute tubular necrosis have been described and include rapid infusions, shorter time intervals between infusions, and higher doses.[25]

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 the 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.[29][30]

Zoledronate-induced ONJ has been extensively described. This relationship seems to be influenced by 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.[24][25]

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.[31]

Ocular adverse drug reactions linked to zoledronate therapy include conjunctivitis, scleritis, and uveitis. Overall, these adverse drug reaction reactions are 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.[24][25]

Drug-Drug Interactions

• Aminoglycosides: Caution is advised when administering bisphosphonates with aminoglycosides due to the potential additive effect that might decrease serum calcium levels for prolonged periods.[32][22]

• Loop diuretics: Caution should be exercised when using zoledronate injection concurrently with loop diuretics due to an increased risk of hypocalcemia.[33]

• Nephrotoxic drugs: Use caution when combining zoledronate injection with other nephrotoxic drugs, such as cyclosporine and NSAIDs.[34][35][36][37]

Contraindications

Box Warnings

The contraindications to using zoledronate depend on the nature and type of disease being treated. Hypocalcemia, acute kidney injury, or CrCl less than or equal to 35 mL/min are contraindications for use in benign bone disease.[38] In treating hypercalcemia of malignancy, zoledronate should be avoided in patients with serum creatinine greater than 4.5 mg/dL.[39] Minimal data exist regarding treating solid tumor bone metastasis patients with a CrCl of less than 30 mL/min.[40] A history of allergic reaction to zoledronate is also a contraindication.[41] This contraindication applies to all indications of zoledronate use.

Warning and Precautions

The significant warnings associated with zoledronate include ONJ, hypocalcemia, and atypical subtrochanteric and diaphyseal femoral fractures, as mentioned above. The National Institute for Occupational Safety and Health classified zoledronate as a hazardous agent. This classification signifies its potential risks in occupational settings, necessitating stringent adherence to safety protocols, including careful handling, storage, and preventive measures to mitigate potential workplace hazards associated with this compound.[42]

Monitoring

The laboratory parameters such as renal function, vitamin D, calcium, magnesium, and phosphorus should be checked before each infusion. Electrolyte imbalances and vitamin D deficiency should be corrected before treatment is initiated.[9] In patients receiving treatment for osteoporosis, periodic monitoring of bone mineral density should be completed to check for treatment response and effectiveness.[9] In patients receiving treatment for Paget disease of bone, alkaline phosphatase requires periodic monitoring.[4] In patients receiving treatment for multiple myeloma, regular monitoring for albuminuria is needed.[6] Markers of bone resorption C-telopeptide and N-telopeptide and makers of bone formation include serum N-terminal propeptide of type I collagen and bone-specific alkaline phosphatase.[43]

Toxicity

In the event of toxicity or overdose, no reversal agents are approved by the FDA for this drug. In a case report, a pediatric patient with osteogenesis imperfecta experienced a substantial 15-fold overdose of zoledronate. The patient received 4 mg (0.37 mg/kg) instead of the intended 0.27 mg (0.025 mg/kg) dosage, resulting in severe hypocalcemia and hypophosphatemia, necessitating calcium and phosphorus supplementation with ergocalciferol administration. Despite supportive care and hemodialysis initiation to address electrolyte imbalances and potentially eliminate excess zoledronate, the patient experienced multiple episodes of nonsustained ventricular tachycardia. This case underscores the need for prolonged monitoring and electrolyte supplementation in pediatric Zoledronate overdose cases to address potential complications, including severe hypocalcemia and hypophosphatemia.[44]

Enhancing Healthcare Team Outcomes

Zoledronate is a versatile medication that can prevent morbidity and mortality across various medical and surgical conditions. Interprofessional collaboration is essential for ensuring safe and effective care, while also emphasizing the importance of healthcare costs and appropriate resource utilization. When selecting treatment for osteoporosis, it is imperative to consider all aspects of the patient. Zoledronate is administered intravenously in a healthcare facility, which may incur higher healthcare costs compared to other options. However, the benefits of zoledronate can be maximized through appropriate patient selection.

Zoledronate counseling involves collaboration among the prescribing clinician, pharmacist, and nurse to address drug interactions and monitor adverse reactions. Optimal patient treatment relies on teamwork among healthcare professionals. Oncologists are consulted for hypercalcemia management, while endocrinologists oversee metabolic bone disease. A study has demonstrated that inpatient administration of zoledronic acid, along with the involvement of Fracture Liaison Service and orthopedic services, can improve pharmacotherapy rates for osteoporosis in patients with fragility fractures.[45] Prescribing zoledronate demands meticulous attention to detail from each member of the patient care team to ensure its safe use. Open communication and collaboration among interprofessional team members can enhance patient outcomes while minimizing adverse drug reactions.