What is the relationship between Zolendronic acid (Zometa) and impaired renal function, as indicated by creatinine clearance?

From the Guidelines

Zoledronic acid dosing should be adjusted based on creatinine clearance (CrCl) to prevent renal toxicity, with reduced doses recommended for patients with mild-to-moderate renal impairment (CrCl 30-60 mL/min) and avoidance of use in patients with severe renal impairment (CrCl <30 mL/min). The most recent and highest quality study, published in 2018 1, recommends that patients with preexisting mild-to-moderate renal impairment should receive a reduced dosage of zoledronic acid, with no changes in infusion time or interval required. Zoledronic acid has not been studied in patients with severe renal impairment and is not recommended for use in these patients.

Key Considerations

• Patients with CrCl ≥30 mL/min can receive zoledronic acid, but with dose adjustments for those with mild-to-moderate impairment
• Zoledronic acid is not recommended for patients with severe renal impairment (CrCl <30 mL/min)
• Monitor renal function before each dose by measuring serum creatinine
• Ensure adequate hydration before administration

Dosing Adjustments

• For patients with CrCl 30-60 mL/min, reduce the dose of zoledronic acid
• No specific dose adjustments are provided in the most recent study, but earlier studies suggest reducing the dose for patients with CrCl <35 mL/min
• The drug's long half-life in bone allows for extended dosing intervals in patients with compromised renal function while maintaining efficacy, as noted in earlier studies 1.

Renal Function Monitoring

• Monitor serum creatinine before each dose
• Avoid infusion times less than 15 minutes with zoledronic acid
• Intermittent evaluation (every 3 to 6 months) of all patients receiving chronic zoledronic acid therapy for the presence of albuminuria and azotemia is recommended, as noted in earlier studies 1.

Comparison with Other Bisphosphonates

• Denosumab may be preferred in patients with compromised renal function due to its lower risk of renal toxicity, as noted in the most recent study 1.
• Pamidronate 90 mg administered over 4 to 6 hours is recommended for patients with extensive bone disease and existing severe renal impairment, as noted in the most recent study 1.

Overall, the most recent and highest quality study 1 provides the best guidance on the use of zoledronic acid in patients with impaired renal function, and its recommendations should be followed to minimize the risk of renal toxicity.

From the FDA Drug Label

Zoledronic Acid Injection is excreted intact primarily via the kidney, and the risk of adverse reactions, in particular renal adverse reactions, may be greater in patients with impaired renal function. Preexisting renal insufficiency and multiple cycles of zoledronic acid injection and other bisphosphonates are risk factors for subsequent renal deterioration with zoledronic acid injection. Zoledronic acid clearance was independent of dose but dependent upon the patient’s creatinine clearance Based on population PK/PD modeling, the risk of renal deterioration appears to increase with AUC, which is doubled at a creatinine clearance of 10 mL/min

The relationship between Zolendronic acid (Zometa) and impaired renal function, as indicated by creatinine clearance, is that impaired renal function increases the risk of adverse reactions, particularly renal adverse reactions. The drug's clearance is dependent on the patient's creatinine clearance, and the risk of renal deterioration increases with decreasing creatinine clearance. Patients with severe renal impairment (creatinine clearance less than 30 mL/min) are at higher risk. 2 2

• Key factors that increase the risk of renal deterioration include:
  • Preexisting renal insufficiency
  • Multiple cycles of zoledronic acid injection and other bisphosphonates
  • Decreased creatinine clearance
• Dose adjustment may be necessary in patients with impaired renal function, but efficacy and safety of adjusted dosing have not been prospectively assessed.

From the Research

Relationship between Zolendronic Acid and Impaired Renal Function

The relationship between zolendronic acid (Zometa) and impaired renal function, as indicated by creatinine clearance, has been investigated in several studies.

• Zoledronic acid is a bisphosphonate used to treat osteoporosis and hypercalcemia related to malignancy, and its safety profile is generally favorable, but there have been reports of acute kidney impairment after its administration, particularly in patients with preexisting kidney impairment or those receiving high cumulative doses 3.
• A study published in 2012 suggested that the dosage of zoledronic acid should be adjusted according to the risk of renal impairment, and that using creatinine clearance (Ccr) as the basis for dosage adjustment may be inappropriate due to the effect of creatinine secretion from the renal tubule on Ccr 4.
• Another study from 2012 found that the incidence of acute renal failure (ARF) was similar between patients with normal baseline renal function receiving standard-dose zoledronic acid and those with mild to moderate renal dysfunction receiving renally adjusted zoledronic acid 5.
• Cases of zoledronic acid-associated renal impairment have been reported in various populations, including patients with multiple myeloma or metastatic cancer, and risk factors for nephrotoxicity include advanced cancer, preexisting renal failure, diabetes, hypertension, and concomitant use of nephrotoxic drugs 6.
• A study published in 2008 found that annual zoledronic acid infusions in osteoporotic postmenopausal women were associated with transient changes in renal function, but long-term renal function was not different from control patients 7.

Key Findings

• Zoledronic acid can cause acute kidney impairment, particularly in patients with preexisting kidney impairment or those receiving high cumulative doses 3, 6.
• The incidence of acute renal failure is similar between patients with normal baseline renal function and those with mild to moderate renal dysfunction receiving renally adjusted zoledronic acid 5.
• Transient changes in renal function can occur after zoledronic acid infusion, but long-term renal function is not significantly affected 7.
• Risk factors for zoledronic acid-associated nephrotoxicity include advanced cancer, preexisting renal failure, diabetes, hypertension, and concomitant use of nephrotoxic drugs 6.