Renal function impairment is a known potential side effect of bisphosphonates, including zoledronic acid, which necessitates careful consideration in patients with pre-existing renal conditions. Despite this, the consensus among experts suggests that the risks associated with its renal toxicity are generally manageable through regular monitoring of renal function through serum creatinine levels before each recommended dose. However, several underlying risk factors including previous bisphosphonate therapy, and use of nephrotoxic medications such as non-steroidal anti-inflammatory drugs (NSAIDs) can potentially exacerbate the renal impairment condition. A 2011 expert review of the literature described the results from phase 3 clinical trials of patients with bone metastases from myeloma, breast, prostate, lung, or other solid tumors. Results from the clinical trials revealed that the incidence of renal impairment following zoledronic acid infusion during two years of 3-4 weekly infusions was approximately 10-15%, demonstrating an overall comparable renal safety profile of zoledronic acid compared to pamidronate. While renal toxicity remains a serious consideration in the use of zoledronic acid, adherence to guidelines on dosing and infusion, along with pre-treatment assessment and regular monitoring of renal function, allows for the safe use of zoledronic acid in a majority of patients. [1], [2], [3], [4]
A meta-analysis of three trials (N= 2,514) compared the 4-week versus 12-week reports of kidney dysfunction in patients with bone metastasis receiving zoledronic acid. A significant difference was not found (risk ratio [RR] 0.67; 95% confidence interval [CI] 0.39 to 1.15; p= 0.15), and both groups generally reported low rates of kidney dysfunction (2.45% in the 4-week group and 1.68% in the 12-week group). [5]
Reports from a French adverse event database revealed that up to July 2004, seven patients (aged 52-70 years) with multiple myeloma or different types of metastatic cancer experienced renal impairment during treatment with zoledronic acid. Four of these patients with different cancer-related histories (one having bone metastasis) developed acute renal impairment with renal toxicity while on zoledronic acid, whereas three of them experienced acute deterioration of preexisting chronic renal failure. The duration of zoledronic acid therapy varied (1-120 days). The mean duration of renal failure was 40 days, with three cases being recovered completely. Death occurred in two of the patients. However, owing to the underlying comorbidities and terminal illness, the causal association of death with zoledronic acid therapy can not be ascertained. While renal toxicity of zoledronic acid appears to be both dose and infusion-time-dependent, close and regular monitoring of renal function is highly advised, particularly in patients with preexisting risk factors or impaired renal function. [6]
A 2017 pilot study, including 23 patients with osteoporosis or fragility fractures, did not find a difference in biomarkers of acute kidney injury (plasma C-terminal FGF23, serum Klotho, or urinary AKI biomarkers) at 30 days from a single 5 mg intravenous (IV) zoledronic acid injection. This pilot study does not reveal a potential direct acute effect of zoledronic acid on kidney function. However, those with GFR <30 mL/min were excluded from the study as recommended by the prescribing information. [7]
A 2018 case report described a successful treatment of hypercalcemia in a 43-year-old female receiving maintenance hemodialysis with a reduced dose of zoledronate. She had received peritoneal dialysis for 6 years and hemodialysis for 3 years and had received a living-related-donor kidney transplant for 21 years. Upon admission, her serum calcium level was elevated at 2.55 mmol/L, progressing to 4.23 mmol/L, despite treatment with low-calcium dialysate baths. A consciousness disorder complicated her case, and the patient was diagnosed with immobilization-induced hypercalcemia after ruling out other causes of hypercalcemia, such as hyperparathyroidism and vitamin D intoxication. A reduced dose of zoledronate (3 mg) was administered intravenously, leading to a rapid decrease in serum calcium level; her corrected serum calcium level was 2.23 mmol/L 14 days after zoledronate treatment and remained at 2.13–2.63 mmol/L thereafter. Three months later, she developed another hypercalcemia (2.05 mmol/L) but was successfully treated with a reduced dose of zoledronate (2 mg) with no adverse effects. The patient was subsequently transferred to another institution for maintenance hemodialysis and rehabilitation. Based on the findings, the authors concluded that reduced-dose zoledronate is a safe and useful treatment option for acute and transient hypercalcemia in hemodialysis patients. However, the findings are limited to a single patient experience, limiting the generalizability to the general hemodialysis population. [8]