The Issue of Renal Safety of Zoledronic Acid from a Nephrologist's Point of View

Abstract

The Oncologist 2005;10:306–308 www.TheOncologist.com Administration of bisphosphonates for cancer bone metastases, especially by the i.v. route, carries a certain, wellestablished risk of deterioration of renal function [1–9]. Although toxic acute tubular necrosis and collapsing focal segmental glomerulosclerosis have been implicated in the mechanism of renal toxicity [10–12], the pathogenesis is still poorly understood. In patients who have pre-existing chronic kidney disease (CKD) or other risk factors for the deterioration of renal function, for example, multiple myeloma, diabetes mellitus, hypertension, or advanced age, the administration of bisphosphonates is to be carried out with caution to avoid its deleterious effect on kidney function [13, 14]. Renal function monitoring guidelines have been introduced to reduce the incidence of this serious, potentially life-threatening, adverse event, and serum creatinine level measurement has been proposed as the primary parameter to assess renal risk and to provide guidance to avoid renal toxicity when zoledronic acid is administered [15]. However, excessive changes in glomerular filtration rate (GFR)—the most important parameter in assessing kidney function—correspond to only small changes in plasma creatinine concentration when patients have near normal to mildly/moderately impaired renal function [16, 17], making plasma creatinine a poor indicator of the corresponding GFR in the earlier stages of CKD. GFR must decline to approximately half the normal level before the serum creatinine concentration rises above the upper limit of normal [18]. Moreover, the plasma creatinine level underestimates renal impairment in those with reduced muscle mass, including women, children, the elderly, and the malnourished [19], many of whom have underlying malignant diseases. Therefore, serum creatinine level is not the optimal tool for establishing administration guidelines for patients treated with zoledronic acid (Zometa®; Novartis Pharmaceuticals Corporation, East Hanover, NJ, http://www.pharma.us.novartis.com), which is known to cause deterioration of renal function—defined as a ≥0.5 mg/dl increase in serum creatinine concentration in patients with normal baseline levels or a ≥1.0 mg/dl elevation in serum creatinine in patients with abnormal baseline levels (≥1.4 mg/dl)—in about 10% of patients receiving this treatment for their cancer-induced bone disease during the course of their treatment [3, 15]. Creatinine clearance and GFR predicted by the CockcroftGault formula or by the equation from the MDRD study [18, 20, 21] would offer a more reliable approach to indicate renal function impairment and to determine and monitor the stage of CKD during the overall course of zoledronic acid therapy. What is extremely worrisome is the fact that among the U.S. adult population at large there are an estimated 5.7 million people with GFRs of 60–89 ml/min per 1.73 m2, a second group of 7.4 million people with GFRs of 30–59 ml/min per 1.73 m2, and another 300,000 people with GFRs of 15–29 ml/min per 1.73 m2, many of whom have normal serum creatinine levels and are not even aware of their CKD [22]. Overall, these three groups account for 2.8%, 3.7%, and 0.13% of the U.S. adult population, respectively, The Oncologist Letter to the Editor