teoclasts.2 Bisphosphonates are divided into 2 classes ac- cording to their ..... ique, Regional Pharmacovigilance Center, Amiens University Hos- pital (CHU) ...
Oncology
Zoledronic Acid and Renal Toxicity: Data from French Adverse Effect Reporting Database Aline Munier, Valerie Gras, Michel Andrejak, Nathalie Bernard, Marie-Josephe Jean-Pastor, Sophie Gautier, Michel Biour, and Ziad Massy
BACKGROUND:
Zoledronic acid–associated renal impairment leading to renal failure has been recently reported in a cohort of US patients. However, the presence of such toxicity in other populations has not yet been determined.
OBJECTIVE: To analyze French cases of zoledronic acid–associated nephrotoxicity. METHODS:
We evaluated available cases with acute deterioration of renal function associated with zoledronic acid therapy drawn from the French Adverse Event Reporting System database until July 1, 2004.
RESULTS:
We identified 4 men and 3 women between the ages of 52 and 70 years, with multiple myeloma or different types of metastatic cancer, who had experienced renal impairment during zoledronic acid therapy. Four patients developed de novo acute renal failure, while the other 3 patients experienced acute deterioration of preexisting chronic renal failure. Renal failure occurred after various durations of zoledronic acid therapy (1–120 days). Three patients completely recovered and one partially recovered their previous renal function after discontinuation of zoledronic acid, but renal impairment was associated with a fatal outcome in 2 cases; the outcome of the other case was unknown. Our data confirm the previously reported risk factors for zoledronic acid–associated nephrotoxicity such as advanced cancer, multiple myeloma, preexisting renal failure, diabetes, hypertension, and concomitant use of nephrotoxic drugs.
CONCLUSIONS:
These cases emphasize the need for regular monitoring of renal function during zoledronic acid treatment, with particular attention to patients with preexisting impaired renal function.
KEY WORDS: zoledronic acid, bisphosphonates: nephrotoxicity, tubular necrosis.
Ann Pharmacother 2005;39:1194-7. Published Online, 14 Jun 2005, www.theannals.com, DOI 10.1345/aph.1E589
oledronic acid, a third-generation nitrogen-containing Z bisphosphonate, is a highly potent inhibitor of osteoclast-mediated bone resorption. Zoledronic acid is indicated in the treatment of malignancy-induced hypercalcemia and as a preventive agent against osteolytic metastases in advanced cancers. A dose of 4 mg of zoledronic acid has been demonstrated to be effective in clinical trials, with superior efficacy to that of 90 mg of pamidronic acid in treatment of patients with malignancy-induced hypercalcemia.1 The structure of bisphosphonates is based on that of pyrophosphate, an endogenous compound that regulates bone reorganization. These drugs therefore bind with high affin-
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ity to hydroxyapatite crystals and prevent the effects of osteoclasts.2 Bisphosphonates are divided into 2 classes according to their chemical structure and mechanism of action. The first class consists of non–nitrogen-containing bisphosphonates (ie, etidronate, clodronate) that are very similar to pyrophosphate and are metabolized into non-hydrolyzable adenosine triphosphate analogs that accumulate inside osteoclasts, leading to osteoclast apoptosis. The other class consists of more potent nitrogen-containing bisphosphonates (ie, zoledronate, pamidronate, alendronate, ibandronate, risedronate) that inhibit farnesylpyrophosphate (FPP) synthase, an enzyme of the mevalonate biosynthetic pathway, leading to the inhibition of prenylation of small γ-glutamyl transpeptidase proteins in osteoclasts. The resulting decrease in prenylated protein levels induces osteoclast apoptosis.3,4
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The most common adverse events of bisphosphonates are flu-like symptoms, fatigue, gastrointestinal reactions, anemia, dyspnea, and edema. Zoledronic acid–associated renal impairment leading to renal failure has been reported in a large cohort of US patients.5 In this study, 72 cases from the Food and Drug Administration Adverse Event Reporting System concerning renal failure associated with zoledronic acid therapy have been reported. Whether this toxicity is present in other populations is currently unknown. In the present report, we discuss 7 cases of zoledronic acid–associated nephrotoxicity drawn from the French Adverse Event Reporting System database from January 1, 2001, to July 1, 2004. Methods The French Pharmacovigilance System (FPS), created in 1973, is based on a network of 31 regional centers. In 1985, the French Pharmacovigilance Database was established, allowing the registration of spontaneous reporting of adverse drug reactions (ADRs). Furthermore, reporting serious or unlabeled ADRs to the FPS has been required for any physician, dentist, or midwife in France since 1995. The cases included in this study were extracted from the database and are based on spontaneous notification, which may underestimate the real frequency. From January 1, 2001, to July 1, 2004, 7 cases were retrospectively selected on the basis of the occurrence of acute deterioration of renal function while patients were using zoledronic acid therapy. In the FPS database, acute renal failure was defined as an increase of serum creatinine concentration ≥1.7 mg/dL or an increase of creatinine levels of ≥50% compared with baseline levels. Data extraction has been done ac-
cording to French regulation regarding FPS, with no need for internal review board approval. Drug causality assessment for each case was carried out using the Naranjo probability scale.6
Results The main characteristics of these cases, concerning 4 men and 3 women between the ages of 52 and 70 years, are summarized in Table 1. Several risk factors predisposing to zoledronic acid–associated nephrotoxicity were identified in the patients’ medical history. The dosage of zoledronic acid complied with the Marketing Authorization Application in all cases. Other potential nephrotoxic drugs in addition to zoledronate were identified in some cases: thalidomide, ketoprofen and iopamidol injection, ramipril, and fosinopil. In all cases, patients experienced renal toxicity with acute renal failure or deterioration of preexisting chronic renal failure, with a mean duration of renal failure of 40 days after evidence of renal dysfunction. Complete recovery was observed after 2 days to 9 months in 3 cases; however, death in a context of multiple organ failure occurred in 2 cases. Discussion Impaired renal function is a rare but serious adverse event of zoledronic acid therapy. In France, 7 cases of nephrotoxicity have been reported to the French Adverse
Table 1. Characteristics of the French Cases of Renal Failure Associated with Zoledronic Acid Age (y)/ Case Gender 1
70/M
2
52/F
3
62/M
4
52/M
5
56/F
6
69/F
7
61/M
Cumulative Dosage (mg)
Contributing Drugs
Time To Onset (days)
Serum Creatinine (mg/dL)a
Outcomeb
History
ADR
prostate cancer, bone metastases, hypertension, CRF metastatic epidermoid carcinoma diabetic nephropathy, CRF, myeloma, hypothyroidism, MI renal cell carcinoma, pleural metastases
deterioration of CRF
16 mg (4 mg/ mo for 4 mo)
none
120
1.7 4
favorable in 9 moc
acute renal failure
4 mg
none
40
NA
death
deterioration of CRF
4 mg
thalidomide
20
3.9 7
partially favorable in 2 mo
acute renal failure
4 mg
ketoprofen, iopamidol, interferon alfa 2a, interleukin-2 spironolactone, furosemide, ramipril allopurinol, fluvastatin, fosinopril, hydrochlorothiazide none
4
1 6
favorable in 9 days
1
0.8 1.6
favorable in 2 days
6
0.8 9
death
90
1.7 3.4
NA
hepatic angioma, acute renal failure multiple myeloma with diffuse amylosis hypertension, acute renal failure dyslipidemia, bronchogenic cancer, bone metastasis prostate cancer, deterioration of CRF bone metastasis, moderate CRF
4 mg
4 mg
12 mg (4 mg/ mo for 3 mo)
ADR = adverse drug reaction; CRF = chronic renal failure; MI = myocardial infarction; NA = not available. The highest levels before and after treatment. b Favorable = complete return to baseline; partially favorable = partial decrease of creatinine. c Renal function worsened after 9 months of pamidronate. a
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Events Reporting System until July 1, 2004. Of note, zoledronic acid was released into the French market on March 20, 2001. In every case, use of the Naranjo probability scale indicated a possible relationship between zoledronic acid and renal impairment.6 In the US study of renal failure associated with zoledronic acid therapy, Chang et al.5 underscored the multifactorial causes of zoledronate-associated toxic renal failure that were also observed in our cases: advanced cancer (cases 1–7), multiple myeloma (cases 3 and 5), preexisting renal failure (cases 1, 3, and 7), diabetes (case 3), hypertension (cases 1 and 6), and concomitant use of nephrotoxic drugs (cases 3, 4, 5, and 6). The specific role of zoledronic acid therapy is difficult to determine in the presence of these risk factors. Other risk factors have also been identified: previous bisphosphonate therapy (62.5% of pts. reported by Chang et al. had received previous bisphosphonate therapy), cancer chemotherapy, severe dehydration, and infusion time
