We report data on a 52-year-old woman who was admitted to our hospital after suffering progressive neurological derangement for several days. These symptoms had been increasing and the patient had become confused and somnolent soon after receiving the third zoledronic acid infusion. Two years before, she had undergone right mastectomy, adjuvant anthracycline-based chemotherapy and endocrine therapy (tamoxifen) for breast cancer. Bone relapse (lumbar and sacral vertebrae and pelvis with both femurs) had recently been diagnosed and she had received palliative radiotherapy, further endocrine therapy (letrozole) and the first infusion of zoledronate. At admission she appeared confused with absence of responsiveness to external stimuli. Transdermal fentanyl used for pain relief was stopped. Laboratory analysis showed severe hypercalcemia with anemia and thrombocytopenia. Reticulocyte count was 6.33% (range 0.602.60), lactate dehydrogenase 685 U/l (range 220480) and bilirubin 1.58 mg/dl (range 0.101.10). Fragmented red blood cells were rare. The coagulation tests were close to normality. Her renal function was impaired (creatinine clearance 46 ml/min, range 70140). This constellation suggested acquired TTP. After correcting hypercalcemia by fluid infusion, diuretics and zoledronate, she remained confused and somnolent. After plasma exchange therapy, her platelet count increased and the neurological disturbances ceased. Considering the resistance to endocrine therapy and the possible paraneoplastic origin of TTP, she was given first-line chemotherapy for metastatic disease (paclitaxel 175 mg/m2). Although the patient received further plasma exchange therapy, she experienced a fatal TTP relapse 20 days after her admission. Neither autopsy nor other post-mortem evaluations were performed.
With the marketed use of zoledronic acid, renal deterioration progressing to renal failure and dialysis has been reported [2]. Acute tubular necrosis has been described as a potential mechanism associated with zoledronic acid. Thus, similar to mitomycin C or cyclosporin [1
], the acute vascular changes described as thrombotic microangiopathy resembling TTP-HUS could be caused by a toxic effect of the drug on renal vascular endothelium. However, in our patient the sudden TTP onset could suggest an immune-mediated reaction associated with zoledronate, as previously described for quinine, ticlopidine and clopdidogrel [1
]. Activity of ADAMTS13, a member of a disintegrin and metalloprotease with thrombospondin type 1 motifs family of metalloproteases, might be inhibited by antibodies that prevent enzyme binding to endothelial cell surfaces or block interactions with cellular or plasmatic modulators or reduce the absolute amount of circulating ADAMTS13 in the plasma [3
, 4
]. Moreover, Boissier et al. [5
] demonstrated that zoledronate is the most potent bisphosphonate in inhibiting the proteolytic activity of metalloproteases.
Because of the serious nature of the reported events, health care professionals should accurately monitor renal function before administering zoledronic acid to their patients [2]. A better understanding of the clinical importance of drug-associated TTP-HUS will require a systematic review of published case reports using explicit criteria for establishing a causeeffect relationship.
1 Department of Medical Oncology, Regina Elena Cancer Institute, Rome; 2 Division of Hematology, Regina Elena Cancer Institute, Rome; 3 Division of Hematology, University Tor Vergata, Rome 4 Division of Hematology, University La Sapienza, Rome, Italy
* Email: gia.fer{at}flashnet.it
References
1. Medina PJ, Sipols JM, George JN. Drug-associated thrombotic thrombocytopenic purpura-hemolytic uremic syndrome. Curr Opin Hematol 2001; 8: 286293.[CrossRef][ISI][Medline]
2. Chang JT, Green L, Beitz J. Renal failure with the use of zoledronic acid. N Engl J Med 2003; 349: 16761679.
3. Zheng XL, Kaufman RM, Goodnough LT, Sadler JE. Effect of plasma exchange on plasma ADAMTS13 metalloprotease activity, inhibitor level, and clinical outcome in patients with idiopathic and nonidiopathic thrombotic thrombocytopenic purpura. Blood 2004; 103: 40434049.
4. Scheiflinger F, Knobl P, Trattner B et al. Nonneutralizing IgM and IgG antibodies to von Willebrand factor-cleaving protease (ADAMTS-13) in a patient with thrombotic thrombocytopenic purpura. Blood 2003; 102: 32413243.
5. Boissier S, Ferreras M, Peyruchaud O et al. Bisphosphonates inhibit breast and prostate carcinoma cell invasion, an early event in the formation of bone metastases. Cancer Res 2000; 60: 29492954.