Toxicity of zoledronic acid after intravenous administration: A retrospective study of 95 dogs

Abstract

Background There is a paucity of veterinary literature on the safety or outcome of zoledronic acid (ZA) use in dogs for either bone pain or hypercalcemia. Hypothesis/Objectives The primary aim was to report the adverse events in dogs receiving intravenous administration of ZA. Animals Ninety‐five dogs with ZA use. Methods A retrospective cohort study was performed; all dogs that received at least 1 dose of ZA and had a serum biochemistry profile performed before and after treatment were reviewed. Diagnosis, indication for treatment, adverse events and survival times were recorded. Results Ninety‐five dogs met the inclusion criteria. Thirty‐one (33%) received multiple intravenous infusions of ZA (range, 2‐7), making a total of 166 administrations in all dogs. The dose range was 0.13 to 0.32 mg/kg, given at intervals of 4 to 6 weeks. Thirteen adverse events were recorded in 10 dogs: azotemia (n = 8), vomiting (n = 2), pancreatitis (n = 1), cutaneous ulceration (n = 1), and diarrhea (n = 1). Zoledronic acid could not be confirmed as the cause of azotemia in any case. The change in serum creatinine concentration from dose to dose was not related to the total dose received ( P = .46). Five dogs (5%) changed Veterinary Comparative Oncology Group Common Terminology Criteria (VCOG‐CTAE) renal/genitourinary grade after administration of ZA; their total dose 0.4 mg/kg (range, 0.26‐0.66) was not significantly different to the group which did not change VCOG‐CTAE renal/genitourinary grade 0.35 mg/kg (range, 0.2‐1.50; P = .93). Conclusions and Clinical Importance Multiple doses of ZA were well tolerated in dogs within this study. A small number of dogs developed progressive azotemia which was not associated with cumulative dose.

Retrospective assessment of tolerability and efficacy of zoledronate in the palliative treatment of cancer‐bearing dogs

“…Ionized calcium levels reduced significantly within the first week following treatment (median 31% decrease) in the small number of cases where both pre and post‐treatment values were available. This is in line with what has been previously reported in a recent study by Brewer et al (median 40% decrease) 24 . Some of the hypercalcaemic patients were being treated with chemotherapy or tyrosine kinase inhibitors, which is a confounding factor for the efficacy of zoledronate, however, for most of these dogs, their neoplastic diseases were refractory to treatment, or the hypercalcaemia developed during the course of treatment.…”

“…Zoledronate appears to be safe and well tolerated, with no adverse events reported following 79% of infusions, which is in line with what has been previously reported by Brewer et al (no adverse events in 89% of dogs). 24 Although adverse events were recorded, they were mostly grade 1 or 2 in severity and, as the majority of patients were being treated with zoledronate alongside chemotherapy and/or analgesia (i.e. NSAIDs), it is possible the concurrent treatments have contributed to these adverse events.…”

“…22 Although some studies report the use of zoledronate in dogs with naturally occurring bone tumours, 19,22,23 there is still a paucity of literature reporting the use of zoledronate in cancer-bearing dogs. A recent study by Brewer et al 24 evaluating the toxicity of zoledronate in the treatment of dogs with bone pain or hypercalcaemia concluded zoledronate is well tolerated, even when multiple doses were administered over time. This study also evaluated the efficacy of zoledronate in the treatment of 9 hypercalcaemic dogs, and together with a small case series of 4 dogs, 25 represent the only reports of zoledronate for the treatment of canine hypercalcaemia.…”

Retrospective Evaluation of Outcome in Dogs With Appendicular Osteosarcoma Following Hypofractionated Palliative Radiation Therapy With or Without Bisphosphonates: 165 Cases (2010–2019)

“…The most clinically important adverse effect of BP administration in dogs is acute renal insufficiency. A recent retrospective evaluation identified azotemia in ~8% of dogs following administration of ZOL, but a causal relationship could not be identified ( 14 ). Other reported abnormalities include electrolyte disturbances and osteonecrosis, the latter of which is clinically important in human medicine, but has thus far only been reported in one dog ( 12 – 15 ).…”

Evaluation of zoledronate for the treatment of canine stage III osteosarcoma: A phase II study

“…As a third‐generation BP, ZOL exhibits a 100‐fold higher anti‐resorptive potency than pamidronate (Fan, 2007 ). The veterinary literature describing ZOL is limited to tolerability studies; it appears well tolerated with rare reports of renal azotaemia and osteonecrosis of the jaw (Brewer et al., 2021 ; Fan, 2007 ). ZOL has been shown to decrease plasma concentrations of CXCR4, a chemokine involved in metastasis, in dogs with OSA (Byrum et al., 2016 ).…”