Seizure associated with zoledronic acid therapy: side-effects or coincidental finding?

Dear Editor

Bisphosphonates have been used in a wide range of malignancies and bone disorders. Recently, there have been a few reports of seizure associated with alendronate and zoledronic acid. We discuss them, along with our experience with use of zoledronic acid.

In a recent series, the authors described three cases of seizures that developed after the administration of zoledronic acid [Tsourdi et al. 2011]. However, among these three cases, hypoglycemia (caused by prior gastric surgery leading to dumping syndrome) was the predisposing factor behind two cases. In the third case, the patient developed a febrile seizure on the second day of zoledronic acid administration. The authors proposed that zoledronic acid induced an acute phase reaction that had lead to lowering of the seizure threshold and resulting seizure. However, the requirement for vasopressor support and response to iv antibiotics suggest intracranial infection rather than simple febrile seizure, which the authors have not ruled out by cerebrospinal fluid (CSF) analysis. In all three cases, the level of 25-(OH)-D has been described as low (<30 ng/ml). Importantly, there was no description about magnesium level.

There are also another two cases of seizures reported in association with the administration of the above drugs, and in both reports, hypocalcemia was thought to represent the underlying mechanism [Navarro et al. 2007; Maclsaac et al. 2002]. However, if we go through these two reports, then the respective authors have described that it is the underlying vitamin D deficiency leading to hypocalcemia causing seizure rather than alendronate or zoledronic acid. The authors of both of the reports propose that the patients might have subclinical hypocalcemia before starting the drugs (as a result of vitamin D deficiency) which was aggravated by the administration of zoledronic acid.

The risk factors for zoledronic-acid-induced hypocalcemia include pre-existing vitamin D deficiency, hypoparathyroidism, hypomagnesemia, and previous thyroid or parathyroid surgery [Tanvetyanon and Stiff, 2006]. These conditions impair the normal release and activity of parathyroid hormone which acts to compensate for low serum calcium by increasing renal absorption of vitamin D and calcium. Pre-existing vitamin D deficiency in a population receiving a bisphosphonate has also been reported in up to 27% [Wang-Gillam et al. 2008]. The elderly and cancer patients are at particular risk of vitamin D insufficiency due to limited Sun exposure, reduced dietary intake and renal impairment. In our experience in children with osteogenesis imperfecta, we found no clinical problems due to hypocalcemia in any of the patients [Panigrahi et al. 2010].

Rapid parenteral administration of bisphosphonates, might lead to hypocalcemia; however, it is infrequent and usually mild. So before initiating bisphosphonate therapy, any disturbances of mineral metabolism (calcium, magnesium) should be corrected. Following the approval and widespread use of bisphosphonates, a number of potential side effects have been identified but with no clear cause and effect relationship. With more widespread use of zoledronic acid in the future, we hope that this picture will become clearer.