Zonisamide for epilepsy does not harm bone health

In treatment‐naïve patients with epilepsy, long-term use of zonisamide exerts no detrimental effects on bone health, a study has found.

“Contrary to the previous results of rat models, our data suggest that zonisamide does not negatively influence bone strength and metabolism; this remained significant after correction for potential confounding factors,” according to study authors Drs Dae Lim Koo and Hyunwoo Nam of the Seoul National University Boramae Hospital in South Korea.

The animal studies administered zonisamide at a daily dose of 80 mg/kg, which is much higher than the recommended dose for humans, Koo and Nam noted. Furthermore, the period of therapy was 5 weeks, which was much shorter compared to the duration explored in the present study. [J Pharmacol Sci 2003;91:313-318 Methods Find Exp Clin Pharmacol 2004;26:769-773]

“We believe that these factors could account for the difference in results between animal and human studies,” they said.

The current analysis included 59 patients with new onset drug‐naïve epilepsy (mean age, 31.5 years; 30 men) who were treated with zonisamide for a mean of 13.1 months (mean dose at the last visit, 173.7 mg/d).

Of the patients, 16 (27 percent) had generalized seizures and 43 (73 percent) had focal seizures with or without secondary generalized seizures. None of them took any medication affecting bone metabolism (eg, calcium supplements, vitamin D, hypoglycaemic agents, glucocorticoids, and selective serotonin reuptake inhibitors) during the study.

After 13 months of zonisamide, dual‐energy X‐ray absorptiometry results showed no significant difference in bone mass density (BMD) and T scores at the lumbar spine (L1‐L4 level) and femoral neck. [Epilepsia 2020;doi:10.1111/epi.16678]

Likewise, there were no marked changes noted in the biochemical markers specific for bone metabolism—bone‐specific alkaline phosphatase, parathyroid hormone, osteocalcin, insulin-like growth factor‐1, C‐telopeptide, and vitamin D3 levels.

In a subgroup analysis defined by sex, women exhibited markedly lower baseline BMD at the femoral neck compared with men (p=0.026), although their mean age and body mass index were similar. Neither BMD nor bone metabolism biomarkers significantly changed in men and women after 13 months of treatment.

“Our results provide evidence that zonisamide can be a favourable treatment option for epilepsy, especially in [those] at risk for bone health problems, including fracture,” Koo and Nam said.

Antiepileptic drugs (AEDs), especially the ones that induce hepatic enzyme (eg, carbamazepine, phenytoin, and phenobarbital), can negatively influence bone health and thereby increase the risk of fracture, they noted. [Epilepsia 2005;46:304-310]

“Reduced levels of vitamin D via the hepatic CYP450 system can be considered an action mechanism of hepatic enzyme inducers. Among hepatic enzyme noninducers, valproate, which is an inhibitor of the CYP-450 enzyme system, can also provoke some adverse effects on bone [health],” they added. [Neurology 2008;70:1586-1593; Pharmacol Res 2004;50:93-97]

Zonisamide, on the other hand, is among the newer-generation AEDs and has been shown to be effective and well-tolerated for treating diverse types of seizures. Koo and Nam pointed out that the minimal effect of this drug on both the CYP450 isoenzyme-inducing system and vitamin D levels may have contributed to the encouraging bone health outcomes in the study.

“A prospective larger study of epileptic patients on zonisamide as monotherapy compared to drug-naïve patients with other AEDs as controls is recommended,” they said.