The neurological safety of epidural pamidronate in rats

Abstract

Background: Pamidronate is a potent inhibitor of osteoclast-mediated bone resorption. Recently, the drug has been known to relieve bone pain. We hypothesized that direct epidural administration of pamidronate could have various advantages over oral administration with respect to dosage, side effects, and efficacy. Therefore, we evaluated the neuronal safety of epidurally-administered pamidronate.

Methods: Twenty-seven rats weighing 250-350 g were equally divided into 3 groups. Each group received an epidural administration with either 0.3 ml (3.75 mg) of pamidronate (group P), 0.3 ml of 40% alcohol (group A), or 0.3 ml of normal saline (group N). A Pinch-toe test, motor function evaluation, and histopathologic examination of the spinal cord to detect conditions such as chromatolysis, meningeal inflammation, and neuritis, were performed on the 2nd, 7th, and 21st day following administration of each drug.

Results: All rats in group A showed an abnormal response to the pinch-toe test and decreased motor function during the entire evaluation period. Abnormal histopathologic findings, including neuritis and meningeal inflammation were observed only in group A rats. Rats in group P, with the exception of 1, and group N showed no significant sensory/motor dysfunction over a 3-week observation period. No histopathologic changes were observed in groups P and N.

Conclusions: Direct epidural injection of pamidronate (about 12.5 mg/kg) showed no neurotoxic evidence in terms of sensory/motor function evaluation and histopathologic examination.

Keywords: epidural injection; neurotoxicity; pamidronate.

Fig. 1

Microscopic findings in spinal cord and nerve on the 2^nd day (A, D, and G), 7^th day (B, E, and H), and 21^st days (C, F, and I) following epidural injection of alcohol (A-C), pamidronate (D-F), and normal saline (G-I). Hematoxylin and eosin stain. Figures in middle and right columns (×200) show the high power view of the adjacent left side column (×40) (A, D, and G). In the epidural alcohol group, marked vaculolar change of posterior funicules (B) and lymphocytic infiltration in the spinal cord (C) are visible. In the epidurally-injected pamidronate and normal saline groups, no vacuolation or inflammation are visible.

Fig. 2

Microscopic findings in spinal cord and nerve following epidural injection of alcohol (A, B), pamidronate (C, D), and normal saline (E, F). Luxol fast blue stain. Right-side figures (×200) (B, D, and F) show the high power view of the adjacent left side column (×40) (A, C, and E). In the epidural alcohol group, pale and diminished myelin is visible, and presented as a purple color (B). In the epidurally-injected pamidronate or normal saline groups, no definite abnormal morphologic findings of myelin are visible.