Antiepileptic Stiripentol May Influence Bones

Abstract

Bone structure abnormalities are increasingly observed in patients chronically treated with antiepileptic drugs (AEDs). The majority of the available data concern older conventional AEDs, while the amount of information regarding newer AEDs, including stiripentol, is limited. The aim of the study was to assess the effect of stiripentol on bones. For 24 weeks, male Wistar rats, received 0.9% sodium chloride (control group) or stiripentol (200 mg/kg/day) (STP group). In the 16th week of the study, we detected lower serum PINP levels in the STP group compared to the control group. In the 24th week, a statistically significant lower 1,25-dihydroxyvitamin D₃ level, higher inorganic phosphate level and higher neutrophil gelatinase-associated lipocalin (NGAL) levels in serum were found in the STP group compared to the control. Micro X-ray computed tomography of the tibias demonstrated lower bone volume fraction, lower trabecular thickness, higher trabecular pattern factor and a higher structure model index in the stiripentol group. Considering the results of this experiment on rats which suggests that long-term administration of stiripentol may impair the cancellous bone microarchitecture, further prospective human studies seem to be justified. However, monitoring plasma vitamin D, calcium, inorganic phosphate and kidney function in patients on long-term stiripentol therapy may be suggested.

Keywords: antiepileptic drug; bone; computed tomography; stiripentol; vitamin D.

Figure 1

The effect of administration of stiripentol on body weight in rats. Results presented as follows: median (lower quartile—upper quartile).

Figure 2

Sample micro X-ray computed tomography images of (a) tibia and (b) femur (C—control group; STP—group that received stiripentol for 24 weeks).

Figure 3

Mechanisms regulating serum calcium and phosphate levels. Serum calcium (Ca²⁺) and phosphates (PO₄³⁻) levels depend on intestinal absorption, kidney excretion and release/deposition in bones. Parathormone (PTH) and 1,25-dihydroxyvitamin D₃ are the most important factors regulating Ca²⁺ and PO₄³⁻ serum levels. Vitamin D increases intestinal Ca²⁺ and PO₄³⁻ absorption. PTH acts similarly, but its action is indirect by increasing 1,25-dihydroxyvitamin D₃ production. Both 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D₃ increase Ca²⁺ and PO₄³⁻ reabsorption in the kidneys, whereas PTH increases reabsorption of calcium but increases kidney excretion of phosphates. In bones, the effect of PTH depends on the dose/concentration. In high doses, it causes Ca²⁺ and PO₄³⁻ reabsorption from bones and low doses it may increase the formation of bones. Similarly, the dual action of 1,25-dihydroxyvitamin D₃ on Ca²⁺ and PO₄³⁻ reabsorption has been described. Vitamin D acts on the parathyroid gland and regulates PTH secretion. Summing up, the net effect of PTH action is increased calcium with decreased phosphates in the serum and the net effect of vitamin D is increased calcium and phosphates in serum.

Figure 4

Analyzed regions of interest (ROI) of the tibia (proximal metaphysis), the femur (distal metaphysis) and the third lumbar vertebra. (A) ROI of the cancellous bone of tibia; (B) ROI of the cortical bone of tibia; (C) ROI of the cancellous bone of femur; (D) ROI of the cortical bone of femur; (E) ROI of the cancellous tissue of vertebra.