Abstract Aim: To determine effects of pre-exist epileptogenesis on Antiepileptic drugs (AEDs) induced bone disorders. Objectives: (1) to determine effects of epileptogenesis on bone weights, histology, and bone biomarkers. (2) to determine effects of two AEDs (Sodium Phenytoin and Carbamazepine) in presence and absence of epileptogenesis on bone weights, histology, and biomarkers (3) to determine effects and mode of action for the interaction between AEDs and epileptogenesis. Methods: One hundred twenty Wister male rats were divided into 6 groups. Group1 were injected with control solution intraperitoneal (IP), group 2 were injected with Pentylenetetrazol (PTZ) 35 mg /kg IP on alternative day regiment for 1,2,3,4, and 5 weeks (wk) to induce epileptogenesis. PTZ effects on muscle tone were monitored by Racine scale. Group3 were injected with Phenytoin (DPH) 20 mg/kg IP. Group 4 were injected with Carbamazepine (CBZ) 25 mg/kg IP. Group 5 were injected with PTZ and DPH. Group 6 were injected with PTZ and CBZ. Femur, and tibia weights, histology and bone biomarkers were measured to monitor drugs effects on bone. Liver enzymes (ALP and ALT) were measured to locate AEDs – PTZ site of action. Results: Rats injected with PTZ alone for 5 wks showed little changes in femur and tibia structure, and, slight decrease in femur and tibia weights compared with rats treated with control solution. They also showed 10.9 %( P > 0.05), and 17.9 % ( P > 0.05), lower serum Calcium (Ca++) and phosphorus (PHOS) levels, and, 25% ( P > 0.05), and 20.3% ( P > 0.05), higher parathyroid (PTH) and 25- hydroxvitamin D (25-OHD) levels respectively . Rats treated with DPH alone showed 11.68%, and 2.17 %( P > 0.05), higher femur and tibia weights respectively compared with control. They also showed 9.66%, 87.4%, and 37.32% higher Ca++, PTH, and 25-OHD serum level compared to control group ( P > 0.05). Rats treated with DPH and PTZ combination showed 15.5 % (P < 0.05) and 5.9% (P> 0.05) lower tibia and femur weights, and, 21.85% lower 25-OHD. On the other hand, CBZ decreases tibia weights by 5.23%, and increases femur weight by 8.45% (P> 0.05). It also decreases Ca++ and PTH by 7.53% and 82.65% (P> 0.05) respectively and increases 25-OHD by 6.33% (P> 0.05). Co-administration of CBZ and PTZ, lower tibia and femur weights by 8.27% and 3% (P> 0.05). CBZ – PTZ treated rats showed 15.22%, 82.62%, and 5.85% lower Ca++, PTH, and 25-OHD levels (P> 0.05). Conclusion: It was concluded that epileptogenesis has negative effects on bone. This effect is augmented by concurrent administration of DPH, and CBZ. 25-OHD synthesis and metabolism in the liver could be the site of epileptogenesis– AEDs interaction. More experiments are required to draw firm conclusion. Recommendation: Bone biomarkers should be examined prior and during AEDs therapy.