Bone Disease Induced by Phenytoin Therapy: Clinical and Experimental Study

Abstract

Previous studies have made references to prolonged treatment with phenytoin as a possible risk factor in the development of osteoporosis and/or osteomalacia. We studied a group of 30 epileptic patients who were under long-term treatment with phenytoin (DPH) in an ambulatory regimen. We found the prevalence of osteoporosis to be 3.3% and of osteopenia to be 56.6%, affecting predominantly the femur, without any significant decrease in bone mineral density of the lumbar spine. These patients were showing signs of bone turnover uncoupling with increases in bone resorption markers. At this time, they also exhibited slight alterations in their phosphocalcium metabolism with trends to hypocalcemia and secondary hyperparathyroidism that was found not to be caused by a vitamin D deficiency as the serum levels of 25(OH)D and 1,25(OH)₂D were normal. With the aims of corroborating these results and to investigate the physiopathological effects on the bone induced by anticonvulsant drugs we developed a further experimental study in which we administered DPH over a 6-week period with a dose of 5 g/kg/day to male Wistar rats that were in the growth phase. This treatment produced a decrease in overall BMD and bone mineral content in the femur. We did not find osteomalacia in the vertebral biopsy, but the administration of DPH to these animals decreased trabecular volume as well as lessened the thickness of osteoid edges together with an uncoupling in bone turnover. There was also a marked decrease in bone formation and a tendency towards increased bone resorption. We have also found a decrease in resistance to fracture by torsion in the biomechanical assay, which translates into an increase in bone fragility. In these male Wistar rats, the administration of DPH produced a tendency towards increasing the markers of resorption and, though changes in serum levels of calcium and phosphorus were not observed, to provoke an increase in the parathyroid hormone levels; with normal levels of 1,25(OH)₂D which has produced the same inclination in rats as in humans.

Effects of the Antiepileptic Drugs Phenytoin, Gabapentin, and Levetiracetam on Bone Strength, Bone Mass, and Bone Turnover in Rats

“…[4][5][6][7] Indeed, it has been reported that long-term treatment with phenytoin resulted in decreased BMD, 10,11) but few studies have examined the effects of the more recently developed newer AEDs on bone metabolism. In present study, we showed that the daily administration of phenytoin 20 mg/kg to rats for 12 weeks resulted in a significant decrease in bone strength and BMD, which was associated with enhanced bone resorption.…”

“…8,9) Previous studies have demonstrated that treatment with phenytoin decreased bone mineral density (BMD) owing to enhanced bone resorption. 10,11) Currently, newly developed AEDs, including gabapentin, topiramate, lamotrigine, and levetiracetam, have been approved for clinical use. 12) Although traditional AEDs, such as phenytoin, continue to be used in patients with epilepsy, the prevalence of the new AEDs has increased.…”

Literature Review and Clinical Presentation of Bilateral Acetabular Fractures Secondary to Seizure Attacks

“…It is also imperative to mention that long-term seizure patients who are under antiepileptic medications affecting intestinal calcium absorption can suffer from anticonvulsant osteopathy [27], which might increase their susceptibility to fracture.…”

The antiepileptic medications carbamazepine and phenytoin inhibit native sodium currents in murine osteoblasts

“…Patients with epilepsy have at least doubled fracture risk . A proportion of patients with epilepsy, particularly those who have taken long‐term antiepileptic drug (AED) therapy, have reduced bone density . Causes of these associations are not fully understood, particularly whether there are direct bone side effects of AEDs.…”