Abstract
Epilepsy is a common neurological disorder worldwide and anti-epileptic drugs (AEDs) are always the first choice for treatment. However, more than 50% of patients with epilepsy who take AEDs have reported bone abnormalities. Cytochrome P450 (CYP450) isoenzymes are induced by AEDs, especially the classical AEDs, such as benzodiazepines (BZDs), carbamazepine (CBZ), phenytoin (PT), phenobarbital (PB), and valproic acid (VPA). The induction of CYP450 isoenzymes may cause vitamin D deficiency, hypocalcemia, increased fracture risks, and altered bone turnover, leading to impaired bone mineral density (BMD). Newer AEDs, such as levetiracetam (LEV), oxcarbazepine (OXC), lamotrigine (LTG), topiramate (TPM), gabapentin (GP), and vigabatrin (VB) have broader spectra, and are safer and better tolerated than the classical AEDs. The effects of AEDs on bone health are controversial. This review focuses on the impact of AEDs on growth and bone metabolism and emphasizes the need for caution and timely withdrawal of these medications to avoid serious disabilities.
Highlights
Epilepsy, a common neurological disorder, affects about 50 million people around the world
Abnormalities in bone and mineral metabolism have been frequently reported in individuals receiving enzyme-inducing AEDs (EIAEDs) because EIAEDs may cause hypocalcemia through triggering the catabolism of vitamin D
In vitro studies demonstrated that PB induces cultured human hepatocytes to increase the mRNA of CYP2C9, CYP2C19 [197], CYP2B6, and 3A4 [199]. Another in vitro study showed that CYP1A2, CYP2B6, and CYP3A4 were significantly induced by OXC and CBZ in HepaRG cells and human hepatocytes [200]
Summary
A common neurological disorder, affects about 50 million people around the world. PT may induce the expression of CYP450, which increases the degradation of bioavailable vitamin D, decreases absorption of calcium in the gut, decreases serum levels of calcium and phosphate, and increases PTH These effects may lead to increased bone turnover, reduced BMD, and increased susceptibility to fractures [79,80,81]. VPA may affect cerebral metabolism, activate GABA receptors to block sodium channels, and modulate calcium and potassium conductance and dopaminergic and serotoninergic transmission [115,116] These mechanisms make VPA a multi-functional medication for absence, partial, and tonic-clonic seizures, bipolar disorder, depression, migraine, personality disorders or mental retardation, dementia and cognitive problems, and a potential chemotherapeutic agent [116]. Serious side effects, teratogenesis, liver toxicity, and associated bone diseases have prompted the search for a newer generation of AEDs to provide better efficacy and fewer side effects (Table 1)
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