Remodelado óseo en pacientes epilépticosestudio de biomarcadores y polimorfismos

Abstract

BONE REMODELING IN EPILEPTIC PATIENTS: STUDY OF BIOMARKERS AND POLYMORPHISMS BACKGROUND. Treatment with antiepileptic drugs (AED) has been associated with side effects on bone health, with a focus on enzyme-inducing AEDs. Classic AEDs (AEDc) that induce the hepatic cytochrome P450 system (phenytoin, phenobarbital, carbamazepine) increase liver hydroxylases and can reduce the amount of 25OHD. Consequently, there is a decrease in circulating calcium levels accompanied by an increase compensatory of parathyroid hormone (PTH) levels. In addition, PTH activates the RANKL molecule, which activates osteoclasts and increases bone resorption. All this leads to alterations in bone mineralization that lead to osteoporosis. Valproic acid is a histone deacetylase inhibitor (HDIs) that can alter the degree of acetylation of certain histones and thus regulate the expression of genes that promote the differentiation and maturation of osteoblasts. Therefore, there is a decrease in bone synthesis that results in osteoporosis. However, it seems that non-inducing AEDs or new AED (AEDn) like Levetiracetam or Eslicarbazepine acetate have also been associated with impaired bone health, but their pathophysiological mechanisms are not yet known. AIM. Evaluate the bone status of epileptic patients in chronic treatment with AED and the possible loss of bone mass throughout the study, also studying differences between AEDc and AEDn. Determine the genotypic frequency of polymorphisms of genes associated with bone metabolism. Develop mathematical models that allow the identification of patients at risk of developing osteoporosis. METHODS. A prospective longitudinal study was conducted in 64 patients with epileptic disorders under monotherapy for more than 12 months with AEDc or AEDn. Two visits are made, one baseline and another at six months, and in each one a series of procedures are carried out: 1) Collection of demographic and clinical variables; 2) Sampling to evaluate: a) phosphocalcic metabolism, renal function and lipid metabolism, b) quantify the bone turnover markers (BTM), formation (osteocalcin (OC), bone alkaline phosphatase (BALP) and amino terminal propeptide of collagen type 1 (P1NP)) and bone resorption (beta-crosslaps (?-CTX) and N-terminal telopeptide of type I collagen (NTX)), c) carry out the genotyping of polymorphisms related to bone metabolism (VDRB- BsmI, VDRF-FokI, ESR-PvuII, ESR-XbaI, CTR-AluI and Col1A1-Sp1) and determine their frequencies; 3) Realization of a bone densitometry to assess bone status and calculate fracture risk using FRAX¿. RESULTS. A higher genotypic frequency of the ESR-PvuII, CTR-AluI and Col1A1-Sp1 polymorphisms has been described in epileptic patients than in healthy population. We have demonstrated an association between the presence of the Col1A1-Sp1 polymorphism and the lower bone mineral density (BMD). A significant increase of vitamin D was detected throughout the study (p <0.001) and lower concentrations of it (15.50 ng / ml vs 20.21 ng / ml), as well as serum calcium (9.40 mg / dl vs 9.76 mg / dl), in patients under treatment with enzyme-inducing AED. Also we observed lower levels of total cholesterol (p = 0.018) and LDL cholesterol (p = 0.014) in the second visit and an association between lipid metabolism and CTR-AluI polymorphism. Regarding BTM, a significant decrease in BALP and NTX levels (p <0.001) was observed and lower levels of OC in patients treated with AEDc (p = 0.036). Women have lower BMD that men but a higher rate of bone loss is observed in men over the study. No significant differences were detected in the densitometry of patients on AEDc/AEDn treatment. The best diagnostic model found includes clinical variables, biochemical markers (BALP) and genetic polymorphisms (ESR1-XbaI and COL1A1-Sp1). CONCLUSIONS. Low bone mass associated with AED use has not been demonstrated although BTM decrease during the study, reflecting a lower bone turnover and perhaps greater fragility. Patients receiving AEDc had lower levels of BTM. Presence of the s allele of the COL1A1-Sp1 polymorphism in people with epilepsy was related to lower bone BMD. Therefore, it would be advisable to evaluate a combination of clinical variables, BTM and genetic polymorphisms to assess bone status and risk of osteoporosis in epileptic patients.