The association of antiepileptic drugs (AEDs) with bone disease, balance function, falls and fractures: studies of the risk

© 2012 Dr. Baemisla Shiek AhmadAims: Patients with epilepsy taking long-term anti-epileptic drug (AED) therapy have been reported to have an elevated risk of fractures, falls, balance impairment and bone disease. In the work for this thesis, four studies were undertaken which were designed to investigate the associations of AED therapy with the prevalence of falls and fractures in patients taking AEDs compared to non-AED users; to assess the level of patient awareness regarding AED-related bone health, falls and fracture risk; to examine potential associations of AED therapy, both recent and long-term, on bone measures; and to evaluate any association of chronic therapy on balance function. Included in the evaluation were risk factors including age, AED polytherapy, therapy length, gender and types of AED (enzyme-inducing vs. non-enzyme inducing). Methods: Data on falls, fracture history and associated risks were collected in 150 epilepsy outpatients taking AEDs and 506 controls, and analysed cross-sectionally by univariate and multivariate methods to assess the prevalence of falls and fractures, and associated factors. Baseline and follow-up bone assessments (separated by at least two years) were performed in two cohorts, including: i) 54 twin and sibling pairs discordant for chronic therapy, and ii) 57 newly-diagnosed epilepsy patients recently started on therapy and 54 controls, using dual energy X-ray absorptiometry, and peripheral quantitative computed tomography. Balance examinations were performed for 26 AED-discordant twin and sibling pairs, with re-assessment at least one year later. The annual rate of change of bone and balance measures were calculated. Cross-sectional and longitudinal data were analyzed by univariate and multivariate analyses. Results: Compared to controls, epilepsy outpatients had a higher risk of fractures at vertebrae (p = 0.037), clavicle (p = 0.019) and ankle sites (p = 0.048), and multiple fracture episodes (p = 0.008). Female users had more non-seizure falls (31% vs. 17%, p = 0.027) and multiple falls (18% vs. 5%, p = 0.028) compared to female non-users. Less than 30% of patients knew of the association of AED use with increased risk for fractures, reduced bone mineral density (BMD) or falls. Prolonged AED therapy (> 20 years) significantly predicted an increased rate of bone loss for forearm BMD (-0.53%/yr; p = 0.040) and whole-body BMD (-0.37%/yr; p = 0.043). AED therapy was a significant predictor of increased bone loss at whole-body BMC (-0.26%/year; p = 0.041). Use of enzyme-inducing AEDs was associated with increased bone loss at the total hip (-1.65%/yr; p = 0.013) and whole-body BMD (-1.41%/yr; p = 0.019). In the initial years of AED therapy carbamazepine monotherapy (an enzyme-inducer) was associated with increased bone loss at the total hip (p = 0.034) and inter-trochanteric regions (p = 0.035). Postural sway deterioration was greater in AED users than non-users, with anterior-posterior (A-P) tilting and a concurrent distraction task (p = 0.016), and medial-lateral tilting without distraction (p = 0.027). In females (but not in the small male subsample), sway deterioration was greater in users with the A-P tilting platform and a concurrent distraction task (p = 0.035). Lower limb muscle strength and gait did not deteriorate over time. Conclusions: AED users demonstrated a higher risk of fractures, particularly with prolonged therapy. Female users were at increased risk of falls than female non-users. Greater BMD loss was associated with prolonged therapy and enzyme-inducing AEDs. Carbamazepine use in early therapy predicted increased hip region bone loss. Postural stability deteriorated over time in AED users compared to non-users. Awareness amongst epilepsy patients of AED-related effects was low. Findings suggests an association between chronic therapy and progressive underlying pathophysiology, adversely affecting bone measures and balance, both risk factors for fractures. Patients may benefit from taking NEIAEDs, rather than EIAEDs, to reduce associated long-term risks of bone fragility. These risks need consideration when managing patients taking AEDs

Associations Between Serum Sodium Concentration and Bone Health Measures in Individuals Who Use Antiepileptic Drugs : A Pilot Study

Hyponatraemia, defined as a serum sodium concentration ([Na+]) below 135 mmol/L, is the most common electrolyte disturbance observed in clinical practice (1). Hyponatraemia is associated with increased risk of osteoporosis (2,3), fractures (4,5), fractures independent of osteoporosis (3,5), and falls (4). One of the common medication classes that cause hyponatraemia is antiepileptic drugs (AEDs), which are often used lifelong in patients with epilepsy, and increasingly in other conditions. AEDs can be classified as hepatic CYP450 enzyme-inducing AEDs (EIAEDs) or non-enzyme-inducing AEDs (NEIAEDs). Certain AEDs, such as carbamazepine and oxcarbazepine, demonstrate stronger associations with hyponatraemia than other AEDs (6). Whilst inducing hyponatraemia, AEDs are also independently associated with increased risk of osteoporosis and fracture (7). However, the underlying mechanisms by which AEDs adversely affect the risk of fragility fracture, and also cause hyponatraemia remain uncertain and likely are multifactorial. A potential association between serum sodium concentration and the risk of fragility fracture in AED users appears not to have been explored previously and could help explain how AEDs are associated with impaired bone health. In this pilot study, we investigated the associations between the risk of fragility fracture (indicated by areal BMD (aBMD), fracture history, and falls history), and serum sodium concentrations in AED users. We hypothesised that AED use is associated with hyponatraemia, which is also associated with low aBMD and an increase in reported history of fractures and falls. Materials and Methods: This was a retrospective study including patients with epilepsy from 3 studies approved by the Human Research Ethics Committee (HREC) at Melbourne Health, Victoria, Australia. All participants provided written consent to participate in the studies