A Cross‐Sectional Study to Assess the Modulation of Wnt Inhibitors following Anti‐Epileptic Drug Therapy and their Correlation with Vitamin D and Receptor Activator of Nuclear Factor κ B Ligand in Indian Women with Epilepsy

Abstract

Long-term anti-epileptic drug (AED) therapy compromises bone health. Although vitamin D deficiency is proposed to be involved, it alone is not held responsible. This accounts for investigating other mechanisms in bone accrual. Recent studies have shown modulation of inhibitors of wnt pathway, sclerostin and dickkopf-1 (DKK-1), in glucocorticoids-induced osteoporosis. We investigated whether AED monotherapy modulates wnt inhibitors in Indian women with epilepsy. Women of age > 20-40 years with the diagnosis of epilepsy and receiving AEDs (carbamazepine, valproate and levetiracetam) for at least a year were enrolled. The results were compared with age-matched healthy controls with no evidence of metabolic bone disease. Women undergoing treatment with AEDs (mean duration: 50.59 ± 37.929 months) exhibited higher serum sclerostin and receptor activator of nuclear factor κ B ligand (RANKL) and lower vitamin D (25-hydroxy vitamin D) and DKK-1 levels when compared to age-matched healthy controls. Sclerostin showed a positive correlation with RANKL, while DKK-1 presented no such relationship. However, no association was evident after adjusting for age, duration of treatment and total daily dose. Although a correlation between wnt inhibitors and RANKL could not be obtained, AEDs displayed changes in serum levels of wnt inhibitors in persons with epilepsy and hence these drugs may compromise bone health through a disturbance in wnt signalling mechanisms.

Carbamazepine, Sodium Valproate and Levetiracetam Modulate Wnt Inhibitors in Indian Women with Epilepsy

“…However, there is no generalized mechanism responsible for such consequences. In our previous study, alteration in Wnt inhibitors was reported following AED therapy in Wistar rats (9) and in Indian women with epilepsy (8). The present study analyzed the effect of individual drugs viz SVP, CBZ and LTM on modulation of Wnt inhibitors in persons with epilepsy.…”

“…Though, CBZ didn't exert significant rise in serum RANKL levels but showed an increasing trend. The role of Wnt inhibitors and RANKL in bony consequences following AED therapy is proven in our previous report where sclerostin was positively correlated with RANKL, while no such effects were observed with DKK-1 (8). Now the individual analysis of drugs showed that the positive correlation observed between sclerostin and RANKL is due to CBZ.…”

“…The study includes sub-group analysis of data of a cross-sectional analytic study conducted at Neuroscience Centre, AIIMS, New Delhi and has been published recently (8). Parveen et al included 32 adult women with epilepsy treated with sodium valproate (SVP), carbamazepine (CBZ) or levetiracetam (LTM) as monotherapy for at least a year.…”

Effect of carbamazepine on the bone health of people with epilepsy: a systematic review and meta-analysis

“…The prevalence of bone abnormalities and bone diseases such as osteopenia, chronic pain, falls and fractures in epileptic patients is at least 50%, [1][2][3] and much attention has been paid to the association between bone health and AED therapy in epilepsy. 4,5 Evidence from a recent meta-analysis found that long-term valproate treatment in children with epilepsy leads to vitamin D deficiency. 6 Carbamazepine (CBZ), a common AED, has been widely used to control seizures in focal epilepsy over the past two decades.…”