A Cross-Sectional Observational Study To Evaluate The Effect Of Anti-Epileptic Drugs On Bone Health In Indians

Origin of proposal

 Epilepsy is a common neurological disorder encountered in both the outpatient and inpatient services of our hospital. There is a growing body of literature describing the association of bone and mineral metabolism mostly assessing bone mineral density (BMD) using DXA scan in patients on antiepileptic drug (AED)therapy for greater than 6months, more often the enzyme inducing AEDs. With increasing use of non-enzyme inducing AEDs of-late, literature investigating the effect of this group of AEDs , particularly in in the Indian population is, however, limited.

  Rationale of the study

 Large trials studying the effect of AEDs on qualitative and quantitative bone health , adjusting for confounding factors are sparse. Currently  national or international guidelines for preventive therapy and treatment of drug induced osteoporosis are not available. This study aims to evaluate the bone health using DXA scan with traditional parameter i.e. BMD assessment along with latest and more precise measures of bone micro-architechture called as Trabecular bone Score (TBS) and also using Bone turn-over markers(BTM)  in persons prescribed  AEDs for more than 6months at our centre. The results of this study are expected to add to existing literature and to assist in goal oriented treatment decisions for this specific population

Research question /hypothesis

 1.What is the effect of  anti-epileptic drug therapy beyond 6months on bone mineral density, trabecular bone score and bone turnover markers in Indian patients?

2.What is the association between anti-epileptic drugs and vitamin D levels?

3.Which among Trabecular bone score – adjusted FRAX (TBS-FRAX) and FRAX tool predict fracture risk better?

 AIMS

 To evaluate the bone health using DXA scan with traditional parameter i.e. BMD assessment along with latest and more precise measures of bone micro-architecture called as Trabecular bone Score (TBS) and also using Bone turn-over markers (BTM) in persons prescribed AEDs for more than 6months at our centre

 The results of this study are expected to add to existing literature and to assist in goal-oriented treatment decisions for this specific population.

  OBJECTIVES

 Primary Objective:

To study the alterations in bone mineral density, trabecular bone score and bone turn-over markers induced by anti-epileptic drugs in Indians.

 Secondary Objective:

 1.To study the effect of anti-epileptic drugs on 25-hydroxy vitamin D levels

2. To compare TBS-FRAX with FRAX tool to predict fracture risk

  Preliminary work done--nil

  METHODOLOGY (WORK PLAN)

STUDY DESIGN

Cross sectional observational Study

 STUDY SETTING

Department of Neurology and Department of Endocrinology, K. S. Hegde Medical College, Mangalore

 STUDY DURATION

2years

  SAMPLE SIZE

Based on the mean comparison of BMD in an earlier publication (7) in patients on AEDs and healthy controls, SD of lumbar spine region in cases = 0.215 and SD of lumbar spine region in controls = 0.131, mean difference = 0.08 and the effect size = 0.46. At 5% level of significance and 80% power of test and at 1:2 ratio, required sample size is 156 cases and 78 healthy using nMaster software Version 2.0.

Inclusion and Exclusion Criteria as mentioned before

STUDY TOOLS

Dual energy Xray Absorptiometry (DXA) scan  for Bone mineral density assessment and Trabecular Bone Score assessment

Serum levels of Vitamin D, Parathormone

Bone Turn Over markers – ProCollagen 1 peptide (P1NP) and C Telo peptide (CTX)

FRAX tool (free online application)

     STUDY PROTOCOL

After obtaining consent 156 patients qualifying for the study shall be recruited as cases, while age sex and body mass index matched 78 healthy subjects shall be recruited as controls. Relevant history shall be obtained and anthropometry detailed will be noted. 2ml blood sample will be obtained for assessment of Vitamin D levels, parathormone levels and bone turn over markers. Both cases and controls will then be subjected to Dual energy Xray absorptiometry scan for obtained bone mineral density and Trabecular Bone score.HBlood ests for – Vitamin D, PTH and BTM

DXA scan for BMD and TBS

Methods of Statistical AnalysisStatistical analysis will be done using SPSS v29. To test the statistical significance of mean comparison of BMD and Bone turn over markers between patients and controls, student t-test will be applied.

 SIGNIFICANCE and key outcome/deliverables

Significance 1: There is little Indian evidence on AEDs and osteoporosis. Our investigation can determine if AED use is linked to osteoporosis, including the effect of duration of AED use on bone health.

Key outcome 1: Early DXA scans can detect fracture risk and inculcate measures for prevention of major osteoporotic fractures.

Significance 2: Data on NewerNEIAEDs and effect on bone density/bone turn-over markers are rare

Key outcome 2: The data on NEIAEDs could prove useful in avoiding the particular drugs in patients with increased fracture risk

Significance 3: Most studies use bone mineral density measurement, which is inaccurate at predicting fracture risk. Our research using TBS to describe bone microarchitecture and BTM to describe bone remodelling will help determine the optimal osteoporosis treatment. It also compares the FRAX with TBS-adjusted FRAX to identify osteoporosis therapeutic candidates.

Key outcome 3: This would better identify candidates for osteoporosis intervention more effectively and aid in practical decision making.

Significance 4: The study could examine Vitamin D deficiency in AED-treated patients and whether it increases the risk of osteoporosis.

Key outcome 4:  Regular vitamin D treatment for patients on AED is practical. This modest procedure may prevent catastrophic fractures.