Medical management of epilepsy, Seizures, Epileptogenesis, Anti-seizure medications, Anti epileptic drugs, status epilepticus, management of seizures, Management of status epilepticus

1. Bone Health And Epilepsy
Presenter : Dr. Vamsi Krishna Koneru
DM Neurology (CMC Vellore)
PDF Epilepsy (JIPMER)
23/11/23

2. Overview
• Normal Bone Mineralisation – Physiology
• Epilepsy, ASM and their influence on bone health
• Review of literature on effect of various types of ASM on bone health
• Final conclusions and take home points

3. Normal Bone Mineralisation – Physiology
• Bone is a dynamic, active tissue.
• Constant reconstruction all through life
• Bone cells include :
• Osteoblasts which builds bone,
• Osteocytes maintains strength, and
• Osteoclasts, which resorb bone.
• The balance between the types of cells
determines the bone density.

5. Normal Bone Mineralisation – Physiology
• Organic matrix:
• Type I collagen forms majority of the organic matrix (approximately 95%)
• Provides bone with resistance to tensile forces.
• Remainder is made up of proteoglycans and non- collagenous proteins
• Osteonectin,
• Osteocalcin and
• Osteopontin.

6. Normal Bone Mineralisation – Physiology
• Mineral matrix:
• Constitutes approximately two-thirds of the total bone matrix
• Mostly made up of calcium & phosphate ions in the form of hydroxyapatite crystals.
• Other constituent ions include magnesium, sodium, potassium and fluoride.
• It provides bone with strength under compressive loads.

7. Normal Bone Mineralisation – Physiology
• The formation of hydroxyapatite is determined by the concentration of calcium and
phosphorus in plasma and extracellular fluid.
• There is a critical limit for the concentrations of calcium and phosphorus ions below, which
the mineralization of organic matrix does not occur.
• Vitamin D, PTH, Calcitonin, Sex hormones play a vital role in maintaining the concentration
of calcium and phosphorous ions

9. Role of - PTH
• Central role in regulating calcium-
phosphate metabolism
• It’s production increases in response to
low serum calcium levels.
• A continuous hypersecretion of PTH, as
occurs in primary hyperparathyroidism,
leads to bone resorption.
• On the other hand when administered at
a low dose and intermittently, PTH exerts
positive effects on bone volume and
microarchitecture

10. Role of - Nutrition
• Nutrition plays a key role in the maintenance of bone health.
• Nutrient store in early childhood and adolescent determines the bone status
in old age.
• A diet low in calcium leads to hypocalcemia, which triggers secondary hyper-
parathyroidism leading to osteoclast activity and calcium release from bone
• Aging changes the calcium metabolism leading to reduced intestinal calcium
absorption but with increased bone resorption.

11. • Childhood and adolescence are critical periods of skeletal bone mineralization.
• Peak bone mineral density (BMD) achieved by the end of adolescence will determine
the risk for pathological fractures and osteoporosis in the later life.
• Any fall in BMD during this decisive period could adversely affect the bone health in
later life
• Keeping in mind the role of nutrition, proper counseling about dietary calcium needs
to be emphasized in all at risk patients
(Preconception period, during pregnancy and during lactation, elderly people etc)
Role of - Nutrition

12. Role of - sex hormones
• Both androgens and estrogens are known to suppress osteoblast apoptosis and
increase osteoclast apoptosis.
• Androgens stimulate osteoblast precursors through triggering interleukin-1β.
• Estrogen decreases Receptor activator of NF-κB ligand (RANK Ligand) and
increases Osteoprotegerin, thus inhibits osteoclast differentiation.
• Furthermore, estrogen decreases bone resorbing cytokines such as interleukin-1,
interleukin-6, and tumor necrosis factor alpha.

14. Others….
• Other influences on the continuous bone remodeling process are :
• Calcitonin
• Thyroid hormone,
• Growth hormone,
• Glucocorticoids,
• Insulin,
• Various growth factors and
• Locally produced cytokines

15. Epilepsy, ASM and their role in bone health

16. ASM and their role in bone health
• Fractures are common in PWE, especially during seizures.
• However, more than 70% of fractures occurring in PWE over age 60 are thought to
be simply osteoporotic in nature, unrelated to injury from seizures. (Sheth et al., 2006)
• Fractures can have serious consequences : (Papaioannou et al., 2009; Ioannidis et al., 2009)
• Pain,
• Disability,
• Loss of independence, and
• Increased mortality

17. ASM and their role in bone health
• Epilepsy is itself known to increase bone loss and the risk of fractures by :
• Restrictions of physical activity imposed by seizures,
• Coexisting neurological deficits, and
• Seizure-related falls
• Bone loss secondary to the usage of ASM
• An increased fracture rate of 2–6 times has been found than seen in general
population.

18. ASM and their role in bone health
• Long term ASM use in patients with epilepsy have been known to induce :
Hypocalcemia,
Hypophosphatemia,
Increased serum alkaline phosphatase,
Hyperparathyroidism,
Hypovitaminosis D
Reduced serum levels of biologically active vitamin D metabolites

19. ASM and their role in bone health.
• Deficiency of Vitamin D is commonly described as a cause for the bone loss in epileptic
patients.
• It has been found that induction of hepatic CYP450 system accelerates the catabolism of
Vitamin D into its inactive metabolites.
• However, finding of Vitamin D deficiency is not consistently seen in all the studies
• Valproic acid, being an enzyme inhibitor, is also associated with decrease in BMD and
increased risk of fractures.
• Hence ASM’s may affect the bone metabolism through mechanisms not only associated
with hepatic enzyme induction.

20. ASM and their role in bone health.
• The reason for decreased BMD with VPA treatment is not well known.
• Valproate had shown suppression of long bone growth by inhibiting cartilage formation and accelerating
ossification of the growth plate
• Valproate association with BMD is probably by hormonal changes as suggested by the development of a Polycystic
Ovary Syndrome.
• EIASM enhance catabolism of sex steroids.
• Decreased intestinal absorption of calcium by phenytoin and phenobarbitone.
• Calcitonin deficiency is another postulated mechanism.
• Both the EIASM and the NEIASM directly affect osteoblast and osteoclast activity.

23. ASM and their role in bone health

24. Review of literature on effect of various types of ASM
on bone health

25. Review of literature on effect of various types of ASM on bone health
• Studies that have compared ASM regimens often find that :
Phenytoin is consistently associated with decrease in BMD
Phenobarbitone is consistently associated with reduced BMD
Sodium Valproate is also consistently associated with reduced BMD
Reports regarding Carbamazepine were conflicting—but mostly Negative BMD effect
Reports regarding Levetiracetam were conflicting – but mostly Positive BMD effect
Insufficient data with regards to other newer ASM (Lamotrigine, Topiramate)

38. • Systemic review analysed 13 observational studies representing 68,973
patients with epilepsy in 2015
• In the EIAED users:
• Five studies illustrated decreased BMD
• Five studies demonstrated irrelevance to BMD
• Two studies reported increased incidence of fracture, and
• One study showed nothing to do with the incidence of fracture

41. • Most of the studies identified were of poor methodological quality
• Failed to control for important fracture risk factors between groups.
• Over half of the studies included were cross sectional analyses
• However, the largest study in the review, by Nicholas et al.,
• Accounted for 92% of all included patients
• High quality,
• Control for an extensive list of important possible confounding factors ( age, duration of epilepsy,
previous AED use, seizures, past fractures and falls, co-morbid illnesses and multiple other
medication including steroids and osteoporosis therapies).
• Showed consistently increased fracture risk associated with EIAEDs across several bone sites and
in both sexes.

43. • Systematic review of 24 studies published in 2021
• Most studies showed with statistical significance that AEDs use was associated with BMD reduction
• Only five studies failed to show statistically significant reduction of BMD
• Among those 5 studies, 3 noted reduced BMD trends were observed with AED use
• Two studies that directly analyzed which treatment, EIAEDs or NEIAEDs, had more significant reduction
of BMD found the opposite result of each other (Ensrud et al., 2008; Salimipour et al., 2013).
• One study found no difference between BMD in EIAEDs and NEIAEDs (Stephen et al., 1999)

45. • Multiple studies compared CBZ with various other NEIAEDs and showed CBZ is
associated with lower BMD
• In contrast, LTG was reported to have minimal detrimental effects on BMD
(Kim et al., 2007; Sheth and Hermann, 2007).

46. • Effects on bone due to AEDs were also considered using biochemical markers for bone formation and resorption :
• Vitamin D,
• Parathyroid hormone (PTH),
• Alkaline phosphatase (ALP),
• Calcium,
• Phosphate,
• Osteocalcin (OCL)] and
• C-terminal cross-linked type 1 collagen telopeptide, pro-peptide type 1
• There were no clear trends observed in serum levels of biochemical markers
• Most studies found no significant correlation with changes in BMD
• One study went on to recommend against frequent measurement of bone markers due to limited prognostic
value of these measurements (Meier and Kraenzlin, 2011).

47. • Patients taking any AED for an extended period of time are at risk of having decreased BMD.
• Little compelling evidence to support that EIAEDs were more harmful to bone than NEIAEDs.
• CBZ seemed to have the least favorable BMD outcomes.
• LTG seemed to show the most bone-protective qualities.

48. • In one RCT patients supplemented with Bisphosphonates, Calcium, and Vitamin
D, had significantly increased LS BMD two years after treatment (Lazzari et al.,
2013).
• Use of only calcium and vitamin D (without bisphosphonates) still improved BMD
in greater than 69 % of patients (Lazzari et al., 2013).

50. • Few studies confirmed osteo- protective effects with taking only :
• Bisphosphonates (Meier and Kraenzlin, 2011) or
• Calcium (Chu et al., 2004)
• One found no difference in BMD with mono or polytherapy with prophylactic
vitamin D supplementation (Tekgul et al., 2005).

53. • Certain limitations in this systematic review:
• Duration of treatment – very heterogenous
• Different combination AED polytherapy were reported in conjunction with long-term use
• In few studies, polytherapy was often reported as an individual group with inadequate
detail of breakdown

56. Conclusion

57. Conclusion
• Long-term AED therapy remains the most significant risk factor for BMD loss.
• There is little compelling evidence to support that the class of EIAEDs are more harmful
to bone health than NEIAEDs.
• Biochemical serum markers of bone turnover do not reliably correlate with changes in
BMD and thus, routine measurement may be clinically unreliable.
• In at risk individuals DEXA evaluation according to the recommended guidelines to be
done

58. Screening
• For individuals with a history of prolonged use (>5 years) of ASMs, with other risk
factors for ASM-induced bone disease :
• High-dose,
• Multidrug regimens
• Low vitamin D intake
• Limited sunlight exposure
• Chronically ill, older, or institutionalized patients
• Low physical activity levels
• Exposure to drugs that induce chronic metabolic acidosis and
• Concomitant therapy with other drugs that induce hepatic enzymes
• Bone mineral density (BMD) testing is recommended (Grade 2C).

59. Calcium and Vitamin D intake
• For patients receiving ASMs, calcium and vitamin D supplementation can be
considered (Grade 2C).
• Although the optimal intake (diet plus supplement) has not been clearly established in
this patient population, the age group-based reference intake for calcium and vitamin
D daily can be used.
• Patients receiving ASMs, particularly enzyme-inducing ASMs, may require higher
doses of vitamin D.
• It is advised to measure serum 25-hydroxyvitamin D (25[OH]D) levels in such patients
to determine whether vitamin D intake is sufficient to maintain levels within the
normal range.

62. Osteoporosis prevention guideline
• Current osteoporosis prevention guideline recommend:
• Adequate calcium and vitamin D intake,
• Weight-bearing exercises,
• Balanced diet,
• Managing gait and vision, and
• Reducing external risk factors, such as alcohol and smoking cessation

63. Pharmacologic therapy for osteoporosis
• The pharmacologic treatment of osteoporosis and fracture in patients taking
ASMs is the same as the treatment of osteoporosis in individuals not on ASM
therapy

64. Take home points
• Timely withdrawal of AEDs is important – to prevent long-term
complications
• Little evidence to support that the class of EIAEDs are more harmful to
bone health than NEIAEDs.
• Among the options available newer ASM like Levetiracetam appear to
have favorable outlook ( Albeit with some controversy )
• Biochemical serum markers of bone turnover are not to be routinely
advised

65. Take home points
• Osteoporosis prevention guidelines to be recommend for all high risk persons.
• Routine supplementation in all epileptic patients is not supported with the
current available best evidence. However can be considered on individual
level
• Need for larger RCT’s to propose guidelines for supplementation of Calcium,
Vitamin D, Bisphosphonates in PWE.
• Pharmacologic treatment of osteoporosis and fracture in patients taking ASMs is
the same as the treatment of osteoporosis in individuals not on ASM therapy

66. THANK YOU