A 2014 systematic review and meta-analysis synthesized data to evaluate the association between antiepileptic drug (AED) use and fracture risk. The meta-analysis utilized a random-effects model to pool results and assess the strength of the association between AED use and fracture risk. Results from the analysis demonstrated a significant increase in fracture risk among AED users, with a relative risk (RR) of 1.86 (95% confidence interval [CI] 1.62–2.12). A notable finding was that both liver enzyme-inducing AEDs (LEI AEDs) and non-LEI AEDs were associated with elevated fracture risk, although the risk was more pronounced for LEI AEDs (RR = 1.18; 95% CI 1.11–1.25). Specific AEDs such as phenobarbiturate (PB), topiramate (TPM), and phenytoin (PHT) were highlighted due to their significant associations with increased fracture risk, showing increases of 78%, 39%, and 70% respectively. The meta-analysis thus underscores a robust link between AED use and heightened fracture risk, particularly with certain LEI AEDs and specific medications like PB, TPM, and PHT. [1]

A 2015 systematic review assessed the effects of antiepileptic drugs (AEDs) and the ketogenic diet on bone health and growth potential in children with epilepsy. The studies were categorized based on whether they reported reduced BMD at any skeletal site. A logistic regression analysis was utilized to evaluate variables such as age, gender distribution, study design, type of AED, presence of co-morbidity, and signs of vitamin D deficiency or osteomalacia. The review identified that both carbamazepine and valproate, often used as monotherapy in 11 studies, were associated with a limited decrease in bone mineral density. Other AEDs, such as oxcarbazepine, levetiracetam, phenytoin, phenobarbital, and topiramate, each examined in single studies, did not report decreased bone density. Importantly, polytherapy with AEDs appeared to correlate with a more significant decrease in bone density compared to monotherapy. A limited number of studies suggested potential impairment in bone growth among users of AEDs. The review highlighted that the absence of vitamin D deficiency or osteomalacia was a crucial determinant for maintaining normal BMD. The findings underscore the need for interventions to correct vitamin D deficiency and ensure adequate calcium intake in pediatric patients undergoing treatment for epilepsy. [2]

A 2021 cross-sectional study assessed the association between AED use and metabolic bone disease in patients with epilepsy, within a large unselected Danish population. The research utilized data from 835 patients attending an Epilepsy Clinic in Glostrup, Denmark, from January 2006 to January 2018. The methodology included collecting demographic information and dual-energy X-ray absorptiometry (DXA) scan results, followed by logistic regression models for statistical analysis. Patients with epilepsy were evaluated for bone mineral density (BMD) changes and categorized based on their AED regimen, distinguishing between enzyme-inducing AEDs (EIAEDs) and non-enzyme-inducing AEDs (NEIAEDs). The 2021 study revealed that the use of EIAEDs was significantly associated with an increased risk of osteoporosis, with odds 2.2 times higher than those using NEIAEDs. Further analysis indicated that the duration of epilepsy and polytherapy with AEDs were additional risk factors; specifically, the likelihood of developing osteoporosis increased when patients were on two or more AEDs. The research highlighted age and body mass index (BMI) as contributing factors, with lower BMI and older age correlating with higher osteoporosis risk. These findings underscore the need for clinicians to consider these risk factors in the management of patients with epilepsy, particularly regarding the selection and combination of AEDs to mitigate the risk of bone health deterioration. [3]

[4] Warnings and Precautions:
Decrease in Bone Mineral Density: has been shown to decrease bone mineral density and bone mineral content in pediatric patients

[4] Decrease in Bone Mineral Density
Results of a one-year active-controlled study in pediatric patients (N=63) demonstrated negative effects of topiramate tablets monotherapy on bone mineral acquisition via statistically significant decreases in bone mineral density (BMD) measured in lumbar spine and in total body less head [see Use in Specific Populations (8.4)]. Twenty-one percent of topiramate tablets- treated patients experienced clinically important reductions in BMD (Z score change from baseline of –0.5 or greater) compared to 0 patients in the control group. Although decreases in BMD occurred across all pediatric age subgroups, patients 6 to 9 years of age were most commonly affected. The sample size and study duration were too small to determine if fracture risk is increased. Decreased BMD in the lumbar spine was correlated with decreased serum bicarbonate, which commonly occurs with topiramate tablets treatment and reflects metabolic acidosis, a known cause of increased bone resorption [see Warnings and Precautions (5.4)]. Although small decreases in some markers of bone metabolism (e.g., serum alkaline phosphatase, calcium, phosphorus, and 1,25-dihydroxyvitamin D) occurred in topiramate tablets-treated patients, more significant decreases in serum parathyroid hormone and 25-hydroxyvitamin D, hormones involved in bone metabolism, were observed, along with an increased excretion of urinary calcium.

[4] Monotherapy treatment for Epilepsy:
A one-year, active-controlled, open-label study with blinded assessments of bone mineral density (BMD) and growth in pediatric patients 4 to 15 years of age, including 63 patients with recent or new onset of epilepsy, was conducted to assess effects of topiramate tablets (N=28, 6 to15 years of age) versus levetiracetam (N=35, 4 to 15 years of age) monotherapy on bone mineralization and on height and weight, which reflect growth. Effects on bone mineralization were evaluated via dual-energy X-ray absorptiometry and blood markers. Table 10 summarizes effects of topiramate tablets at 12 months for key safety outcomes including BMD, height, height velocity, and weight. All Least Square Mean values for topiramate tablets and the comparator were positive. Therefore, the Least Square Mean treatment differences shown reflect a topiramate tablets-induced attenuation of the key safety outcomes. Statistically significant effects were observed for decreases in BMD (and bone mineral content) in lumbar spine and total body less head and in weight. Subgroup analyses according to age demonstrated similar negative effects for all key safety outcomes (i.e., BMD, height, weight).

[4] Medication guide:
Topiramate tablets can increase the level of acid in your blood (metabolic acidosis). If left untreated, metabolic acidosis can cause brittle or soft bones (osteoporosis, osteomalacia, osteopenia), kidney stones, can slow the rate of growth in children, and may possibly harm your baby if you are pregnant. Metabolic acidosis can happen with or without symptoms.

A search of the published medical literature revealed 2 studies investigating the researchable question:

What is the long-term data of topiramate's effect on bone density

C - Multiple studies with limitations or conflicting results  Read more→