Influences of bone and mineral metabolism in epilepsy

Introduction: Patients with epilepsy are at increased risk for metabolic bone disease, low bone mineral density and fractures.

Areas covered: This article reviews the predictors and mechanisms of bone loss in patients with epilepsy. It provides information regarding the basic bone biology, evidences of osteopathy with epilepsy and the potential mechanisms of its pathogenesis. This review shows that long-term use of antiepileptic drugs (AEDs) is associated with the risk of osteopathy. However, age, gender, low body mass, severity of epilepsy, co-morbid conditions, institutionalization and calcium and vitamin D deficiencies are additional and modified risk factors. AEDs may indirectly accelerate bone loss through hypovitaminosis D, hypocalcemia and hyperparathyroidism or reduce bone accrual through decreasing the levels of calcitonin, growth factors and vitamin K. Also, AEDs may directly accelerate osteoclastic (bone loss) and/or reduce osteoblastic (bone formation) activities, the main cells involved in bone remodeling.

Expert opinion: Understanding the basic bone biology and the pathophysiology of the disturbed bone and mineral metabolism in epilepsy will aid in identification and monitoring of patients at risk and in planning appropriate prophylactic and therapeutic measures.     

Emerging drugs for partial onset seizures

Importance of the field: Patients with epilepsy have recurrent unproved seizures. Epilepsy is common, with a prevalence range that centers at around 1%. Patients with epilepsy can have a poor quality of life and suffer significant social stigma. Despite the availability of a large number of antiepileptic drugs (AEDs) including standard and newer ones, a significant percentage of patients with epilepsy remain poorly controlled.

Areas covered in this review: In this review, we briefly summarize data on the available AEDs, then present current information on the emerging AEDs, including their chemical structure, pharmacology, mechanism of action, and efficacy and adverse event profile in clinical trials. The AEDs included are rufinamide, lacosamide, eslicarbazepine, retigabine, brivaracetam, ganaxolone, stiripentol and carisbamate. Most of the literature related to these AEDs was published in the past 5 years.

What the reader will gain: The reader will become familiar with the pharmacology of emerging AEDs and the results of clinical trials with these AEDs. The reader will also be able to assess the advantages of AEDs and their potential respective places in the treatment of epilepsy.

Take home message: The emerging AEDs offer predominantly improved pharmacokinetics and tolerability and occasionally new mechanisms of action. They will probably have a modest impact on drug-resistant epilepsy.     

Pharmacotherapy for children and adolescents with epilepsy

Introduction: Childhood epilepsies are the most frequent neurological problems that occur in children. Despite the introduction of new antiepileptic drugs (AEDs) 25 – 30% of children with epilepsy remain refractory to medical therapy.

Areas covered: This review aims to highlight the main published data on the treatment of childhood epilepsy. The electronic database, PubMed, and abstract proceedings were used to identify studies. The aim of antiepileptic therapy should be to provide complete seizure control, if possible without the burden of any side effect. Since 1993, new agents have been approved for use as an antiepileptic. Although there are few published data (especially in pediatric populations) to establish that the second-generation AEDs are more efficacious than the older AEDs, they appear to have better tolerability.

Expert opinion: Old AEDs are efficacious agents that continue to play a major role in the current treatment of epilepsy. These agents actually remain the first-line treatment for many specific seizure types or epileptic syndromes. The new AEDs were initially approved as adjunct agents and – subsequently – as monotherapy for various seizure types in the adult and children. Despite these improvements, few AEDs are now considered to be a first-choice for the treatment of epilspsy in children.     

Extended-release lamotrigine in the treatment of patients with epilepsy

Importance to the field: Epilepsy is a neurological disorder primarily characterized by recurrent, unprovoked seizures resulting from excessive or synchronous neuronal activity in the brain. Depending on the case definition and population studied, the lifetime prevalence of epilepsy in the USA is estimated to be 1.2 – 2.9%. In general, epilepsy is related to a significant increased risk of mortality and injury. A cornerstone of epilepsy management is use of antiepileptic drugs (AEDs). This review focuses on the AED lamotrigine, with particular emphasis on the extended-release formulation, in the management of patients with epilepsy, and the significant clinical issues that may be relevant with once-daily AED therapy.

Areas covered in this review: An introductory section overviews the prevalence of epilepsy, current treatment recommendations for patients with epilepsy, and unmet needs in epilepsy management. This is followed by an overview of the AED market with currently available and developing compounds, a summary of lamotrigine and extended-release lamotrigine, clinical efficacy and tolerability studies with extended-release lamotrigine, and regulatory issues. The review concludes with an expert opinion summary on the important issue of treatment adherence, the possible role of extended-release lamotrigine in adherence enhancement, and additional research and areas which need further focus for optimal epilepsy outcomes.

What the reader will gain: The reader will gain familiarity with extended-release (once-daily) lamotrigine and clinical issues that may be relevant to once-daily use. Once-daily AED use might be one way to simplify the epilepsy treatment regimen and can pave the way for other approaches that can maximize adherence, such as a frank discussion of risks, benefits, and attitudes towards treatment – all critical components of a strong and positive doctor–patient relationship.

Take home message: The AED lamotrigine is widely used in clinical settings and has become available in a once-daily extended-release version, which may minimize serum concentration fluctuation and presumably would both reduce patient burden and maximize treatment adherence as opposed to the immediate-release version of the compound. Adverse effects and safety concerns between the immediate- and extended-release versions of lamotrigine seem similar based upon interpretation of the limited literature.     

Emerging drugs for the management of cancer treatment induced bone loss

Areas covered in this review: We focus our attention on data on the efficacy of currently available and emerging drugs for the management of cancer treatment induced bone loss (CTIBL) found in a PubMed research from 1997 till today.

Importance of the field: One of the most common and severe safety issues of the antihormonal therapy in both sexes is the CTIBL and the related fragility fractures. In postmenopausal women with estrogenic receptor positive breast cancer, the third-generation aromatase inhibitors (AIs) are the standard therapy. Observational retrospective studies have found that AIs treated patients had a high rate of bone loss and fracture risk (RR 1.3). Also in men with prostate cancer receiving androgen deprivation therapy, the increase in bone turnover and the consequent bone loss are very rapid and sustained significantly increasing the fracture risk.

What the reader will gain: The aim of our review is to provide the current evidences for the management of bone loss and fracture risk in this subpopulation.

Take home message: The very high rate of bone loss and the high incidence of fractures indicate that cancer patients at risk of CTIBL need to be carefully monitored and stratified for fracture risk. Although there is a strong evidence of efficacy in prevention of bone loss and reduction of fracture risk for many drugs approved for postmenopausal osteoporosis (PMO) and male osteoporosis, for CTIBL there are actually no drugs approved for this indication.     

Risk of osteoporosis and fracture incidence in patients on antipsychotic medication

Introduction: In patients suffering from schizophrenia and bipolar disorder, antipsychotics are the mainstay of treatment worldwide. By blocking D₂ brain mesolimbic receptors, antipsychotics are believed to reduce and control psychotic experiences, but recent evidence has suggested that they may also have adverse effects on bone mineral architecture and fracture incidence.

Areas covered: This study reviews current literature surrounding the use of antipsychotics and their effects on bone homeostasis. The primary medical search engines used for the study are Ovid MEDLINE (1950 – April 2010), EMBASE (1988 – April 2010) and PsychINFO (1987 – April 2010) databases.

Expert opinion: Typical antipsychotics, in addition to the atypical antipsychotics risperidone and amisulpride, have been shown to increase serum prolactin levels in in vivo human studies. Results from animal and human in vitro and in vivo studies have demonstrated that high concentrations of prolactin have been shown to adversely affect bone cell metabolism and accelerate the rate bone mineral density loss, thereby increasing fracture risk. Increasing awareness of the side effect profile of antipsychotic medications on bone metabolism may prompt clinicians to screen patients at high risk of antipsychotic-induced osteoporosis and provide treatment, which may reduce the incidence of potentially avoidable fractures.     

Pharmacotherapy for tonic–clonic seizures

Introduction: Occurrence of generalized tonic–clonic seizures (GTCS) is one of the most important risk factors of seizure-related complications and comorbidities in patients with epilepsy. Their prevention is therefore an important aspect of therapeutic management both in idiopathic generalized epilepsies and in focal epilepsies.

Areas covered: It has been shown that the efficacy of antiepileptic drugs (AEDs) varies across epilepsy syndromes, with some AEDs efficacious against focal seizures with secondary GTCS (sGTCS) but aggravating primary GTCS (pGTCS). In patients with pGTCS, evidence-based data support the preferential use of valproic acid, lamotrigine, levetiracetam and topiramate. In patients with sGTCS, all AEDs approved in the treatment of focal epilepsies might be used.

Expert opinion: Both in pGTCS and sGTCS, additional data are required, specifically to inform about the relative efficacy of AEDs in relation to each other. Although valproic acid might be the most efficacious drug in idiopathic generalized epilepsies, it should be avoided in women of childbearing age due to its safety profile. In patients with sGTCS, AEDs for which the impact on this seizure type has been formally evaluated and which have demonstrated greater efficacy than placebo might preferentially be used, such as lacosamide, perampanel and topiramate.     

An update on the problem of osteoporosis in people with epilepsy taking antiepileptic drugs

Introduction: Antiepileptic drugs (AEDs) have been associated with a negative impact on bone health. Comorbid disorders in patients with epilepsy may require drugs exerting a pro-osteoporotic effect, so a possibility of untoward interactions with AEDs is probable.

Areas covered: This review discusses evidence related to the deteriorating influence of AEDs on bone, demonstrating generally stronger negative effects of conventional AEDs. Lamotrigine seems to be a safer AED in this regard. Further, literature data indicate that generally AEDs can lower the serum concentration of vitamin D. Importantly, pediatric patients are of greater risk of bone problems during therapy with AEDs, which is probably due to their effects on bone-forming processes.

Expert opinion: Supplementation with vitamin D and calcium is frequently recommended in patients taking AEDs chronically. Whether to add a bisphosphonate remains an open question due to the limited data on this issue. A possibility of negative interactions exists between AEDs and other pro-osteoporotic drugs: glucocorticoids, proton pump inhibitors and aromatase inhibitors. Depression is a frequent comorbidity in patients with epilepsy. Clinical data indicate that antidepressant drugs may also increase the risk of fractures. Again, patients with epilepsy and depression may be exposed to a greater risk of osteoporosis.     

Pharmacological treatment of biliary cirrhosis with ursodeoxycholic acid

Importance of the field: Primary biliary cirrhosis is a cholestatic liver disease that at one time was the leading indication for liver transplantation. Treatment with ursodeoxycholic acid has clearly improved the natural history of primary biliary cirrhosis.

Areas covered in this review: The treatment of primary biliary cirrhosis with a focus on ursodeoxycholic acid is covered. Papers related to treatment of primary biliary cirrhosis and associated conditions, using a variety of drugs but with a focus on ursodeoxycholic acid, are included. The papers reviewed date from 1984 – 2009.

What will the reader gain: The reader will gain an up-to-date understanding of current treatment strategies for primary biliary cirrhosis using ursodeoxycholic acid and an appreciation of what conditions are improved with this therapy and what associated conditions are not.

Take-home message: Ursodeoxycholic acid in a dose of 13 – 15 mg/kg/day should be considered in all patients with primary biliary cirrhosis who have abnormal liver enzymes.     

Pharmacotherapy of the third-generation AEDs: lacosamide,retigabine and eslicarbazepine acetate

Introduction: The search for new, more effective antiepileptic drugs (AEDs) continues. The three most recently approved drugs, the so-called third-generation AEDs, include lacosamide, retigabine and eslicarbazepine acetate and are licensed as adjunctive treatment of partial epilepsy in adults.

Areas covered: For the above three AEDs, their mechanisms of action, pharmacokinetic characteristics, drug–drug interactions, pharmacotherapeutics, dose and administration and therapeutic drug monitoring are reviewed in this paper.

Expert opinion: Lacosamide and retigabine act through novel mechanisms, while eslicarbazepine acetate, a pro-drug for eslicarbazepine, acts in a similar manner to several other AEDs. All three AEDs are associated with linear pharmacokinetic and rapid absorption and undergo metabolism. Their drug–drug interaction profile is low (lacosamide and retigabine) to modest (eslicarbazepine) in propensity. At the highest approved doses for the three AEDs, responder rates were similar. The most commonly observed adverse effects compared with placebo were dizziness, headache, diplopia and nausea for lacosamide; dizziness, somnolence and fatigue for retigabine and dizziness and somnolence for eslicarbazepine acetate. The precise role that these new AEDs will have in the treatment of epilepsy and whether they will make a significant impact on the prognosis of intractable epilepsy is not yet known and will have to await further clinical experience.     

Zoledronic acid

Importance of the field: Both bone metastases and fragility fractures due to bone loss result in considerable morbidity affecting quality of life and independence as well as placing complex demands on healthcare resources. Zoledronic acid is a widely used intravenous bisphosphonate that reduces this skeletal morbidity in both benign and malignant conditions.

Area covered in this review: The incidence, clinical importance and prevention strategies to minimize side effects associated with the use of zoledronic acid are discussed with a particular focus on use in oncology where intensive monthly scheduling is required. This potentially increases the risk for adverse events over the 6 – 12 monthly administration used to treat benign bone diseases.

What the reader will gain: A detailed understanding of the generally favorable safety profile of zoledronic acid, but particularly the potential for renal dysfunction and osteonecrosis of the jaw.

Take home message: When compared to many other therapies, especially in the cancer setting, the severity of adverse events related to zoledronic acid is generally mild and, with the exception of the acute phase response causing transient fever, myalgia and bone pain, side effects are infrequent. Thus, the benefits of treatment with zoledronic acid within its licensed indications almost always outweigh the risks.     

The effect of antiepileptic drugs on the kidney function and structure

Introduction: Long-term use of antiepileptic drugs (AEDs) is associated with number of somatic conditions. Data from experimental, cross-sectional and prospective studies have evidence for the deleterious effect of some AEDs on the kidney.

Areas covered: This review summarized the current knowledge of the effect of AEDs on the kidney including evidence and mechanisms. Fanconi syndrome was reported with valproate (VPA) therapy in severely disabled children with epilepsy. Renal tubular acidosis and urolithiasis were reported with acetazolamide, topirmate and zonisamide, drugs with carbonic anhydrase inhibition properties. Increased levels of urinary N-acetyl-beta-D-glucosaminidase (NAG) to urinary creatinine (U-NAG/UCr), urinary excretion of α1-micrglobulin, β-galactosidase activity; and urinary malondialdehyde to creatinine (MDA/Cr), markers of renal glomerular and tubular injury, were reported with chronic use of some AEDs (VPA, carbamazepine and phenytoin). The mechanism(s) of kidney dysfunction/injury induced by AEDs is unknown. Experimental and clinical studies have shown that VPA induces oxidative stress, mitochondrial deficits, carnitine deficiency and inflammation and fibrosis in renal tissue in mice and in vitro studies.

Expert commentary: It seems reasonable to monitor kidney function during treating patients with epilepsy at high risk of kidney injury (e.g. on combined therapy with more than one AED, severely disabled children, etc).     

Safinamide in the treatment of Parkinson's disease

Importance of the field: Current therapy for Parkinson's disease (PD) is primarily directed at reversing the motor symptoms that are the consequence of dopamine deficiency and includes levodopa, dopamine agonists and monoamine oxidase (MAO) B inhibitors. New drugs offering both dopaminergic and non-dopaminergic actions could offer a significant advantage.

Areas covered in this review: This review surveys the current treatment strategies for PD. Defining unmet needs and how a new compound – safinamide, which has both dopaminergic and non-dopaminergic actions – might address these.

What the reader will gain: The reader will gain an understanding of safinamide and its mechanisms of action, including reversible MAOB inhibition and reduced dopamine reuptake with antiglutamatergic effects, and how it may potentially provide improvement of PD motor symptoms with an antidyskinetic effect through its effect on glutamate release. The clinical trial profile of safinamide is reviewed. Early results are promising in terms of improved motor function and reduced ‘OFF’ time. Additional Phase III trials are now in progress for this adjunctive indication. Finally, the reader will understand the potential role for safinamide in the selection and sequencing of drugs for PD.

Take home message: safinamide combines both dopaminergic and non-dopaminergic actions that may add a new dimension to PD treatment options as an adjunct to current drugs. Its efficacy is under active evaluation in Phase III clinical trials.     

Emerging drugs for high-grade osteosarcoma

Importance of the field: Osteosarcoma (OS) is the most common primary malignant bone tumour in children and adolescents. This review focuses on the most promising therapeutic markers and drugs which may potentially be considered for innovative high-grade OS treatments.

Areas covered in this review: The list of drugs and compounds reviewed has been generated by taking into account those which target markers of potential clinical interest for high-grade OS and have been included in Phase I, II or III clinical trials. The literature search covers the last 40 years, starting from the first OS chemotherapy reports of the early 1970s. Particular relevance was given to reports and reviews on new targeted therapies of possible clinical usefulness for high-grade OS.

What the reader will gain: This review gives an updated overview of novel therapeutic approaches which have been or are going to be evaluated in Phase I/II/III clinical studies for high-grade OS.

Take home message: On the basis of the information that has emerged so far, it can be predicted that in the next 5 – 10 years, new agents to be included in innovative treatment strategies for selected subgroups of high-grade OS patients may become available.     

Bazedoxifene when paired with conjugated estrogens is a new paradigm for treatment of postmenopausal women

Importance of the field: The concept of the tissue selective estrogen complex (TSEC) combining a selective estrogen receptor modulator (SERM) with one or more estrogens, aims to provide comparable efficacy to combination estrogen and progestin therapy for symptomatic menopausal women with a uterus without the need for a progestin.

Areas covered in this review: Published multi-center randomized blinded clinical trials with bazedoxifene alone and paired in combination with conjugated estrogens show an effect in hot flashes, vaginal atrophy, quality of life measures, sleep, bone density, and breast and uterine safety.

What the reader will gain: A new concept for menopausal women, bazedoxifene with conjugated estrogens (BZA-CE) TSEC, appears to provide the selective benefits of a SERM with additional benefits of estrogen without the need for a progestin. Preclinical studies with bazedoxifene alone showed that it was antagonistic in the uterine and breast tissue while an agonist in the bone. Phase II and III clinical studies of BZA-CE reveal relief from hot flashes and vaginal atrophic changes, and improvement in bone density, quality of life and sleep without breast or uterine stimulation.

Take home message: Bazedoxifene paired with conjugated estrogens in postmenopausal women relieves vasomotor symptoms and vulvovaginal atrophic changes with prevention of bone loss. Adverse events include a twofold increase risk of venous thrombosis. No evidence of stimulation of the breast, uterus or ovary was seen.     

Adjunctive antiepileptic drugs in adult epilepsy: how the first add-on could be the last

Importance of the field: In adult epilepsies, incomplete seizure control under monotherapy affects ～ 20 – 25% of patients with idiopathic generalized epilepsies (IGE) and ～ 20 – 40% of patients with epilepsies with focal seizures (FE). The choice of an adjunctive therapy is therefore a common event.

Areas covered in this review: Efficacy studies of add-on anti-epileptic drugs for adult epilepsies – approved since the early 1990s until 2008 – were reviewed. An exception was made for valproate.

What the reader will gain: Efficacy studies give important clues for add-on drug choice but – beyond this – we encourage physicians to consider other parameters, especially co-morbidity(ies) and special situation(s). According to clinical and pharmacological data, an original, practical approach is proposed, by which decisions are based on three main criteria, which aim to optimize patients' seizure control and quality of life. The need for drugs that act not only on ‘ictogenesis’ but also on ‘epileptogenesis’ is also discussed briefly.

Take home message: Given the increasing disposal of anti-epileptic drugs, the choice of an add-on therapy appears to be partly based on subjective criteria (physician opinions and preferences). In fact, the selection criteria can be clarified as: treatment decisions rely not only on seizure type, efficacy and tolerability profiles but also on patient-related factors.     

Almotriptan for the acute treatment of adolescent migraine

Importance of the field: Migraine is a common problem affecting 10 – 20% of adolescents. Its treatment has three fundamental components: bio-behavioral interventions, preventive measures, and acute drug therapy. In June 2009, the US FDA approved almotriptan, a 5-HT1B/1D receptor agonist, for the acute treatment of migraine in adolescents aged 12 – 17 years – the first ‘triptan’ to be approved for adolescents.

Areas covered in this review: This review will provide an overview of migraine in adolescents focusing on epidemiology, pathophysiology, classification and a review of treatment options with attention on the evidence from the past 5 years surrounding almotriptan.

What the reader will gain: Given its recent FDA approval, it is important to for clinicians and pharmacists to become familiar with the clinical spectrum of migraine in teenagers and with recent evidence on this newly approved agent, almotriptan.

Take home message: Almotriptan is a safe, effective, and approved agent for the acute treatment of migraine headache in adolescents.     

Influences of bone and mineral metabolism in epilepsy

INTRODUCTION: Patients with epilepsy are at increased risk for metabolic bone disease, low bone mineral density and fractures. AREAS COVERED: This article reviews the predictors and mechanisms of bone loss in patients with epilepsy. It provides information regarding the basic bone biology, evidences of osteopathy with epilepsy and the potential mechanisms of its pathogenesis. This review shows that long-term use of antiepileptic drugs (AEDs) is associated with the risk of osteopathy. However, age, gender, low body mass, severity of epilepsy, co-morbid conditions, institutionalization and calcium and vitamin D deficiencies are additional and modified risk factors. AEDs may indirectly accelerate bone loss through hypovitaminosis D, hypocalcemia and hyperparathyroidism or reduce bone accrual through decreasing the levels of calcitonin, growth factors and vitamin K. Also, AEDs may directly accelerate osteoclastic (bone loss) and/or reduce osteoblastic (bone formation) activities, the main cells involved in bone remodeling. EXPERT OPINION: Understanding the basic bone biology and the pathophysiology of the disturbed bone and mineral metabolism in epilepsy will aid in identification and monitoring of patients at risk and in planning appropriate prophylactic and therapeutic measures.     

Hyponatremia induced by antiepileptic drugs in patients with epilepsy

Introduction: Hyponatremia induced by antiepileptic drugs (AEDs) has not received sufficient attention in patients with epilepsy.

Areas covered: We reviewed articles between 1966 and 2015 about hyponatremia as an adverse effect of AEDs in patients with epilepsy. The incidence, clinical symptoms, onset times of AEDs-induced hyponatremia are discussed in detail, as are the risk factors associated with AEDs-induced hyponatremia and mechanisms underlying its development. We also briefly describe strategies for treating AED-induced hyponatremia.

Expert opinion: Carbamazepine and oxcarbazepine are the most common AEDs which induce hyponatremia in patients with epilepsy. Recently, other AEDs, such as eslicarbazepine, sodium valproate, lamotrigine, levetiracetam and gabapentin have also been reported to cause hyponatremia. Understanding the risk associated with AED-induced hyponatremia and taking effective measures to combat serum sodium imbalance induced by AED therapy are necessary.     

Suicide and epilepsy: do antiepileptic drugs increase the risk?

Introduction: Years after the US FDA issued an alert on an increased risk of suicide ideation and behavior in people with epilepsy treated with antiepileptic drugs (AEDs), this issue still remains controversial. The FDA alert was based on a meta-analysis of clinical trials of AEDs in all indications.

Areas covered: We discuss major methodological problems of this meta-analysis. Available evidence coming from the published studies is also discussed highlighting that the majority of them are also affected by major methodological limitations, which do not allow an absolute conclusion.

Expert opinion: Suicide in epilepsy is a complex phenomenon but most agree that suicide rates are higher in people with epilepsy when compared to the general population. Screening for suicide seems to be appropriate and well-designed prospective studies are urgently needed in order to clarify fully a possible role of AEDs.