Monitoring and Treating BDL in Epilepsy

April 1, 2007

Antiepileptic drugs (AEDs) were first demonstrated to cause bone density loss (BDL) more than 40 years ago-since then, researchers have been determining which therapies cause BDL, why BDL occurs, and how BDL should be prevented and treated. Methods to monitor, prevent, and treat BDL in these patients differ greatly, and some physicians are calling for better guidance in this area.

Antiepileptic drugs (AEDs) were first demonstrated to cause bone density loss (BDL) more than 40 years ago-since then, researchers have been determining which therapies cause BDL, why BDL occurs, and how BDL should be prevented and treated. Methods to monitor, prevent, and treat BDL in these patients differ greatly, and some physicians are calling for better guidance in this area.

Physicians and patients tend to overlook the long-term consequences of AED use, and most believe BDL only becomes problematic after many years of treatment, said Raj Sheth, MD, professor of neurology at the University of Wisconsin School of Medicine and Public Health, Madison. He has been studying bone health in patients with epilepsy for more than 10 years, and his current research has shown that AEDs can cause significant BDL in pediatric patients within 1 to 5 years of use.

"It is surprising, because people think that this is a problem that happens 10 or 20 years down the line, so why should we bother thinking about it now," he said. "Even though there are no guidelines, patients should be monitored through screenings for bone health, such as the use of dual-energy x-ray absorptiometry (DEXA) scans."

While his study is still ongoing, he presented interim results on 34 patients who were compared with 24 controls (mean age, 13 years for both groups) with comparable calcium intake, activity levels, height, weight, and sex.1 Valproate and carbamazepine were most frequently prescribed in these patients. Patients with additional physical and neurological deficits, such as cerebral palsy, were not included in the study.

Patients treated with AEDs had an average bone mass density Z-score of 20.31 compared with an average score of +0.71 in the control group. This showed that children treated with AEDs experience significant osteopenia and that the treatments may prevent accrual of bone mass density or induce accelerated bone loss, said Sheth.

Sheth focused his study on pediatric patients because adults often present with other risk factors for BDL. "Many times there are several more complicated things going on. For example, a patient may smoke, which may reduce bone density," he said. "In children, obviously, some of those factors are taken out."

Based on the results of his research, Sheth recommends that his patients take calcium and vitamin D supplements. According to him, any pediatric patient with a fracture should undergo a DEXA scan to determine whether the cause is pathological. Sheth also specifies that patients taking agents that induce hepatic cytochrome P-450 enzyme activation, including phenobarbital, phenytoin, carbamazepine, and primidone-which have been shown to cause BDL-should be followed conscientiously.

There is still no solid explanation for why these enzyme-inducing AEDs may cause BDL, according to Alison Pack, MD, assistant professor of clinical neurology at Columbia University Medical Center, New York City. She is currently conducting a study examining BDL in women treated with phenytoin, carbamazepine, and lamotrigine (Lamictal) and recently presented interim results.2

Of 76 women treated with these medications, measurements were taken using DEXA at baseline and at 1 year. Significant amounts of BDL were shown in 15 patients who had been treated with phenytoin. A mean change of more than 2% in BDL was seen.

"Phenytoin is one of the most commonly used drugs, and we know that it causes BDL, but carbamazepine is confusing," Pack said. "There are some studies that suggest abnormalities, others do not. Some studies have also shown that valproate causes a significant loss of bone density, but it is an inhibitor. So, the mechanism of action is just not clear."

MONOTHERAPY VERSUS POLYTHERAPY
Another study presented by Sheth at the annual meeting of the American Epilepsy Society this past December showed that AED polytherapy causes greater BDL than does monotherapy in pediatric patients.3 Bone density tests were performed in 33 patients treated with monotherapy carbamazepine, valproate, and lamotrigine; 40 patients treated with AED polytherapy; and 36 controls. Age, height, and weight were not statistically different among groups. Although average Z-scores for patients recieving monotherapy were similar to controls (about 0.5), patients receiving AED polytherapy had Z-scores of 20.04.

"One of the factors is that patients on polytherapy are more likely to be on enzyme-inducing agents such as phenytoin and carbamazepine," said Sheth. "There could be an cumulative effect if the patient is taking 2 enzyme-inducing agents, causing vitamin D levels to become lower. But patients on monotherapy were more likely to be taking a single agent and not an enzyme-inducing agent."

Other studies have shown similar results. Mohamad Mikati, MD, director of the Adult and Pediatric Epilepsy Program and professor and chairman in the Department of Pediatrics and colleagues at the American University of Beirut, Lebanon, and colleagues also found that polytherapy is more likely to be associated with osteopenia of greater severity than is monotherapy.4 Since 2002, when the study was published, Mikati has validated these results with a larger database. The results of this study have been submitted for publication.

In general, physicians prefer patients maintain AED monotherapy rather than polytherapy, according to Paul Levisohn, MD, associate professor in the Department of Neurology at The Children's Hospital, Denver, and a member of the American Epilepsy Society's (AES) guideline development committee. "I teach residents that you rarely get enough improvement in seizure control in terms of benefit to warrant the increased adverse effects, such as [a decrease in] bone health, but also other adverse effects, such as cognitive effects, drug-drug interactions, and so forth," he said. "So this is one more factor that reinforces use of monotherapy and the use of drugs where we have a better feel for what their adverse effects are."

THE VITAMIN D CONNECTION
Many researchers have hypothesized that AEDs may cause BDL by reducing vitamin D levels; however, the results of Pack's recent study have brought this into question. Her research showed that serum vitamin D metabolites did not differ between patients at baseline and after 1 year of AED treatment.2

"This is interesting because it has been postulated that enzyme-inducing agents, such as phenytoin, result in increased catabolism and decreased vitamin D levels. With that you have decreased absorption of calcium," Pack said. "But we did not see data to support that mechanism."

It is not clear whether vitamin D levels in patients taking AEDs differ significantly from levels in the general population, Pack said. "If you look at the endocrine literature, vitamin D has become a very big issue, and the definition of vitamin D insufficiency has changed," she said. "It used to be thought that a patient with an insufficiency had levels below 20 mg/mL, but newer data are pointing to 30 mg/mL." But studies have shown that treatment with high doses of vitamin D substantially improves bone density in patients. High doses of vitamin D were shown to substantially increase bone density in adults in a recent study by Mikati and colleagues.5

The investigators studied the effects of 1 year of vitamin D treatment in adults and pediatric patients who were ambulatory and had been treated with long-term AED therapy. A group of adults and pediatric patients received low-dose treatment at 400 IU/d, a group of adults received high-dose treatment at 4000 IU/d, and a group of pediatric patients received high-dose treatment at 2000 IU/d.

DEXA scans at baseline showed that BDL was more significant in adults who had been treated with AEDs than age- and sex-matched controls reported in the literature. After 1 year of treatment with vitamin D, bone density improved significantly in the high-dose adult group but not in the low-dose adult group. In the pediatric groups, patients treated with both high-dose and low-dose vitamin D showed significant improvements in bone density.

"Our study provides information that favors the use of the higher dose of vitamin D treatment, at least initially in adults," said Mikati. "Subsequently following up on the vitamin D levels and bone density can help physicians adjust the dose of vitamin D and decide on possible further treatment. In children, both the high and low dose regimens were of equal efficacy, which means that further studies possibly with longer follow-up are needed." Hypervitaminosis may not be a concern; massive doses-more than 50,000 IU daily-have been linked with vitamin D poisoning.

The study shows that adequate calcium intake and vitamin D supplementation should be reinforced at each clinic visit, according to Ghada El-Hajj Fuleihan, MD, MPH, coauthor of the paper and director of the Calcium Metabolism and Osteoporosis Program and professor of medicine at the American University of Beirut.

"Adult patients on chronic AEDs are at risk for lower bone mass," Fuleihan told Applied Neurology. "Bone density measurement at the start of AED use, and periodically thereafter, is indicated both in adults and children. Monitoring serum 25-hydroxyvitamin D levels is helpful to determine a vitamin D replacement dose in individual patients."

But Pack is skeptical of the results of this study. "Mikati's study did not have its own control group, so you wonder whether there's really an issue with the drugs or the actual population," she said.

However, Pack still recommends that all her patients take vitamin D supplements along with calcium. "There are consistent studies that show that repleting vitamin D in these patients is a good thing," she said. "I certainly test my patients' vitamin D levels, and I think that's a reasonable thing to do in one's practice."

GUIDELINES NEEDED
Most physicians agree that guidelines to prevent and treat BDL in patients treated with AEDs would be useful. Sheth said that the AES should consider this issue. But Levisohn said that the AES has not yet decided to create formal guidelines for the management of BDL in these patients.

Patients who learn about BDL because of AED use also are interested in seeing guidelines established, according to Patricia Gibson, MSSW, assistant professor in the Department of Neurology, director and associate director of the Epilepsy Information Service at the Wake Forest University Baptist Medical Center, Winston-Salem, North Carolina. She runs a nationwide epilepsy hotline and holds conferences for patients and doctors on this issue. "I've been talking to patients daily since 1976. Patient management on this is all over the place, and we've got to start looking at it more closely."

But Pack warns that new guidelines should not encourage overly aggressive monitoring. "I think we should be careful in terms of throwing these guidelines around and who we suggest should be screened," she said. "I know colleagues of mine would disagree about that." She suggested that physicians look to recent endocrine studies on fracture risk to learn more about the prevention and treatment of BDL.

Researchers also agree that more studies are needed to examine the risk of BDL and fractures in these patients. "Repeatedly, we see epilepsy patients with calcium and bone problems like fractures, osteopenia, rickets, and hypocalcemia; yet, there has been a paucity of studies addressing the issue and, more important, how to deal with it," said Mikati.

"The work Dr Sheth and other researchers are doing is beginning to push neurologists to think more about this," said Levisohn. "As a result, we'll see more studies on the issue of bone density."

References:

REFERENCES1. Sheth RD, Drezner M, Hermann BP. Children treated for epilepsy have significant reduction in bone mineral density. Epilepsia. 2005;46S:161.
2. Pack AM, Morrell MJ, Randall A, et al. Calciotropic hormones, bone turnover markers, and rates of bone loss in young women with epilepsy. Presented at: 28th Annual Meeting of the American Society for Bone and Mineral Research; September 18, 2006; Philadelphia. Abstract.
3. Sheth RD, Hermann BP. Bone mineral density in children: osteopenic effects of AED monotherapy vs polytherapy. Presented at: Annual Meeting of the American Epilepsy Society; December 3, 2006; San Diego. Abstract.
4. Farhat G, Yamout B, Mikati MA, et al. Effect of antiepileptic drugs on bone density in ambulatory patients. Neurology. 2002;58:1348-1353.
5. Mikati MA, Dib L, Yamout B, et al. Two randomized vitamin D trials in ambulatory patients on anticonvulsants: impact on bone. Neurology. 2006;67: 2005-2014.