BALTIMORE – Levetiracetam had effects on bone mineral density and markers of bone turnover that were similar to those seen with the older antiepileptic drugs carbamazepine and sodium valproate in a 12-month, randomized, controlled trial of 84 patients with partial epilepsy.
The finding was counter to the expectation that levetiracetam (Keppra) would have neutral or more benign effects on bone health because of its "cleaner pharmacokinetics – no effect on vitamin D metabolism – and a different mechanism of action," study investigator Dr. Terence J. O’Brien said in an interview. "Most [experts] thought it would be better for bone health. However, there is a previous study in rats that did show effect on bone. ... The clinical message is that neurologists need to monitor bone heath on all their patients chronically treated with AEDs."
Chronic antiepileptic drug use has been associated with increased risk of both bone disease and fracture, as well as weight gain and insulin resistance. It has been hoped that newer antiepileptic drugs with different mechanisms of action would minimize or eliminate these effects. One of these newer agents, levetiracetam, has a novel mechanism of action, binding to the SV2A receptors that interfere with synaptic vesicle exocytosis. It is not hepatically metabolized, so it does not affect hormonal levels.
"The clinical message is that neurologists need to monitor bone heath on all their patients chronically treated with antiepileptic drugs."
"There are plenty of reasons to believe it would have fewer bone and metabolic effects, but this had never been tested before in a randomized, controlled trial," said Dr. O’Brien, a professor of medicine at the University of Melbourne and head of the department of medicine at the Royal Melbourne Hospital.
Of 84 patients randomized to open-label substitution monotherapy with either levetiracetam or carbamazepine or valproate in the KONQUEST trial, 40 levetiracetam patients and 30 carbamazepine/valproate patients completed an assessment at 15 months. Dosing in the trial was flexible, and was increased or decreased by the treating neurologist according to tolerability and seizure control.
Dual energy X-ray absorptiometry (DXA) measurements of areal bone mineral density (aBMD) in the forearm was significantly lower at 15 months in both the levetiracetam and carbamazepine/valproate groups, compared with measurements taken at 3 months, but more so for levetiracetam, with reductions of 1.4% (P less than .001) and 0.96% (P = .015), respectively. Peripheral quantitative CT measurement of trabecular BMD in the radius was also reduced in both groups, by 2.25% (P = .005) with levetiracetam and by 2.9% (P = .001) for the older AEDs. There were no differences from 3-month assessments in aBMD of the lumbar spine or hip in either treatment group.
Markers of bone formation and resorption were among the secondary end points. The bone resorption marker beta C-terminal telopeptide of type 1 collagen was reduced in both treatment groups, by 12.8% (P = .021) with levetiracetam and by 15.6% (P = .028) with carbamazepine/valproate. However, the bone formation marker procollagen type 1 N-terminal propeptide was reduced only with the older AEDs, by 20.9% (P = .008). There were no differences in vitamin D or other markers of calcium homeostasis, Dr. O’Brien said.
Reduction in serum markers of bone turnover suggests reduced bone remodeling with AEDs, "an atypical mechanism for bone loss which warrants further study," he said.
In the interview, he added that the lack of effect on markers of bone formation for levetiracetam may indicate some differences in the mechanism of its effect, or may just have been a lack of power.
The exploratory end points of femoral neck aBMD, total bone area (trabecular), trabecular bone mineral content, and total bone area (cortical) were all significantly reduced in both groups. However, the anthropometric exploratory end points of weight and body mass index were increased only with the older AEDs, by 2.0% (P = .039) and 2.15% (P = .044), respectively.
There are no clear guidelines for bone health monitoring in patients on AEDs. "What we recommend is when you start the drug, [get] a baseline, and then [monitor] every 3-5 years. Vitamin D levels should also be checked and supplemented if deficient," he said in the interview.
A UCB Pharma spokeswoman declined to comment on the findings of KONQUEST. The study was partially funded by the company, but it had no role in its design, data collection, analysis, or interpretation. Dr. O’Brien said that he had no additional disclosures.