Long-term anticonvulsant therapy leads to low bone mineral density — evidence for direct drug effects of phenytoin and carbamazepine on human osteoblast-like cells

Abstract

Anticonvulsant therapy causes changes in calcium and bone metab olism and may lead to decreased bone mass with the risk of osteo porotic fractures. The two widely used antiepileptic drugs pheny toin and carbamazepine are recognized to have direct effects on bone cells. The aim of our study was to measure the influence of long-term treatment with antiepileptic drugs on bone mineral den sity (BMD) and to look on direct effects of carbamazepine and phenytoin on human osteoblast-like cells.BMD was measured by dual-energy X-ray absorptiometry. Mark ers of bone formation and bone resorption were determined in serum and urine. Data of 59 patients were compared to 55 age and sex matched controls. Direct effects of phenytoin and carbama zepine on human osteoblast-like cells were investigated in exper imental studies.BMD in the lumbar spine region (L2 through L4) was significantly lower in the patient group as compared to controls (p < 0.0004). At femoral sites BMD was lower in patients, but this difference did not reach statistical significance. The decrease in BMD at both sites was dependent on the duration of therapy. Excretion of pyridinoline crosslinks was markedly increased in the patients. 25-hydroxyvitamin D3 and 1,25-dihydroxy-vitamin D3 were significantly de creased in patients. Proliferation rate of human osteoblast-like cells was increased by phenytoin in low doses. Both, phenytoin and car bamazepine inhibited cell growth at concentrations equivalent to therapeutic doses for the treatment of epileptic diseases. Our clinical and experimental data indicate that long-term treat ment with anticonvulsant drugs leads to a lower BMD. The exper imentally observed decrease in bone cell proliferation might be clinically associated with impaired new bone formation. Beside alterations in calcium and vitamin D homeostasis leading to osteomalazia, direct effects of anticonvulsant drugs on bone cells may contribute to the damaging effects on the skeletal system.

<b>Effects of the antiepileptic drugs topiramate and lamotrigine on bone metabolism in </b><b>rats </b>

“…According to bone histomorphometry in this study, phenytoin treatment significantly increased bone resorption, resulting in increase of eroded surface (ES/BS), osteoclast number (N.Oc/BS), and osteoclast surface (Oc.S/BS) in the proximal tibia metaphysis. Our data show that the observed decrease in BMD of phenytoin-treated rats is associated with elevated bone resorption, consistent with previous findings (11,37). Topiramate is a relatively weak carbonic anhydrase inhibitor that may result in adverse effects on bone metabolism by compliance.…”

“…A prospective study showed that the decrease in bone mineral density (BMD) of patients treated with phenytoin was 1.8%/year (9). Phenytoin has been reported to cause bone loss due to suppressed bone formation (24, 25) or enhanced bone resorption (11,37). In Europe and the United States, all the AEDs developed after the 1990s are classified as "newer AEDs".…”

Molecular mechanisms responsible for the impact of antiepileptic therapy on bone mineral density of epileptic patients

“…В более ранних работах рассматривались и другие ме-ханизмы воздействия фермент-индуцирующих ПЭП на ко-стную ткань: ингибирование ФТ всасывания кальция в ки-шечнике [23,24]; повышение активности остеокластов под влиянием ФТ [25]; ингибирование пролиферации остеобла-стов КБЗ или ФТ [6]; дефицит витамина К [26], дефицит кальцитонина [27]; увеличение уровня гомоцистеина [28]. Имеются противоречивые данные исследований о влиянии фермент-индуцирующих ПЭП на биохимические показате-ли костного метаболизма и МПК.…”

“…Данные изменения связывают с дли-тельным применением противоэпилептических препаратов (ПЭП), типом ПЭП, политерапией и другими факторами [5][6][7][8]. Кроме того, высокая частота приступов, низкая фи-зическая активность, снижение концентрации внимания, координаторные нарушения, вызванные, помимо прочего, и приемом ПЭП, приводят к повышенной травматизации пациентов с эпилепсией [9,10] и увеличению риска перело-мов, обусловленных ОП.…”

Adverse Metabolic Effects of Antiepileptic Drug Treatment

“…Furthermore, valproate, a CYP450 inhibitor, has also been shown to have an adverse effect on bone health, probably via completely different mechanisms (Sheth et al, 1995;Sato et al, 2001;Guo et al, 2001;. Decreased intestinal absorption of calcium, resistance to parathyroid hormone, calcitonin deficiency, interference with vitamin K metabolism, and a direct drug-effect on bone cell functions have also been suggested as possible mechanisms (Feldkamp et al, 2000;Petty et al, 2007). Other indirect effects of the drugs, such as hormonal changes, increases in homocysteine, reduction in insulin growth factor 1, and the effect of valproate as a histone deacetylase inhibitor, thereby reducing collagen I and osteonectin, may also contribute (Fuller et al, 2010).…”