The effects of phenytoin on calcium uptake in osteoblastic cells

Dziak, Rosemary; Vernillo, Anthony T.; Rifkin, Barry R.

doi:10.1002/jbmr.5650030408

Cited by 15 publications

(3 citation statements)

References 30 publications

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“…phenytoin and carbamazepin, on human osteoblast-like bone cells. Both drugs have been suspected to influence bone metabolism and BMD (Valimaki et al, 1994;Sheth et al, 1995;Hoikka et al, 1984;Dziak et al, 1988).…”

Section: Introductionmentioning

confidence: 99%

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

Feldkamp

Becker

Witte

et al. 2012

Exp Clin Endocrinol Diabetes

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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.

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Section: Introductionmentioning

confidence: 99%

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

Feldkamp

Becker

Witte

et al. 2012

Exp Clin Endocrinol Diabetes

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“…One of these is bone turnover, which reflects changes in the rate of bone remodeling, assessed by measurements of alterations in biochemical markers of bone resorption and formation. Animal studies have suggested that PHT causes bone loss due to elevated bone resorption (Takahashi et al, 2000; Onodera et al, 2001; Takahashi et al, 2004), but PHT may also affect bone‐forming osteoblasts directly via a biphasic mechanism, as low doses seem to stimulate and high therapeutic doses to inhibit osteoblast proliferation and differentiation (Dziak et al, 1988; Ohta et al, 1995; Lau et al, 1995; Ikedo et al, 1999; Feldkamp et al, 2000). For VPA there is evidence for decreased (Tsukahara et al, 2002), unaltered (Guo et al, 2001), or increased bone turnover (Rieger‐Wettengl et al, 2001; Sato et al, 2001; Oner et al, 2004).…”

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confidence: 99%

Levetiracetam, Phenytoin, and Valproate Act Differently on Rat Bone Mass, Structure, and Metabolism

Svalheim²,

et al. 2007

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Summary:Purpose: Long-term treatment with antiepileptic drugs (AEDs) is associated with increased risk of fractures. Phenytoin (PHT) and valproate (VPA) have both been suggested to influence bone health, whereas levetiracetam (LEV) is scarcely studied. The present study compares the effect of these AEDs on bone mass, biomechanical strength, and bone turnover in rats.Methods: Female rats received PHT (50mg/kg), VPA (300mg/kg), or LEV (50 and 150mg/kg) for 90 days. Dissected femurs were analyzed using dual energy x-ray absorptiometry (DXA), three-point cantilever bending, and histomorphological evaluation. Serum levels of biochemical bone turnover markers were monitored using immunoassay quantification.Results: PHT and VPA reduced bone mineral density (BMD) and content (BMC) in one or more bone compartments, whereas LEV did not. VPA induced increased bone turnover, whereas modest changes were observed for PHT. Interestingly, low-dose LEV was associated with reduced biomechanical strength of the femoral neck (mainly trabecular bone). In addition, low-dose LEV treatment resulted in significantly reduced levels of serum osteocalcin, a marker of bone formation. Histomorphological analyses indicated increased retention of cartilage remnants at the growth plate metaphysis of rats treated with low-dose LEV vs. controls.Conclusions: PHT, VPA, and LEV exert differential effects on bone mass and strength, suggesting different mechanisms of action. The weakening effect of low-dose LEV on the femoral neck, despite a constant BMD, suggests a primary effect on bone quality. These findings warrant further human studies of possible adverse effects of LEV on bone development and growth, particularly in children and adolescents.

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“…A possible mechanism may be the Bsm I VDR polymorphism affecting calcium metabolism, and/or osteoblast and osteoclast function. In previous studies, AEDs, especially CYP enzyme inducer, have been shown to induce bone loss via the alteration of osteoclast differentiation and function (Dziak et al., 1988; Koide et al., 2009). Vitamin D receptor polymorphism, when present, can alter bone metabolism and, therefore, affect the susceptibility to the osteopenic effects of AEDs.…”

Section: Discussionmentioning

confidence: 99%

The association between BsmI polymorphism and bone mineral density in young patients with epilepsy who are taking phenytoin

et al. 2013

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SUMMARYPurpose: This study sought to determine the association between BsmI polymorphism and bone mineral density, 25-hydroxyvitamin D, and parathyroid hormone levels in patients with epilepsy. Methods: We recruited ambulatory young adults with epilepsy who were taking phenytoin. Data regarding demographics, basic laboratory studies, history of clinical epilepsy, parathyroid hormone, and vitamin D levels, as well as BsmI polymorphism of the vitamin D receptor (VDR) gene, were obtained. The bone mineral density (BMD) of the lumbar spine and left femur were measured using dual-energy x-ray absorptiometry. Key Findings: Ninety-four patients were included in the study. BsmI polymorphism had a statistically significant lower T-score of the lumbar spine and left femoral neck than patients with wild-type VDR gene (p < 0.01 and p < 0.01, respectively). In addition, patients with BsmI polymorphism had a statistically significant lower z-score of the lumbar spine and left femoral neck than patients with wild-type VDR gene (p < 0.01 and p < 0.01, respectively). The 25-hydroxyvitamin D level in patients with wild-type genes was higher than in epileptic patients with BsmI polymorphism (p < 0.01 and p < 0.01, respectively). Parathyroid hormone level in patients with wild-type VDR gene or patients having BsmI polymorphism was not correlated with BMD at either site. Significance: In patients with epilepsy taking phenytoin, having BsmI polymorphism was associated with lower BMD.

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The effects of phenytoin on calcium uptake in osteoblastic cells

Cited by 15 publications

References 30 publications

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

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

Levetiracetam, Phenytoin, and Valproate Act Differently on Rat Bone Mass, Structure, and Metabolism

The association between BsmI polymorphism and bone mineral density in young patients with epilepsy who are taking phenytoin

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