Phenytoin increases markers of osteogenesis for the human species in vitro and in vivo.

Abstract

Phenytoin therapy is a well recognized cause of gingival hyperplasia, a condition characterized by increased gingival collagen synthesis, and may also cause acromegalic-like facial features. Based on these clinical findings suggestive of anabolic actions, we sought to test the hypothesis that phenytoin acts on normal bone cells to induce osteogenic effects. To test the direct actions of phenytoin on human bone cells, we measured the dose responses to phenytoin for [3H]thymidine incorporation, cell number, alkaline phosphatase specific activity, and collagen synthesis in human hip bone-derived cells. Phenytoin significantly and reproducibly increased [3H]thymidine incorporation, cell number, alkaline phosphatase specific activity, and collagen synthesis in a biphasic manner with optimal stimulatory doses between 5-10 mumol/L. Thus, micromolar concentrations of phenytoin can act directly on human bone cells to stimulate osteoblast proliferation and differentiation. We next sought to test the hypothesis that phenytoin stimulates bone formation in humans in vivo. Accordingly, three serum biochemical markers of bone formation, i.e. osteocalcin, skeletal alkaline phosphatase, and procollagen C-terminal extension peptide, were measured in 39 male epileptic patients, 20-60 yr of age, with an average duration of phenytoin therapy of 10.5 +/- 1.62 yr (mean +/- SEM). In this group of patients, the mean serum phenytoin level was 9.56 +/- 0.90 mg/L (mean +/- SEM; equivalent to 34.9 +/- 3.3 mumol/L). Thirty apparently healthy male subjects of similar age and taking no medication were included as controls. Serum calcium, 25-hydroxyvitamin D3, and PTH levels in the phenytoin-treated patients were not significantly different from those in the age-matched controls and were within the clinical laboratory normal range of our hospitals, indicating that the patients did not develop hypocalcemia, vitamin D deficiency, or secondary hyperparathyroidism. Serum levels of osteocalcin, skeletal alkaline phosphatase, and procollagen peptide in the phenytoin-treated patients were significantly increased compared to those in the age-matched subjects; in each case these biochemical markers were significantly correlated with the serum phenytoin level, but not with the dose or duration of phenytoin treatment. These findings are consistent with the interpretation that phenytoin increases the bone formation rate in humans in vivo.(ABSTRACT TRUNCATED AT 400 WORDS)

Antiepileptic Drug–Induced Bone Loss in Young Male Patients Who Have Seizures

“…Moreover, recent in vitro studies have shown that AEDs directly stimulate osteoblast activity. 19 Thus, it is possible that the younger male skeleton with enhanced bone turnover from AED therapy may require a substantially higher calcium intake to adequately suppress bone resorption and optimize bone mineralization. Alternatively, the AED effect may involve the same mechanism that causes agerelated bone loss that could accelerate this process in younger patients.…”

Phenytoin enhances the phosphorylation of epidermal growth factor receptor and fibroblast growth factor receptor in the subventricular zone and promotes the proliferation of neural precursor cells and oligodendrocyte differentiation

“…The pharmacological effect of phenytoin is achieved by blocking sodium and calcium ion channels in neurons (Tunnicliff, ; Shaw et al ., ), which reduces neurotransmitter release, tetanic postsynaptic potentiation and neuronal firing rate (Kaindl et al ., ). One of the side‐effects of phenytoin medication is the abnormal cellular growth (hyperplasia) of several tissues, such as oral mucosa (Sano et al ., ), bone (Lau et al ., ), heart (Zhou et al ., ) and skin (Shaw et al ., ). Additionally, topical phenytoin administration promotes cutaneous wound healing by stimulating proliferation of granular tissue (Shaw et al ., ) and increasing connective tissue growth factor (Kantarci et al ., ).…”

Phenytoin at Micromolar Concentrations is an Osteogenic Agent for Human-mandible-derived Bone Cells in vitro

“…It has been reported that bone alkaline phosphatase (ALP) isoenzyme activity, a marker of bone formation, was substantially increased in phenytoin-treated patients (Hahn and Avioli, 1975). We recently presented preliminary evidence that epileptic patients with long-term use of phenytoin exhibited significantly higher serum levels of osteocalcin, a serum marker for bone formation (Brown et al, 1984), than did age-matched patients (Lau et al, 1994). Furthermore, patients on anti-epileptic drugs showed significantly higher serum levels of several biochemical bone formation markers (skeletal ALP, osteocalcin, and the Cterminal extension peptide of type I procollagen) than did control subjects (Valimaki et al, 1994).…”