Increased circulating levels of γ-carboxyglutamic acid-containing protein and decreased bone mass in children on anticonvulsant therapy

Takeshita, Noritaka; Seino, Yutaka; Ishida, Hideyuki; Seino, Yoshiki; Tanaka, Hiroyuki; Tsutsumi, Chiharu; Ogata, Katsumi; Kiyohara, Keizi; Katô, Hiroshi; Nozawa, Masumi; Akiyama, Yasuhiro; Hara, Kuniko; Imura, Hiroo

doi:10.1007/bf02556465

Cited by 39 publications

(20 citation statements)

References 27 publications

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“…However, in previous works of this nature, other authors have found an increase in these bone formation markers [13, 14, 21, 23, 55,61,62,63] and in vitro, in human osteoblast cultures, having demonstrated an osteogenic effect of the DPH that brings with it an increase in the number of osteoblasts, an increase in the synthesis of collagen, and an increase in the production of BGP [10,11,12,13, 15, 23, 61]. With respect to the BGP, it seems that the treatment of an altered or different BGP, not γ-carboxylated, passes directly to the serum, not to the bone matrix which would nevertheless be deficient in osteocalcin [15].…”

Section: Discussionmentioning

confidence: 89%

“…In the degree of mineralization, we have noted two forms in our patient groups: one with low mineralization (low bone turnover) or osteomalacia [4,59,60,61,62] and the other with high mineralization (high bone turnover) typical of the hyperparathyroid states characterized by a depleting cortical bone and conservation of the trabecular bone [26]. Cases with normal mineralization have also been described.…”

Section: Discussionmentioning

confidence: 92%

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Bone Disease Induced by Phenytoin Therapy: Clinical and Experimental Study

et al. 2009

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Previous studies have made references to prolonged treatment with phenytoin as a possible risk factor in the development of osteoporosis and/or osteomalacia. We studied a group of 30 epileptic patients who were under long-term treatment with phenytoin (DPH) in an ambulatory regimen. We found the prevalence of osteoporosis to be 3.3% and of osteopenia to be 56.6%, affecting predominantly the femur, without any significant decrease in bone mineral density of the lumbar spine. These patients were showing signs of bone turnover uncoupling with increases in bone resorption markers. At this time, they also exhibited slight alterations in their phosphocalcium metabolism with trends to hypocalcemia and secondary hyperparathyroidism that was found not to be caused by a vitamin D deficiency as the serum levels of 25(OH)D and 1,25(OH)₂D were normal. With the aims of corroborating these results and to investigate the physiopathological effects on the bone induced by anticonvulsant drugs we developed a further experimental study in which we administered DPH over a 6-week period with a dose of 5 g/kg/day to male Wistar rats that were in the growth phase. This treatment produced a decrease in overall BMD and bone mineral content in the femur. We did not find osteomalacia in the vertebral biopsy, but the administration of DPH to these animals decreased trabecular volume as well as lessened the thickness of osteoid edges together with an uncoupling in bone turnover. There was also a marked decrease in bone formation and a tendency towards increased bone resorption. We have also found a decrease in resistance to fracture by torsion in the biomechanical assay, which translates into an increase in bone fragility. In these male Wistar rats, the administration of DPH produced a tendency towards increasing the markers of resorption and, though changes in serum levels of calcium and phosphorus were not observed, to provoke an increase in the parathyroid hormone levels; with normal levels of 1,25(OH)₂D which has produced the same inclination in rats as in humans.

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Section: Discussionmentioning

confidence: 89%

Section: Discussionmentioning

confidence: 92%

Bone Disease Induced by Phenytoin Therapy: Clinical and Experimental Study

et al. 2009

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“…Urinary pyridinolines may be increased 3-fold whereas the increases in markers of bone formation and the serum marker of bone resorption, CTX-MMP, are smaller. The increases in men (50±100%) are greater than in women (10±30%) and appear to be independent of the type of anticonvulsant drug [110,111]. Thiazide diuretics decrease bone turnover.…”

Section: Drugsmentioning

confidence: 91%

Preanalytical Variability of Biochemical Markers of Bone Turnover

Hannon

Eastell

2000

Osteoporosis International

222

142

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“…Patients under anticonvulsant therapy (phenytoin and phénobarbital) were selected for this trial because this association of drugs induces more marked effects on calciotropic hormones [11], PTH values did not change in our patients when compared to controls and showed a negative correlation with CaC values, which was a physio logical condition [ 12], CT did not change either, and, as is the case under physiological conditions, there was a posi tive correlation with CaC [13], As in our case, although with a younger population group, Takesita et al [14] did neither observe PTH nor CT changes. Other authors, such as Weinstein et al [15], found decreased ionic calcium and increased PTH.…”

Section: Discussionmentioning

confidence: 53%

“…On the other hand, Schmitt et al [ 16] reported that 27% of the patients under anticonvulsant treatment had hypocalcemia, and Hahn et al [17] also pointed out that calcemia levels were decreased, and PTH levels were increased. Mosekilde et al [ 18] just like Take sita et al [14] and us, also did not find PTH changes; and calcemia changes were neither observed by Murchinson et al [19] nor by Takesita et al [14], We consider that such discrepancies depend on the techniques used. We evaluated CaC while other authors [ 15] reported changes in ionic calcium.…”

Section: Discussionmentioning

confidence: 58%

Long-Term Influence of Anticonvulsant Agents on Calcitonin, Parathyroid Hormone and Osteocalcin

Rico

Seijas²,

Rubio-Arias³

et al. 1992

Eur Neurol

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It has been reported that anticonvulsant drugs decrease serum calcitonin; this effect may be dose dependent and/or hypocalcemia dependent. The objective of the present study is to assess such a dependence and to evaluate other parameters in relation to calcitonin. Serum calcitonin, parathyroid hormone and osteocalcin were determined through RIA, and serum calcium, total protein and alkaline phosphatase through an autoanalyzer in 17 patients undergoing long-term treatment with phenytoin and phenobarbital. At the same time, 20 normal subjects were studied and served as controls. In the patients, no changes were observed in calcitonin, parathormone, osteocalcin and calcemia corrected for protein, and there was a statistically significant increase in alkaline phosphatase values (p < 0.001). Calcemia correlated positively with calcitonin (p < 0.01) and negatively with parathormone (p < 0.05). There was no calcitonin correlation with the anticonvulsant dosage or with the total doses ingested. Increased alkaline phosphatase levels in the presence of normal osteocalcin figures suggest a hepatic origin of the former. The fact that there were no calcitonin level changes but a correlation did exist between calcitonin and calcemia leads us to think that any hormonal changes induced by anticonvulsant agents may act indirectly through changes induced in serum calcium.

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Increased circulating levels of γ-carboxyglutamic acid-containing protein and decreased bone mass in children on anticonvulsant therapy

Cited by 39 publications

References 27 publications

Bone Disease Induced by Phenytoin Therapy: Clinical and Experimental Study

Bone Disease Induced by Phenytoin Therapy: Clinical and Experimental Study

Preanalytical Variability of Biochemical Markers of Bone Turnover

Long-Term Influence of Anticonvulsant Agents on Calcitonin, Parathyroid Hormone and Osteocalcin

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