Immunosuppressive therapy is considered as one of the factors inducing to the onset of osteoporosis after organ transplantation. Chronic immunosuppressive therapy after transplantation is required for organ transplant patients, and it is important to prevent the occurrence of osteoporotic fractures to maintain the quality of life in patients. In this study, we examined the effects of cyclosporine and tacrolimus on bone metabolism in rats. Five-week-old male Wistar rats were treated orally with 15 mg/kg cyclosporine or 1.5 mg/kg tacrolimus daily for 4 weeks. Each of cyclosporine and tacrolimus significantly reduced the bone strength of the femoral mid-diaphysis and bone mineral density of the tibia and femur. Bone histomorphometry showed that the administration of both drugs resulted in a decrease in bone volume, number and thickness of trabeculae, and an increase in trabecular separation. Bone formation parameters such as osteoid volume, osteoblast surface, mineralizing surface, mineral apposition rate, and bone formation rate significantly increased in the cyclosporine-treated group. Bone resorption parameters such as eroded surface, osteoclast surface, and osteoclast number significantly increased in both the cyclosporine- and the tacrolimus- treated groups. These results showed that cyclosporine increases both bone formation and bone resorption, leading to a high-turnover bone loss, and that tacrolimus increases bone resorption without affecting bone formation, leading to bone loss.

Musculocontractural Ehlers-Danlos syndrome caused by mutations in CHST14 (mcEDS-CHST14) is a recently delineated disorder, characterized by craniofacial, skeletal, visceral, and ocular malformations; and progressive cutaneous, skeletal, vascular, and visceral fragility-related manifestations. Spinal lesions, though one of the most serious complications, have not been investigated systematically. In this study, we report detailed and comprehensive information about spinal lesions of 12 patients with a mean age at the first visit of 13.4 years. Eight patients (66.7%) had scoliosis with a Cobb angle ≥10°, including one with severe scoliosis with a Cobb angle ≥45°. Five patients (41.7%) had kyphosis at the thoracolumbar junction with a kyphotic angle ≥20°. Three patients (25%) developed severe thoracolumbar kyphosis with a kyphotic angle ≥50° accompanied by thoracic lordosis with a wedge-like vertebral deformity and anterior vertebral osteophyte at the thoracolumbar junction, and two of them underwent surgical correction: complicated by fistula formation in one and performed safely and effectively through two-staged operation in the other. Six patients (50.0%) had cervical kyphosis, all of whom except one had kyphosis ≥20° at the thoracolumbar level. Two patients (16.7%) had atlantoaxial subluxation, and 10 patients (83.3%) had cervical vertebral malformations. Patients with mcEDS-CHST14 are susceptible to develop scoliosis, thoracolumbar kyphosis, and cervical kyphosis; and are recommended to have regular surveillance including total spine radiology. The present findings also suggest the critical role of dermatan sulfate in the development and maintenance of the spine.

Thiazolidinediones (TZDs) are synthetic peroxisome proliferator-activated receptor gamma (PPARγ) agonists used as therapy for type 2 diabetes. However, clinical studies reported that the therapeutic modulation of PPARγ activity using TZDs may induce negative effects on bone metabolism. This study aimed to evaluate the effect of the TZD pioglitazone on bone metabolism in rats. Male Wistar rats were treated orally with pioglitazone 5 or 20 mg/kg daily for 24 weeks. Bone strength was evaluated using a 3-point bending method, and bone histomorphometry was analyzed. Bone mineral density (BMD) was measured using quantitative computed tomography, and serum biochemical markers were examined. Pioglitazone caused a decrease in cortical and trabecular BMD of whole femur. A reduction in bone strength properties of the femoral mid-diaphysis was observed in the 20 mg/kg pioglitazone treated group. Bone histomorphometric analysis revealed that osteoblast surface and mineralizing surface were decreased, whereas osteoclast surface and number were increased after treatment with 20 mg/kg pioglitazone. Altogether, this study demonstrated that pioglitazone may repress bone formation and facilitate bone resorption. The resulting imbalance of bone metabolism leads to a reduction in BMD with a subsequent increase in bone fragility.

Dipeptidyl peptidase-4 inhibitor, type 2 diabetes mellitus, bone fragility Recently, it has been suggested that glucose-dependent insulinotropic polypeptide (GIP) and glucagonlike peptide 1 (GLP-1), which play important roles in the homeostasis of glucose metabolism, could be involved in the regulation of bone metabolism. Inhibitors of dipeptidyl peptidase 4 (DPP-4), an enzyme that degrades GIP and GLP-1, are widely used clinically as a therapeutic agent for diabetes. However, the effects of DPP-4 inhibitors on bone metabolism remain unclear. In this study, we investigated the effects of linagliptin, a DPP-4 inhibitor, on bone fragility induced by type 2 diabetes mellitus (T2DM). Non-diabetic mice were used as controls, and T2DM mice were administered linagliptin orally on a daily basis for 12 weeks. In T2DM mice, decreased bone mineral density was observed in the lower limb bones along with low serum osteocalcin levels and high serum tartrate-resistant acid phosphatase-5b (TRAP) levels. In contrast, the decreased serum osteocalcin levels and increased serum TRAP levels observed in T2DM mice were significantly suppressed after the administration of linagliptin 30 mg/kg. Bone histomorphometric analysis revealed a reduced osteoid volume and osteoblast surface with an increase in the eroded surface and number of osteoclasts in T2DM mice. This decreased bone formation and increased bone resorption observed in the T2DM mice were suppressed and trabecular bone volume increased following the administration of 30 mg/kg linagliptin. Collectively, these findings suggest that linagliptin may improve the microstructure of trabecular bone by inhibiting both a decrease in bone formation and an increase in bone resorption induced by T2DM.

Long-term treatment with antiepileptic drugs (AEDs) is accompanied by reduced bone mass that is associated with an increased risk of bone fractures. Although phenytoin has been reported to adversely influence bone metabolism, little is known pertaining to more recent AEDs. The aim of this study was to evaluate the effects of gabapentin or levetiracetam on bone strength, bone mass, and bone turnover in rats. Male Sprague-Dawley rats were orally administered phenytoin (20 mg/kg), gabapentin (30 or 150 mg/kg), or levetiracetam (50 or 200 mg/kg) daily for 12 weeks. Bone histomorphometric analysis of the tibia was performed and femoral bone strength was evaluated using a three-point bending method. Bone mineral density (BMD) of the femur and tibia was measured using quantitative computed tomography. Administration of phenytoin significantly decreased bone strength and BMD, which was associated with enhanced bone resorption. In contrast, treatment with gabapentin (150 mg/kg) significantly decreased bone volume and increased trabecular separation, as shown by bone histomorphometric analysis. Moreover, the bone formation parameters, osteoid volume and mineralizing surface, decreased after gabapentin treatment, whereas the bone resorption parameters, osteoclast surface and number, increased. Levetiracetam treatment did not affect bone strength, bone mass, and bone turnover. Our data suggested that gabapentin induced the rarefaction of cancellous bone, which was associated with decreased bone formation and enhanced bone resorption, and may affect bone strength and BMD after chronic exposure. To prevent the risk of bone fractures, patients prescribed a longterm administration of gabapentin should be regularly monitored for changes in bone mass.Key words gabapentin; levetiracetam; osteoblast; osteoclast; rat Epilepsy is a chronic neurological disorder characterized by recurrent seizures. 1) Pharmacotherapy with antiepileptic drugs (AEDs) is the mainstay of treatment for epilepsy and is effective in the prevention of seizures. Patients with epilepsy usually require long-term treatment with AEDs; thus, the prevention of side effects is important in the continuation of medication.The bone is a metabolically active organ that undergoes continuous remodeling from bone resorption by osteoclasts and bone formation by osteoblasts.2) Under healthy conditions, the balance between bone formation and bone resorption is always uniform; thus, bone strength and bone mass are maintained. Certain pathological states and drugs affect normal bone remodeling, which can induce skeletal disorders, such as osteopenia or osteoporosis.3) A serious side effect associated with long-term administration of AEDs is the elevated risk of bone fracture owing to a decrease in bone mass.4-7) Patients taking AEDs are approximately 2-6 times more at risk of bone fracture than healthy individuals are. 8,9) Previous studies have demonstrated that treatment with phenytoin decreased bone mineral density (BMD) owing to enhanced bone resorption.10,11) Currently, new...