Percutaneous corrective osteotomy for Kirner's deformity: a case report.

Kirner's deformity is a rare skeletal deformity first described in Germany in 1927. It is characterized by progressive palmar-radial curvature of the distal phalanx of the small finger. Here, we present the case of a 15-year-old boy with Kirner's deformity in both little fingers, who was treated with percutaneous corrective osteotomy. This was followed by a successful outcome after 36 months.

Celecoxib, a selective cyclooxygenase-2 inhibitor, reduces level of a bone resorption marker in postmenopausal women with rheumatoid arthritis.

AIM: Celecoxib (CEL), a selective cyclooxygenase-2 (COX-2) inhibitor, has been reported to suppress osteoclastogenesis in vitro, reduce levels of bone resorption markers in ovariectomized (OVX) mice, and prevent bone destruction in rheumatoid arthritis (RA) model mice; however, no clinical data has been reported. Here, we prospectively evaluated the changes in bone turnover markers in RA patients who switched from nonsteroidal anti-inflammatory drugs (NSAIDs) to CEL, to examine the effects of selective COX-2 inhibitor on bone metabolism. METHODS: RA patients who had been treated with NSAIDs for more than 12 weeks were switched to CEL (400 mg/day) without any other changes in previously prescribed medications. Urinary type I collagen cross-linked N-telopeptide (uNTX), serum bone alkaline phosphatase (BAP), C-reactive protein (CRP), erythrocyte sedimentation rate (ESR) and matrix metalloproteinase-3 (MMP-3) were evaluated before switching to CEL and 16 weeks later. RESULTS: Significant reductions in uNTX, a bone resorption marker, were observed in 60 female patients (P = 0.042), especially in 52 postmenopausal women (P = 0.033). However, uNTX level did not significantly change in premenopausal women or in men. There were no significant changes in BAP, a bone formation marker. CRP significantly decreased (P = 0.007), while ESR and MMP-3 were unchanged. CONCLUSION: CEL reduced the levels of a bone resorption marker in postmenopausal RA patients, suggesting that this drug may attenuate the accelerated osteoclastic bone resorption associated with menopause.

Clinical results of alendronate monotherapy and combined therapy with menatetrenone (VitK2) in postmenopausal RA patients.

OBJECTIVES: We aimed to evaluate the clinical efficacy of monotherapy with alendronate and combined therapy with alendronate and menatetrenone (vitamin K2 [VitK2]) in postmenopausal rheumatoid arthritis (RA) patients with osteoporosis or osteopenia. METHODS: Sixty-two postmenopausal RA patients with untreated osteoporosis or osteopenia (lumbar spine bone density ≤80 % of young adult mean [YAM]) were enrolled: 39 had abnormal serum undercarboxylated osteocalcin (ucOC) levels (>4.5 ng/mL) and received combined therapy with alendronate (35 mg/week) and VitK2 (45 mg/day) (ALN + K group); 23 had normal ucOC levels (≤4.5 ng/mL) and received alendronate monotherapy (35 mg/week) (ALN group). The clinical results for the 57 patients in both groups were evaluated after 1-year treatment. RESULTS: The mean baseline/follow-up (FU) lumbar spine bone density (%YAM) values were 73.0/76.8 % (P < 0.01) in the ALN + K group and 77.0/80.3 % (P < 0.01) in the ALN group; a significant increase was shown in both groups. Mean proximal femoral bone density values at baseline/FU were 71.4/73.8 (P < 0.01) in the ALN + K group and 71.4/71.6 % (not significant; NS) in the ALN group; a significant increase was shown in the ALN + K group only. Serum ucOC levels were normalized in the ALN + K group at FU. At FU, bone metabolism markers [bone-specific alkaline phosphatase (BAP) and N-terminal cross-linked telopeptides of type I collagen] were decreased in both groups. One patient in the ALN + K group and three in the ALN group suffered new fractures. CONCLUSIONS: Combined therapy with alendronate and VitK2 decreases bone metabolism marker levels and serum ucOC levels, and increases lumbar spine and femoral neck bone density in postmenopausal RA patients with abnormal ucOC levels and osteoporosis or osteopenia.

Celecoxib, a cyclooxygenase-2 inhibitor, improved upper gastrointestinal lesions in rheumatoid arthritis patients as assessed by endoscopic evaluation.

We prospectively evaluated the effects of celecoxib (CEL) on the gastrointestinal (GI) tract of rheumatoid arthritis (RA) patients with endoscopically identified GI mucosal injury after therapeutic switching from the long-term use of traditional nonsteroidal anti-inflammatory drugs (NSAIDs). Upper GI endoscopy was performed on RA patients who had been treated with NSAIDs for ≥3 months. GI mucosal injury was evaluated according to the modified LANZA score. Patients with mucosal injury without ulcers were switched from NSAIDs to CEL, while those with ulcers were switched to CEL with famotidine after ulcer healing. At week 16 of treatment, GI mucosal injury was endoscopically revaluated. An efficacy analysis was performed before therapeutic switching and at 8 and 16 weeks post-switching. Endoscopic analysis revealed GI mucosal injury, including six ulcers, in 45 of the 82 patients (54.9%). Sixteen weeks after switching to CEL, LANZA scores were significantly improved [2.1 ± 0.8 (pre-switching) vs. 1.6 ± 1.3, P = 0.0073] in patients with LANZA scores of 1, 2, or 3 (n = 35). The Disease Activity Score using 28 joint counts (DAS28) [erythrocyte sedimentation rate item score (ESR4) (P = 0.0257) and C-reactive protein item score (CRP4) (P = 0.0031)] was also significantly improved by week 16. Based on these results, we conclude that preexisting NSAID-induced upper GI injury is improved following therapeutic switching to CEL without any reduction in analgesic efficacy.

Stimulation of ectopic bone formation in response to BMP-2 by Rho kinase inhibitor: a pilot study.

The small GTPase Rho and Rho-associated protein kinase (Rho kinase, ROCK) signal participates in a variety of biological functions including vascular contraction, tumor invasion, and penile erection. Evidence also suggests Rho-ROCK is involved in signaling for mesenchymal cellular differentiation. However, whether it is involved in osteoblastic differentiation is unknown. We therefore asked whether Rho-ROCK signaling participates in recombinant human bone morphogenetic protein (rhBMP-2)-induced osteogenesis both in vitro and in vivo. Continuous delivery of a specific ROCK inhibitor (Y-27632) enhanced ectopic bone formation induced by rhBMP-2 impregnated into an atelocollagen carrier in mice without affecting systemic bone metabolism. Treatment with Y-27632 also enhanced the osteoblastic differentiation of cultured murine neonatal calvarial cells. These effects were associated with increased expression of BMP-4 gene. Expression of a dominant negative mutant of ROCK in ST2 cells promoted osteoblastic differentiation, while a constitutively active mutant of ROCK attenuated osteoblastic differentiation and the ROCK inhibitor reversed this phenotype. Thus, ROCK inhibits osteogenesis, and a ROCK inhibitor in combination with the local delivery of rhBMP/collagen composite may be clinically applicable for stimulating bone formation.

Use of hydroxyapatite ceramics for treatment of nonunited osseous defect after open fracture of lower limbs.

INTRODUCTION: Osseous defects in nonunited open fracture of the lower limbs are difficult to treat. Autogenous bone grafting is a promising treatment options, but a finite amount of autogenous bone graft is available from each individual and donor site morbidity remains a problem. These limitations have prompted the development and use of synthetic biomaterials such as hydroxyapatite (HA) ceramics. However, little information is available regarding the challenging cases such as nonunited open fractures The purpose of the present study is to evaluate the outcomes associated with the treatment of osseous defects in nonunited open fracture using novel HA ceramics. METHODS: Twelve bones (4 femora and 8 tibias) in 11 patients (10 men and 1 woman), with an average age of 49.1 (range 19-71) years, with nonunited osseous defects after open fracture were treated by the grafting of HA ceramics alone or with autogenous iliac bone followed by internal or external fixation. RESULTS: The patients were followed for an average of 25.2 months in average (range 10.3 -58.1 months). Finally, 11 of 12 fractures united clinically and radiographically, while one fracture required a second procedure for additional autogenous iliac bone grafting. The average time to union from the index surgery was 5.6 months (median 5.3 months, range 2.3-11 months.). Radiographs showed good incorporation of grafted HA into the host bone in most of the united cases. As a complication, transient wound drainage was found in two cases. CONCLUSION: The current protocol using the HA ceramics appears to be safe and efficacious for the treatment of osseous defects after the open fractures.

Distraction osteogenesis for correction of three-dimensional deformities with shortening of lower limbs by Taylor Spatial Frame.

INTRODUCTION: Surgical results of correction of three-dimensional deformities with shortening of lower limbs by simple two-ring system of Taylor Spatial Frame have been reported. The deformities were caused by various kinds of skeletal disorders. METHODS: Ten cases were successfully corrected using distraction osteogenesis, being one case showed recurrence of deformity due to the nature of the disease. RESULTS: The ranges of corrected deformities were 5 degrees-55 degrees in coronal angulation, 2 degrees-47 degrees in sagittal angulation, and 5 degrees-40 degrees in rotational deformities. Amount of lengthening ranged from 1.2 to 6.0 cm. Pin-site infection occurred in five cases, being no other complications. External fixation index was longer in a group of rotational correction over 10 degrees. CONCLUSION: The current report seems the first series of cases with four-dimensional deformities treated by distraction osteogenesis by TSF and may help to determine the indication of use of TSF in case of treatment of patients suffering from deformities in the lower limbs.

Correction of deformity and shortening due to post traumatic epiphyseal arrest by distraction osteogenesis.

Growth arrest in the epiphyseal plate during childhood often causes both periarticular deformities and limb length discrepancy, leading to compartmental osteoarthrosis and gait disturbance or spinal disorders, respectively. Distraction osteogenesis using external fixators with hinge systems appears to be useful for the simultaneous correction of deformity and shortening. In this paper, we evaluated cases of lower limbs with periarticular deformities and limb length discrepancy after epiphyseal plate injury that has been treated by distraction osteogenesis using external fixators. This is the first report regarding the outcomes of distraction osteogenesis for a group of patients having deformity and limb length discrepancy due to traumatic arrest of the physis. Successful outcomes may promise the use of this method as the first choice for the treatment of growth disorders after the arrest of the epiphyseal plate in the lower limbs. However, treatment under 20 years of age may provide a better outcome with a lower incidence of complications.

Treatment of periprosthetic femoral fracture after cementless total hip arthroplasty with Ilizarov external fixation.

A 72-year-old woman with periprosthetic femoral fracture after cementless total hip arthroplasty (THA) underwent external fixation using the Ilizarov method. Although open reduction and internal fixation with a condylar plate system were initially attempted, deep infection with methicillin-resistant Staphylococcus aureus at the fracture site occurred 2 weeks postoperatively. Six weeks after removal of the plating system, the fracture was stabilized with external fixation using the Ilizarov method and went on to successful fusion at 3 months. To our knowledge, this is the first report in which Ilizarov external fixation has been used for periprosthetic femoral fracture after THA. Although this is a rare situation, where periprosthetic fracture and infection coexist, Ilizarov external fixation is a safe and reliable method for periprosthetic femoral fracture with infection.

Treatment of relapsed idiopathic clubfoot by complete subtalar release combined with the Ilizarov method.

This study presents the clinical and radiographic outcomes of 6 feet (4 patients) with relapsed idiopathic clubfoot that were treated with a combination of subtalar release and the Ilizarov method. The mean patient age at the time of the surgery was 7.4 years (range, 4.5-10.5 years), and the mean follow-up was 5.1 years (range, 2.0-7.3 years). All cases achieved a plantigrade foot, better walking ability, and parental satisfaction with the result. Ankle joint range of motion increased from a mean of 17 degrees (range, 10-30 degrees) preoperatively to 45 degrees (range, 35-65 degrees) at final follow-up. The talocalcaneal angle improved from a mean of 26 degrees (range, 15-34 degrees) preoperatively to 55 degrees (range, 47-65 degrees) at follow-up. The mean tibiocalcaneal angle improved from 95 degrees (range, 87-115 degrees) preoperatively to 80 degrees (77-83 degrees) at follow-up, whereas the talometatarsal angle improved from a preoperative mean of -19 degrees (range, -35 to -10 degrees) to 3.5 degrees (range, -5 to 7 degrees) at follow-up. Recurrence was observed in only 1 foot with forefoot adductus, caused by a pin tract infection and early fixator removal. These cases suggest the Ilizarov method combined with subtalar release are beneficial for the treatment of relapsed idiopathic clubfoot.

[Fracture repair and bone morphogenetic protein (BMP)].

The process of fracture healing involves a number of regenerative mechanisms underlying the skeletal systems, and bone morphogenetic protein (BMP) has been believed to be a key molecule during the reaction. Recent investigations showed that several members of BMPs are induced and activated by the impact of fracture, and play important roles via BMP receptors/Smads pathways. BMPs are newly synthesized by callus-forming cells near the fracture site, and form a "BMP-network" at the fracture callus. The "BMP-network" contributes to the regulation of callus formation, and the network contains noggin, sonic hedgehog (Shh), hepatocyte growth factor (HGF), and vascular endothelial cell growth factor (VEGF). Potential roles of BMPs during fracture repair open the way towards the formulation of new therapeutic strategies for promising fracture management. Recent molecular technologies with use of recombinant BMP and gene therapy will lead to the development of less-invasive and more successful fracture treatment.

A case of Paget's disease treated by distraction osteogenesis.

Paget's disease is a localized bone disorder marked by increased turnover usually associated with a deformity of the affected bone. Distraction osteogenesis may be a useful method for correcting the deformity. A 57-year-old woman with Paget's disease had a 3 cm limb-length discrepancy with a 47 degrees procurvatum deformity of the ipsilateral femur. Distraction osteogenesis using a Taylor Spatial Frame was performed, leading to complete correction of the procurvatum deformity and limb-length discrepancy. After improvement of the limb-length discrepancy, the patient felt more comfortable than she had before surgery with less low back pain. This result suggests distraction osteogenesis may be appropriate for the treatment of some severe, complex deformities of the lower limbs in patients with Paget's disease.

Leptin regulates chondrocyte differentiation and matrix maturation during endochondral ossification.

Leptin has been suggested to mediate a variety of actions, including bone development, via its ubiquitously expressed receptor (Ob-Rb). In this study, we investigated the role of leptin in endochondral ossification at the growth plate. The growth plates of wild-type and ob/ob mice were analyzed. Effects of leptin on chondrocyte gene expression, cell cycle, apoptosis and matrix mineralization were assessed using primary chondrocyte culture and the ATDC5 cell differentiation culture system. Immunohistochemistry and in situ hybridization showed that leptin was localized in prehypertrophic chondrocytes in normal mice and that Ob-Rb was localized in hypertrophic chondrocytes in normal and ob/ob mice. Growth plates of ob/ob mice were more fragile than those of wild-type mice in a mechanical test and were broken easily at the chondro-osseous junction. The growth plates of ob/ob mice showed disturbed columnar structure, decreased type X collagen expression, less organized collagen fibril arrangement, increased apoptosis and premature mineralization. Leptin administration in ob/ob mice led to an increase in femoral and humeral lengths and decrease in the proportional length of the calcified hypertrophic zone to the whole hypertrophic zone. In primary chondrocyte culture, the matrix mineralization in ob/ob chondrocytes was stronger than that of wild-type mice; this mineralization in both types of mice was abolished by the addition of exogenous leptin (10 ng/ml). During ATDC5 cell differentiation culture, exogenous leptin at a concentration of 1-10 ng/ml (equivalent to the normal serum concentration of leptin) altered type X collagen mRNA expression and suppressed apoptosis, cell growth and matrix calcification. In conclusion, we demonstrated that leptin modulates several events associated with terminal differentiation of chondrocytes. Our finding that the growth plates of ob/ob mice were fragile implies a disturbance in the differentiation/maturation process of growth plates due to depletion of leptin signaling in ob/ob mice. These findings suggest that peripheral leptin signaling plays an essential role in endochondral ossification at the growth plate.

Alendronate inhibits bone resorption at the bone-screw interface.

In the current study, we investigated whether the systemic administration of alendronate, a third-generation bisphosphonate, suppressed the loosening of screws at the bone-screw interface. We systemically administered alendronate to rats fitted with external fixators. External fixators with two half pins were applied to the right femurs of rats, and alendronate was administrated once a week during a 5-week postoperative period. Radiographic, histologic, and immunohistochemical findings subsequently were analyzed. Treatment with alendronate reduced the width of the fibrous loosening membrane and the number of osteoclasts at the bone-screw interface. These findings indicate that systemic treatment with alendronate exerts an inhibitory effect on local bone resorption at the bone-screw interface.

Localization of RANKL in osteolytic tissue around a loosened joint prosthesis.

Osteoclastogenesis is a key event of the cellular reaction in prosthetic loosening. Immunohistochemistry and reverse transcription-polymerase chain reaction (RT-PCR) were used to study the localization and expression of receptor activator of nuclear factor kappa B ligand (RANKL), a potent factor for osteoclastogenesis in the membranous tissue formed around loosened prosthetic joint implants. RANKL was identified in a wide variety of cells appearing in this membranous tissue. At least three types of RANKL-positive cells were identified, including prolyl 4-hydroxylase (PH)-positive fibroblast lineage cells, CD68 cells, and tartrate-resistant acid phosphatase (TRAP)-positive mononuclear and multi-nucleated macrophage lineage cells. Tumor necrosis factor (TNF)-alpha-converting enzyme (TACE) was colocalized with RANKL in these cells, suggesting the in-situ release of this factor. RT-PCR confirmed the actual expression of the RANKL and TACE genes in the tissues around the loosened implant. These observational findings indicate the possible synthesis of RANKL by fibroblast and macrophage lineage cells, and suggest the in-situ involvement of RANKL in both osteoclastogenesis and osteoclastic bone resorptive events occurring in prosthetic joint loosening.

Bone morphogenetic proteins in bone tumors.

Bone morphogenetic proteins (BMPs), inducers of ectopic bone formation in vivo, are present in a number of osteosarcomas. BMPs are responsible for reactive bone formation, including periosteal reactions by normal osteoblasts, rather than production of tumorous osteoid by tumor cells. Osteosarcomas producing BMPs contain less-differentiated mesenchymal cells, resulting in a poorer prognosis for those patients. BMPs are also expressed in malignant fibrous histiocytomas (MFHs) of bone and dedifferentiated chondrosarcomas exhibiting undifferentiated features. However, BMPs in MFH do not show any osteoinductive activity in vivo, suggesting that those BMPs may be inactive forms and have additional functions unrelated to bone formation. Among benign bone tumors, BMPs are expressed in osteoid osteomas or osteoblastomas and effect reactive bone formation such as a surrounding sclerosis. BMPs and a BMP receptor (BMPRIB) are also detected in the cartilage cap in osteochondroma, suggesting that BMP signaling via BMPRIB might be involved in the pathogenesis of osteochondroma. Clinically, BMPs have utility as diagnostic and prognostic markers for characterizing the stage of differentiation of mesenchymal cells and mesenchymal tumors, and they may be of value in predicting the prognosis of sarcoma patients. This article reviews the accumulated information on BMPs in bone tumors, including the most recent findings, and discusses the biological and clinical significance of BMPs in bone tumors.