Chondromodulin is necessary for cartilage callus distraction in mice.

Chondromodulin (Cnmd) is a glycoprotein known to stimulate chondrocyte growth. We examined in this study the expression and functional role of Cnmd during distraction osteogenesis that is modulated by mechanical forces. The right tibiae of the mice were separated by osteotomy and subjected to slow progressive distraction using an external fixator. In situ hybridization and immunohistochemical analyses of the lengthened segment revealed that Cnmd mRNA and its protein in wild-type mice were localized in the cartilage callus, which was initially generated in the lag phase and was lengthened gradually during the distraction phase. In Cnmd null (Cnmd-/-) mice, less cartilage callus was observed, and the distraction gap was filled by fibrous tissues. Additionally, radiological and histological investigations demonstrated delayed bone consolidation and remodeling of the lengthened segment in Cnmd-/- mice. Eventually, Cnmd deficiency caused a one-week delay in the peak expression of VEGF, MMP2, and MMP9 genes and the subsequent angiogenesis and osteoclastogenesis. We conclude that Cnmd is necessary for cartilage callus distraction.

Safe and persistent growth-promoting effects of vosoritide in children with achondroplasia: 2-year results from an open-label, phase 3 extension study.

PURPOSE: Achondroplasia is caused by pathogenic variants in the fibroblast growth factor receptor 3 gene that lead to impaired endochondral ossification. Vosoritide, an analog of C-type natriuretic peptide, stimulates endochondral bone growth and is in development for the treatment of achondroplasia. This phase 3 extension study was conducted to document the efficacy and safety of continuous, daily vosoritide treatment in children with achondroplasia, and the two-year results are reported. METHODS: After completing at least six months of a baseline observational growth study, and 52 weeks in a double-blind, placebo-controlled study, participants were eligible to continue treatment in an open-label extension study, where all participants received vosoritide at a dose of 15.0 µg/kg/day. RESULTS: In children randomized to vosoritide, annualized growth velocity increased from 4.26 cm/year at baseline to 5.39 cm/year at 52 weeks and 5.52 cm/year at week 104. In children who crossed over from placebo to vosoritide in the extension study, annualized growth velocity increased from 3.81 cm/year at week 52 to 5.43 cm/year at week 104. No new adverse effects of vosoritide were detected. CONCLUSION: Vosoritide treatment has safe and persistent growth-promoting effects in children with achondroplasia treated daily for two years.

Morphometric Analysis of Subaxial Cervical Spine with Myelopathy: A Comparison with the Normal Population.

INTRODUCTION: The specific morphology and differences between patients with cervical spondylotic myelopathy (CSM) and those with normal spines remain unclear. This study aimed to evaluate and determine the features of cervical spine morphology on reconstructive CT. METHODS: We investigated that axial reconstructive CT scans of the cervical spine at C3 to C7 were obtained from 309 individuals (97 CSM patients and 212 controls). Those of the optimal pedicle diameter were selected, and the following parameters were measured: (a) sagittal diameter of the spinal canal (b) transverse diameter of the spinal canal, (c) pedicle width, (d) lateral mass thickness, (e) transverse diameter of the foramen, (f) sagittal diameter of the vertebral body, and (g) transverse diameter of the vertebral body. The following ratios were calculated using these values: the sagittal-transverse ratio and the canal-body ratio. RESULTS: Most parameters differed significantly between the sexes in both groups. The parameters without the mean sagittal diameter of the spinal canal were significantly larger in men than in women. However, the mean sagittal diameter of the spinal canal did not differ significantly between the sexes in CSM patients. The sagittal-transverse ratio and canal-body ratio were significantly smaller in the CSM patients at all levels. According to relative operating characteristic curves of the sagittal diameter of the spinal canal, sagittal-transverse ratio, and canal-body ratio, the sensitivity from C3 to C7 in both sexes was > 60% at the threshold. In men, the specificity from C3 to C7 was also >60% at the threshold. CONCLUSIONS: The morphometry of the sagittal diameter of the spinal canal, sagittal-transverse ratio, and canal-body ratio on axial reconstructive CT images appears useful for distinguishing cervical spinal canal stenosis involving myelopathy.

Once-daily, subcutaneous vosoritide therapy in children with achondroplasia: a randomised, double-blind, phase 3, placebo-controlled, multicentre trial.

BACKGROUND: There are no effective therapies for achondroplasia. An open-label study suggested that vosoritide administration might increase growth velocity in children with achondroplasia. This phase 3 trial was designed to further assess these preliminary findings. METHODS: This randomised, double-blind, phase 3, placebo-controlled, multicentre trial compared once-daily subcutaneous administration of vosoritide with placebo in children with achondroplasia. The trial was done in hospitals at 24 sites in seven countries (Australia, Germany, Japan, Spain, Turkey, the USA, and the UK). Eligible patients had a clinical diagnosis of achondroplasia, were ambulatory, had participated for 6 months in a baseline growth study and were aged 5 to less than 18 years at enrolment. Randomisation was done by means of a voice or web-response system, stratified according to sex and Tanner stage. Participants, investigators, and trial sponsor were masked to group assignment. Participants received either vosoritide 15·0 µg/kg or placebo, as allocated, for the duration of the 52-week treatment period administered by daily subcutaneous injections in their homes by trained caregivers. The primary endpoint was change from baseline in mean annualised growth velocity at 52 weeks in treated patients as compared with controls. All randomly assigned patients were included in the efficacy analyses (n=121). All patients who received one dose of vosoritide or placebo (n=121) were included in the safety analyses. The trial is complete and is registered, with EudraCT, number, 2015-003836-11. FINDINGS: All participants were recruited from Dec 12, 2016, to Nov 7, 2018, with 60 assigned to receive vosoritide and 61 to receive placebo. Of 124 patients screened for eligibility, 121 patients were randomly assigned, and 119 patients completed the 52-week trial. The adjusted mean difference in annualised growth velocity between patients in the vosoritide group and placebo group was 1·57 cm/year in favour of vosoritide (95% CI [1·22-1·93]; two-sided p<0·0001). A total of 119 patients had at least one adverse event; vosoritide group, 59 (98%), and placebo group, 60 (98%). None of the serious adverse events were considered to be treatment related and no deaths occurred. INTERPRETATION: Vosoritide is an effective treatment to increase growth in children with achondroplasia. It is not known whether final adult height will be increased, or what the harms of long-term therapy might be. FUNDING: BioMarin Pharmaceutical.

Forearm lengthening by distraction osteogenesis: A report on 5 limbs in 3 cases.

Radioulnar length discrepancy causes pain and decreases function of the wrist, forearm, and elbow. Limb lengthening, which has been used in the treatment of various deformities of the forearm, is necessary to restore balance between the ulna and radius. We treated 5 limbs in 3 patients (2 boys, 1 girl; mean age 9.3 years old) with radioulnar length discrepancy by distraction osteogenesis of either the ulna or radius using external fixators. We dissected the interosseous membrane between the ulna and radius in 3 limbs in 2 cases and did not do so in 2 limbs of 1 case. These cases include 2 cases with hereditary multiple exostoses, and 1 case with multiple epiphyseal dysplasia. The results were investigated and evaluated in this study, using appropriate clinical and radiographic parameters, noting the state of the interosseous membrane, which has an important role in forearm stability. The mean fixation period was 113 days. The mean distraction distance was 22.8 mm. The mean follow-up period was 637.7 days. The mean ulnar shortening and radial articular angle respectively improved from 7.4 mm and 30.2° preoperatively to -0.1 mm and 34.8° postoperatively. Balance between the ulna and radius was restored, and the results showed significant improvements in range of motion of the joints. However, 2 unintended radial head subluxations occurred in 2 limbs without dissection of the interosseous membrane. In addition, a keloid remained in 1 limb due to pin site infection. Forearm lengthening by distraction osteogenesis was useful in our cases. It is important to recognize the function of the interosseous membrane when lengthening is performed by osteotomy of the proximal ulna by gradual distraction with an external fixator.

Microdeletions on 6p22.3 are associated with mesomelic dysplasia Savarirayan type.

INTRODUCTION: Mesomelic dysplasias are a group of skeletal disorders characterised by shortness of the middle limb segments (mesomelia). They are divided into 11 different categories. Among those without known molecular basis is mesomelic dysplasia Savarirayan type, characterised by severe shortness of the middle segment of the lower limb. OBJECTIVE: To identify the molecular cause of mesomelic dysplasia Savarirayan type. METHODS AND RESULTS: We performed array comparative genomic hybridisation in three unrelated patients with mesomelic dysplasia Savarirayan type and identified 2 Mb overlapping de novo microdeletions on chromosome 6p22.3. The deletions encompass four known genes: MBOAT1, E2F3, CDKAL1 and SOX4. All patients showed mesomelia of the lower limbs with hypoplastic tibiae and fibulae. We identified a fourth patient with intellectual disability and an overlapping slightly larger do novo deletion also encompassing the flanking gene ID4. Given the fact that the fourth patient had no skeletal abnormalities and none of the genes in the deleted interval are known to be associated with abnormalities in skeletal development, other mutational mechanisms than loss of function of the deleted genes have to be considered. Analysis of the genomic region showed that the deletion removes two regulatory boundaries and brings several potential limb enhancers into close proximity of ID4. Thus, the deletion could result in the aberrant activation and misexpression of ID4 in the limb bud, thereby causing the mesomelic dysplasia. CONCLUSIONS: Our data indicate that the distinct deletion 6p22.3 is associated with mesomelic dysplasia Savarirayan type featuring hypoplastic, triangular-shaped tibiae and abnormally shaped or hypoplastic fibulae.

Local administration of zoledronic acid for giant cell tumor of bone.

Giant cell tumor of bone is a locally aggressive tumor with a high local recurrence rate. Several adjuvant therapies have been employed to reduce the recurrence rate, but their effectiveness remains controversial. The authors attempted local administration of zoledronic acid, a nitrogen-containing bisphosphonate that strongly inhibits bone resorption, as an adjuvant treatment for histologically proven giant cell tumor of bone in 5 patients at their institution. After biopsy, 4 patients were treated with local administration of zoledronic acid with artificial bone and 1 was treated with zoledronic acid without artificial bone. Histologic response to the treatment was evaluated with surgically resected specimens. The 4 patients treated with artificial bone showed local control, with histologic tumor necrosis rates of 90%, 90%, 50%, and 10%. Magnetic resonance imaging showed poor gadolinium enhancement, and histologic examination after local zoledronic acid treatment showed tumor necrosis. One patient without artificial bone showed no histologic tumor necrosis and had local recurrence in soft tissue 18 months after tumor resection. A 3-week waiting period between biopsy and zoledronic acid treatment appears reasonable from the histological study. Complication of this therapy was delayed wound healing and it occurred in 2 cases. Taken together, this case series suggests that local administration of zoledronic acid with artificial bone is a potential adjuvant therapy for giant cell tumor of bone. On the other hand, effective local administration of zoledronic acid requires some bone matrix, including artificial bone. Campanacci's grading is important for predicting the effect of local administration of zoledronic acid.

Hypertrophic chondrocytes in the rabbit growth plate can proliferate and differentiate into osteogenic cells when capillary invasion is interposed by a membrane filter.

The fate of hypertrophic chondrocytes during endochondral ossification remains controversial. It has long been thought that the calcified cartilage is invaded by blood vessels and that new bone is deposited on the surface of the eroded cartilage by newly arrived cells. The present study was designed to determine whether hypertrophic chondrocytes were destined to die or could survive to participate in new bone formation. In a rabbit experiment, a membrane filter with a pore size of 1 µm was inserted in the middle of the hypertrophic zone of the distal growth plate of ulna. In 33 of 37 animals, vascular invasion was successfully interposed by the membrane filter. During 8 days, the cartilage growth plate was enlarged, making the thickness 3-fold greater than that of the nonoperated control side. Histological examination demonstrated that the hypertrophic zone was exclusively elongated. At the terminal end of the growth plate, hypertrophic chondrocytes extruded from their territorial matrix into the open cavity on the surface of the membrane filter. The progenies of hypertrophic chondrocytes (PHCs) were PCNA positive and caspase-3 negative. In situ hybridization studies demonstrated that PHCs did not express cartilage matrix proteins anymore but expressed bone matrix proteins. Immunohistochemical studies also demonstrated that the new matrix produced by PHCs contained type I collagen, osteonectin, and osteocalcin. Based on these results, we concluded that hypertrophic chondrocytes switched into bone-forming cells after vascular invasion was interposed in the normal growth plate.

Magnetic resonance imaging in adolescent symptomatic navicular tuberosity.

BACKGROUND: The accessory navicular bone is one of the most common accessory ossicles, which sometimes become symptomatic. Abnormalities in magnetic resonance (MR) image, e. g. edema-like bone marrow pattern, have been reported for symptomatic accessory navicular. However, it has not been completely understood the edema-like bone marrow pattern correlates to the symptom of navicular tuberosity. METHODS: We investigated the edema-like bone marrow pattern in correlation with alleviation of the symptom and the presence of accessory navicular bone. Ten adolescents with pain localized to the navicular tuberosity were recruited and seven cases were further examined with consecutive MR images. RESULTS: Edema-like bone marrow pattern was found in all symptomatic navicular but not in asymptomatic navicular. Intensity of the pattern diminished with alleviation of the symptom. Moreover, this correlation was recognized even in the patients who had no accessory navicular bones. CONCLUSIONS: MR images could be used not only for diagnosis but for monitor of healing in adolescent symptomatic navicular. There may be different pathologic mechanism for adolescent symptomatic navicular tuberosity, such as an osteitis, in adolescents.

Navigation-Assisted Total Knee Arthroplasty for Osteoarthritis with Extra-Articular Femoral Deformity and/or Retained Hardware.

Total knee arthroplasty (TKA) for osteoarthritis (OA) patients with extra-articular deformity is still challenging because angular deformity, canal sclerosis, or the retained hardware that precludes the use of the traditional intramedullary guide. In addition, atypical bone cut for intra-articular correction leads to imbalanced soft tissue gap. Furthermore, corrective osteotomy should be considered for severe deformity or para-articular deformity cases. Recently, navigation-assisted TKA has been reported to increase the accuracy of prosthetic positioning and limb alignment. This system can calculate mechanical axis regardless of extra-articular deformity, canal sclerosis, or retained hardware. Accordingly, navigation surgery has been considered to be a powerful option especially in TKAs with extra-articular deformity cases. Here, we report 3 successful navigation-assisted TKAs for osteoarthritis with extra-articular deformities and/or retained hardware. Navigation-assisted TKA is an effective and reliable alternative for patients with extra-articular deformities.

Early changes in muscle atrophy and muscle fiber type conversion after spinal cord transection and peripheral nerve transection in rats.

BACKGROUND: Spinal cord transection and peripheral nerve transection cause muscle atrophy and muscle fiber type conversion. It is still unknown how spinal cord transection and peripheral nerve transection each affect the differentiation of muscle fiber type conversion mechanism and muscle atrophy. The aim of our study was to evaluate the difference of muscle weight change, muscle fiber type conversion, and Peroxisome proliferator-activated receptor-γ coactivatior-1α (PGC-1α) expression brought about by spinal cord transection and by peripheral nerve transection. METHODS: Twenty-four Wistar rats underwent surgery, the control rats underwent a laminectomy; the spinal cord injury group underwent a spinal cord transection; the denervation group underwent a sciatic nerve transection. The rats were harvested of the soleus muscle and the TA muscle at 0 week, 1 week and 2 weeks after surgery. Histological examination was assessed using hematoxylin and eosin (H&E) staining and immunofluorescent staing. Western blot was performed with 3 groups. RESULTS: Both sciatic nerve transection and spinal cord transection caused muscle atrophy with the effect being more severe after sciatic nerve transection. Spinal cord transection caused a reduction in the expression of both sMHC protein and PGC-1α protein in the soleus muscle. On the other hand, sciatic nerve transection produced an increase in expression of sMHC protein and PGC-1α protein in the soleus muscle. The results of the expression of PGC-1α were expected in other words muscle atrophy after sciatic nerve transection is less than after spinal cord transection, however muscle atrophy after sciatic nerve transection was more severe than after spinal cord transection. CONCLUSION: In the conclusion, spinal cord transection diminished the expression of sMHC protein and PGC-1α protein in the soleus muscle. On the other hand, sciatic nerve transection enhanced the expression of sMHC protein and PGC-1α protein in the soleus muscle.

A massive chondroblastoma in the proximal humerus simulating malignant bone tumors.

Chondroblastoma is a mostly benign bone neoplasm that typically affects the second decade of life and exhibits a lytic lesion in the epiphysis of long bones. We report an extreme case of massive, destructive chondroblastoma of the proximal humerus in a 9-year-old girl. It was difficult to differentiate using imaging information the lesion from malignant bone tumors such as osteosarcoma. Histopathological examination from biopsy proved chondroblastoma. The tumor was resected after preoperative transcatheter embolization. Reconstructive procedure for the proximal humerus was not performed due to the local destruction. The present case demonstrates clinical and radiological differentiations of the massive chondroblastoma from the other lesions and histopathological understandings for this lesion.

Subchondral cysts in dysplastic osteoarthritic hips communicate with the joint space: analysis using three-dimensional computed tomography.

INTRODUCTION: Bone cyst formation in hips increases as osteoarthritis worsens. Although bone cysts in hips have been described in many studies, their etiology remains unclear and under debate. The purpose of this study was to investigate the communication between a bone cyst and the joint space, as well as the relationship between the severity of osteoarthritis and the formation of subchondral bone cysts in dysplastic hips. METHOD: We studied bone cysts from 150 dysplastic hips in 97 patients by computed tomography (CT) and plain radiography. We investigated the distribution of the bone cysts and the presence or absence of a communication path between the cysts and the joint space by three-dimensional (3D) CT. RESULT: Of the 150 hips, 94 acetabula and 55 femoral heads were found to contain cysts. Of the 94 hips containing acetabular cysts, 89 and 5 hips showed black lines and gray lines connecting the cyst and the joint space, respectively, on 3D-CT. The rate of cyst presentation in the hip increased as the joint space became narrower. The number of hips that possessed cysts in the anterior and/or middle portion was significantly higher than that in the posterior portions. CONCLUSION: Bone cysts in dysplastic osteoarthritic hips were found to communicate with the joint space in all cases. This suggests that the formation and enlargement of the cysts in dysplastic hips may be greatly influenced by the joint fluid. Cyst formation was initially observed in the anterior acetabulum, gradually progressing to involve the entire joint, including the posterior acetabulum and the femoral head, with worsening of the osteoarthritis.

Endoscope-assisted excision of a juxtafacet cyst in an adolescent athlete: a case report.

BACKGROUND: Juxtafacet cysts (JFCs) are a cause of back and radicular pain that can be treated conservatively and operatively. Such strategies include lumbosacral brace, epidural injection, open surgery, and minimally invasive surgery; although surgical treatment is usually reserved for unsuccessful conservative treatment. The role of minimally invasive surgery in athletic youth with JFCs has yet to be determined. PATIENTS/MATERIAL AND METHODS: The patient is a 16-year-old basketball player with a JFC. We performed endoscope-assisted cystectomy. RESULTS: Endoscope-assisted JFC excision immediately and completely resolved the patient's lower back and leg pain with no recurrence of symptoms 4 years after surgery. CONCLUSION: We suggest that JFCs of the lumbar spine be a part of the differential diagnosis in young patients with back and radicular pain. Furthermore, we recommend that endoscope-assisted surgery be employed in the treatment of JFCs in young athletes.

Usefulness of transcatheter arterial embolization prior to excision of hypervascular musculoskeletal tumors.

The objective of this study was to evaluate the usefulness of transcatheter arterial embolization prior to surgical excision of musculoskeletal tumors. We reviewed the records of nine patients (3 females and 6 males) who received arterial embolization prior to excision of musculoskeletal tumors in our hospital from December 2009 to April 2010. We evaluated tumor region, size, histopathology, feeding artery, embolic material, and blood loss during surgery. We compared the actual amount of intraoperative bleeding with arterial embolization to estimated amounts of bleeding without embolization predicted by three orthopedic surgeons. Arterial embolization was performed on the same day or within 5 days before surgery. Operations were performed as planned in all patients without serious complications. The amount of intraoperative bleeding was 35-4200 mL and there was significantly less bleeding with arterial embolization compared with the estimated amounts (p<0.01). Our results show that arterial embolization prior to resection of hypervascular musculoskeletal tumors reduces the amount of bleeding during surgery and contributes to patient safety.

Long-term outcomes of lumbar posterior apophyseal end-plate lesions in children and adolescents.

BACKGROUND: A lesion of the lumbar posterior apophyseal end plate in children and adolescents causes symptoms similar to those associated with a herniated disc. However, the end-plate lesion and the herniated disc differ in terms of pathology. The purpose of this study was to clarify the long-term clinical and radiographic outcomes in children and adolescents who were treated either surgically or conservatively for a lumbar posterior apophyseal end-plate lesion. METHODS: We identified twenty-four consecutive patients who had been treated in the sports clinic of our hospital. The mean age at the first medical examination was 14.5 years. The mean follow-up time was 13.8 years. The mean age at the time of final follow-up was 28.4 years. All twenty-four patients had symptomatic low back pain with sciatica. All but two were active in sports. Sixteen patients were treated conservatively, and eight patients underwent surgical intervention. Skeletal maturity was evaluated on the basis of the appearance of the secondary ossification center of L3. RESULTS: The apophyseal stage ("A" stage), which was assigned when the secondary ossification center of the vertebral body was visible on radiographs, was seen most frequently. Both the surgically treated group and the conservatively treated group demonstrated progressive disc degeneration at the involved level. The average Roland-Morris Disability Questionnaire (RDQ) score was 1.3 for the patients treated conservatively and 1.8 for those treated surgically, a nonsignificant difference. One patient developed spinal stenosis after twelve years of conservative treatment. One patient treated surgically demonstrated severe lumbar instability. There were no significant associations between the magnetic resonance imaging (MRI) findings and RDQ scores. Histological examination of surgical specimens showed irregular alignment of the anulus fibrosus, with degenerative matrix and chondrocytes without a nucleus. CONCLUSIONS: The long-term outcome for patients with a posterior end-plate lesion is favorable, regardless of whether it is treated surgically or nonsurgically.

Angiogenesis and myogenesis in mouse tibialis anterior muscles during distraction osteogenesis: VEGF, its receptors, and myogenin genes expression.

Angiogenesis and myogenesis occur in the surrounding skeletal muscles following distraction osteogenesis, but their molecular mechanisms remain unclear. The present study investigated morphological features of lengthened muscles and the time course change of vascular endothelial growth factor (VEGF), its receptors (VEGFR-1 and VEGFR-2) and myogenin gene expression profiles related to angiogenesis and myogenesis in tibialis anterior (TA) muscles with a mouse model of distraction osteogenesis, which involves 1 week of waiting period (latency phase), 2 weeks of intermittent distraction (distraction phase), and 5 weeks of remodeling period (consolidation phase). Macroscopic findings showed that lengthened TA muscles increased to approximately 42% longer and 10% heavier at the end of the process when compared to pre-surgery. During the distraction phase, VEGF and its receptors were induced in the vascular endothelial cells, myogenin-positive satellite cells and myocytes, and subsequently, capillary progression and myogenesis were increased. Real-time RT-PCR showed that Vegf, Vegfr-1, Vegfr-2, and myogenin genes expression was enhanced during the muscle lengthening. Vegf and Vegfr-1 were upregulated following the recession of angiogenesis at the consolidation phase. We conclude that upregulation of VEGF and its receptors by mechanical tension-stress could be involved in the process of angiogenesis and myogenesis in lengthened muscles.

A case of osteoid osteoma of the trapezoid bone: the efficiency of dynamic magnetic resonance imaging for the detection of osteoid osteoma localized at the atypical site.

The occurrence of osteoid osteoma of the carpus is rare, particularly of the trapezoid. We present a case of a ten-year-old girl with osteoid osteoma of the trapezoid in whom surgical excision of the lesion was successful. Useful information for the diagnosis of the lesion was mainly provided by dynamic magnetic resonance imaging.

MRI changes of the spinal subdural space after lumbar spine surgeries: report of two cases.

Although magnetic resonance imaging (MRI) is frequently used to assess the lumbar spine, there are few reports in the medical literature that have evaluated using MRI immediately following spinal surgery. Furthermore, descriptions of the subdural changes after lumbar spine surgery are also infrequent. In this paper, we present two cases with subdural change seen on MRI immediately after lumbar surgery. Both the patients had mild symptoms that resolved spontaneously, and the follow-up MRI scans showed resolution of the subdural changes. Subdural changes should be considered as one of the possible causes of unexpected symptoms in patients following lumbar spinal surgery.