Targeting TGF-ß for treatment of osteogenesis imperfecta.

BACKGROUNDCurrently, there is no disease-specific therapy for osteogenesis imperfecta (OI). Preclinical studies demonstrate that excessive TGF-ß signaling is a pathogenic mechanism in OI. Here, we evaluated TGF-ß signaling in children with OI and conducted a phase I clinical trial of TGF-ß inhibition in adults with OI.METHODSHistology and RNA-Seq were performed on bones obtained from children. Gene Ontology (GO) enrichment assay, gene set enrichment analysis (GSEA), and Ingenuity Pathway Analysis (IPA) were used to identify dysregulated pathways. Reverse-phase protein array, Western blot, and IHC were performed to evaluate protein expression. A phase I study of fresolimumab, a TGF-ß neutralizing antibody, was conducted in 8 adults with OI. Safety and effects on bone remodeling markers and lumbar spine areal bone mineral density (LS aBMD) were assessed.RESULTSOI bone demonstrated woven structure, increased osteocytes, high turnover, and reduced maturation. SMAD phosphorylation was the most significantly upregulated GO molecular event. GSEA identified the TGF-ß pathway as the top activated signaling pathway, and IPA showed that TGF-ß1 was the most significant activated upstream regulator mediating the global changes identified in OI bone. Treatment with fresolimumab was well-tolerated and associated with increases in LS aBMD in participants with OI type IV, whereas participants with OI type III and VIII had unchanged or decreased LS aBMD.CONCLUSIONIncreased TGF-ß signaling is a driver pathogenic mechanism in OI. Anti-TGF-ß therapy could be a potential disease-specific therapy, with dose-dependent effects on bone mass and turnover.TRIAL REGISTRATIONClinicalTrials.gov NCT03064074.FUNDINGBrittle Bone Disorders Consortium (U54AR068069), Clinical Translational Core of Baylor College of Medicine Intellectual and Developmental Disabilities Research Center (P50HD103555) from National Institute of Child Health and Human Development, USDA/ARS (cooperative agreement 58-6250-6-001), and Sanofi Genzyme.

Neuraxial and regional anesthesia in surgical patients with osteogenesis imperfecta: a narrative review of literature.

BACKGROUND AND OBJECTIVES: Regional and neuraxial anesthesia techniques have become instrumental in the perioperative period yet have not been well described in patients with osteogenesis imperfecta (OI), a congenital connective tissue disorder characterized by skeletal dysplasia and fragility. Patients with skeletal dysplasia present unique perioperative challenges that warrant consideration of these techniques despite their relative contraindication in this population due to reports of increased bleeding with surgery, skeletal fragility concerns with positioning, and risk of spinal cord injury with continuous neuraxial catheters. The aim of this narrative review was to evaluate literature describing the use of regional and neuraxial techniques in patients with OI and any associated clinical outcomes. METHODS: All available literature from inception to July 2020 was retrieved, according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, from MEDLINE, Embase, Google Scholar and The Cochrane Library. Three authors reviewed all references for eligibility, abstracted data, and appraised quality. RESULTS: Of 412 articles initially identified, 42 met our inclusion criteria, yielding 161 cases with regional and/or neuraxial techniques described. In 117 (72.6%) of the 161 cases, neuraxial technique was performed, including 76 (64.9%) epidural, 7 (5.9%) caudal, 5 (4.2%) combined spinal epidural, and 29 (24.7%) spinal procedures. In 44 (27.4%) of the 161 cases, the use of regional anesthesia was described. Our review was confounded by incomplete data reporting and small sample sizes, as most were case reports. There were no randomized controlled trials, and the two single-center retrospective data reviews lacked sufficient data to perform meta-analysis. While complications or negative outcomes related to these techniques were not reported in any of the cases, less than half specifically discuss outcomes beyond placement and immediate postoperative course. CONCLUSIONS: There is insufficient evidence to validate or refute the potential risks associated with the use of regional and neuraxial techniques in patients with OI. This review did not uncover any reports of negative sequelae related to the use of these modalities to support relative contraindication in this population; however, further research is needed to adequately assess clinically relevant outcomes such as complications and opioid-sparing effect.

Initial Experience With Percutaneous IM Rodding of the Humeri in Children With Osteogenesis Imperfecta.

BACKGROUND: To report a single-center surgical experience treating humeral deformity and fractures in children with osteogenesis imperfecta (OI) using the Fassier-Duval (FD) intramedullary elongating rods. METHODS: A retrospective review was conducted between December 2005 and July 2013 of all OI patients who underwent FD rodding with a minimum of 1-year follow-up. All patients were also being concurrently treated with bisphosphonates. RESULTS: Eighteen patients underwent internal fixation on a total of 35 humeri: 7 males and 11 females with an average age of 49 months. Thirty-five procedures were performed using FD rodding, with 5 utilizing only the male portion. Thirty procedures were primary FD implantation and 5 were revisions. Twelve patients had type III OI and 6 patients type IV OI. Indications for surgery included recurrent fracture, severe bowing deformity, and pain. Osteotomy methods included closed osteoclasis, percutaneous, or open osteotomies. Two patients required transfusions during their hospital stay. At our determined endpoint, 23 humeri (65.7%) had acceptable results with a mean follow-up time of 43 months (SD=27) with no revision. The remaining 12 humeri (34.3%) necessitated revision with a mean time to revision of 35 months (SD=29). Reasons for revision included: migration resulting in pain and functional difficulty (8.6%), migration with bowing (8.6%), and hardware failure secondary to trauma (8.6%). In addition, 2 revisions were required for nonunion (5.7%) and 1 for malunion (2.9%). To our knowledge, all other osteotomies performed during surgery resulted in bony union. CONCLUSIONS: The use of the FD system for correction of humeral deformity demonstrates a reasonable option to improve comfort and function in children with recurrent fractures and deformity secondary to OI. The FD system allows for decreased revision rates and less morbid instrumentation. LEVEL OF EVIDENCE: Level IV-retrospective case series.

Mid-term Results of Femoral and Tibial Osteotomies and Fassier-Duval Nailing in Children With Osteogenesis Imperfecta.

BACKGROUND: Patients with osteogenesis imperfecta (OI) have significant burden of both fractures and bony deformities. The present approach to care in this disorder is a combination of surgical care with intramedullary rod fixation, cyclic bisphosphonate therapy, and rehabilitation with goal of maximizing patient function and quality of life. METHODS: Retrospective chart review identified 58 children with OI who had realignment osteotomies with Fassier-Duval (FD) intramedullary nailing of the lower extremity by a single surgeon. This is a consecutive series treated between 2003 and 2010. Postoperatively, patients were followed up clinically and radiologically. Motor function was assessed using the Brief Assessment of Motor Function score and the walking scale subset of the Gillette Functional Assessment Questionnaire. RESULTS: Fifty-eight patients had 179 lower extremity FD intramedullary rods placed. This technique allowed for intervention on multiple long bones, with 29% having bilateral femur and tibial rodding in the same procedure. Revisions were required in 53% of patients, which occurred at a mean time of 52 months after initial rodding surgery. In most cases, revision surgery was related to patient growth and subsequent fracture, although rod migration did occur in a minority of patients. Nonunion or incomplete union was 14.5% in this series. Bisphosphonate infusion was not postponed after surgical procedures. Patients had improvement in mobility status at the latest follow-up. CONCLUSIONS: This series lends evidence to the medium-term utility of FD intramedullary rods as an effective and less invasive platform for stabilization and correction of deformity in long bones of patients with OI. Relatively low blood loss and relatively short hospitalizations were noted. Nonunion rate was comparable with existing literature noting that our patients did not have postsurgical postponement of bisphosphonate therapy. LEVEL OF EVIDENCE: Therapeutic study to investigate the results of treatment with FD rods. Retrospective case series model of Level IV evidence quality.

Progressive valgus angulation of the ankle secondary to loss of fibular congruity treated with medial tibial hemiepiphysiodesis and fibular reconstruction.

The fibula is an important stabilizer of the lateral ankle. Discontinuity of the fibular shaft can lead to progressive pain and shortening of the fibula, ultimately causing loss of lateral support to the ankle. Two children, who sustained segmental bone loss of the shaft of the fibula, developed progressive symptomatic valgus of the ankle with widening of the mortice and lateral subluxation of the talus. Both patients were treated with fibular plating and grafting with tricalcium sulfate with acute reconstitution of fibular length. Distal medial tibial hemiepiphysiodesis was simultaneously performed. One patient required revision plating and grafting 14 months after the index surgery because of plate failure. The valgus angulation and the widened medial mortice were corrected in the ankles of both patients, who returned to full activities. The patients were followed to maturity; the correction has been maintained, and they remain asymptomatic. The technique used in these cases can correct valgus angulation secondary to loss of fibular congruity rather than only halting progression of the deformity.

Childhood obesity case statement.

OBJECTIVE: The goal of this publication is to raise awareness of the impact of childhood obesity on the musculoskeletal health of children and its potential long-term implications. METHODS: Relevant articles dealing with musculoskeletal disorders either caused by or worsened by childhood obesity were reviewed through a Pub Med search. Efforts to recognize and combat the childhood obesity epidemic were also identified through Internet search engines. This case statement was then reviewed by the members of the pediatric specialty group of the US Bone and Joint Initiative, which represents an extensive number of organizations dealing with musculoskeletal health. RESULTS: Multiple musculoskeletal disorders are clearly caused by or worsened by childhood obesity. The review of the literature clearly demonstrates the increased frequency and severity of many childhood musculoskeletal disorders. Concerns about the long-term implications of these childhood onset disorders such as pain and degenerative changes into adulthood are clearly recognized by all the member organizations of the US Bone and Joint Initiative. CONCLUSIONS: It is imperative to recognize the long-term implications of musculoskeletal disorders caused by or worsened by childhood obesity. It is also important to recognize that the ability to exercise comfortably is a key factor to developing a healthy lifestyle and maintaining a healthy body weight. Efforts to develop reasonable and acceptable programs to increase physical activity by all facets of society should be supported. Further research into the long-term implications of childhood musculoskeletal disorders related to childhood obesity is necessary.

Osteogenesis imperfecta caused by PPIB mutation with severe phenotype and congenital hearing loss.

Osteogenesis imperfecta (OI) is an inherited disorder of connective tissue typically caused by defects in either COL1A1 or COL1A2. A number of other genes causative of this disorder have been found, including PPIB, which forms one subunit of the prolyl 3-hydroxylase enzyme complex. Patients with homozygous or compound heterozygous mutations in this gene have OI with a trend toward lethal or severe phenotype. We present a Native American female with prenatal diagnosis of OI. Long bones were shortened with significant rhizomelia. At birth, fractures were present in ribs, humerii, and femurs. She had significant respiratory disease at birth, and required oxygen throughout her life. She also had recurrent pneumonias, one of which ultimately caused her death at age 16 mo. She also had significant bilateral sensorineural hearing loss. Molecular testing showed that the patient was homozygous for a single nucleotide substitution in PPIB (c. 136-2A>G). Patients with OI caused by PPIB mutations have had variable disease, but with majority of either with perinatal lethality or progressively deforming severe disease. Patients with OI due to PPIB mutation have shown some differences in phenotype. There appears to be a trend toward rhizomelic shortening and less severe bowing of the extremities, as compared to patients with comparably severe OI caused by COL1A1 or COL1A2 mutation. Congenital hearing loss may be an inconsistent feature of this condition, or may have co-occurred in our patient for unrelated reasons. Still, patients with OI caused by PPIB mutation should have appropriate early and regular management of their hearing.

Distal humerus atrophic nonunion in a child with osteogenesis imperfecta.

UNLABELLED: Atrophic nonunion of the distal humerus in children with osteogenesis imperfecta is a vexing and disabling problem. Traditional treatments, including casting, intramedullary nailing, plating and bone grafting have not been universally successful. We report on a case of successful treatment of one atrophic nonunion of the distal humerus in ad 2 year 10 month old child with type III OI who had failed more traditional treatments. The treatment used a combination of telescoping intramedullary nails, locking plate fixation and bone morphogenic protein. LEVEL OF EVIDENCE: Level IV.

Childhood obesity case statement.

OBJECTIVE: The goal of this publication is to raise awareness of the impact of childhood obesity on the musculoskeletal health of children and its potential long-term implications. METHODS: Relevant articles dealing with musculoskeletal disorders either caused by or worsened by childhood obesity were reviewed through a Pub Med search. Efforts to recognize and combat the childhood obesity epidemic were also identified through Internet search engines. This case statement was then reviewed by the members of the pediatric specialty group of the US Bone and Joint Initiative, which represents an extensive number of organizations dealing with musculoskeletal health. RESULTS: Multiple musculoskeletal disorders are clearly caused by or worsened by childhood obesity. The review of the literature clearly demonstrates the increased frequency and severity of many childhood musculoskeletal disorders. Concerns about the long-term implications of these childhood onset disorders such as pain and degenerative changes into adulthood are clearly recognized by all the member organizations of the US Bone and Joint Initiative. CONCLUSIONS: It is imperative to recognize the long-term implications of musculoskeletal disorders caused by or worsened by childhood obesity. It is also important to recognize that the ability to exercise comfortably is a key factor to developing a healthy lifestyle and maintaining a healthy body weight. Efforts to develop reasonable and acceptable programs to increase physical activity by all facets of society should be supported. Further research into the long-term implications of childhood musculoskeletal disorders related to childhood obesity is necessary.

The incidence of spondylolysis and spondylolisthesis in children with osteogenesis imperfecta.

BACKGROUND: Spondylolysis and spondylolisthesis are common abnormalities of the lumbar spine. The incidence of these diagnoses is recognized in the healthy population. However, their incidence in osteogenesis imperfecta (OI) patients is less well defined. METHODS: This is a retrospective radiographic review of patients treated in the OI clinic from a single institution. Lateral radiographs were reviewed on all available patients to assess the incidence of spondylolysis and spondylolisthesis in this patient population. The morphology of the pedicle and pars interarticularis was also evaluated to identify any abnormalities or dysplasia of these structures. RESULTS: One hundred ten of the 139 patients treated in the OI clinic met the inclusion criteria for this study. Of these patients, 79% (87 of 110) were ambulatory. The overall incidence of spondylolysis in this pediatric OI population was found to be 8.2% (9 of 110) at an average age of 7.5 years. The incidence of spondylolisthesis was 10.9% (12 of 110) at an average age of 6.5 years with 75% (3 of 12) being isthmic type and 25% (3 of 12) dysplastic. The combined incidence of spondylolysis and spondylolisthesis was 19.2%. Incidentally, the pedicle length was noted to be elongated in 40.0% (44 of 110) of this OI population. CONCLUSIONS: This study found that the incidence of spondylolysis in a group of children with OI was much higher than in the normal pediatric population, which has been reported to be 2.6% to 4.0%. This incidence was also found to be higher than previously reported incidence of spondylolysis in OI patients (5.3%). The incidence of spondylolisthesis was also found to be much higher than that of the normal pediatric population (4.2%). It is important to recognize this higher incidence of these abnormalities and to anticipate future associated symptoms and potential worsening listhesis that can clinically affect the lifestyles of these children and potentially require surgical treatment. The clinical significance of these findings will necessitate long-term follow-up.

The reemergence of the trampoline as a recreational activity and competitive sport.

The recreational use of trampolines is widespread and growing rapidly around the world. The reported incidence of significant injuries continues to increase despite more than three decades of attempts to educate the public on the inherent dangers of trampolines and appropriate safety rules for their use. Competitive trampolining also is growing, although there is scant medical literature related to training issues and injuries to assist the physician in guiding and treating these athletes. It is anticipated that with the increased use of trampolines and with the evolution of ever more complex competitive techniques and routines, the potential for catastrophic injuries in competition will increase. This article discusses awareness of the risks and attempts to mitigate injuries. It remains unclear, from an injury risk standpoint, whether trampolines can be used with an acceptable degree of safety.

Surgical treatment of osteogenesis imperfecta: current concepts.

PURPOSE OF REVIEW: The treatment of osteogenesis imperfecta requires a multidisciplinary team to maximize function and comfort, and decrease fracture incidence. Medical treatment with bisphosphonates has allowed for safer, more effective surgical management of children with osteogenesis imperfecta. The purpose of this review is to outline treatment indications and choices of surgical techniques based on recent clinical studies, and in addition to identify persistent clinical problems addressed in recent literature. RECENT FINDINGS: Several new intramedullary rodding surgical techniques and modifications of older techniques have been developed to correct deformities of the long bones. These techniques decrease the trauma associated with surgical treatment. The newer techniques limit postoperative immobilization, enabling earlier rehabilitation, and allowing for treatment of multiple bones simultaneously. SUMMARY: Recent medical and surgical advances have allowed improved safety, function and comfort in treating children with osteogenesis imperfecta. The selection of surgical techniques is dependent on surgeon experience, severity of disease and patient function, and availability of specific instrumentation. Intramedullary fixation rather than plating is preferred, and allowing early protected weight bearing and rehabilitation of children with ambulatory potential is the ideal goal.

Case reports: osteonecrosis of the capitate: a pediatric case report.

We present what we think is the first documented occurrence of osteonecrosis of the capitate in a skeletally immature patient. Atraumatic osteonecrosis of the capitate is rare, and all reported cases have occurred in adults. Our pediatric patient was treated with observation and limited immobilization. He achieved a full recovery clinically and radiographically after 1 year. A review of the literature pertaining to osteonecrosis of the capitate also is provided.

Total stapled, total intra-abdominal (TSTI) laparoscopic Roux-en-Y gastric bypass: one leak in 1000 cases.

BACKGROUND: Variations in technique of laparoscopic Roux-en-Y gastric bypass (LRYGBP) have been reported. These changes, mainly in the construction of the gastro-jejunostomy, are intended to decrease complications. METHODS: 1000 consecutive LRYGBPs were performed using the Total Stapled Total Intra-abdominal (TSTI) technique antecolic and antegastric approach. Technical details and results, including perioperative morbidity and mortality, are reported. RESULTS: Although the correction or improvement of the most serious co-morbidities with the use of the TSTI technique were similar to results reported by other gastric bypass surgeons, we noted a considerable difference in the development of leaks using this surgical approach. Current literature on gastric bypass reports a 2-5% incidence of leaks. Using the TSTI approach, the incidence of leaks at our facility was 0.1% (one in 1000 cases). After analysis of the factors involved, it was concluded that the use of the antecolic and antegastric approach in gastric bypass, as described in the TSTI,should be an important consideration by the surgeon. This technique, which uses a circular stapler, was found to be easy to perform while maintaining a reproducible, controlled opening of the anastomosis. CONCLUSION: Although this was a non-randomized study, the results found a considerable improvement in the incidence of morbidity and mortality, and a remarkable decrease in the frequency of leaks.

Trampoline injuries.

As the popularity of trampolines has increased during the past 10 years, so has the number of injuries sustained using them. Whether there is an actual increase in the risk associated with the use of a trampoline for the same number of exposure hours is not known. The marked increase in emergency room visits related to trampoline injuries might reflect only the increased number of trampolines now available for recreational use or the creative manner in which they are being used. The complex factors related to trampolines, their use, and the possible injuries will be discussed. A liberal use of Internet references will be used because this is where much of the advertising and information available to the public regarding trampolines currently is disseminated.