Multicenter Series of Deformity Correction Using Guided Growth in the Setting of Osteogenesis Imperfecta.

BACKGROUND: The mainstay of deformity correction and fracture prevention for patients with osteogenesis imperfecta (OI) includes osteotomies and intramedullary rodding. Guided growth, described in the setting of skeletal dysplasias, offers a less invasive means of deformity correction. We report a multicenter case series of guided growth procedures in the setting of OI. METHODS: We retrospectively reviewed patients with OI at three institutions from April 2012 to April 2019: 18 patients underwent guided growth for angular deformity correction with minimum 1-year follow-up or full deformity correction and removal of guided growth hardware. Clinical characteristics, deformity measurements, and complications were collected. Distal femoral and proximal tibial hemiepiphysiodesis was performed using figure-of-eight plates and screws, and distal tibial medial hemiepiphysiodesis with cannulated screws. Preoperative and postoperative lateral distal femoral angle, medial proximal tibial angle, and lateral distal tibial angle were measured. Frequency and descriptive statistics were completed. RESULTS: Eighteen patients with OI (five-I, four-III, six-IV, three-V) underwent 33 guided growth procedures with mean follow-up of 3.09 years; all received routine bisphosphonate treatment. Preoperative and postoperative mean joint angles were measured. The location for hemiepiphysiodesis included 8 distal femoral medial, 2 distal femoral lateral, 8 proximal tibial medial, 3 proximal tibial lateral, and 12 distal tibial medial. Twelve of the 33 procedures were in patients who had an intramedullary rod; 1 demonstrated backout of the epiphyseal and metaphyseal screws of a distal femoral medial figure-of-eight plate. It was revised to a larger plate with longer screws and removed upon completion of deformity correction. CONCLUSION: Guided growth may be used as an effective means of angular deformity correction with dysplastic OI bone. Having an intramedullary rod did not preclude the use of a guided growth technique. One procedure demonstrated screw backout. Given the short stature associated with OI, performing a guided growth procedure at an early enough age to allow time for correction should be considered. LEVEL OF EVIDENCE: Level IV-case series.

Outcomes of Pediatric Osteogenesis Imperfecta Patients Requiring Port-a-Cath Placement for Long-Term Vascular Access.

Intravenous (iv) bisphosphonates are widely used to treat the skeletal manifestations of osteogenesis imperfecta (OI). Obtaining peripheral iv access in pediatric patients with OI is often difficult and traumatic. Although this may be mitigated with surgically placed iv ports (port-a-caths), surgeons may be hesitant to perform this procedure on these children because of the lack of safety data. This study aims to gain better insight into the safety and efficacy of port-a-cath use in this population and identify risk factors for port-a-cath complications. In the present study, we conducted a retrospective cohort analysis of patient characteristics and the incidence of port-a-cath-related complications in children with OI. Fifty-three port-a-caths were placed in 29 children (21 males and 8 females). Of the 29 patients, most are OI type III (n = 18), followed by type I (n = 4), type IV (n = 4), and type V (n = 3). At the time of initial port-a-cath placement, the median age was 52 months (10-191 months), and the median weight was 7.9 kg (5.1-41.1 kg). Most patients (n = 20) weighed less than 10 kg during initial placement. Weight correlated significantly with OI type (p = 0.048), sex (p = 0.03), and vessel used (p = 0.02). Median initial port-a-cath longevity was 43 months (1-113 months), and we found no significant difference in port-a-cath longevity between sexes, OI types, or vessels used. Most patients (n = 19) required multiple port-a-cath placements. There is a significant difference (p = 0.02) between the number of placements and OI type, with type IV having more than type III. Port-a-cath removal was almost always due to mechanical complications (n = 19) but also for infection (n = 1) and malposition (n = 1). Eight patients still had their initial port-a-caths in place at the conclusion of this study. These findings indicate that complications associated with port-a-cath placement are mild and can be used to safely deliver iv bisphosphonates to pediatric OI patients. © 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

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.