RARE DISEASE
Congenital pseudoarthrosis of the tibia
Congenital pseudoarthrosis of the tibia
Congenital pseudoarthrosis of the tibia
Synonyms: Congenital pseudarthrosis of the tibia
Synonyms: Congenital pseudarthrosis of the tibia
Synonyms: Congenital pseudarthrosis of the tibia
Drug discovery
1
drug
With orphan designation
Overview
Congenital pseudoarthrosis of the tibia (CPT) is a rare pediatric bone disorder characterized by anterolateral bowing and spontaneous nonunion of the tibia, often progressing to refractory fractures. Pathogenesis involves abnormal periosteal function, fibrous hamartoma formation, and disrupted bone metabolism, with 50-80% linked to neurofibromatosis type 1. Treatment focuses on achieving bone union while addressing deformities, limb-length discrepancies, and recurrent fractures through multimodal surgical approaches [1][8][15].
Therapies
Surgical: Excision of pseudarthrosis with bone grafting (autograft/vascularized fibular), Ilizarov external fixation [3][15], intramedullary rods [4][13], and cross-union techniques [13].
Adjuncts: Perioperative bisphosphonates, BMP [4][15], and biological augmentation (periosteal grafts [13]).
Salvage: Amputation considered after ≥3 failed surgeries [1][4].
Categories: rare bone diseases, rare developmental anomalies during embryogenesis, rare genetic diseases
Research Papers
372 drug discovery papers about Congenital pseudoarthrosis of the tibia, with 2 first-in-class and 1 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
372 drug discovery papers about Congenital pseudoarthrosis of the tibia, with 2 first-in-class and 1 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
cell therapies
2026-02-05 | Reconstruction With the Contralateral Fibula for Isolated Congenital Pseudarthrosis of the Fibula.
Congenital pseudarthrosis of the tibia (CPT) remains one of the most challenging conditions to manage in pediatric orthopedics. Fibular pseudarthrosis, often associated with CPT, is similarly resistant to treatment. In contrast, isolated congenital pseudarthrosis of the fibula (ICPF) is a rare condition for which no standardized treatment has been established. Here, we report four pediatric cases of ICPF treated with a novel reconstruction technique using the contralateral fibula. All patients achieved bony union at the pseudarthrotic lesion of the affected fibula. The donor sites of the contralateral fibula were reconstructed with β-tricalcium phosphate blocks. No fractures occurred at the reconstructed sites, and no recurrence of pseudarthrosis was observed. At final follow-up, which corresponded to skeletal maturity, all patients demonstrated mild ankle deformity on radiographs but no functional impairment.
2025-09-27 | An Autologous Human Adipose Stem Cell-Derived 3D Osteogenic Implant for Bone Grafting: From Development to First-in-Human Experience.
Background: NVD003 is an autologous, adipose tissue-derived stem cell-based tissue-engineered bone graft substitute with pro-osteogenic, anti-resorptive, and pro-angiogenic properties. Here, we describe highlights from the NVD003 preclinical development program as well as early clinical experience. Methods: NVD003 is produced in a Good Manufacturing Practice-controlled process from adipose stem cells collected during a minimally invasive liposuction procedure. The final implant is a ready-to-use moldable putty with fixed mineral content and predefined physiologic ranges of osteogenic cells and bioactive growth factors. Preclinical pharmacology studies were conducted in nude rats using a paravertebral implantation model, and subsequently, in a femoral critical-sized bone defect (CSBD) model. In a first-in-human Phase 1b/2a study, NVD003 was used for fracture osteosynthesis with classical fixation material in nine adults with recalcitrant lower limb non-union. NVD003 was also used at the discretion of treating physicians in four pediatric patients surgically treated for congenital pseudarthrosis of the tibia (CPT) with the Masquelet technique. Efficacy was evaluated as clinical healing and in terms of bone formation, bone union, and bone remodeling on radiographs and computed tomography using the extended Lane and Sandhu Scale. Results: Preclinical studies indicated that NVD003 requires cellularity for its bioactivity and moreover facilitates bone union when used as a graft material in femoral CSBD. In the clinical study, nine adult participants were successfully grafted with NVD003 and completed study follow-up to 24 months, with extended safety follow-up to 5 years ongoing. No adverse events were considered related to NVD003. Maximal bone formation occurred between 3 and 12 months post-implantation; the mean time to clinical healing was 6 months and the mean time to radiological union was 17 months. Ultimately, 89% (8/9) of patients achieved bone union without refracture. All four pediatric patients with CPT also achieved lasting bone union following grafting with NVD003. No safety signals were observed over a mean follow-up of 62.1 months. Conclusions: NVD003 represents a safe, autologous bone graft substitute product without side effects of heterotopic ossification or bone resorption. NVD003 facilitated bone union in adult and pediatric patients even under severe pathophysiological conditions.
2025-02-24 | Vascularized Deep Femoral Periosteal Flap: Anatomical Study and Clinical Application in Congenital Pseudarthrosis of the Tibia in Two Cases.
Vascularized periosteal transplants have proven to be highly effective and rapid in promoting bone healing in biologically complex nonunions in children, with several reported donor sites. This study aimed to assess the feasibility of harvesting a vascularized diaphyseal femoral periosteal flap (VDFPF) from cadavers and evaluate its clinical application in two cases of bilateral congenital pseudarthrosis of the tibia. This study investigated the periosteal branches of the deep femoral vessels (DFV) supplying the femoral diaphysis in 19 previously latex-injected cadavers. The femur was divided into four segments. The distance from the midpoint of the inguinal ligament to the origin of the DFV and the number of periosteal branches were recorded. The vascularized diaphyseal femoral periosteal flap (VDFPF) was used to treat one side in two patients with bilateral congenital pseudarthrosis of the tibia (aged 14 and 2 years). The DFV's origin was located at a mean of 4.2 cm (range 2.8-8.5 cm) distal to the midpoint of the inguinal ligament. In 15 cases, the DFV coursed adjacent to the second and third quarters of the femoral shaft, providing a mean number of 5 (range 4-8) periosteal branches, allowing for the harvesting of a new pure vascularized periosteal flap. Healing of congenital pseudarthrosis of the tibia occurred within 3 months in both patients, with no donor or recipient site complications at the final follow-up of 13 months. The VDFPF may be an effective periosteal transplant and a viable alternative to other large free periosteal transplants used in children for treating complex non-unions, especially when tibial and fibular donors are not available. Bone union was fast compared to other techniques used to treat these challenging cases.
2025-01-15 | Vascularized Periosteal Grafts for Bone Union in Children: A Systematic Review.
The periosteum is the main organ responsible for bone regeneration. Vascularized Periosteal Grafts (VPG) have demonstrated exceptional efficacy and speed in facilitating bone union among children with challenging bone healing conditions. Despite their promising results, the overall impact of these interventions has yet to be comprehensively evaluated through systematic review. This systematic review aimed to provide comprehensive insights into bone union outcomes and complications related to the use of VPG in children. MEDLINE/PubMed, Embase, Web of Science, Clinicaltrials.gov, and Cochrane Library were searched from database inception to September 2023 and screened for relevant studies. Data were collected regarding patient demographics, disease, treatment, anatomical location, graft used, donor and receptor vessels, skin paddle monitoring, follow-up duration, time to union, consolidation, and complications. The correlation between age and bone union was assessed using Pearson and Spearman correlation coefficients, as appropriate. Study quality was assessed using the Methodological Index for Non-randomized Studies Criteria. A total of 15 studies involving 135 patients were included. All the studies were classified as Level 4 evidence. The mean MINORS score was 5.1 ± 1. The aim of the VPG was nonunion treatment in 90 patients (67%), nonunion prevention in 35 patients (26%), and bone union acceleration in 10 patients (7%). The origin of the bone union problem was traumatic in 59 cases (44%), congenital pseudoarthrosis of the tibia or fibula in 48 patients (35%), oncologic in 23 patients (17%), and infectious in 5 patients (4%). Nine different sources of periosteal flaps were used to enhance bone union. Bone union rate was 96% with a mean time of 4.2 months (range 1-18 months). Spearman test showed a non-statistically significant negative correlation between age and bone union time (r = -0.3, p = 0.759). VPGs are a safe and reliable treatment for promoting bone union, especially in the context of complex pediatric bone-healing challenges.
2024-10-01 | Reconstruction of bone defects around the ankle with retrograde gentamicin-coated tibial intramedullary nail (ETN PROtect™) for tibiotalocalcaneal arthrodesis: a case series.
The objective of this study was to describe the use of retrograde gentamicin-coated tibial intramedullary nail (ETN PROtect™) in patients with tibial defects who required a tibiotalocalcaneal arthrodesis (TTC). Consecutive series case review of seven men treated with TTC using retrograde PROtect™ between January 2018 and December 2023. The main outcomes evaluated were fracture union, complications, and the health-related quality of life using the EuroQol five-dimension three-level questionnaire (EQ-5D-3L). The mean age was 45.3 ± 8.0 years. Six patients had a clinical history of chronic osteomyelitis, and one case underwent TTC for congenital pseudoarthrosis. Fracture union was achieved in 5 of 7 patients between 4 and 11 months after surgery. Three patients developed complications; two patients had fistulas, and one had persistent pain. At the end of the follow-up, a median of 70 points (interquartile range: 60 to 90) on the EQ-5D-3L was reported. No complications directly attributed to the use of the PROtect™ were reported. TTC with retrograde PROtect™ is a prophylactic treatment option in patients with tibial defects treated with external fixation requiring a tibiotalar and subtalar arthrodesis. This novel use of PROtect™ allows simultaneous fixation of the tibiotalocalcaneal joint and protection of the regenerated bone, facilitating earlier rehabilitation in patients at high risk for postoperative infections.
proteins
2024-12-10 | Efficacy of the Cross-Union Protocol in the Treatment of Congenital Tibial Pseudarthrosis: A Comparative Study
Background Congenital Pseudarthrosis of the Tibia (CPT) is a rare pediatric condition presenting substantial challenges for orthopedic surgeons aiming to achieve bone union, with subsequent complications such as refractures being common. The aim of the present study is to evaluate the results of our intentional cross-union protocol and to compare these outcomes with those obtained from our previously used techniques. Materials and Methods Sixteen patients, with a mean age of 4.8 years (range: 1-13.3 years), who were treated with the intentional cross-union protocol were included in Group A. Eleven patients, with a mean age of 3.5 years (range: 1.3-7.6 years), who primarily underwent intramedullary rodding with bone graft, were included in Group B. The intentional cross-union protocol involved cross-union of the tibia and fibula, autogenous iliac bone grafting, and the insertion of bone morphogenetic protein 2 (BMP-2) aimed at achieving tibia-fibula cross-union. Retrospective evaluation of serial radiographs was conducted, and the outcomes regarding union and any subsequent complications were analyzed. Results A total of 27 patients with CPT were included in the study. All 16 patients (100%) in Group A successfully achieved primary union. Among the 11 patients in Group B, only 4 cases achieved primary union, with a primary healing rate of 36.4%. Seven cases with delayed healing required 2-4 revision surgeries for final healing. The time to union was significantly shorter in Group A (3.37 ± 0.64 months) compared to Group B (8.67 ± 3.0 months). The cross-sectional area of union was also significantly larger in Group A (6.71 ± 0.58 cm²) compared to Group B (1.18 ± 0.19 cm²). In Group A, there were no cases of refracture, whereas in Group B, 7 cases (77.8%) experienced refracture, indicating a statistically significant difference. Conclusions Our study demonstrates that the Cross-union protocol is highly effective for achieving union and preventing refracture in CPT. With such significant improvement, it has notably altered the prognosis of this challenging condition. Level of Evidence: IV
2022-04-04 | Congenital Pseudarthrosis of the Tibia Associated With Cleidocranial Dysostosis: Case Report and Literature Review.
We describe a case of 2 individually rare diseases existing comorbidly in the form of congenital pseudarthrosis of the tibia (CPT) coincident with cleidocranial dysostosis and provide a review of the literature, including the sole preexisting documented coincidence. Understanding, treatment, and surgical protocol of CPT have changed considerably since this comorbidity was last reported. Updates include synostosis, periosteal grafting, the use of bone morphogenetic protein, and bisphosphonates. Our case varies from the previous in associated disorder and family history. The relationship between CBFA1 and RUNX2 genes may hold the key, but further study is needed.
2019-06-22 | Management of Congenital Pseudoarthrosis of the Tibia and Fibula
Congenital pseudoarthrosis of the tibia and fibula are rare conditions that share common treatment strategies. The purpose of this review is to provide an overview of the recent developments in treatments for both conditions. Recent literature has focused on the use of BMP and on gait analysis as a tool for measuring long-term functional outcomes. Recent study has indicated rhBMP-2 may shorten the time to initial healing of pseudoarthroses, but not guarantee bony union. Children with initial fractures before the age of four have been shown to have long-term gait outcomes that may be ultimately comparable to children with prostheses. Both congenital pseudoarthrosis of the tibia and fibula are challenging conditions to treat, which require comprehensive approaches to account for both the biological and mechanical components of the conditions.
2018-04-01 | rhBMP-2 and Intramedullary Fixation in Congenital Pseudarthrosis of the Tibia
Background: In congenital pseudarthrosis of the tibia, use of intramedullary (IM) fixation and autogenous bone graft has long been the standard of care. This study was undertaken to determine whether the addition of rhBMP-2 to this treatment method further enhances healing potential. Methods: Twenty-one patients with congenital pseudarthrosis of the tibia were evaluated. Fifteen of these patients had neurofibromatosis type 1 (NF1). All had IM fixation and autogenous bone graft, followed by a BMP-soaked collagen sponge wrapped around both the fracture site and bone graft. A minimum 2 years’ follow-up was required. Results: Follow-up averaged 7.2 years (range, 2.1 to 12.8 y). Sixteen of 21 tibias achieved bone union following the index surgery, at an average 6.6 months postoperatively. The 5 persistent nonunions occurred in NF1 patients. Further surgery was undertaken in these 5 NF1 patients, including the use of BMP. One of the 5 healed, 1 had persistent nonunion, and 3 eventually had amputation. Of the 16 patients who healed initially following the index surgery, 5 refractured (3 had NF1). Of these 5 patients, the IM fixation at the index surgery did not cross the ankle joint, and refracture occurred at the rod tip in 4. Three of these 5 patients healed following further surgery, 1 had persistent nonunion, and 1 had amputation. All of those with eventual amputation had NF1. No deleterious effects related to the use of BMP-2 were recognized in any patient. Conclusions: The addition of rhBMP-2 appears to be helpful in shortening the time required to achieve fracture union in those who healed, but its use does not insure that healing will occur. Level of Evidence: Level IV—therapeutic, case series.
2018-01-31 | In silico clinical trials for pediatric orphan diseases
Abstract To date poor treatment options are available for patients with congenital pseudarthrosis of the tibia (CPT), a pediatric orphan disease. In this study we have performed an in silico clinical trial on 200 virtual subjects, generated from a previously established model of murine bone regeneration, to tackle the challenges associated with the small, pediatric patient population. Each virtual subject was simulated to receive no treatment and bone morphogenetic protein (BMP) treatment. We have shown that the degree of severity of CPT is significantly reduced with BMP treatment, although the effect is highly subject-specific. Using machine learning techniques we were also able to stratify the virtual subject population in adverse responders, non-responders, responders and asymptomatic. In summary, this study shows the potential of in silico medicine technologies as well as their implications for other orphan diseases.
small molecules
2025-05-04 | Pamidronate regulates the osteogenic differentiation of periosteal-derived mesenchymal stem cells in congenital tibial pseudarthrosis via OPG/RANKL.
Congenital pseudarthrosis of the tibia (CPT) is one of the most challenging conditions in orthopedics. Previous research indicates a strong association between CPT and neurofibromatosis type 1 (NF1). The clinical application of pamidronate has demonstrated efficacy in enhancing bone healing and alleviating NF1-associated bone pathology in specific CPT cases. Nevertheless, the precise mechanistic basis for these therapeutic effects remains poorly characterized, warranting further investigation. In this study, mesenchymal stem cells (MSCs) were isolated from patients with congenital pseudarthrosis of the tibia (CPT MSCs) and from patients undergoing corrective osteotomy (control group). We examined cell conditions post-treatment with pamidronate disodium at concentrations of 0 nM, 10 nM, 100 nM, and 1 μM, evaluating proliferation, toxicity, and differentiation potential, while investigating its effects on the OPG/RANKL pathway. Additionally, we analyzed the alterations in mitogen-activated protein kinase signaling and its correlation with the regulatory expression of OPG/RANKL genes. This study demonstrated that the proliferation and osteogenic differentiation of CPT MSCs were significantly lower than those of the control group. Treatment with pamidronate disodium enhanced both proliferation and osteogenic differentiation in CPT MSCs. Furthermore, pamidronate disodium treatment decreased RANKL expression and increased OPG protein levels in CPT MSCs, activating p38 and ERK1/2 signaling pathways. Notably, the co-administration of p38 or ERK1/2 inhibitors significantly diminished the proliferation and osteogenic differentiation of CPT MSCs treated with pamidronate disodium. Pamiphosphonate disodium can promote the proliferation and osteogenic differentiation of CPT MSCs by activating p38 and ERK1/2 signaling.
2025-03-20 | The role of bisphosphonate and bone morphogenetic proteins in congenital pseudoarthrosis of the tibia management: a literature review
Congenital pseudoarthrosis of the tibia (CPT) is a rare medical condition characterized by a congenital absence of union in the tibia, which causes the leg to flex anterolaterally. Despite the use of several surgical techniques for the treatment of CPT, there is still a significant risk of failure with surgical interventions. Recent studies have shown that bisphosphonates (BP) and bone morphogenetic proteins (BMP) can be effective adjuncts to surgical procedures, increasing the success rate of bone union and reducing the chance of re-fracture. This review aimed to evaluate the role of BP and BMP in CPT. In this review, a comprehensive literature evaluation was conducted using the PRISMA method. The databases used to search for information included PubMed, ScienceDirect, and Google Scholar for the past 10 years. Six articles were included in this review. The results showed that using pharmacological agents such as BMP and BP is considered safe for pediatric patients as an adjunctive treatment to surgery. This combination can effectively increase the speed of bone union and prevent re-fractures. The small sample size, different protocols, and different doses may have impacted the study results, which should be thoroughly explained.
2024-06-26 | MEK-SHP2 inhibition prevents tibial pseudarthrosis caused by NF1 loss in Schwann cells and skeletal stem/progenitor cells.
Congenital pseudarthrosis of the tibia (CPT) is a severe pathology marked by spontaneous bone fractures that fail to heal, leading to fibrous nonunion. Half of patients with CPT are affected by the multisystemic genetic disorder neurofibromatosis type 1 (NF1) caused by mutations in the NF1 tumor suppressor gene, a negative regulator of RAS-mitogen-activated protein kinase (MAPK) signaling pathway. Here, we analyzed patients with CPT and Prss56-Nf1 knockout mice to elucidate the pathogenic mechanisms of CPT-related fibrous nonunion and explored a pharmacological approach to treat CPT. We identified NF1-deficient Schwann cells and skeletal stem/progenitor cells (SSPCs) in pathological periosteum as affected cell types driving fibrosis. Whereas NF1-deficient SSPCs adopted a fibrotic fate, NF1-deficient Schwann cells produced critical paracrine factors including transforming growth factor-β and induced fibrotic differentiation of wild-type SSPCs. To counteract the elevated RAS-MAPK signaling in both NF1-deficient Schwann cells and SSPCs, we used MAPK kinase (MEK) and Src homology 2 containing protein tyrosine phosphatase 2 (SHP2) inhibitors. Combined MEK-SHP2 inhibition in vivo prevented fibrous nonunion in the Prss56-Nf1 knockout mouse model, providing a promising therapeutic strategy for the treatment of fibrous nonunion in CPT.
2023-04-17 | Management of congenital pseudoarthrosis using Ilizarov Device-Delsuth, oghara experience.
Congenital pseudoarthrosis of the tibia (CPT) is a rare and very difficult pediatric orthopedic condition to manage. It occurs spontaneously or from a trivial trauma. It results from a dysplastic periosteum that is more osteoclastic and less osteoblastic in nature. Successful treatment targets excision of the dysplastic periosteum and replacement with viable one and bone graft ± bone morphogenic proteins to aid union. Stabilization of the union site with intramedullary implants is advised to prevent refracture. To highlight the outcome of treatment of CPT with the Ilizarov procedure, bone graft, and use of bisphosphonate (sodium alendronate). This is a retrospective study of five patients treated for CPT using the Ilizarov procedure, bone graft, and use of bisphosphonate in the Delta State University Teaching Hospital, Oghara in Delta State, Nigeria. Inclusion criteria were patients that had a fracture of the tibia ± fibula spontaneously or from minor trauma. Exclusion criteria were patients that had pathological fractures or fractures from significant trauma. The outcome was graded into good, fair and poor. Five patients were seen in this study. The male/female ratio was 2:3. The age was 6-18 years (mean = 11.5 years). The limb length discrepancy was 6-12 cm (mean = 7.2 cm) pre-operation and zero after completion of distraction. There was the loss of some regeneration in two patients at the end of consolidation. Two patients had hypertrophic CPT, while three patients had atrophic. Union was good in four and fair in one. Complications seen were ankle stiffness bending of the regenerate and loss of length of regenerate. CPT is a rare condition worldwide that is associated with non-union and complicated by post-operation refracture or non-union has been successfully treated with a procedure that entails use of Ilizarov technique, bone graft bisphosphonate and support with intramedullary nails.
2022-04-28 | Overview of Physical and Pharmacological Therapy in Enhancing Bone Regeneration Formation During Distraction Osteogenesis
Distraction osteogenesis (DO) is a kind of bone regeneration technology. The principle is to incise the cortical bone and apply continuous and stable distraction force to the fractured end of the cortical bone, thereby promoting the proliferation of osteoblastic cells in the tension microenvironment and stimulating new bone formation. However, the long consolidation course of DO presumably lead to several complications such as infection, fracture, scar formation, delayed union and malunion. Therefore, it is of clinical significance to reduce the long treatment duration. The current treatment strategy to promote osteogenesis in DO includes gene, growth factor, stem-cell, physical and pharmacological therapies. Among these methods, pharmacological and physical therapies are considered as safe, economical, convenience and effective. Recently, several physical and pharmacological therapies have been demonstrated with a decent ability to enhance bone regeneration during DO. In this review, we have comprehensively summarized the latest evidence for physical (Photonic, Waves, Gas, Mechanical, Electrical and Electromagnetic stimulation) and pharmacological (Bisphosphonates, Hormone, Metal compounds, Biologics, Chinese medicine, etc) therapies in DO. These evidences will bring novel and significant information for the bone healing during DO in the future.
gene therapies
2024-05-31 | METTL3 promotes the osteogenic differentiation of periosteum-derived MSCs via regulation of the HOXD8/ITGA5 axis in congenital pseudarthrosis.
Congenital pseudarthrosis of the tibia (CPT) is a dominant health challenge in pediatric orthopedics. The essential process in the development of CPT is the limited capacity of mesenchymal stem cells (MSCs) derived from CPT to undergo osteogenic differentiation. Our research aimed to elucidate the role and mechanism of methyltransferase-like 3 (METTL3) in the osteogenic differentiation process of CPT MSCs. The osteogenic differentiation medium was used to culture MSCs, and the detection of osteogenic differentiation was performed using Alizarin Red S and alkaline phosphatase (ALP) assays. Gene or protein expression was assessed by quantitative real-time polymerase chain reaction (qRT-PCR), Western blot, or immunofluorescence (IF) staining. The m6A modification of Homeobox D8 (HOXD8) was verified by methylated RNA immunoprecipitation (MeRIP) assay. Interactions between METTL3 and HOXD8 or HOXD8 and integrin alpha 5 (ITGA5) promoter were validated by the luciferase reporter gene, RIP, and chromatin immunoprecipitation (ChIP) assays. METTL3 overexpression enhanced CPT MSCs' osteogenic differentiation. METTL3 stabilized the HOXD8 in an m6A-dependent manner. Moreover, the overexpressed ITGA5 up-regulated the CPT MSCs' osteogenic differentiation. Further, HOXD8 could transcriptionally activate ITGA5. METTL3 increased the transcription of ITGA5 via HOXD8 to enhance the osteogenic differentiation of CPT MSCs. METTL3 promoted osteogenic differentiation via modulating the HOXD8/ITGA5 axis in CPT MSCs.
cell therapies
2026-02-05 | Reconstruction With the Contralateral Fibula for Isolated Congenital Pseudarthrosis of the Fibula.
Congenital pseudarthrosis of the tibia (CPT) remains one of the most challenging conditions to manage in pediatric orthopedics. Fibular pseudarthrosis, often associated with CPT, is similarly resistant to treatment. In contrast, isolated congenital pseudarthrosis of the fibula (ICPF) is a rare condition for which no standardized treatment has been established. Here, we report four pediatric cases of ICPF treated with a novel reconstruction technique using the contralateral fibula. All patients achieved bony union at the pseudarthrotic lesion of the affected fibula. The donor sites of the contralateral fibula were reconstructed with β-tricalcium phosphate blocks. No fractures occurred at the reconstructed sites, and no recurrence of pseudarthrosis was observed. At final follow-up, which corresponded to skeletal maturity, all patients demonstrated mild ankle deformity on radiographs but no functional impairment.
2025-09-27 | An Autologous Human Adipose Stem Cell-Derived 3D Osteogenic Implant for Bone Grafting: From Development to First-in-Human Experience.
Background: NVD003 is an autologous, adipose tissue-derived stem cell-based tissue-engineered bone graft substitute with pro-osteogenic, anti-resorptive, and pro-angiogenic properties. Here, we describe highlights from the NVD003 preclinical development program as well as early clinical experience. Methods: NVD003 is produced in a Good Manufacturing Practice-controlled process from adipose stem cells collected during a minimally invasive liposuction procedure. The final implant is a ready-to-use moldable putty with fixed mineral content and predefined physiologic ranges of osteogenic cells and bioactive growth factors. Preclinical pharmacology studies were conducted in nude rats using a paravertebral implantation model, and subsequently, in a femoral critical-sized bone defect (CSBD) model. In a first-in-human Phase 1b/2a study, NVD003 was used for fracture osteosynthesis with classical fixation material in nine adults with recalcitrant lower limb non-union. NVD003 was also used at the discretion of treating physicians in four pediatric patients surgically treated for congenital pseudarthrosis of the tibia (CPT) with the Masquelet technique. Efficacy was evaluated as clinical healing and in terms of bone formation, bone union, and bone remodeling on radiographs and computed tomography using the extended Lane and Sandhu Scale. Results: Preclinical studies indicated that NVD003 requires cellularity for its bioactivity and moreover facilitates bone union when used as a graft material in femoral CSBD. In the clinical study, nine adult participants were successfully grafted with NVD003 and completed study follow-up to 24 months, with extended safety follow-up to 5 years ongoing. No adverse events were considered related to NVD003. Maximal bone formation occurred between 3 and 12 months post-implantation; the mean time to clinical healing was 6 months and the mean time to radiological union was 17 months. Ultimately, 89% (8/9) of patients achieved bone union without refracture. All four pediatric patients with CPT also achieved lasting bone union following grafting with NVD003. No safety signals were observed over a mean follow-up of 62.1 months. Conclusions: NVD003 represents a safe, autologous bone graft substitute product without side effects of heterotopic ossification or bone resorption. NVD003 facilitated bone union in adult and pediatric patients even under severe pathophysiological conditions.
2025-02-24 | Vascularized Deep Femoral Periosteal Flap: Anatomical Study and Clinical Application in Congenital Pseudarthrosis of the Tibia in Two Cases.
Vascularized periosteal transplants have proven to be highly effective and rapid in promoting bone healing in biologically complex nonunions in children, with several reported donor sites. This study aimed to assess the feasibility of harvesting a vascularized diaphyseal femoral periosteal flap (VDFPF) from cadavers and evaluate its clinical application in two cases of bilateral congenital pseudarthrosis of the tibia. This study investigated the periosteal branches of the deep femoral vessels (DFV) supplying the femoral diaphysis in 19 previously latex-injected cadavers. The femur was divided into four segments. The distance from the midpoint of the inguinal ligament to the origin of the DFV and the number of periosteal branches were recorded. The vascularized diaphyseal femoral periosteal flap (VDFPF) was used to treat one side in two patients with bilateral congenital pseudarthrosis of the tibia (aged 14 and 2 years). The DFV's origin was located at a mean of 4.2 cm (range 2.8-8.5 cm) distal to the midpoint of the inguinal ligament. In 15 cases, the DFV coursed adjacent to the second and third quarters of the femoral shaft, providing a mean number of 5 (range 4-8) periosteal branches, allowing for the harvesting of a new pure vascularized periosteal flap. Healing of congenital pseudarthrosis of the tibia occurred within 3 months in both patients, with no donor or recipient site complications at the final follow-up of 13 months. The VDFPF may be an effective periosteal transplant and a viable alternative to other large free periosteal transplants used in children for treating complex non-unions, especially when tibial and fibular donors are not available. Bone union was fast compared to other techniques used to treat these challenging cases.
2025-01-15 | Vascularized Periosteal Grafts for Bone Union in Children: A Systematic Review.
The periosteum is the main organ responsible for bone regeneration. Vascularized Periosteal Grafts (VPG) have demonstrated exceptional efficacy and speed in facilitating bone union among children with challenging bone healing conditions. Despite their promising results, the overall impact of these interventions has yet to be comprehensively evaluated through systematic review. This systematic review aimed to provide comprehensive insights into bone union outcomes and complications related to the use of VPG in children. MEDLINE/PubMed, Embase, Web of Science, Clinicaltrials.gov, and Cochrane Library were searched from database inception to September 2023 and screened for relevant studies. Data were collected regarding patient demographics, disease, treatment, anatomical location, graft used, donor and receptor vessels, skin paddle monitoring, follow-up duration, time to union, consolidation, and complications. The correlation between age and bone union was assessed using Pearson and Spearman correlation coefficients, as appropriate. Study quality was assessed using the Methodological Index for Non-randomized Studies Criteria. A total of 15 studies involving 135 patients were included. All the studies were classified as Level 4 evidence. The mean MINORS score was 5.1 ± 1. The aim of the VPG was nonunion treatment in 90 patients (67%), nonunion prevention in 35 patients (26%), and bone union acceleration in 10 patients (7%). The origin of the bone union problem was traumatic in 59 cases (44%), congenital pseudoarthrosis of the tibia or fibula in 48 patients (35%), oncologic in 23 patients (17%), and infectious in 5 patients (4%). Nine different sources of periosteal flaps were used to enhance bone union. Bone union rate was 96% with a mean time of 4.2 months (range 1-18 months). Spearman test showed a non-statistically significant negative correlation between age and bone union time (r = -0.3, p = 0.759). VPGs are a safe and reliable treatment for promoting bone union, especially in the context of complex pediatric bone-healing challenges.
2024-10-01 | Reconstruction of bone defects around the ankle with retrograde gentamicin-coated tibial intramedullary nail (ETN PROtect™) for tibiotalocalcaneal arthrodesis: a case series.
The objective of this study was to describe the use of retrograde gentamicin-coated tibial intramedullary nail (ETN PROtect™) in patients with tibial defects who required a tibiotalocalcaneal arthrodesis (TTC). Consecutive series case review of seven men treated with TTC using retrograde PROtect™ between January 2018 and December 2023. The main outcomes evaluated were fracture union, complications, and the health-related quality of life using the EuroQol five-dimension three-level questionnaire (EQ-5D-3L). The mean age was 45.3 ± 8.0 years. Six patients had a clinical history of chronic osteomyelitis, and one case underwent TTC for congenital pseudoarthrosis. Fracture union was achieved in 5 of 7 patients between 4 and 11 months after surgery. Three patients developed complications; two patients had fistulas, and one had persistent pain. At the end of the follow-up, a median of 70 points (interquartile range: 60 to 90) on the EQ-5D-3L was reported. No complications directly attributed to the use of the PROtect™ were reported. TTC with retrograde PROtect™ is a prophylactic treatment option in patients with tibial defects treated with external fixation requiring a tibiotalar and subtalar arthrodesis. This novel use of PROtect™ allows simultaneous fixation of the tibiotalocalcaneal joint and protection of the regenerated bone, facilitating earlier rehabilitation in patients at high risk for postoperative infections.
proteins
2024-12-10 | Efficacy of the Cross-Union Protocol in the Treatment of Congenital Tibial Pseudarthrosis: A Comparative Study
Background Congenital Pseudarthrosis of the Tibia (CPT) is a rare pediatric condition presenting substantial challenges for orthopedic surgeons aiming to achieve bone union, with subsequent complications such as refractures being common. The aim of the present study is to evaluate the results of our intentional cross-union protocol and to compare these outcomes with those obtained from our previously used techniques. Materials and Methods Sixteen patients, with a mean age of 4.8 years (range: 1-13.3 years), who were treated with the intentional cross-union protocol were included in Group A. Eleven patients, with a mean age of 3.5 years (range: 1.3-7.6 years), who primarily underwent intramedullary rodding with bone graft, were included in Group B. The intentional cross-union protocol involved cross-union of the tibia and fibula, autogenous iliac bone grafting, and the insertion of bone morphogenetic protein 2 (BMP-2) aimed at achieving tibia-fibula cross-union. Retrospective evaluation of serial radiographs was conducted, and the outcomes regarding union and any subsequent complications were analyzed. Results A total of 27 patients with CPT were included in the study. All 16 patients (100%) in Group A successfully achieved primary union. Among the 11 patients in Group B, only 4 cases achieved primary union, with a primary healing rate of 36.4%. Seven cases with delayed healing required 2-4 revision surgeries for final healing. The time to union was significantly shorter in Group A (3.37 ± 0.64 months) compared to Group B (8.67 ± 3.0 months). The cross-sectional area of union was also significantly larger in Group A (6.71 ± 0.58 cm²) compared to Group B (1.18 ± 0.19 cm²). In Group A, there were no cases of refracture, whereas in Group B, 7 cases (77.8%) experienced refracture, indicating a statistically significant difference. Conclusions Our study demonstrates that the Cross-union protocol is highly effective for achieving union and preventing refracture in CPT. With such significant improvement, it has notably altered the prognosis of this challenging condition. Level of Evidence: IV
2022-04-04 | Congenital Pseudarthrosis of the Tibia Associated With Cleidocranial Dysostosis: Case Report and Literature Review.
We describe a case of 2 individually rare diseases existing comorbidly in the form of congenital pseudarthrosis of the tibia (CPT) coincident with cleidocranial dysostosis and provide a review of the literature, including the sole preexisting documented coincidence. Understanding, treatment, and surgical protocol of CPT have changed considerably since this comorbidity was last reported. Updates include synostosis, periosteal grafting, the use of bone morphogenetic protein, and bisphosphonates. Our case varies from the previous in associated disorder and family history. The relationship between CBFA1 and RUNX2 genes may hold the key, but further study is needed.
2019-06-22 | Management of Congenital Pseudoarthrosis of the Tibia and Fibula
Congenital pseudoarthrosis of the tibia and fibula are rare conditions that share common treatment strategies. The purpose of this review is to provide an overview of the recent developments in treatments for both conditions. Recent literature has focused on the use of BMP and on gait analysis as a tool for measuring long-term functional outcomes. Recent study has indicated rhBMP-2 may shorten the time to initial healing of pseudoarthroses, but not guarantee bony union. Children with initial fractures before the age of four have been shown to have long-term gait outcomes that may be ultimately comparable to children with prostheses. Both congenital pseudoarthrosis of the tibia and fibula are challenging conditions to treat, which require comprehensive approaches to account for both the biological and mechanical components of the conditions.
2018-04-01 | rhBMP-2 and Intramedullary Fixation in Congenital Pseudarthrosis of the Tibia
Background: In congenital pseudarthrosis of the tibia, use of intramedullary (IM) fixation and autogenous bone graft has long been the standard of care. This study was undertaken to determine whether the addition of rhBMP-2 to this treatment method further enhances healing potential. Methods: Twenty-one patients with congenital pseudarthrosis of the tibia were evaluated. Fifteen of these patients had neurofibromatosis type 1 (NF1). All had IM fixation and autogenous bone graft, followed by a BMP-soaked collagen sponge wrapped around both the fracture site and bone graft. A minimum 2 years’ follow-up was required. Results: Follow-up averaged 7.2 years (range, 2.1 to 12.8 y). Sixteen of 21 tibias achieved bone union following the index surgery, at an average 6.6 months postoperatively. The 5 persistent nonunions occurred in NF1 patients. Further surgery was undertaken in these 5 NF1 patients, including the use of BMP. One of the 5 healed, 1 had persistent nonunion, and 3 eventually had amputation. Of the 16 patients who healed initially following the index surgery, 5 refractured (3 had NF1). Of these 5 patients, the IM fixation at the index surgery did not cross the ankle joint, and refracture occurred at the rod tip in 4. Three of these 5 patients healed following further surgery, 1 had persistent nonunion, and 1 had amputation. All of those with eventual amputation had NF1. No deleterious effects related to the use of BMP-2 were recognized in any patient. Conclusions: The addition of rhBMP-2 appears to be helpful in shortening the time required to achieve fracture union in those who healed, but its use does not insure that healing will occur. Level of Evidence: Level IV—therapeutic, case series.
2018-01-31 | In silico clinical trials for pediatric orphan diseases
Abstract To date poor treatment options are available for patients with congenital pseudarthrosis of the tibia (CPT), a pediatric orphan disease. In this study we have performed an in silico clinical trial on 200 virtual subjects, generated from a previously established model of murine bone regeneration, to tackle the challenges associated with the small, pediatric patient population. Each virtual subject was simulated to receive no treatment and bone morphogenetic protein (BMP) treatment. We have shown that the degree of severity of CPT is significantly reduced with BMP treatment, although the effect is highly subject-specific. Using machine learning techniques we were also able to stratify the virtual subject population in adverse responders, non-responders, responders and asymptomatic. In summary, this study shows the potential of in silico medicine technologies as well as their implications for other orphan diseases.
small molecules
2025-05-04 | Pamidronate regulates the osteogenic differentiation of periosteal-derived mesenchymal stem cells in congenital tibial pseudarthrosis via OPG/RANKL.
Congenital pseudarthrosis of the tibia (CPT) is one of the most challenging conditions in orthopedics. Previous research indicates a strong association between CPT and neurofibromatosis type 1 (NF1). The clinical application of pamidronate has demonstrated efficacy in enhancing bone healing and alleviating NF1-associated bone pathology in specific CPT cases. Nevertheless, the precise mechanistic basis for these therapeutic effects remains poorly characterized, warranting further investigation. In this study, mesenchymal stem cells (MSCs) were isolated from patients with congenital pseudarthrosis of the tibia (CPT MSCs) and from patients undergoing corrective osteotomy (control group). We examined cell conditions post-treatment with pamidronate disodium at concentrations of 0 nM, 10 nM, 100 nM, and 1 μM, evaluating proliferation, toxicity, and differentiation potential, while investigating its effects on the OPG/RANKL pathway. Additionally, we analyzed the alterations in mitogen-activated protein kinase signaling and its correlation with the regulatory expression of OPG/RANKL genes. This study demonstrated that the proliferation and osteogenic differentiation of CPT MSCs were significantly lower than those of the control group. Treatment with pamidronate disodium enhanced both proliferation and osteogenic differentiation in CPT MSCs. Furthermore, pamidronate disodium treatment decreased RANKL expression and increased OPG protein levels in CPT MSCs, activating p38 and ERK1/2 signaling pathways. Notably, the co-administration of p38 or ERK1/2 inhibitors significantly diminished the proliferation and osteogenic differentiation of CPT MSCs treated with pamidronate disodium. Pamiphosphonate disodium can promote the proliferation and osteogenic differentiation of CPT MSCs by activating p38 and ERK1/2 signaling.
2025-03-20 | The role of bisphosphonate and bone morphogenetic proteins in congenital pseudoarthrosis of the tibia management: a literature review
Congenital pseudoarthrosis of the tibia (CPT) is a rare medical condition characterized by a congenital absence of union in the tibia, which causes the leg to flex anterolaterally. Despite the use of several surgical techniques for the treatment of CPT, there is still a significant risk of failure with surgical interventions. Recent studies have shown that bisphosphonates (BP) and bone morphogenetic proteins (BMP) can be effective adjuncts to surgical procedures, increasing the success rate of bone union and reducing the chance of re-fracture. This review aimed to evaluate the role of BP and BMP in CPT. In this review, a comprehensive literature evaluation was conducted using the PRISMA method. The databases used to search for information included PubMed, ScienceDirect, and Google Scholar for the past 10 years. Six articles were included in this review. The results showed that using pharmacological agents such as BMP and BP is considered safe for pediatric patients as an adjunctive treatment to surgery. This combination can effectively increase the speed of bone union and prevent re-fractures. The small sample size, different protocols, and different doses may have impacted the study results, which should be thoroughly explained.
2024-06-26 | MEK-SHP2 inhibition prevents tibial pseudarthrosis caused by NF1 loss in Schwann cells and skeletal stem/progenitor cells.
Congenital pseudarthrosis of the tibia (CPT) is a severe pathology marked by spontaneous bone fractures that fail to heal, leading to fibrous nonunion. Half of patients with CPT are affected by the multisystemic genetic disorder neurofibromatosis type 1 (NF1) caused by mutations in the NF1 tumor suppressor gene, a negative regulator of RAS-mitogen-activated protein kinase (MAPK) signaling pathway. Here, we analyzed patients with CPT and Prss56-Nf1 knockout mice to elucidate the pathogenic mechanisms of CPT-related fibrous nonunion and explored a pharmacological approach to treat CPT. We identified NF1-deficient Schwann cells and skeletal stem/progenitor cells (SSPCs) in pathological periosteum as affected cell types driving fibrosis. Whereas NF1-deficient SSPCs adopted a fibrotic fate, NF1-deficient Schwann cells produced critical paracrine factors including transforming growth factor-β and induced fibrotic differentiation of wild-type SSPCs. To counteract the elevated RAS-MAPK signaling in both NF1-deficient Schwann cells and SSPCs, we used MAPK kinase (MEK) and Src homology 2 containing protein tyrosine phosphatase 2 (SHP2) inhibitors. Combined MEK-SHP2 inhibition in vivo prevented fibrous nonunion in the Prss56-Nf1 knockout mouse model, providing a promising therapeutic strategy for the treatment of fibrous nonunion in CPT.
2023-04-17 | Management of congenital pseudoarthrosis using Ilizarov Device-Delsuth, oghara experience.
Congenital pseudoarthrosis of the tibia (CPT) is a rare and very difficult pediatric orthopedic condition to manage. It occurs spontaneously or from a trivial trauma. It results from a dysplastic periosteum that is more osteoclastic and less osteoblastic in nature. Successful treatment targets excision of the dysplastic periosteum and replacement with viable one and bone graft ± bone morphogenic proteins to aid union. Stabilization of the union site with intramedullary implants is advised to prevent refracture. To highlight the outcome of treatment of CPT with the Ilizarov procedure, bone graft, and use of bisphosphonate (sodium alendronate). This is a retrospective study of five patients treated for CPT using the Ilizarov procedure, bone graft, and use of bisphosphonate in the Delta State University Teaching Hospital, Oghara in Delta State, Nigeria. Inclusion criteria were patients that had a fracture of the tibia ± fibula spontaneously or from minor trauma. Exclusion criteria were patients that had pathological fractures or fractures from significant trauma. The outcome was graded into good, fair and poor. Five patients were seen in this study. The male/female ratio was 2:3. The age was 6-18 years (mean = 11.5 years). The limb length discrepancy was 6-12 cm (mean = 7.2 cm) pre-operation and zero after completion of distraction. There was the loss of some regeneration in two patients at the end of consolidation. Two patients had hypertrophic CPT, while three patients had atrophic. Union was good in four and fair in one. Complications seen were ankle stiffness bending of the regenerate and loss of length of regenerate. CPT is a rare condition worldwide that is associated with non-union and complicated by post-operation refracture or non-union has been successfully treated with a procedure that entails use of Ilizarov technique, bone graft bisphosphonate and support with intramedullary nails.
2022-04-28 | Overview of Physical and Pharmacological Therapy in Enhancing Bone Regeneration Formation During Distraction Osteogenesis
Distraction osteogenesis (DO) is a kind of bone regeneration technology. The principle is to incise the cortical bone and apply continuous and stable distraction force to the fractured end of the cortical bone, thereby promoting the proliferation of osteoblastic cells in the tension microenvironment and stimulating new bone formation. However, the long consolidation course of DO presumably lead to several complications such as infection, fracture, scar formation, delayed union and malunion. Therefore, it is of clinical significance to reduce the long treatment duration. The current treatment strategy to promote osteogenesis in DO includes gene, growth factor, stem-cell, physical and pharmacological therapies. Among these methods, pharmacological and physical therapies are considered as safe, economical, convenience and effective. Recently, several physical and pharmacological therapies have been demonstrated with a decent ability to enhance bone regeneration during DO. In this review, we have comprehensively summarized the latest evidence for physical (Photonic, Waves, Gas, Mechanical, Electrical and Electromagnetic stimulation) and pharmacological (Bisphosphonates, Hormone, Metal compounds, Biologics, Chinese medicine, etc) therapies in DO. These evidences will bring novel and significant information for the bone healing during DO in the future.
gene therapies
2024-05-31 | METTL3 promotes the osteogenic differentiation of periosteum-derived MSCs via regulation of the HOXD8/ITGA5 axis in congenital pseudarthrosis.
Congenital pseudarthrosis of the tibia (CPT) is a dominant health challenge in pediatric orthopedics. The essential process in the development of CPT is the limited capacity of mesenchymal stem cells (MSCs) derived from CPT to undergo osteogenic differentiation. Our research aimed to elucidate the role and mechanism of methyltransferase-like 3 (METTL3) in the osteogenic differentiation process of CPT MSCs. The osteogenic differentiation medium was used to culture MSCs, and the detection of osteogenic differentiation was performed using Alizarin Red S and alkaline phosphatase (ALP) assays. Gene or protein expression was assessed by quantitative real-time polymerase chain reaction (qRT-PCR), Western blot, or immunofluorescence (IF) staining. The m6A modification of Homeobox D8 (HOXD8) was verified by methylated RNA immunoprecipitation (MeRIP) assay. Interactions between METTL3 and HOXD8 or HOXD8 and integrin alpha 5 (ITGA5) promoter were validated by the luciferase reporter gene, RIP, and chromatin immunoprecipitation (ChIP) assays. METTL3 overexpression enhanced CPT MSCs' osteogenic differentiation. METTL3 stabilized the HOXD8 in an m6A-dependent manner. Moreover, the overexpressed ITGA5 up-regulated the CPT MSCs' osteogenic differentiation. Further, HOXD8 could transcriptionally activate ITGA5. METTL3 increased the transcription of ITGA5 via HOXD8 to enhance the osteogenic differentiation of CPT MSCs. METTL3 promoted osteogenic differentiation via modulating the HOXD8/ITGA5 axis in CPT MSCs.
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Drug Discovery Landscape
1 orphan drug designation for Congenital pseudoarthrosis of the tibia.
1 orphan drug designation for Congenital pseudoarthrosis of the tibia.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
autologous osteogenic cells cultured from adipose tissue derived stem cells embedded in extracellular matrix with demineralized bone matrix. | cell therapies | FDA | 2016-06-30 | — | Novadip Biosciences |
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