Epidemiology of long bone non-unions in Spain

Epidemiological and ecological studies on long bone non-unions (NU) are scarce, based on different populations and methodologies. The aim of this study was to produce a descriptive analysis of the femur, tibia, and humerus non-union epidemiology in Spain. Methods Data were obtained from the Minimum Basic Data (Conjunto Mínimo Básico de Datos, CMBD) Hospital Discharge Database of the Spanish Ministry of Health, according to the ICD9-CM coding for diagnoses and procedures, and from the National Institute of Statistics for population, generating secondary databases with the reported cases that included the code 733.82 in a disaggregated manner, by age (categorized in 5 intervals), gender, Spanish region, and calendar year (1997-2015). Percentage of non-unions related to fractures in the previous year, annual prevalence (expressed per 100,000 person-years) and period prevalence (expressed per 100,000 person-period) were calculated by age, gender, and Spanish regions. The Odds ratio (OR) was estimated with a confidence of 95% using a logistic regression model per anatomical site. Results A mean of 235,446 fractures in all locations were annually reported in Spain from 1997 to 2015. Regarding non-union of long bones (femur, tibia and humerus), a total of 37,053 cases were found, representing a yearly mean of 1,950 cases. The proportion of long bone fractures that evolved into a non-union was 4% (1.4% femur, 1.5% tibia, and 1% humerus). The mean annual prevalence rate of NU in Spain was estimated in 4.5 (3.7-4.9) cases per 100,000 persons-year. The overall NU prevalence in Spain was estimated in 86 cases per 100,000 persons. By the type of bone, the period prevalence (per 100,000 persons-period) of the femur NU was 31, of the tibia 33, and of the humerus 22. Conclusions This description of the epidemiology of long bone non-unions in Spain confirms that the overall non-union rate has been stable from 2000 to 2015, higher in the tibia and in the femur compared to the humerus. NU occurred more frequently in aged females than in males in the femur and the humerus, while the tibia non-unions were more frequent in males and younger ag

Implantation of autologous expanded mesenchymal stromal cells in hip osteonecrosis through percutaneous forage: Evaluation of the operative technique

Bone forage to treat early osteonecrosis of the femoral head (ONFH) has evolved as the channel to percutaneously deliver cell therapy into the femoral head. However, its efficacy is variable and the drivers towards higher efficacy are currently unknown. The aim of this study was to evaluate the forage technique and correlate it with the efficacy to heal ONFH in a multicentric, multinational clinical trial to implant autologous mesenchymal stromal cells expanded from bone marrow (BM‐hMSCs). Methods: In the context of EudraCT 2012‐002010‐39, patients with small and medium‐sized (mean volume = 13.3%, range: 5.4 to 32.2) ONFH stage II (Ficat, ARCO, Steinberg) C1 and C2 (Japanese Investigation Committee (JIC)) were treated with percutaneous forage and implantation of 140 million BM‐hMSCs in a standardized manner. Postoperative hip radiographs (AP—anteroposterior and lateral), and MRI sections (coronal and transverse) were retrospectively evaluated in 22 patients to assess the femoral head drilling orientation in both planes, and its relation to the necrotic area. Results: Treatment efficacy was similar in C1 and C2 (coronal plane) and in anterior to posterior (transverse plane) osteonecrotic lesions. The drill crossed the sclerotic rim in all cases. The forage was placed slightly valgus, at 139.3 ± 8.4 grades (range, 125.5–159.3) with higher dispersion (f = 2.6; p = 0.034) than the anatomical cervicodiaphyseal angle. Bonferroni’s correlation between both angles was 0.50 (p = 0.028). More failures were seen with a varus drill positioning, aiming at the central area of the femoral head, outside the weight‐bearing area (WBA) (p = 0.049). In the transverse plane, the anterior positioning of the drill did not result in better outcomes (p = 0.477). Conclusion: The forage drilling to deliver cells should be positioned within the WBA in the coronal plane, avoiding varus positioning, and central to anterior in the transverse plane. The efficacy of delivered MSCs to regenerate bone in ONFH could be influenced by the drilling direction. Standardization of this surgical technique is desirable.The research leading to these results has received funding from the European Research Council under the European Union’s Seventh Framework Programme (FP7/FP7-HEALTH-2009): REBORNE Project, Grant Agreement 24187

Defining the most effective patient blood management combined with tranexamic acid regime in primary uncemented total hip replacement surgery

The application of patient blood management (PBM) combined with tranexamic acid administration (TXA) results in decreased total blood loss volume (TVB) and transfusions in total hip replacements (THRs). Dosages, timing, and routes of administration of TXA are still under debate as all these aspects, as well as interpatient variations, may a ect the e cacy of the protocol. This study aims to examine the e ectiveness of timing and route of administration of TXA in combination with PBM by reducing the TBV following THR surgery. Consecutive primary uncemented THRs operated by a single surgical and anaesthetic team had the data prospectively collected and then retrospectively studied. Five treatment groups were formed, reflecting the progressive evolution of our protocol. Group 1 included patients managed with PBM alone (preoperative erythrocyte mass optimisation to at least 14 g/dL haemoglobin (Hb), hypotensive spinal anaesthesia and restrictive red blood cell transfusion criteria). Group 2 included patients with PBM and topical 3 g TXA diluted in normal saline to a total volume of 50 mL. Group 3 were patients with PBM and an IV dose of 20 mg/kg TXA at induction, followed by 20 mg/kg TXA as a continuous infusion for the duration of the operation. Group 4 consisted of patients managed as per Group 3 plus another 20 mg/kg TXA at three-hour post-procedure. Group 5 (combined): PBM and IV TXA as per Group 4 and topical TXA as per Group 2. A generalised linear model with the treatment group as an independent variable was modelled, using TBV as the dependent variable. The transfusion rate for all groups was 0%. TBV at 24 h, oscillated from 613.5 337.63 mL in Group 1 to 376.29 135.0 mL in Group 5. TBV at 48 h oscillated from 738.3 367.3 mL (PBM group) to 434 155.2 mL (PBM + combined group). The multivariate regression model confirmed a significant decrease of TBV in all groups with TXA compared with the PBM-only group. Overweight and preoperative Hb were confirmed to significantly influence TBV. The optimal regime to achieve the least TBV and a transfusion rate of 0% requires PBM and one loading 20 mg/kg dose of TXA, followed by continuous infusion of 20 mg/kg for the duration of the operation in uncemented THRs. Additional doses of TXA did not add a clear benefi

Osteonecrosis of the femoral head safely healed with autologous, expanded, bone marrow-derived mesenchymal stromal cells in a multicentric trial with minimum 5 years follow-up

Background: Osteonecrosis (ON) of the femoral head represents a potentially severe disease of the hip where the lack of bone regeneration may lead to femoral head collapse and secondary osteoarthritis, with serious pain and disability. The aim of this European, multicentric clinical trial was to prove safety and early efficacy to heal early femoral head ON in patients through minimally invasive surgical implantation of autologous mesenchymal stromal cells (MSC) expanded from bone marrow (BM) under good manufacturing practices (GMP). Methods: Twenty-two patients with femoral head ON (up to ARCO 2C) were recruited and surgically treated in France, Germany, Italy and Spain with BM-derived, expanded autologous MSC (total dose 140 million MSC in 7 mL). The investigational advanced therapy medicinal product (ATMP) was expanded from BM under the same protocol in all four countries and approved by each National Competent Authority. Patients were followed during two years for safety, based on adverse events, and for efficacy, based on clinical assessment (pain and hip score) and imaging (X-rays and MRIs). Patients were also reviewed after 5 to 6 years at latest follow-up for final outcome. Results: No severe adverse event was recalled as related to the ATMP. At 12 months, 16/20 per protocol and 16/22 under intention-to-treat (2 drop-out at 3 and 5 months) maintained head sphericity and showed bone regeneration. Of the 4 hips with ON progression, 3 required total hip replacement (THR). At 5 years, one patient (healed at 2 years visit) was not located, and 16/21 showed no progression or THR, 4/21 had received THR (all in the first year) and 1 had progressed one stage without THR. Conclusions: Expanded MSCs implantation was safe. Early efficacy was confirmed in 80% of cases under protocol at 2 years. At 5 years, the overall results were maintained and 19% converted to THR, all in the first yearThe research leading to these results has received funding from the European Research Council under the European Union’s Seventh Framework Programme (FP7/FP7-HEALTH-2009): REBORNE Project, Grant Agreement 241876. Work in EFS and stromalab was also supported by the Agence Nationale pour la Recherche for support of the national infrastructure: “ECELLFRANCE

Feasibility and safety of treating non-unions in tibia, femur and humerus with autologous, expanded, bone marrow-derived mesenchymal stromal cells associated with biphasic calcium phosphate biomaterials in a multicentric, non-comparative trial

Background: ORTHO-1 is a European, multicentric, first in human clinical trial to prove safety and feasibility after surgical implantation of commercially available biphasic calcium phosphate bioceramic granules associated during surgery with autologous mesenchymal stromal cells expanded from bone marrow (BM-hMSC) under good manufacturing practices, in patients with long bone pseudarthrosis. Methods: Twenty-eight patients with femur, tibia or humerus diaphyseal or metaphyso-diaphyseal non-unions were recruited and surgically treated in France, Germany, Italy and Spain with 100 or 200 million BM-hMSC/mL associated with 5–10 cc of bioceramic granules. Patients were followed up during one year. The investigational advanced therapy medicinal product (ATMP) was expanded under the same protocol in all four countries, and approved by each National Competent Authority. Findings: With safety as primary end-point, no severe adverse event was reported as related to the BM-hMSC. With feasibility as secondary end-point, the participating production centres manufactured the BM-hMSC as planned. The ATMP combined to the bioceramic was surgically delivered to the non-unions, and 26/28 treated patients were found radiologically healed at one year (3 out of 4 cortices with bone bridging). Interpretation: Safety and feasibility were clinically proven for surgical implantation of expanded autologous BM-hMSC with bioceramic. Funding: EU-FP7-HEALTH-2009, REBORNE Project (GA: 241876).The research leading to these results has received funding from the European Research Council under the European Union's Seventh Framework Programme (FP7/FP7-HEALTH-2009); REBORNE Project (GA: 241876

A Multicentric, Open-Label, Randomized, Comparative Clinical Trial of Two Different Doses of Expanded hBM-MSCs Plus Biomaterial versus Iliac Crest Autograft, for Bone Healing in Nonunions after Long Bone Fractures: Study Protocol

ORTHOUNION is a multicentre, open, comparative, three-arm, randomized clinical trial (EudraCT number 2015-000431-32) to compare the efficacy, at one and two years, of autologous human bone marrow-derived expanded mesenchymal stromal cell (hBM-MSC) treatments versus iliac crest autograft (ICA) to enhance bone healing in patients with diaphyseal and/or metaphysodiaphyseal fracture (femur, tibia, and humerus) status of atrophic or oligotrophic nonunion (more than 9 months after the acute fracture, including recalcitrant cases after failed treatments). The primary objective is to determine if the treatment with hBM-MSCs combined with biomaterial is superior to ICA in obtaining bone healing. If confirmed, a secondary objective is set to determine if the dose of 100 × 106 hBM-MSCs is noninferior to that of 200 × 106 hBM-MSCs. The participants (n = 108) will be randomly assigned to either the experimental low dose (n = 36), the experimental high dose (n = 36), or the comparator arm (n = 36) using a central randomization service. The trial will be conducted in 20 clinical centres in Spain, France, Germany, and Italy under the same clinical protocol. The confirmation of superiority for the proposed ATMP in nonunions may foster the future of bone regenerative medicine in this indication. On the contrary, absence of superiority may underline its limitations in clinical use

Volume and location of bone regeneration after autologous expanded mesenchymal stromal cells in hip osteonecrosis <subtitle>a pilot study</subtitle>

AimsSuccessful cell therapy in hip osteonecrosis (ON) may help to avoid ON progression or total hip arthroplasty (THA), but the achieved bone regeneration is unclear. The aim of this study was to evaluate amount and location of bone regeneration obtained after surgical injection of expanded autologous mesenchymal stromal cells from the bone marrow (BM-hMSCs).MethodsA total of 20 patients with small and medium-size symptomatic stage II femoral head ON treated with 140 million BM-hMSCs through percutaneous forage in the EudraCT 2012-002010-39 clinical trial were retrospectively evaluated through preoperative and postoperative (three and 12 months) MRI. Then, 3D reconstruction of the original lesion and the observed postoperative residual damage after bone regeneration were analyzed and compared per group based on treatment efficacy.ResultsThe mean preoperative lesion volume was 18.7% (SD 10.2%) of the femoral head. This reduced to 11.6% (SD 7.5%) after three months (p = 0.015) and 3.7% (SD 3%) after one year (p < 0.001). Bone regeneration in healed cases represented a mean 81.2% (SD 13.8%) of the initial lesion volume at one year. Non-healed cases (n = 1 stage progression; n = 3 THAs) still showed bone regeneration but this did not effectively decrease the ON volume. A lesion size under mean 10% (SD 6%) of the femoral head at three months predicted no ON stage progression at one year. Regeneration in the lateral femoral head (C2 under Japanese Investigation Committee (JCI) classification) and in the central and posterior regions of the head was predominant in cases without ON progression.ConclusionBone regeneration was observed in osteonecrotic femoral heads three months after expanded autologous BM-hMSC injection, and the volume and location of regeneration indicated the success of the therapy.Cite this article: Bone Joint Res 2022;11(12):881–889

Osteonecrosis of the Femoral Head Safely Healed with Autologous, Expanded, Bone Marrow-Derived Mesenchymal Stromal Cells in a Multicentric Trial with Minimum 5 Years Follow-Up

International audienceBackground: Osteonecrosis (ON) of the femoral head represents a potentially severe disease of the hip where the lack of bone regeneration may lead to femoral head collapse and secondary osteoarthritis, with serious pain and disability. The aim of this European, multicentric clinical trial was to prove safety and early efficacy to heal early femoral head ON in patients through minimally invasive surgical implantation of autologous mesenchymal stromal cells (MSC) expanded from bone marrow (BM) under good manufacturing practices (GMP). Methods: Twenty-two patients with femoral head ON (up to ARCO 2C) were recruited and surgically treated in France, Germany, Italy and Spain with BM-derived, expanded autologous MSC (total dose 140 million MSC in 7 mL). The investigational advanced therapy medicinal product (ATMP) was expanded from BM under the same protocol in all four countries and approved by each National Competent Authority. Patients were followed during two years for safety, based on adverse events, and for efficacy, based on clinical assessment (pain and hip score) and imaging (X-rays and MRIs). Patients were also reviewed after 5 to 6 years at latest follow-up for final outcome. Results: No severe adverse event was recalled as related to the ATMP. At 12 months, 16/20 per protocol and 16/22 under intention-to-treat (2 drop-out at 3 and 5 months) maintained head sphericity and showed bone regeneration. Of the 4 hips with ON progression, 3 required total hip replacement (THR). At 5 years, one patient (healed at 2 years visit) was not located, and 16/21 showed no progression or THR, 4/21 had received THR (all in the first year) and 1 had progressed one stage without THR. Conclusions: Expanded MSCs implantation was safe. Early efficacy was confirmed in 80% of cases under protocol at 2 years. At 5 years, the overall results were maintained and 19% converted to THR, all in the first year