Bisphosphonate-Related Atypical Femoral Fractures in Patients with Autoimmune Disease Treated with Glucocorticoids: Surgical Results for 20 Limbs.

BACKGROUND: Glucocorticoids induce osteoporosis, while bisphosphonates treat it, yet both can lead to atypical femoral fractures. Patients on both agents may face challenges in healing from such fractures due to their pathophysiology and pharmacological effects. METHODS: Intramedullary nail surgery was performed on 20 limbs in 19 patients with atypical femoral fractures and autoimmune diseases, who had received bisphosphonates for GC-induced osteoporosis. The average durations of glucocorticoid and bisphosphonate use were 17 and 9 years (standard deviation: 7.59 and 4.35), respectively, and the mean follow-up period was 66 months. Fifteen and five limbs were fractured at the subtrochanter and diaphysis, respectively. The surgical techniques (type of nail) and additional procedures performed in these cases were examined. The post-operative alignment and reduction status on radiographs were examined to determine their relationship with post-operative outcomes. RESULTS: Cephalomedullary long nails were inserted in nine limbs and antegrade intramedullary nails in 11 limbs. As an additional surgical procedure, open reduction, bone grafting and drilling were carried out on six, two, and five limbs, respectively. Regarding malalignment on radiographs, AP images showed varus in four limbs, and lateral images showed extension in two limbs. Regarding the cortical discontinuity, the distal fragment of the 11th limb shifted posteriorly in the lateral view. Gaps at the fracture sites were observed in 11 limbs. As a result, bone union was confirmed in 13 limbs. Five of the seven nonunion limbs required additional surgery. When comparing union and nonunion, open reduction and drilling were involved in nonunion limbs. CONCLUSION: The surgical outcomes of atypical femoral fractures in patients with autoimmune disease and on long-term glucocorticoids and bisphosphonates were poor. Although it is not possible to affirm for sure based on these results alone, management with prophylactic surgery before complete fracture is considered to be required to improve outcomes.

Safety and Osteointegration of Titanium Screws Coated with a Fibroblast Growth Factor-2-Calcium Phosphate Composite Layer in Non-Human Primates: A Pilot Study.

Spinal instrumentation surgery for older patients with osteoporosis is increasing. Implant loosening may occur due to inappropriate fixation in osteoporotic bone. Developing implants that achieve stable surgical results, even in osteoporotic bone, can reduce re-operation, lower medical costs, and maintain the physical status of older patients. Fibroblast growth factor-2 (FGF-2) promotes bone formation; thus, coating pedicle screws with an FGF-2-calcium phosphate (FGF-CP) composite layer is hypothesized to enhance osteointegration in spinal implants. We designed a long-term implantation pilot study that estimated the safety and bone-forming efficacy of pedicle screws coated with an FGF-CP composite layer in cynomolgus monkeys. Titanium alloy screws, either uncoated (controls) or aseptically coated with an FGF-CP composite layer, were implanted in the vertebral bodies of six female adult cynomolgus monkeys (three monkeys per group) for 85 days. Physiological, histological, and radiographic investigations were performed. There were no serious adverse events, and no radiolucent areas were observed around the screws in either group. The bone apposition rate in the intraosseous region was significantly higher in the FGF-CP group than in the controls. Moreover, as analyzed by Weibull plots, the bone formation rate of the FGF-CP group exhibited a significantly higher regression line slope than the control group. These results demonstrated that there was significantly less risk of impaired osteointegration in the FGF-CP group. Our pilot study suggests that FGF-CP-coated implants could promote osteointegration, be safe, and reduce the probability of screw loosening.

Clinical Trial for the Safety and Feasibility of Pedicle Screws Coated with a Fibroblast Growth Factor-2-Apatite Composite Layer for Posterior Cervical Fusion Surgery.

To solve the instrument loosening problem, we developed a fibroblast growth factor-2-calcium phosphate composite layer as a novel coating material to improve screw fixation strength. The primary aim of the present study was to demonstrate the safety and feasibility of screws coated with the FGF-2-calcium phosphate composite layer for posterior instrumented surgery of the cervical spine. The trial design was a single-arm, open-label, safety and feasibility study. Patients receiving fusion of the cervical spine from C2 (or C3) to C7 (or T1) were recruited. The primary endpoint to confirm safety was any screw-related adverse events. Seven patients who underwent posterior fusion surgery of the cervical spine were enrolled in the present study. The coated pedicle screws were inserted bilaterally into the lowest instrumented vertebrae. There was only one severe adverse event unrelated with the coated screw. Three out of the fourteen coated screws showed loosening. The present results prove the safety and feasibility of pedicle screws coated with the FGF-2-calcium phosphate composite layer for fusion surgery in the cervical spine. This is the first step to apply this novel surface coating in the field of spine surgery.

Safety of terminally gamma-ray-sterilized screws coated with fibroblast growth factor 2-calcium phosphate composite layers in non-human primates.

Screws coated with fibroblast growth factor 2 (FGF-2)-calcium phosphate (CP) composite layers exhibit enhanced soft tissue and bone formation and angiogenesis because of the biological activity of FGF-2. Furthermore, the mitogenic activity of the FGF-2 within the composite layers remains unchanged after gamma-ray sterilization, which may improve the storage stability prior to clinical use. However, the in vivo safeties of these screws as spinal implants remain unknown. Here, a randomized controlled trial, involving non-human primates, investigated the safety of using FGF-2-CP composite layer-coated screws after either gamma-ray sterilization or aseptic processing. Titanium alloy screws coated with FGF-2-CP composite layers and subjected to either gamma-ray sterilization at 25 kGy (GS group) or aseptic storage (AS group) were implanted into the vertebral bodies of two cynomolgus monkeys exceeding 12 weeks (day 99). Physiological, histological, and radiographic investigations were performed to evaluate the safeties of the screws. There were no serious adverse events, such as surgical site infection, significant loss of body weight, or abnormal blood test results. No radiolucent areas were observed around the screws from the GS or AS group throughout the study. In the intraosseous region, no significant differences were observed in bone and fibrous tissue apposition rates and rate of bone formation between the two groups (p = 0.49, 0.77, and 0.11, respectively). Neither tumor lesions nor accumulation of lymphocytes and neutrophils were observed in either group. Our data suggest that FGF-2-CP composite layer-coated screws subjected to terminal gamma-ray sterilization are as safe as those fabricated in aseptic processing.

Reconstruction of hook grip function of the fingers in patients with traumatic brachial plexus injury.

We described a reconstruction method for restoring hook grip function of the fingers in patients with total brachial plexus injury. The paralysed latissimus dorsi muscle was transferred to the upper limb as a pedicle flap and sutured to the flexor digitorum profundus tendons. The muscle was then reanimated with two intercostal donor nerves to the thoraco-dorsal nerve. Fourteen young adult patients (mean 23 years, range 17 to 32 years) with traumatic brachial plexus injury who underwent reconstruction using this technique from 2000 to 2019. After mean follow-up of 65 months (range 20 to 170), finger flexion of strength greater than or equal to M3 was achieved in 10 of the 14 patients. The mean weight that could be lifted using a hook grip was 2.6 kg, and that which could be lifted with both hands was 4.1 kg. The intercostal nerve-innervated latissimus dorsi muscle transfer can provide useful hook grip hand function without the need to sacrifice donor vessels or healthy muscles.Level of evidence: IV.

Novel method for selecting slices of the same cross-sectional view from digital tomosynthesis for monitoring posterior spinal instrumentation.

BACKGROUND: A method to evaluate pedicle screw loosening on digital tomosynthesis images is yet to be established owing to lack of methods for selecting slices of the same cross-sectional view. We aimed to develop an objective method for selecting slices of the same cross-sectional view on digital tomosynthesis images. METHODS: First, an objective method of pixel selection was developed by measuring the size of glass disk and titanium alloy screw on digital tomosynthesis images followed by comparison with the actual sizes. Second, a method for selecting slices of the same cross-sectional view was explored on a bone model with posterior spinal instrumentation using the screw centerline and rod curvature as indicators of the same cross section. The angle between the screw centerline and rod was calculated to verify the accuracy in obtaining the same cross-sectional view. Third, the method for selecting slices of the same cross-sectional view was applied to six patients after posterior lumbar spinal instrumentation. RESULTS: The pixel selection method enabled objective determination of a pixel on the peripheral lines of objects with an error as low as 200 µm in distance measurements on titanium alloy and glass. The mean differences of rod-screw angles between two slices were less than 1° and were not statistically significant in the bone model and patient images. CONCLUSION: A method for selecting slices of the same cross-sectional view on digital tomosynthesis images was successfully developed. This method can enable objective and quantitative evaluations of pedicle screw loosening.

Closed total talar dislocation without fracture in a rare college athlete case.

Total talar dislocation without a fracture is an extremely rare injury. It is often the result of high-energy trauma, such as that incurred after a fall, or owing to motor or vehicular accidents. Talar dislocations have poor outcomes owing to the frequent complications of infection, avascular necrosis and osteoarthritis attributed to open dislocations. We report herein a closed total talar dislocation without a fracture in a college athlete who was injured during sports activities. Specifically, a 20-year-old man was injured during a soccer game this led to a closed total talar dislocation. We performed closed reduction with image guidance subject to a popliteal sciatic nerve block, and placed a plaster cast below the knee. Radiographic studies after reduction revealed no associated fractures. After an eight week no-weight bearing period, we confirmed that there were no avascular necrosis signs on magnetic resonance images. Based on these findings, partial weight bearing was allowed. At 18 months post trauma, the athlete continues to play soccer despite the fact that he experiences a slight pain and limited range of motion. The blood supply to the talus is limited, and trauma, such as dislocation, can easily injure the blood supply, thus resulting in complications, such as avascular necrosis. The talus vascularity of the presented case was maintained by superior branches. We think that it is important to a) perform closed reduction early on, b) avoid any type of surgical operation that damages the limited talus blood supply, and c) allow weight bearing after the lack of avascular necrosis signs is confirmed. Although there is no standardized treatment, the talar dislocation treatment should be chosen to preserve the blood supply to the talus as much as possible.

Randomized trial of granulocyte colony-stimulating factor for spinal cord injury.

Attenuation of the secondary injury of spinal cord injury (SCI) can suppress the spread of spinal cord tissue damage, possibly resulting in spinal cord sparing that can improve functional prognoses. Granulocyte colony-stimulating factor (G-CSF) is a haematological cytokine commonly used to treat neutropenia. Previous reports have shown that G-CSF promotes functional recovery in rodent models of SCI. Based on preclinical results, we conducted early phase clinical trials, showing safety/feasibility and suggestive efficacy. These lines of evidence demonstrate that G-CSF might have therapeutic benefits for acute SCI in humans. To confirm this efficacy and to obtain strong evidence for pharmaceutical approval of G-CSF therapy for SCI, we conducted a phase 3 clinical trial designed as a prospective, randomized, double-blinded and placebo-controlled comparative trial. The current trial included cervical SCI [severity of American Spinal Injury Association (ASIA) Impairment Scale (AIS) B or C] within 48 h after injury. Patients are randomly assigned to G-CSF and placebo groups. The G-CSF group was administered 400 µg/m2/day × 5 days of G-CSF in normal saline via intravenous infusion for five consecutive days. The placebo group was similarly administered a placebo. Allocation was concealed between blinded evaluators of efficacy/safety and those for laboratory data, as G-CSF markedly increases white blood cell counts that can reveal patient treatment. Efficacy and safety were evaluated by blinded observer. Our primary end point was changes in ASIA motor scores from baseline to 3 months after drug administration. Each group includes 44 patients (88 total patients). Our protocol was approved by the Pharmaceuticals and Medical Device Agency in Japan and this trial is funded by the Center for Clinical Trials, Japan Medical Association. There was no significant difference in the primary end point between the G-CSF and the placebo control groups. In contrast, one of the secondary end points showed that the ASIA motor score 6 months (P = 0.062) and 1 year (P = 0.073) after drug administration tend to be higher in the G-CSF group compared with the placebo control group. Moreover, in patients aged over 65 years old, motor recovery 6 months after drug administration showed a strong trend towards a better recovery in the G-CSF treated group (P = 0.056) compared with the control group. The present trial failed to show a significant effect of G-CSF in primary end point although the subanalyses of the present trial suggested potential G-CSF benefits for specific population.

Closed reduction and minimally invasive surgical treatment of type IIIa fragility fractures of the pelvis associated with ipsilateral periprosthetic femur fracture: A case report.

Patients with fragility fractures of the pelvic ring (FFP) are elderly and, from the perspective of surgical invasion, percutaneous and stable fixation may be a superior surgical method than open reduction and internal fixation (ORIF). While in the case of FFP type IIIa, ORIF, as a rule, typically requires open reduction of the displaced ilium via an anterior intrapelvic approach and/or lateral window of the ilioinguinal approach. We have reported here the case of an 89-year-old woman who suffered from FFP type IIIa with ipsilateral periprosthetic femur fracture that was surgically treated. The iliac fracture was approached in a minimally invasive manner using the traction operation while preparing for femoral shaft fracture surgery, which did not require open reduction, and showed favorable outcomes.

Delayed union of a surgically treated fragility fracture of the pelvis: A case report.

INTRODUCTION: There are no universally accepted treatment strategies for fragility fractures of the pelvis (FFPs). The incidence of delayed union or non-union of Type IIIa FFP is still unknown. PRESENTATION OF CASE: We describe a case of delayed union of a Type IIIa FFP. A 96-year-old female patient who lives independently accidentally fell when exiting a car. The diagnosis of Type IIIa FFP with displaced left ilium and left pubic rami fracture. Surgical repair was performed using an anterior intrapelvic approach with constructs made using two reconstruction contoured plates to bridge the medial edge and middle part of the fracture. This case was revealed delayed union. The periodic CT examinations were performed to determine the progress of bone union. The patient returned to most social activities including living independently and the Modified Majeed score was 94 at 12 months post-operation. DISCUSSION: For the case of TypeⅢa FFP, soft tissue is spread over a wide area. When the fracture site of ilium was exposed, the cortical bone was found to be thin with poor blood flow. There is a possibility that the blood flow was hindered by subperiosteal elevation of the iliacus muscle from the internal iliac fossa in this case. CONCLUSION: Non-union of the iliac wings is relatively rare following high-energy pelvic ring fractures. The incidence of delayed union or non-union of Type IIIa FFP remains unknown; therefore, careful follow-up of patients who undergo treatment is necessary to reduce the risk of delayed union.

Acute mitral valve regurgitation causing severe alveolar hemorrhage.

BACKGROUND: Acute mitral regurgitation could occur without common symptoms like hemodynamic instability, but with dyspnea, hemoptysis, and right-sided infiltration on radiography. We report a case of severe alveolar hemorrhage caused by acute mitral regurgitation, which occurred in the absence of shock. CASE PRESENTATION: A 40-year-old man presented with dyspnea with bloody phlegm and hypoxia, despite being hemodynamically stable. Chest radiography revealed right-sided infiltration, and bronchoscopy showed fresh bloody phlegm in his tracheae. No specific findings were detected with any tests. After treatment with several medications and support with extracorporeal membrane oxygenation, his condition improved, although the etiology of the disease remained unknown. Transthoracic and transesophageal echocardiogram revealed severe mitral valve regurgitation with ruptured mitral chordae tendineae. These suggested that the sudden onset of mitral valve regurgitation had caused severe alveolar hemorrhage. CONCLUSION: Severe alveolar hemorrhage, especially with right-sided infiltration on chest radiography, should be considered a symptom of acute mitral regurgitation.

Surgical results of atypical femoral fractures in long-term bisphosphonate and glucocorticoid users - Relationship between fracture reduction and bone union.

Atypical femoral fracture (AFF) associated with bisphosphonate (BP) use is common, and its pathophysiology is considered to involve severely suppressed bone turnover. Surgical results following AFF fixation have not been optimal, with some cases resulting in delayed union or nonunion. Regarding bone healing, glucocorticoid (GC) has similar properties to BP. We investigated the surgical results of AFF fixation in both users of BP and GC, especially with regard to intraoperative fracture reduction. We included 12 AFFs in 11 patients with a follow-up over one year who all took GC for autoimmune disease and BP for management of GC-induced osteoporosis. Their mean age was 62 years and 10 patients were female. Six fractures were located in the subtrochanteric region of the femur and six were in the diaphysis. Intramedullary nails were used to treat all fractures. Union rate was recorded, and the status of the reduction immediately after the operation was analyzed. Four of the 12 cases developed nonunion, and three of them required additional surgery. The relationship between alignment, cortical continuity, fracture gap, and bone union was not significant. In the nonunion cases, cortical continuity on the anteroposterior and lateral views were never confirmed. Even if cortical continuity in either of the views was there, the two limbs resulted in nonunion. One third of the patients with AFF secondary to long-term BP and GC use developed nonunion despite their fracture reductions being acceptable. We consider strict reduction should be needed for these cases with disadvantage condition to bone union.

For how long do denervated muscles in children retain the ability to regenerate?: Restoration of elbow flexion and shoulder function by partial nerve transfer in a child with long-standing poliomyelitis-like paralysis.

BACKGROUND: In infant poliomyelitis or poliomyelitis-like paresis, there has been no means of treating residual paralysis and the policy has been to wait until an affected infant has grown sufficiently to enable tendon transfer or arthrodesis. However, recent reports have described relatively good results for early surgical intervention in the form of nerve transfer. METHODS: In a 4-year and 6-month-old child we transferred a partial ulnar nerve for elbow flexor reconstruction even 3 years and 10 months after the onset of poliomyelitis-like palsy and also transferred partial accessory and radial nerves for shoulder function restoration 6 months after the first operation. RESULTS: Elbow flexor restored M4 on the British Medical Research Council scale. The shoulder subluxation resolved, however, the strengths of the deltoid and infraspinatus remained almost M1. At the most recent clinical examination, the patient was 18 years old and the active range of motion of patient's left elbow was 0°-125°, and those of the whole shoulder girdle were abduction 35°, flexion 60°, extension 30° and external rotation 0°. CONCLUSIONS: The outcomes we achieved may support partial nerve transfer techniques as viable treatment options for persistent long-standing motor deficits following poliomyelitis-like palsy in children. However, we recommend performing partial nerve transfer as early as possible after recovery from flaccid paralysis and also use of nerves that derive from narrow spinal cord segments. After denervation, children's neuromuscular systems seem to have the ability to regenerate after a much longer period than has generally been believed. This speculation is based on only a single case report; thus, more experience is needed before this generalization can confidently be made.

Study protocol for the G-SPIRIT trial: a randomised, placebo-controlled, double-blinded phase III trial of granulocyte colony-stimulating factor-mediated neuroprotection for acute spinal cord injury.

INTRODUCTION: Granulocyte colony-stimulating factor (G-CSF) is generally used for neutropaenia. Previous experimental studies revealed that G-CSF promoted neurological recovery after spinal cord injury (SCI). Next, we moved to early phase of clinical trials. In a phase I/IIa trial, no adverse events were observed. Next, we conducted a non-randomised, non-blinded, comparative trial, which suggested the efficacy of G-CSF for promoting neurological recovery. Based on those results, we are now performing a phase III trial. METHODS AND ANALYSIS: The objective of this study is to evaluate the efficacy of G-CSF for acute SCI. The study design is a prospective, multicentre, randomised, double-blinded, placebo-controlled comparative study. The current trial includes cervical SCI (severity of American Spinal Injury Association (ASIA) Impairment Scale B/C) within 48 hours after injury. Patients are randomly assigned to G-CSF and placebo groups. The G-CSF group is administered 400 µg/m2/day×5 days of G-CSF in normal saline via intravenous infusion for 5 consecutive days. The placebo group is similarly administered a placebo. Our primary endpoint is changes in ASIA motor scores from baseline to 3 months. Each group includes 44 patients (88 total patients). ETHICS AND DISSEMINATION: The study will be conducted according to the principles of the World Medical Association Declaration of Helsinki and in accordance with the Japanese Medical Research Involving Human Subjects Act and other guidelines, regulations and Acts. Results of the clinical study will be submitted to the head of the respective clinical study site as a report after conclusion of the clinical study by the sponsor-investigator. Even if the results are not favourable despite conducting the clinical study properly, the data will be published as a paper. TRIAL REGISTRATION NUMBER: UMIN000018752.