Successful treatment of atypical femoral fracture with autogenous bone grafting in a patient on denosumab for bone metastasis from breast cancer: A case report.

Atypical femoral fractures (AFFs) occur with minor trauma and are believed to be a potential complication of the prolonged use of antiresorptive agents, such as bisphosphonate and denosumab, for the treatment of bone metastasis. In comparison with typical femoral fractures, AFFs have a higher incidence of complications, including implant failure and delayed union or nonunion. This report describes the case of a 42-year-old woman who developed denosumab-associated AFF after denosumab therapy for bone metastasis from breast cancer. Surgical treatment with IMN was performed after open anatomical reduction. To reduce the risk of delayed union and nonunion, the autogenous bone graft obtained from the iliac crest was conducted. The radiograph taken 5 weeks after surgery showed callus formation. Full weight bearing was allowed 3 months after surgery. Six months postoperatively, radiographs and computed tomography images demonstrated bone union. Twelve months after surgery, the patient was able to walk easily without pain. For cancer patients with bone metastasis whose life expectancy may be limited, a decline in physical activity can be fatal. Consequently, it is crucial to avoid a decrease in activities of daily living brought about by delayed union or nonunion. In this regard, autogenous bone grafting is a viable and effective technique for the treatment of AFFs in patients with bone metastases.

Successful treatment of humeral shaft nonunion with romosozumab: A case report.

Romosozumab is a humanized monoclonal anti-sclerostin antibody (Scl-Ab) that binds and inhibits sclerostin, thereby increasing bone formation and decreasing bone resorption. In 2019, the Japanese Ministry of Health, Labor and Welfare, and the FDA approved romosozumab for treating osteoporosis in men and in postmenopausal women at high risk of fracture. In the past decade, pharmacological systemic treatments using molecules in use for the treatment of the osteoporosis have been reported. Herein we reported the case of a 67-year-old woman with nonunion of humerus shaft fracture, in whom bone union could not be achieved after 11 months of conservative treatment; however, successful bone healing was achieved after once-a-month administration of romosozumab for 6 months. To our knowledge, this is the first case reporting the successful use of romosozumab for treating established nonunion. Romosozumab can aid in promoting bone healing of nonunion in patients not willing to undergo surgical intervention.

Endochondral Bone Tissue Engineering Using Human Induced Pluripotent Stem Cells.

The use of induced pluripotent stem cells (iPSCs) shows potential in bone regenerative strategies. In this study, we investigated whether implantation of chondrogenically differentiated iPSC-derived mesenchymal stem cells (iMSCs) can lead to successful bone regeneration in nude mice with bone defects. Two human iPSC clones (201B7 and 454E2) were used. After generating iMSCs, chondrogenic differentiation was achieved by three-dimensional pellet culture. Thereafter, a 2-mm defect was created in the radius of nude mice, and chondrogenically differentiated iMSC pellets were transplanted in the defect. Microcomputed tomography imaging was performed 8 weeks posttransplantation to assess bone regeneration. All (100%) radii in the 201B7 cell-derived pellet transplantation group and 7 of 10 (70%) radii in the 454E2 cell-derived pellet transplantation group showed bone union. In contrast, 2 of 11 radii (18%) in the control group showed bone union. Thus, the experimental groups showed significantly higher bone union rates than the control group (p < 0.05). Histological analysis 2 weeks postimplantation in the experimental groups revealed hypertrophic chondrocytes within grafted iMSC pellets and the formation of woven bone around them. This hypertrophic chondrocyte transitioning to newly formed bone suggests that the cartilaginous template can trigger endochondral bone ossification (ECO). Four weeks postimplantation, the cartilage template was reduced in size; newly formed woven bone was predominant in the defect site. New vessels were surrounded by a matrix of woven bone, and hypertrophic chondrocytes transitioning to newly formed bone indicated the progression of ECO. Eight weeks postimplantation, the pellets were completely resorbed and replaced by bone; complete bone union was observed. Dense mature bone developed with evidence of lamellar-like bone formation. Collectively, our results suggest that using iMSC-based cartilage grafts recapitulating the morphogenetic process of ECO in the context of embryonic skeletogenesis is a promising strategy for repairing large bone defects. Impact statement We investigated whether implantation of chondrogenically differentiated iPSC-derived mesenchymal stem cells (iMSCs) could lead to the successful regeneration of bone defects in vivo. We implanted two different clones of human induced pluripotent stem cells into a radial bone defect model. Eleven of 11 (100%) and 7 of 10 (70%) radii in the 201B7 and 454E2 cell-derived pellet transplantation groups, respectively, showed bone union, which were significantly higher than those in the control group [only 2 of 11 radii (18%)]. Overall, our results support the use of iMSC-based cartilage grafts recapitulating the morphogenetic process of endochondral bone ossification for repairing large bone defects.

Delayed Union of Stress Fracture of the First Rib in a Yoga Instructor: A Case Report.

CASE: We describe the case of a 38-year-old woman, a yoga instructor, who had pain in the right shoulder and scapular region of 4 months' duration while performing yoga. Radiography and computed tomography diagnosed delayed union of a first rib stress fracture. The delayed union of stress fracture of the first rib was successfully treated with the limiting of yoga activity and low-intensity pulsed ultrasound (LIPUS). CONCLUSIONS: Physicians should be aware that even yoga posing can cause stress fractures of the first rib. LIPUS therapy may be effective for delayed union in addition to rest.

Altered microRNA profile during fracture healing in rats with diabetes.

BACKGROUND: MicroRNAs (miRNAs) are a class of small non-coding RNA molecules that regulate gene expression. There is increasing evidence that some miRNAs are involved in the pathology of diabetes mellitus (DM) and its complications. We hypothesized that the functions of certain miRNAs and the changes in their patterns of expression may contribute to the pathogenesis of impaired fractures due to DM. METHODS: In this study, 108 male Sprague-Dawley rats were divided into DM and control groups. DM rats were created by a single intravenous injection of streptozotocin. Closed transverse femoral shaft fractures were created in both groups. On post-fracture days 5, 7, 11, 14, 21, and 28, miRNA was extracted from the newly generated tissue at the fracture site. Microarray analysis was conducted with miRNA samples from each group on post-fracture days 5 and 11. The microarray findings were validated by real-time polymerase chain reaction (PCR) analysis at each time point. RESULTS: Microarray analysis revealed that, on days 5 and 11, 368 and 207 miRNAs, respectively, were upregulated in the DM group, compared with the control group. The top four miRNAs on day 5 were miR-339-3p, miR451-5p, miR-532-5p, and miR-551b-3p. The top four miRNAs on day 11 were miR-221-3p, miR376a-3p, miR-379-3p, and miR-379-5p. Among these miRNAs, miR-221-3p, miR-339-3p, miR-376a-3p, miR-379-5p, and miR-451-5p were validated by real-time PCR analysis. Furthermore, PCR analysis revealed that these five miRNAs were differentially expressed with dynamic expression patterns during fracture healing in the DM group, compared with the control group. CONCLUSIONS: Our findings will aid in understanding the pathology of impaired fracture healing in DM and may support the development of molecular therapies using miRNAs for the treatment of impaired fracture healing in patients with DM.

Transcutaneous carbon dioxide application inhibits muscle atrophy after fracture in rats.

BACKGROUND: Muscle atrophy causes difficulty in resuming daily activities after a fracture. Because transcutaneous carbon dioxide (CO2) application has previously upregulated oxygen pressure in the local tissue, thereby demonstrating its potential in preventing muscle atrophy, here we investigated effects of CO2 application on muscle atrophy after femoral shaft fracture. METHODS: Thirty fracture model rats were produced and randomly divided into a no treatment (control group) and treatment (CO2 group) groups. After treatment, the soleus muscle was dissected at post-fracture days 0, 14, and 21. Evaluations were performed by measuring muscle weight and performing histological examination and gene expression analysis. RESULTS: Muscle weight was significantly higher in the CO2 group than in the control group. Histological analysis revealed that the muscle fiber cross-sectional area was reduced in both groups. Nevertheless, the extent of atrophy was lesser in the CO2 group. Muscle fibers in the control group tended to change into fast muscle fibers. Vascular staining revealed that more capillary vessels surrounded the muscle fibers in the CO2 group than in the control group. Messenger RNA (mRNA) analysis revealed that the CO2 group had a significantly enhanced expression of genes that were related to muscle synthesis. CONCLUSION: Transcutaneous CO2 application may be a novel therapeutic strategy for preventing skeletal muscle atrophy after fracture.

Topical cutaneous application of carbon dioxide via a hydrogel for improved fracture repair: results of phase I clinical safety trial.

BACKGROUND: Clinicians have very limited options to improve fracture repair. Therefore, it is critical to develop a new clinically available therapeutic option to assist fracture repair biologically. We previously reported that the topical cutaneous application of carbon dioxide (CO2) via a CO2 absorption-enhancing hydrogel accelerates fracture repair in rats by increasing blood flow and angiogenesis and promoting endochondral ossification. The aim of this study was to assess the safety and efficacy of CO2 therapy in patients with fractures. METHODS: Patients with fractures of the femur and tibia were prospectively enrolled into this study with ethical approval and informed consent. The CO2 absorption-enhancing hydrogel was applied to the fractured lower limbs of patients, and then 100% CO2 was administered daily into a sealed space for 20 min over 4 weeks postoperatively. Safety was assessed based on vital signs, blood parameters, adverse events, and arterial and expired gas analyses. As the efficacy outcome, blood flow at the level of the fracture site and at a site 5 cm from the fracture in the affected limb was measured using a laser Doppler blood flow meter. RESULTS: Nineteen patients were subjected to complete analysis. No adverse events were observed. Arterial and expired gas analyses revealed no adverse systemic effects including hypercapnia. The mean ratio of blood flow 20 min after CO2 therapy compared with the pre-treatment level increased by approximately 2-fold in a time-dependent manner. CONCLUSIONS: The findings of the present study revealed that CO2 therapy is safe to apply to human patients and that it can enhance blood flow in the fractured limbs. TRIAL REGISTRATION: This study has been registered in the UMIN Clinical Trials Registry (Registration number: UMIN000013641, Date of registration: July 1, 2014).

Medial clavicle pseudarthrosis successfully treated with an inverted distal clavicle locking plate.

INTRODUCTION: Medial clavicle fractures are rare injuries. Symptomatic nonunion arises up to 8% of medial clavicle fractures when treated conservatively. PRESENTATION OF CASE: A 53-year-old man sustained a left medial clavicle fracture and was treated conservatively at another hospital. Nine months after his initial injury, he was referred to our institution. We diagnosed pseudarthrosis of the medial clavicle. We performed open reduction and internal fixation using an inverted distal clavicle locking plate. At the 1-year follow-up, radiographs showed bone union. DISCUSSION: This is the first reported case of medial clavicle pseudarthrosis treated with an inverted distal clavicle anatomical locking plate. There are several advantages in using this plate. CONCLUSION: This method is a good treatment option.

Topical cutaneous application of CO2 accelerates bone healing in a rat femoral defect model.

BACKGROUND: Bone defects may occur because of severe trauma, nonunion, infection, or tumor resection. However, treatments for bone defects are often difficult and have not been fully established yet. We previously designed an efficient system of topical cutaneous application of carbon dioxide (CO2) using a novel hydrogel, which facilitates CO2 absorption through the skin into the deep area within a limb. In this study, the effect of topical cutaneous application of CO2 on bone healing was investigated using a rat femoral defect model. METHODS: In this basic research study, an in vivo bone defect model, fixed with an external fixator, was created using a rat femur. The affected limb was shaved, and CO2 was applied for 20 min/day, 5 days/week. In the control animals, CO2 gas was replaced with air. Radiographic, histological, biomechanical, and genetic assessments were performed to evaluate bone healing. RESULTS: Radiographically, bone healing rate was significantly higher in the CO2 group than in the control group at 4 weeks (18.2% vs. 72.7%). The degree of bone healing scored using the histopathological Allen grading system was significantly higher in the CO2 group than in the control group at 2 weeks (1.389 ± 0.334 vs. 1.944 ± 0.375). The ultimate stress, extrinsic stiffness, and failure energy were significantly greater in the CO2 group than in the control group at 4 weeks (3.2 ± 0.8% vs. 38.1 ± 4.8%, 0.6 ± 0.3% vs. 41.5 ± 12.2%, 2.6 ± 0.8% vs. 24.7 ± 5.9%, respectively.). The volumetric bone mineral density of the callus in micro-computed tomography analysis was significantly higher in the CO2 group than in the control group at 4 weeks (180.9 ± 43.0 mg/cm3 vs. 247.9 ± 49.9 mg/cm3). Gene expression of vascular endothelial growth factor in the CO2 group was significantly greater than that in the control group at 3 weeks (0.617 ± 0.240 vs. 2.213 ± 0.387). CONCLUSIONS: Topical cutaneous application of CO2 accelerated bone healing in a rat femoral defect model. CO2 application can be a novel and useful therapy for accelerating bone healing in bone defects; further research on its efficacy in humans is warranted.

Escherichia coli-derived BMP-2-absorbed ß-TCP granules induce bone regeneration in rabbit critical-sized femoral segmental defects.

PURPOSE: This study investigated whether Escherichia coli-derived bone morphogenetic protein (BMP)-2 (E-BMP-2) adsorbed onto ß-tricalcium phosphate (ß-TCP) granules can induce bone regeneration in critical-size femoral segmental defects in rabbits. METHODS: Bone defects 20 mm in size and stabilized with an external fixator were created in the femur of New Zealand white rabbits, which were divided into BMP-2 and control groups. E-BMP-2-loaded ß-TCP granules were implanted into defects of the BMP-2 group, whereas defects in the controls were implanted with ß-TCP granules alone. At 12 and 24 weeks after surgery, radiographs were obtained of the femurs and histological and biomechanical assessments of the defect area were performed. Bone regeneration was quantified using micro-computed tomography at 24 weeks. RESULTS: Radiographic and histologic analyses revealed bone regeneration in the BMP-2 group but not the control group; no fracturing of newly formed bone occurred when the external fixator was removed at 12 weeks. At 24 weeks, tissue mineral density, the ratio of bone volume to total volume, and volumetric bone mineral density of the callus were higher in the BMP-2 group than in control animals. In the former, ultimate stress, extrinsic stiffness, and failure energy measurements for the femurs were higher at 24 weeks than at 12 weeks. CONCLUSION: E-BMP-2-loaded ß-TCP granules can effectively promote bone regeneration in long bone defects.

Locking plate osteosynthesis for a femoral fracture and subsequent nonunion in a patient with osteopetrosis.

INTRODUCTION: Osteopetrosis is a skeletal disorder characterized by increased osteodensity and a remodeling defect. The fragility of dense sclerotic bones may lead to an increased incidence of fractures. Although internal fixation can be performed, technical challenges may be experienced because of the increased bone density. Complications such as delayed union, nonunion, or implant failure may occur postoperatively. PRESENTATION OF CASE: We describe a patient with autosomal-dominant osteopetrosis type 2 who suffered a shaft fracture below a plate of his right femur. We performed osteosynthesis with a single locking plate. Union was delayed, and plate breakage occurred along with nonunion of the fracture. The nonunion was addressed using double locking plates, which secured fixation and allowed complete fracture healing. DISCUSSION: There were three reasons of nonunion in our case. First, we left gaps between the fragments. Second, we used mainly cerclage wires, rather than screws, for plate fixation, which led to inadequate stability. Third, the patient was large (height 167 cm, weight 93.1 kg), so the single plate provided insufficient fixing force. We then used double locking plates and attained stronger internal fixation with complete fracture healing. CONCLUSION: Double plating with locking plates may be an effective treatment option for femoral fractures in patients with osteopetrosis.

Minimally Invasive Treatment for Tibial Malrotation after Locked Intramedullary Nailing.

Rotational malreduction is a potential complication of intramedullary nailing for tibial shaft fractures. We experienced a symptomatic case of a 24° externally rotated malunion that we treated with minimally invasive corrective osteotomy. A 49-year-old man sustained a tibial shaft spiral fracture with a fibula fracture. He had been initially treated elsewhere with a reamed statically locked intramedullary nail. Bone union had been obtained, but he complained of asymmetry of his legs, difficulty walking and running, and the inability to ride a bicycle. We decided to perform corrective osteotomy in a minimally invasive fashion. After a 1 cm incision was made at the original fracture site, osteotomy for the affected tibia was performed with an osteotome after multiple efforts at drilling around the nail with the aim of retaining it. Fibula osteotomy was also performed at the same level. Two Kirschner wires that created an affected rotational angle between the fragments were inserted as a guide for correction. The distal locking screws were removed. Correct rotation was regained by matching the two wires in a straight line. Finally, the distal locking screws were inserted into new holes. The patient obtained bony union and has returned to his preinjury activities with no symptoms.

Increase in carbon dioxide accelerates the performance of endurance exercise in rats.

Endurance exercise generates CO2 via aerobic metabolism; however, its role remains unclear. Exogenous CO2 by transcutaneous delivery promotes muscle fibre-type switching to increase endurance power in skeletal muscles. Here we determined the performance of rats running in activity wheels with/without transcutaneous CO2 exposure to clarify its effect on endurance exercise and recovery from muscle fatigue. Rats were randomised to control, training and CO2 groups. Endurance exercise included activity-wheel running with/without transcutaneous CO2 delivery. Running performance was measured after exercise initiation. We also analysed changes in muscle weight and muscle fibres in the tibialis anterior muscle. Running performance improved over the treatment period in the CO2 group, with a concomitant switch in muscle fibres to slow-type. The mitochondrial DNA content and capillary density in the CO2 group increased. CO2 was beneficial for performance and muscle development during endurance exercise: it may enhance recovery from fatigue and support anabolic metabolism in skeletal muscles.

Triweekly administration of parathyroid hormone (1-34) accelerates bone healing in a rat refractory fracture model.

BACKGROUND: Some reports have shown that intermittent parathyroid hormone (PTH) (1-34) treatment for patients with delayed union or nonunion have led to successful healing. In this study, we investigated whether systemic intermittent administration of PTH (1-34) has a beneficial effect on bone healing in a rat refractory fracture model. METHODS: We created a refractory femoral fracture model in 32 rats with periosteal cauterization that leads to atrophic nonunion at 8 weeks after surgery. Half the rats received subcutaneous intermittent human PTH (1-34) injections at a dosage of 100 µg/kg, thrice a week for 8 weeks. The other half received the vehicle only. At 8 weeks after fracture, radiographic, histological and mechanical assessments were performed. RESULTS: Radiographic assessments showed that the union rate was significantly higher in the PTH group than in the control group (P < 0.05). The degree of fracture repair as scored using the Allen grading system in histological assessment was significantly greater in the PTH group than in the control group (P < 0.05). The ultimate stress and stiffness measurements were significantly greater in the PTH group than in the control group (p < 0.05). CONCLUSIONS: We demonstrated that triweekly administration of PTH (1-34) increased union rate and accelerated bone healing in a rat refractory fracture model, suggesting that systemic administration of PTH (1-34) could become a novel and useful therapy for accelerating fracture healing in patients at high risk of delayed union or nonunion.

Clinical Experience With the Use of Low-Intensity Pulsed Ultrasound (LIPUS) in the Treatment of Atypical Femoral Fractures.

OBJECTIVE: The aim of this study was to report the clinical results of atypical femoral fractures (AFFs) treated with low-intensity pulsed ultrasound (LIPUS). MATERIALS AND METHODS: The data on AFFs that were surgically treated in our hospital from 2010 to 2016 was retrospectively analyzed. AFF was diagnosed based on the criteria defined by the second report of an ASBMR task force. RESULTS: Seven fractures in 6 cases were included in this study. Two fractures were referred to us as being nonunion. Five fractures were subtrochanteric fractures and 2 fractures were shaft fractures. Five fresh AFFs were fixed with an intramedullary nail and 2 nonunion fractures were fixed with plates. LIPUS was used in 6 fractures. Bone union was achieved in 5 fractures with the average time to union being 17 months (5-29). In 4 out of the 6 fractures treated with LIPUS, bone union was achieved after 14 months on average. In the other 2 LIPUS-treated fractures, bone union was not achieved even at 1 year after surgery. DISCUSSION: It is known that AFF healing tends to be very slow. Some case reports indicate that AFF healing might be accelerated by LIPUS. In the current series, the subtrochanteric fracture that was not treated with LIPUS healed at 29 months after surgery, which was much longer than the average time to union in the 5 fractures that were treated with LIPUS. Although our number of cases is small, LIPUS may be a potentially useful tool for accelerating AFF repair.

Altered expression of SDF-1 and CXCR4 during fracture healing in diabetes mellitus.

PURPOSE: Diabetes mellitus (DM) is known to impair fracture healing. The purpose of this study was to elucidate and compare the gene expression patterns and localization of stromal cell-derived factor 1 (SDF-1) and CXC chemokine receptor 4 (CXCR4) during fracture healing of the femur in rats with and without DM. METHODS: Closed transverse fractures were created in the femurs of rats equally divided into a DM group and control group; DM was induced by streptozotocin. At post-fracture days five, seven, 11, 14, 21 and 28, total RNA was extracted from the fracture callus and mRNA expression levels of SDF-1 and CXCR4 were measured by real-time polymerase chain reaction. Localization of SDF-1 and CXCR4 proteins at the fracture site was determined by immunohistochemistry at days 21 and 28. RESULTS: SDF-1 expression was significantly lower in the DM group than in the healthy group on days 21 and 28, and showed a significant difference between days 14 and 21 in the healthy group. There was no significant difference in CXCR4 expression levels between the healthy and DM groups at any time point. On day 21 immunoreactivity of SDF-1 and CXCR4 was detected at the fracture site of the healthy group but no immunoreactivity was observed in the DM group. On day 28, immunoreactivity of SDF-1 and CXCR4 was detected at the fracture site in both groups. CONCLUSION: Gene expression and localization of SDF-1 and CXCR4 was altered during fracture healing, which may contribute to the impaired fracture healing in DM.

Thrombin-antithrombin III complex tests.

PURPOSE: Patients with fractures of the pelvis and/or lower extremities are at a high risk of developing postoperative venous thromboembolism (VTE). The purpose of this study was to determine whether the thrombin-antithrombin III complex (TAT) tests could be used for postoperative screening of VTE in patients with lower limb or pelvic fractures. METHODS: We enrolled 133 patients who underwent surgical treatment for fracture of the pelvis or lower extremities. TAT and D-dimer levels were compared in patients with and without VTE. Receiver operating characteristic (ROC) curve analysis was done and the appropriate TAT and D-dimer cutoff levels were determined for VTE screening. RESULTS: VTE was diagnosed in 41 patients (30.8%). Patients with VTE had significantly higher levels of TAT and D-dimer on postoperative days 1, 3, and 7 than those without VTE, respectively. ROC curve analysis suggested that TAT test at postoperative day 7 had the highest accuracy for predicting postoperative VTE. With the optimal cutoff TAT level of 3.0 ng/mL, sensitivity and specificity were 93.3% and 70.1%, respectively. With the optimal cutoff D-dimer level of 7.4 µg/mL, sensitivity and specificity were 93.3% and 57.0%, respectively. CONCLUSION: TAT levels measured at postoperative day 7 could be the most useful parameter for screening postoperative VTE. TAT can be used as a screening tool for screening postoperative VTE in patients with lower limb and pelvic fractures.

Proposal of new classification of femoral trochanteric fracture by three-dimensional computed tomography and relationship to usual plain X-ray classification.

PURPOSE: Classification of femoral trochanteric fractures is usually based on plain X-ray findings using the Evans, Jensen, or AO/OTA classification. However, complications such as nonunion and cut out of the lag screw or blade are seen even in stable fracture. This may be due to the difficulty of exact diagnosis of fracture pattern in plain X-ray. Computed tomography (CT) may provide more information about the fracture pattern, but such data are scarce. In the present study, it was performed to propose a classification system for femoral trochanteric fractures using three-dimensional CT (3D-CT) and investigate the relationship between this classification and conventional plain X-ray classification. METHODS: Using three-dimensional (3D)-CT, fractures were classified as two, three, or four parts using combinations of the head, greater trochanter, lesser trochanter, and shaft. We identified five subgroups of three-part fractures according to the fracture pattern involving the greater and lesser trochanters. In total, 239 femoral trochanteric fractures (45 men, 194 women; average age, 84.4 years) treated in four hospitals were classified using our 3D-CT classification. The relationship between this 3D-CT classification and the AO/OTA, Evans, and Jensen X-ray classifications was investigated. RESULTS: In the 3D-CT classification, many fractures exhibited a large oblique fragment of the greater trochanter including the lesser trochanter. This fracture type was recognized as unstable in the 3D-CT classification but was often classified as stable in each X-ray classification. CONCLUSIONS: It is difficult to evaluate fracture patterns involving the greater trochanter, especially large oblique fragments including the lesser trochanter, using plain X-rays. The 3D-CT shows the fracture line very clearly, making it easy to classify the fracture pattern.

Antibiotic-impregnated calcium phosphate cement as part of a comprehensive treatment for patients with established orthopaedic infection.

BACKGROUND: The treatment of established orthopaedic infection is challenging. While the main focus of treatment is wide surgical debridement, systemic and local antibiotic administration are important adjuvant therapies. Several reports have described the clinical use of antibiotic-impregnated calcium phosphate cement (CPC) to provide local antibiotic therapy for bone infections. However, these were all individual case reports, and no case series have been reported. We report a case series treated by a single surgeon using antibiotic-impregnated CPC as part of a comprehensive treatment plan in patients with established orthopaedic infection. METHODS: We enrolled 13 consecutive patients with osteomyelitis (n = 6) or infected non-union (n = 7). Implantation of antibiotic-impregnated CPC was performed to provide local antibiotic therapy as part of a comprehensive treatment plan that also included wide surgical debridement, systemic antibiotic therapy, and subsequent second-stage reconstruction surgery. We investigated the rate of successful infection eradication and systemic/local complications. The concentration of antibiotics in the surgical drainage fluids, blood, and recovered CPC (via elution into a phosphate-buffered saline bath) were measured. RESULTS: The mean follow-up period after surgery was 50.4 (range, 27-73) months. There were no cases of infection recurrence during follow-up. No systemic toxicity or local complications from the implantation of antibiotic-impregnated CPC were observed. The vancomycin concentration in the fluid from surgical drainage (n = 6) was 527.1 ± 363.9 µg/mL on postoperative day 1 and 224.5 ± 198.4 µg/mL on postoperative day 2. In patients who did not receive systemic vancomycin therapy (n = 3), the maximum serum vancomycin level was <0.8 µg/mL. In vitro vancomycin elution was observed from the CPC that was surgically retrieved (n = 2). CONCLUSIONS: Implantation of antibiotic-impregnated CPC is an option to provide local antibiotic therapy as part of a comprehensive treatment plan.

Human pseudoarthrosis tissue contains cells with osteogenic potential.

INTRODUCTION: Nonunion is a challenging problem that may occur after certain bone fractures. The treatment of nonunion is closely related to its type. To develop an effective treatment strategy for each type of nonunion, biological analysis of nonunion tissue is essential. Pseudoarthrosis is a distinct pathologic entity of nonunion. To understand the pathology of pseudoarthrosis, we investigated the cellular properties of pseudoarthrosis tissue-derived cells (PCs) in vitro. PATIENTS AND METHODS: PCs were isolated from four patients with pseudoarthrosis and cultured. Cells were evaluated for cell-surface protein expression by using flow cytometry. Osteogenic differentiation capacity was assessed by using Alizarin Red S staining, alkaline phosphatase (ALP) activity assay, and reverse transcription polymerase chain reaction (RT-PCR) after osteogenic induction. Chondrogenic differentiation capacity was assessed via Safranin O staining and RT-PCR after chondrogenic induction. RESULTS: PCs were consistently positive for the mesenchymal stem cell-related markers CD29, CD44, CD105, and CD166, but were negative for the haematopoietic-lineage markers CD31, CD34, CD45, and CD133. Alizarin Red S staining revealed that PCs formed a mineralised matrix that was rich in calcium deposits after osteogenic induction. ALP activity under osteogenic conditions was significantly higher than that under control conditions. Gene expression of ALP, Runx2, osterix, osteocalcin, and bone sialoprotein was observed in PCs cultured under osteogenic conditions. Induced pellets were negatively stained by Safranin O staining. Gene expression of aggrecan, collagen II, collagen X, SOX5, and SOX9 was not observed. CONCLUSION: We have shown for the first time the properties of cells in patients with pseudoarthrosis. Our results indicated that osteogenic cells existed in the pseudoarthrosis tissue. This study might provide insights into understanding the pathology of pseudoarthrosis and improving the treatment for pseudoarthrosis.