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Abstract Background Low-intensity pulsed ultrasound (LIPUS) is a non-invasive therapy that accelerates fracture healing. As a new treatment method for fracture, we recently reported that the transcutaneous application of CO2 accelerated fracture healing in association with promoting angiogenesis, blood flow, and endochondral ossification. We hypothesized that transcutaneous CO2 application, combined with LIPUS, would promote bone fracture healing more than the single treatment with either of them. Methods Femoral shaft fractures were produced in 12-week-old rats. Animals were randomly divided into four groups: the combination of CO2 and LIPUS, CO2, LIPUS, and control groups. As the transcutaneous CO2 application, the limb was sealed in a CO2-filled bag after applying hydrogel that promotes CO2 absorption. Transcutaneous CO2 application and LIPUS irradiation were performed for 20 min/day, 5 days/week. At weeks 1, 2, 3, and 4 after the fractures, we assessed the fracture healing process using radiography, histology, immunohistochemistry, real-time PCR, and biomechanical assessment. Results The fracture healing score using radiographs in the combination group was significantly higher than that in the control group at all time points and those in both the LIPUS and CO2 groups at weeks 1, 2, and 4. The degree of bone fracture healing in the histological assessment was significantly higher in the combination group than that in the control group at weeks 2, 3, and 4. In the immunohistochemical assessment, the vascular densities of CD31- and endomucin-positive microvessels in the combination group were significantly higher than those in the control and LIPUS groups at week 2. In the gene expression assessment, significant upregulation of runt-related transcription factor 2 (Runx2) and vascular endothelial growth factor (VEGF) was detected in the combination group compared to the LIPUS and CO2 monotherapy groups. In the biomechanical assessment, the ultimate stress was significantly higher in the combination group than in the LIPUS and CO2 groups. Conclusion The combination therapy of transcutaneous CO2 application and LIPUS had a superior effect in promoting fracture healing through the promotion of angiogenesis and osteoblast differentiation compared to monotherapy.

Abstract The interconnected structures in a 3D scaffold allows the movement of cells and nutrients. Therefore, this study aimed to investigate the in-vivo bioactivity of 3D-printed β-tricalcium phosphate (β-TCP) and hydroxyapatite (HAP) scaffolds that replicate biological bone. This study included 24-week-old male New Zealand white rabbits. A cylindrical bone defect with a diameter of 4.5 mm and a depth of 8 mm was created in the lateral aspect of the distal femur. A 3D-printed scaffold was implanted in the right femur (experimental side), whereas the left femur was kept free of implantation (control side). Micro-CT analysis and histological observations of the bone defect site were conducted at 4, 8, and 12 weeks postoperatively to track the bone repair progress. No evidence of new bone tissue formation was found in the medullary cavity of the bone defect on the control side. In contrast, on the experimental side, the 3D scaffold demonstrated sufficient bioactivity, leading to the growth of new bone tissue. Over time, new bone tissue gradually extended from the periphery toward the center, a phenomenon evident in both micro-CT images and biopsy staining. In the current study, we observed that the cells involved in bone metabolism adhered, spread, and proliferated on our newly designed 3D-printed scaffold with a bone microstructure. Therefore, it is suggested that this scaffold has sufficient bioactivity to induce new bone formation and could be expected to be a more useful artificial bone than the existing version. Graphical Abstract

Aims: Continuous local antibiotic perfusion (CLAP) has recently attracted attention as a new drug delivery system for orthopaedic infections. CLAP is a direct continuous infusion of high-concentration gentamicin (1,200 μg/ml) into the bone marrow. As it is a new system, its influence on the bone marrow is unknown. This study aimed to examine the effects of high-concentration antibiotics on human bone tissue-derived cells. Methods: Cells were isolated from the bone tissue grafts collected from six patients using the Reamer-Irrigator-Aspirator system, and exposed to different gentamicin concentrations. Live cells rate, apoptosis rate, alkaline phosphatase (ALP) activity, expression of osteoblast-related genes, mineralization potential, and restoration of cell viability and ALP activity were examined by in vitro studies. Results: The live cells rate (the ratio of total number of cells in the well plate to the absorbance-measured number of live cells) was significantly decreased at ≥ 500 μg/ml of gentamicin on day 14; apoptosis rate was significantly increased at ≥ 750 μg/ml, and ALP activity was significantly decreased at ≥ 750 μg/ml. Real-time reverse transcription-polymerase chain reaction results showed no significant decrease in the ALP and activating transcription factor 4 transcript levels at ≥ 1,000 μg/ml on day 7. Mineralization potential was significantly decreased at all concentrations. Restoration of cell viability was significantly decreased at 750 and 1,000 μg/ml on day 21 and at 500 μg/ml on day 28, and ALP activity was significantly decreased at 500 μg/ml on day 28. Conclusion: Our findings suggest that the exposure concentration and duration of antibiotic administration during CLAP could affect cell functions. However, further in vivo studies are needed to determine the optimal dose in a clinical setting. Cite this article: Bone Joint Res 2024;13(3):92–101.

Abstract Background We previously demonstrated that CD34 + cell transplantation in animals healed intractable fractures via osteogenesis and vasculogenesis; we also demonstrated the safety and efficacy of this cell therapy in an earlier phase I/II clinical trial conducted on seven patients with fracture nonunion. Herein, we present the results of a phase III clinical trial conducted to confirm the results of the previous phase studies using a larger cohort of patients. Methods CD34 + cells were mobilized via administration of granulocyte colony-stimulating factor, harvested using leukapheresis, and isolated using magnetic cell sorting. Autologous CD34 + cells were transplanted in 15 patients with tibia nonunion and 10 patients with femur nonunion, who were followed up for 52 weeks post transplantation. The main outcome was a reduction in time to heal the tibia in nonunion patients compared with that in historical control patients. We calculated the required number of patients as 15 based on the results of the phase I/II study. An independent data monitoring committee performed the radiographic assessments. Adverse events and medical device failures were recorded. Results All fractures healed during the study period. The time to radiological fracture healing was 2.8 times shorter in patients with CD34 + cell transplantation than in the historical control group (hazard ratio: 2.81 and 95% confidence interval 1.16–6.85); moreover, no safety concerns were observed. Conclusions Our findings strongly suggest that autologous CD34 + cell transplantation is a novel treatment option for fracture nonunion. Trial registration UMIN-CTR, UMIN000022814. Registered on 22 June 2016.

In this study, we examined the proliferation capability and osteogenic and chondrogenic differentiation potential of non-hypertrophic nonunion cells (NHNCs), and the effect of Escherichia coli-derived BMP-2 (E-BMP-2) on them. We enrolled five patients with non-hypertrophic nonunion. NHNCs isolated from nonunion tissue sampled during surgery were cultured, passaged, counted every 14 days, and analyzed. NHNCs were homogenous fibroblastic adherent cells and long-lived through at least 10 passages, with a slight decline. The cells were consistently positive for mesenchymal stem cell-related markers CD73 and CD105, and negative for the hematopoietic markers CD14 and CD45. NHNCs could differentiate into osteoblast lineage cells; however, they did not have strong calcification or sufficient chondrogenic differentiation capability. E-BMP-2 did not affect the proliferative capability of the cells but improved their osteogenic differentiation capability by increasing alkaline phosphatase activity and upregulating the gene expression of osterix, bone sialoprotein, and osteocalcin. E-BMP-2 enhanced their chondrogenic differentiation capability by upregulating the gene expression of aggrecan and collagen type II. We showed, for the first time, that NHNCs have the capacity to differentiate into osteoblast-lineage cells, although the chondrogenic differentiation potential was poor. Local application of E-BMP-2 with preservation of nonunion tissue is a potential treatment option for non-hypertrophic nonunion.

Bone-modifying agents (BMAs), with bone-resorptive inhibitory effects, such as zoledronic acid and denosumab, are widely used at higher doses for bone-related events caused by bone metastasis of malignant tumors. These drugs have been suggested to be associated with atypical femoral fractures (AFFs), and the relationship between BMAs and AFFs has attracted attention. To investigate the clinical features including bone union time of AFFs in patients administered BMA for bone metastasis, we conducted a retrospective multicenter study. Thirty AFFs from 19 patients were enrolled in this study. Thirteen patients had bilateral AFFs, and nineteen AFFs had prodromal symptoms. Eighteen AFFs underwent surgery after complete fracture, three failed to achieve bone union and required nonunion surgery, and 11 AFFs that achieved bone union had an average period until bone union of 16.2 months, which was much longer than that previously reported for ordinary AFFs. Seven patients discontinued the BMAs, but not due to AFFs. Stopping BMAs in patients with bone metastasis would make it difficult to secure their performance of activities of daily living, and AFF with BMA administration might require a longer time for union. Therefore, it would be important to prevent incomplete AFF from becoming complete AFF via prophylactic internal fixation.

Abstract Background Our objective was to evaluate the location of popliteal artery (PA) in osteotomy planes during high tibial osteotomy (HTO) and to determine a safer angle for screw drilling to the tibial tuberosity during distal tuberosity osteotomy (DTO). Methods Twenty knees in 20 patients who underwent contrast-enhanced computed tomography for cardiovascular diseases were examined. Osteotomy planes for open-wedge HTO (OWHTO) and hybrid closed-wedge HTO (hybrid CWHTO) were created using three-dimensional bone models. The distance from the posterior cortex of the tibia to the PA (dPC-PA) in the osteotomy planes was measured in the virtual osteotomy planes. The dangerous point (Point D1) was defined as the point 17.5 mm away from PA, setting the working length of the bone saw as 35 mm. The distance between the most medial point of the tibial cortex (Point M) and Point D1 in OWHTO and the most lateral point (Point L) and Point D1 in hybrid CWHTO were examined (dM-D1 and dL-D1, respectively). The location of Point D1 to the osteotomy line (%D1) was expressed as percentage, setting the start and end of the osteotomy line as 0% and 100%, respectively. To determine the safe angle for screw drilling in DTO, the angle between the line tangential to the medial cortex of the tibia and that passing through the center of the tibial tuberosity and PA were measured. Results In OWHTO and hybrid CWHTO, the mean dPC-PA was 10.6 mm (6.9–16.5 mm) and 10.2 mm (7.3–15.4 mm), respectively. The mean dM-D1 in OWHTO was 25.9 mm (24.6–27.2 mm) and dL-D1 in hybrid CWHTO was 5.1 mm (2.9–7.4 mm). The mean %D1 was 47.6 ± 3.7% in OWHTO and 9.3 ± 4.1% in hybrid CWHTO, respectively. The minimal angle between the two lines in DTO was 35.2°. Conclusion PAs could run within 10 mm from the posterior cortex in the osteotomy planes of HTO. Therefore, proper posterior protection is necessary when cutting posterior cortex. An angle of less than 35° against the medial cortex line would be safe for screw fixation to avoid vascular injury in DTO.

Background/objective: The purpose of this study was to report the outcomes of a clinical trial conducted in Japan to assess the safety and effectiveness of third-generation autologous chondrocyte implantation (ACI) using IK-01 (CaReS™), which does not require flap coverage, in the treatment of patients with focal cartilage injury of the knee. Methods: This was an open label, exploratory clinical trial. Patients were enrolled between June 2012 and September 2016. The primary endpoint of the study was the International Knee Documentation Committee (IKDC) score at 52 weeks after implantation. The IKDC, Lysholm, and visual analog scale (VAS) scores were evaluated at the time of screening and at 4, 12, 24, 36, and 52 weeks after implantation. Improvements from the baseline scores were evaluated using the equation “(postoperative score) − (preoperative score).” Magnetic resonance imaging (MRI) was performed at 2, 12, 24, and 52 weeks after implantation, and MRI measurements were evaluated using T1 rho and T2 mapping. Results: Nine patients were enrolled in this study and were examined for safety. Product quality did not satisfy the specification in one patient, and bacterial joint infection occurred in one patient. As a result, seven patients were included in the outcome analyses. The mean IKDC score significantly improved from 36.4 preoperatively to 74.1% at 52 weeks after implantation (p

Abstract Background A link between tendinopathy and oxidative stress has been recently reported. Nicotinamide mononucleotide (NMN) is a precursor of nicotinamide adenine dinucleotide, which plays an important role in cell redox homeostasis. The aim of this study was to evaluate the antioxidant effect of NMN on tendinopathy in vitro and in vivo. Methods Tenocytes from healthy Sprague-Dawley rats were cultured in regular glucose (RG) and high-glucose (HG) conditions with or without NMN, and were divided into four groups: RG NMN(−), RG NMN(+), HG NMN(−), and HG NMN(+). Cell viability, reactive oxygen species (ROS) accumulation, apoptotic rate, and mRNA expression of nicotinamide adenine dinucleotide phosphate oxidase (NOX)1, NOX4, interleukin (IL)6, sirtuin (SIRT)1, and SIRT6 were investigated. In addition, rats with collagenase-induced tendinopathy were treated with or without NMN. Immunostaining of NOX1 and NOX4; mRNA expression of SIRT1, SIRT6, and IL6; and superoxide dismutase (SOD) activity measurements in the Achilles tendon were performed. Results NMN increased the expression of SIRT1 and SIRT6 in rat tenocytes, but decreased the levels of NOX1, NOX4, IL6, ROS, and apoptosis. In Achilles tendons with collagenase-induced tendinopathy, NMN increased the mRNA expression of SIRT1 and SIRT6, as well as SOD activity; while suppressing protein expression of NOX1 and NOX4, and mRNA expression of IL6. Conclusion The in vitro and in vivo results of this study show that NMN exerts an antioxidant effect on tendinopathy by promoting the expression of SIRT while inhibiting that of NOX.

Abstract Background To improve implant survival through accelerated early bone remodeling during total hip arthroplasty (THA), hydroxyapatite (HA) is widely used as a bioactive coating, which is believed to enhance initial fixation by osseointegration. We aimed to investigate the relationship between stem insertion alignment and postoperative bone mineral density (BMD) changes in patients with full hydroxyapatite-coated (HA) compaction short stem and short tapered-wedge stem. Methods This retrospective cohort study enrolled 115 consecutive patients (115 joints) undergoing THA using the full HA compaction short (n = 59) and short tapered-wedge (n = 56) stems. Stem alignment, including anteversion, valgus, and anterior tilt were measured by a three-dimensional template using computed tomography data. Post-operative peri-prosthetic BMD was measured by dual-energy X-ray absorptiometry. The relationship between stem alignment and BMD changes in the stems was analyzed. Results Patterns of peri-prosthetic BMD changes were similar in both groups. Stem insertion alignments of anteversion, valgus, and anterior tilt were different between the two stem types. Stem alignment of valgus and anterior tilt did not affect peri-prosthetic BMD in either of the stem type. An absolute anteversion difference between stem anteversion and original canal anteversion caused significant peri-prosthetic BMD loss in Gruen zones one and seven in the tapered-wedge stem. However, stem alignment of absolute anteversion difference did not affect BMD changes in the HA compaction stem. Conclusions Peri-prosthetic bone remodeling remained unaffected by stem alignment after THA with the new short full HA compaction stem.

Abstract Background Induced membrane (IM) is the key component of Masquelet reconstruction surgery for the treatment of bone defects. IM is formed around the cement spacer and is known to secrete growth factors and osteoinductive factors. However, there is limited evidence available concerning the presence of osteoinductive factors in IM. This study aimed to investigate the existence of bone morphogenetic proteins (BMPs) in IM harvested from patients during the treatment of bone defects using the Masquelet technique. Methods This study involved six patients whose bone defects had been treated using the Masquelet technique. The affected sites were the femur (n = 3) and the tibia (n = 3). During the second-stage surgery, 1 cm2 pieces of IM were harvested. Histological sections of IM were immunostained with anti-BMP-4, 6, 7, and 9 antibodies. Human bone tissue served as the positive control. Results The presence of BMP-4, 6, 7, and 9 was observed in all IM samples. Further, immunolocalization of BMP-4, 6, 7, and 9 was observed in blood vessels and fibroblasts in all IM samples. Immunolocalization of BMP-4, 6, 7, and 9 was also observed in bone tissue within the IM in one sample, in which osteogenesis inside the IM was observed. Conclusions This study showed that osteoinductive factors BMP-4, 6, 7, and 9 were present in the IM harvested from patients, providing evidence indicating that the Masquelet technique effectively contributes to healing large bone defects. Therefore, it may be possible for surgeons to omit the addition of BMPs to bone grafts, given the endogenous secretion of BMPs from the IM.

Abstract Background While the precise measurement of the range of motion (ROM) of the elbow joint is important for clinical assessment and rehabilitation, problems include low accuracy and reproducibility in goniometer measurements due to the influence of soft tissue. The purpose of this study was to validate elbow joint motion analysis using a three-dimensional electromagnetic sensor system (EMS). Methods The accuracy and reproducibility of the EMS system were evaluated at four angles (0°, 45°, 90°, and 135°) using a model bone of the humerus and forearm. In addition, the maximum extension and maximum flexion of six elbows of six healthy volunteers were assessed by radiographic and EMS measurements. Accuracy was assessed by calculating the mean value of the measurement angle, standard deviation, Pearson’s correlation coefficient, and the Bland–Altman method. Reproducibility was assessed by calculating the intra-rater and inter-rater reliabilities using intraclass correlation coefficients. Results In the model bone evaluation, the mean angles of the EMS measurement were 1.2° ± 2.0°, 45.4° ± 2.1°, 91.7° ± 2.4°, and 134.6° ± 2.7° at 0°, 45°, 90°, and 135°, respectively. In the in vivo evaluation, the elbow angles at the maximum extension with the EMS and radiographic angles were 4.7° ± 3.0° and 2.7° ± 2.0°, respectively, and the angles at maximum flexion were 131.8° ± 13.0° and 130.8° ± 4.5°, respectively. There were statistically significant correlations between the EMS and radiographic measurements; the Bland–Altman plots indicated that the two methods were almost in agreement for both extension and flexion. Conclusions This method of measuring ROM of the elbow joint using EMS showed high accuracy, reliability, and reproducibility. The current results demonstrated the possibility of using the electromagnetic system to provide an accurate evaluation of the elbow joint in clinical settings.

Abstract Introduction Excellent outcomes of arthroscopic rotator cuff repair for small and medium tears have been recently reported. However, re-tears after surgery have been a common complication after surgical repair of large and massive rotator cuff tears and often occur in early postoperative phase. It was previously reported that basic fibroblast growth factor and platelet-rich plasma enhanced rotator cuff tear healing. We hypothesized that this combined therapy could enhance rotator cuff healing after rotator cuff repair in a rat model. This study aimed to evaluate the efficacy of combined therapy of platelet-rich plasma and basic fibroblast growth factor with gelatin-hydrogel sheet. Methods To create a rotator cuff defect, the infraspinatus tendon of Sprague Dawley rat was resected from the greater tuberosity. The infraspinatus tendons were repaired and covered with gelatin-hydrogel sheet impregnated with PBS (control group), basic fibroblast growth factor (bFGF group), platelet-rich plasma (PRP group), or both basic fibroblast growth factor and platelet-rich plasma (combined group). Histological examinations were conducted using hematoxylin and eosin, safranin O, and immunofluorescence staining, such as Isolectin B4, type II collagen at 2 weeks postoperatively. For mechanical analysis, ultimate failure load of the tendon-humeral head complex was evaluated at 6 weeks postoperatively. Results In the hematoxylin and eosin staining, the tendon maturing score of the combined group was higher than that of the control group at postoperative 2 weeks. In the safranin O staining, stronger proteoglycan staining was observed in the combined group compared with the other groups at postoperative 2 weeks. Vascular staining with isolectin B4 in 3 treatment groups was significantly higher than that in the control group. Type II collagen expression in the combined group was significantly higher than those in the other groups. The ultimate failure load of the combined group was significantly higher than that of the control group. Conclusion Combined therapy of basic fibroblast growth factor and platelet-rich plasma promoted angiogenesis, tendon maturing and fibrocartilage regeneration at the enthesis, which could enhance the mechanical strength. It was suggested that combined basic fibroblast growth factor and platelet-rich plasma might enhance both tendon and bone–tendon junction healing, and basic fibroblast growth factor and platelet-rich plasma might be synergistic.

Purpose Fracture-related infections are difficult to treat because of the formation of biofilms around implants. Systemic antibiotics are notoriously ineffective against biofilms due to their insufficient penetration of tissues with poor vascularity. The goal of treating fracture-related infections is to achieve bone union while retaining the implant. Our proposal of continuous local antibiotic perfusion is a sustained local delivery system of sufficient antibiotics to bone and soft tissue infection sites, including to bone marrow via needles as intra-medullary antibiotics perfusion and to soft-tissue via double-lumen subcutaneous tubes as intra-soft tissue perfusion. Methods In this study, we examined the outcomes of 40 patients treated for fracture-related infections using continuous local antibiotic perfusion between 2015 and 2021 at Steel Memorial Hirohata Hospital, Himeji, Japan. Result The antibiotic used for continuous local antibiotic perfusion was gentamicin in all cases. Implant removal was required in five patients. Two patients required toe amputation and knee arthrodesis, while the remaining 38 patients achieved fracture union. Only one case of transient acute renal injury as a systemic side effect was observed, but it soon resolved. The blood concentration of gentamicin could be adjusted to less than the trough level. Conclusions Continuous local antibiotic perfusion is a novel local drug delivery system that has the potential of delivering sufficient concentrations of antibiotics with few systemic side effects; it is a useful option for the treatment of fracture-related infections.

Background: Coronal shear fractures of the distal humerus are rare injuries, and fragmentation of the capitellum and trochlea with posterior comminution is challenging for surgeons. We retrospectively evaluated the functional outcomes of patients with coronal shear fractures managed with open reduction and internal fixation, focusing on the number of trochlea fragments in Dubberley type 3B fractures. Materials and methods: The functional outcomes of 25 patients, including 8 patients with type 3B fractures, with a mean age (and standard deviation) of 57 ± 20 years, were evaluated at a mean follow-up duration of 15 ± 9 months. Type 3B fractures were classified into two groups: those with two trochlea fragments or less group (group A) and those with three or more fragments (group B). Patient outcomes were assessed with clinical and radiographic examination, range of motion, and the Mayo Elbow Performance scale (MEPS). Results: Two patients with type 3B in group B experienced nonunion, and two patients with type 3B in group A and 1 patient with type 1B demonstrated avascular necrosis on radiographs. The average MEPS score was 96.3 points (range, 70-100), with 18 excellent, 5 good, and 1 fair results. The average range of motion was 10 ± 8 to 130 ± 12. The MEPS score worsened as Dubberley classification progressed from type 1 to type 3 (98.3 vs. 96.7 vs. 88, P = .014, respectively) and subtypes A to B (97.9 vs. 90, P = .014, respectively). In comparing groups A and B, the MEPS score was significantly worse in group B (93.8 vs. 76.3, P = .006). Conclusion: Our open reduction and internal fixation results were largely good, although functional outcomes were diminished as Dubberley classification progressed from type 1 to type 3 and subtype A to B. Type 3B fractures with three trochlea fragments or more in the elderly were the most difficult to treat with open reduction and internal fixation and possibly 1-term total elbow arthroplasty.

Abstract Background Rich vascularity of the induced membrane (IM) is important for Masquelet reconstruction surgery. The factors affecting IM vascularity are not completely understood. This study aimed to investigate these factors using histological samples of human IMs. Methods We retrospectively evaluated 36 patients whose bone defects were treated using the Masquelet technique. Two clinical pathologists analyzed histological sections of IM pieces (1 cm2). The number of blood vessels per 1 mm2 was counted and compared among men and women, femur or tibia, with and without free flap surgery, antibiotic impregnation to the cement, osteogenesis inside the membrane, smoking, and diabetes mellitus. The number of blood vessels within the same patient was compared among different time points. Correlation analysis was performed among blood vessel numbers and patient age, duration of cement spacer placement, and histological grading scales (inflammation, foreign body reaction, and fibrosis). Results IM formation with rich vascularity and some inflammation, foreign body reaction, and fibrosis were histologically confirmed in all patients. We found 37.4 ± 19.1 blood vessels per 1 mm2. The number of blood vessels was significantly lower in patients with than in those without free flap surgery; it was higher in patients with osteogenesis inside the IM. No significant correlations were found in any of the analyses. Conclusion Sex, patient age, smoking, diabetes mellitus, femur or tibia, duration of cement spacer placement, and antibiotic impregnation to the cement did not affect IM vascularization. IM vascularization was reduced in patients with than in those without free flap surgery.

Abstract Introduction Previous studies have reported that alignment changes depend on the patient’s position in orthopedic surgery. However, it has not yet been well examined how the patient’s position affects the preoperative planning in high-tibial osteotomy (HTO). Therefore, the aim of this study was to investigate the effects of the patient’s position on preoperative planning in HTO. Materials and methods A total of 60 knees in 55 patients who underwent HTO were retrospectively examined. Virtual preoperative planning for medial open-wedge HTO (OWHTO), lateral closed-wedge HTO (CWHTO), and hybrid CWHTO were performed by setting the percentage of the weight-bearing line (%WBL) at 62% as an optimal alignment. The correction angle differences between the supine and standing radiographs were measured. The virtual %WBL (v%WBL) was determined by applying the correction angle obtained from the standing radiograph to the supine radiograph. The %WBL discrepancy (%WBLd) was calculated as v%WBL − 62 (%) to predict the possible correction errors during surgeries. A single regression analysis was performed to examine the correlation between the correction angle difference and %WBLd. Results The mean correction angle was significantly higher when the preoperative planning was based on standing radiographs than when based on supine radiographs (P

Abstract Background Novel therapeutic strategies for the healing of nonunion, which has serious effects on the quality of life of patients, are needed. We evaluated the therapeutic effect of local transplantation of human stromal vascular fraction (SVF) cells on fracture healing in a rat non-healing fracture model and compared the effects between freshly isolated (F) and cryopreserved (C)-SVFs. Methods Non-healing fracture model was induced in the femur of female immunodeficient rats (F344/N Jcl rnu/rnu) with cauterizing periosteum. Immediately after the creation of non-healing fracture, rats received local transplantation of F and C-SVFs suspended in phosphate-buffered saline (PBS) or the same volume of PBS without cells using the same scaffold as a control group. During 8 weeks post-surgery, radiologic, histological, immunohistochemical, and biomechanical analyses were performed to evaluate fracture healing. The comparison of radiological results was performed with a chi-square test, and the multiple comparisons of immunohistochemical, histological, and biomechanical results among groups were made using a one-way analysis of variance. A probability value of 0.05 was considered to denote statistical significance. Results At week 8, in 60% of animals receiving F-SVF cells and in 50% of animals receiving C-SVF cells, the fracture radiologically healed with bone union whereas nonunion was observed in the control group. The healing potential was also confirmed by histological and biomechanical assessments. One of the mechanisms underlying healing involving intrinsic angiogenesis/osteogenesis was enhanced in F- and C-SVF groups compared with that in the control group. Human cell-derived vasculogenesis/osteogenesis, which was also confirmed in an in vitro differentiation assay, was also enhanced in the F- and C-SVF groups compared with that in the control groups and could be another mechanism for healing. Conclusions SVF cells can enhance bone healing and cryopreserved cells have almost equal potential as fresh cells. SVF cells can be used for improving nonunion bone fracture healing as an alternative to other mesenchymal stem cells and the effect of SVF cells can be maintained under cryopreservation.

Abstract Background Recently, a standardized uptake value (SUV) has been used to evaluate bone single-photon emission computed tomography (SPECT). The aim of this study was to investigate quantitative SPECT imaging of uninfected nonunion to compare hypertrophic nonunion and non-hypertrophic nonunion using volume-based parameters. Methods We evaluated 23 patients with uninfected nonunion who underwent SPECT acquisition 3 h after an injection of 99mTc-hydroxymethylene diphosphonate or 99mTc-methylene diphosphonate from April 2014 to November 2019. We reconstructed the acquired data and performed voxel-based quantitative analysis using the GI-BONE software. Quantitative parameters, maximum SUV (SUVmax), peak SUV (SUVpeak), and mean SUV (SUVmean) in the high and low uptake areas of nonunion were compared between hypertrophic nonunion and non-hypertrophic nonunion. The contralateral limb was used as a control, and the ratios of the quantitative parameters were calculated. Results The values for the quantitative parameters (high uptake area/low uptake area, respectively), SUVmax control ratio (12.13 ± 4.95/6.44 ± 4.71), SUVpeak control ratio (11.65 ± 4.58/6.45 ± 4.64), and SUVmean control ratio (11.94 ± 5.03/6.28 ± 4.95) for hypertrophic nonunion were higher than those for non-hypertrophic nonunion (7.82 ± 4.76/3.41 ± 2.09 (p = 0.065/0.12), 7.56 ± 4.51/3.61 ± 2.23 (p = 0.065/0.22), and 7.59 ± 5.18/3.05 ± 1.91 (p = 0.076/0.23)). Conclusions SUVmax, SUVpeak, and SUVmean control ratios obtained from bone SPECT images can quantitatively evaluate the biological activity of nonunions and may be an effective evaluation method for treatment decisions, especially the necessity of autologous bone grafting.

Although immobility is a common cause of muscle atrophy, the mechanism underlying this causality is unclear. We here show that Krüppel-like factor 15 (KLF15) and IL-6 are upregulated in skeletal muscle of limb-immobilized mice and that mice with KLF15 deficiency in skeletal muscle or with systemic IL-6 deficiency are protected from immobility-induced muscle atrophy. A newly developed Ca2+ bioimaging revealed that the cytosolic Ca2+ concentration ([Ca2+]i) of skeletal muscle is reduced to below the basal level by immobilization, which is associated with the downregulation of Piezo1. Acute disruption of Piezo1 in skeletal muscle induced Klf15 and Il6 expression as well as muscle atrophy, which was prevented by antibodies against IL-6. A role for the Piezo1/KLF15/IL-6 axis in immobility-induced muscle atrophy was validated in human samples. Our results thus uncover a paradigm for Ca2+ signaling in that a decrease in [Ca2+]i from the basal level triggers a defined biological event.

Abstract Background Cancer stem cells (CSCs) are considered to be responsible for tumor initiation, formation, and poor prognosis of cancer patients. However, the rarity of CSCs in clinical samples makes it difficult to elucidate characteristics of CSCs, especially in osteosarcoma (OS). The aim of this study is to verify whether it is possible to generate CSC-like cells by transducing defined factors into an OS cell line. Methods We retrovirally transduced the Octamer-binding transcription factor 3/4 (OCT3/4), Kruppel-like factor 4 (KLF4), and SRY-box transcription factor 2 (SOX2) genes into the MG-63 human OS cell line (MG-OKS). Parental and GFP-transduced MG-63 cells were used as negative control. We assessed the properties of the generated cells in vitro and in vivo. Multiple comparisons among groups were made using a one-way analysis of variance (ANOVA) followed by post hoc testing with Tukey’s procedure. Results MG-OKS cells in vitro exhibited the significantly increased mRNA expression levels of CSC markers (CD24, CD26, and CD133), decreased cell growth, increased chemoresistance and cell migration, and enhanced sphere formation. Notably, MG-OKS cells cultured under osteogenic differentiation conditions showed strongly positive staining for both Alizarin Red S and alkaline phosphatase, indicating osteogenesis of the cells. Gene ontology analysis of microarray data revealed significant upregulation of epidermal-related genes. Tumors derived from MG-OKS cells in vivo were significantly larger than those from other cells in μCT analysis, and immunohistochemical staining showed that Ki-67, osteocalcin, and HIF-1α-positive cells were more frequently detected in the MG-OKS-derived tumors. Conclusions In this study, we successfully generated OS CSC-like cells with significantly enhanced CSC properties following transduction of defined factors.

Abstract Background We hypothesized that preoperative pelvic morphology may affect postoperative anterior coverage and postoperative clinical range of motion (ROM) leading to postoperative pincer type femoroacetabular impingement (FAI). The aim of this study was to evaluate the relationships between preoperative bone morphology and postoperative ROMs to prevent postoperative FAI after periacetabular osteotomy. Methods Sixty-eight patients (71 hips) with hip dysplasia participated in this study and underwent curved PAO. The acetabular fragment was usually moved only by lateral rotation of the acetabulum, without intraoperative anterior or posterior rotation. The pre- and postoperative three-dimensional center-edge (CE) angles were measured and compared to the postoperative ROM. Results Preoperative medial anterior CE angle was significantly associated with postoperative anterior CE angle, and the correlation coefficient of medial anterior CE and postoperative anterior CE was higher than the coefficient of preoperative anterior CE and postoperative anterior CE (preoperative anterior CE, rr = 0.27, p = 0.020; preoperative medial anterior CE, rr = 0.54, p < 0.001). Femoral anteversion correlated with postoperative internal rotation angle at 90° flexion (r = 0.32, p = 0.021). In multiple linear regressions, postoperative internal rotation angle at 90° flexion angle was significantly affected by both medial CE angle through the medial one fourth of femoral head and femoral anteversion. Conclusions Preoperative medial anterior acetabular coverage was associated with postoperative anterior acetabular coverage. Further, the combination with preoperative medial anterior acetabular coverage and femoral anteversion can predict postoperative internal rotation at 90° flexion. Therefore, the direction of acetabular reorientation should be carefully considered when the patients have high preoperative medial anterior CE angle and small femoral anteversion.

Abstract 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.

Abstract Background Rad is the prototypic member of a subfamily of Ras-related small G-proteins and is highly expressed in the skeletal muscle of patients with type II diabetes. Our previous microarray analysis suggested that Rad may mediate fracture nonunion development. Thus, the present study used rat experimental models to investigate and compare the gene and protein expression patterns of both Rad and Rem1, another RGK subfamily member, in nonunions and standard healing fractures. Methods Standard healing fractures and nonunions (produced via periosteal cauterization at the fracture site) were created in the femurs of 3-month-old male Sprague-Dawley rats. At post-fracture days 7, 14, 21, and 28, the fracture callus and fibrous tissue from the standard healing fractures and nonunions, respectively, were harvested and screened (via real-time PCR) for Rad and Rem1 expression. The immunolocalization of both encoded proteins was analyzed at post-fracture days 14 and 21. At the same time points, hematoxylin and eosin staining was performed to identify the detailed tissue structures. Results Results of real-time PCR analysis showed that Rad expression increased significantly in the nonunions, compared to that in the standard healing fractures, at post-fracture days 14, 21, and 28. Conversely, immunohistochemical analysis revealed the immunolocalization of Rad to be similar to that of Rem1 in both fracture types at post-fracture days 14 and 21. Conclusions Rad may mediate nonunion development, and thus, may be a promising therapeutic target to treat these injuries.

Purpose In our hospital, cases of bone and soft tissue infections have been treated with continuous local antibiotics perfusion that allows for continuous circulation of antibiotics throughout the infected lesion. We termed this treatment “intramedullary antibiotics perfusion (iMAP)” for bone infection such as fracture-related infection (FRI) and “intrasoft tissue antibiotics perfusion” for soft tissue infection. Many cases are treated with both modalities. To introduce iMAP, this study focused on the patients with FRI treated with iMAP and reviewed their treatment outcomes. Methods We included 10 patients with FRI treated with iMAP between 2004 and 2017. The iMAP needles were inserted near the infected lesion, and an aminoglycoside antimicrobial was continuously administered. Patient characteristics, pathogenic bacteria, administered antibiotics, duration of administration, concentrations of antibiotics in blood and leachate fluid, fracture union rate, implant retention rate, and complications were studied. Results The mean age of patients was 59.9 years, and the mean follow-up period was 2.5 years. Affected bones were the tibia ( n = 8), humerus ( n = 1), and fibula ( n = 1). Deep infections developed on average 29.9 days after osteosynthesis. Pathogenic bacteria were methicillin-susceptible Staphylococcus aureus ( n = 6), methicillin-resistant S. aureus ( n = 2), and unknown ( n = 2). Average iMAP duration was 17.1 days. In all patients, infection was eradicated while preserving the implants, and fracture union was achieved without complications. Conclusion iMAP is a novel local drug delivery system allowing high concentrations of antibiotics to be administered without complications and is useful in the treatment of FRI.

Abstract 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).

Abstract 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.

Background: Skeletal related events due to metastatic bone tumors markedly affect the activities of daily living (ADL) and quality of life (QOL) in cancer patients. We focused on multidisciplinary therapy for metastatic bone tumors. This study aimed to evaluate the outcomes of surgical treatment for metastatic bone tumors in the extremities. Methods: We retrospectively reviewed 114 patients who underwent surgical treatment for metastatic bone tumors of the extremities between 2008 and 2019 and 69 patients were reassessed for more than 6 months after surgery. The most common primary tumor was renal, followed by lung, thyroid, and breast cancers. We assessed 69 patients’ performance status (PS), Barthel Index (BI) for ADL, EuroQol 5 Dimensions (EQ-5D) for QOL, and numerical rating scale (NRS) for pain and analyzed these postoperative values relative to preoperative values using Friedman’s test. The postoperative overall survival and the prognostic factors were evaluated using the Kaplan-Meier method, the log-rank test and Cox proportional hazards analysis. Results: The 1-year overall survival rate was 59%, and the median survival time after surgery was 20 months. Primary tumor, visceral metastasis, and surgical procedure were risk factors correlated with overall survival. PS, BI, EQ-5D, and NRS improved at 3 months after surgery and these improvements were maintained for 6 months after surgery regardless of the surgical procedure. Conclusions: The significant factors affecting survival after surgical treatment for bone metastases included the primary tumor, presence of visceral metastases, and internal fixation without tumor resection or curettage. Surgical treatment for metastatic bone tumors effectively reduced pain and improved PS, ADL, and QOL postoperatively after 3 months.

Introduction. Although the recommended treatment for humeral shaft nonunion is compression plating with autologous bone grafting, we treated a case of humeral shaft nonunion with an intramedullary nail (IMN) without bone grafting. Presentation of Case. Osteosynthesis with IMN was performed on a 24-year-old man with a humeral shaft fracture at another hospital. However, bony union was not obtained 1 year after the first surgery, and he was referred to our institution. We treated the nonunion with exchange nailing without autologous bone grafting using compression function of the nail, leading to bony union at 7 months postoperatively. At the final follow-up 2 years and 4 months postoperatively, the patient had full range of motion in the left shoulder and elbow joints. Discussion. Compression plating with autologous bone grafting is reported to be the gold standard for the treatment of humeral shaft nonunion. IMN is advantageous for minimal invasion; however, the conventional type of IMN cannot apply compression force between fragments and does not have sufficient stability against rotational force. In this case, we used an IMN that could apply compression between the fragments and which had rotational stability via many screws. We did not perform bone grafting because the current nonunion was adjudged to be biologically active, and we achieved good functional results. Conclusion. We treated humeral shaft nonunion using IMN with compression, but without bone grafting, leading to successful clinical outcomes. This strategy might be an appropriate choice for the treatment of humeral shaft nonunion with biological activity.

Tumor-induced osteomalacia (TIO) is a rare skeletal disease caused by hypersecretion of fibroblast growth factor 23 (FGF-23) from neoplasms of mesenchymal origin; patients with TIO present with insufficiency fractures, progressive bone pain, and delayed fracture unions. Herein, we report the case of a 48-year-old man with an insufficiency fracture in his left femoral neck associated with TIO. The causative tumor located in the patient’s maxillary sinus had been resected; however, complete resection was impossible due to the location of the tumor. Therefore, the patient’s osteomalacia persisted, and he experienced a left femoral neck fracture in the absence of severe trauma. Because delayed fracture union was anticipated in this patient, we performed an internal fixation using an implant with a lateral plate for angular stability and multiple screws for rotational stability. Although fracture union took 15 months, the patient’s postoperative course was uneventful, and he could walk without any symptoms or assistance at his most recent follow-up 30 months after surgery. In TIO, hypersecretion of FGF-23 leads to increased renal excretion of phosphorus, increased bone resorption of calcium and phosphorus, decreased osteoblastic bone mineralization, and decreased gastrointestinal absorption of calcium and phosphorus, leading to insufficiency fractures and delayed fracture unions. Diagnosis of TIO is often delayed due to its rarity and vague symptoms. Total resection of the causative tumor is the optimal treatment; however, in cases wherein complete tumor resection is impossible, drug therapy may be insufficient, and the underlying TIO pathology, including bone fragility, may persist. Early diagnosis of TIO is important for preventing insufficiency fractures; however, when fractures are unavoidable, the surgical treatment of femoral neck fractures in patients with osteomalacia should account for a longer time frame for complete fracture union and therefore utilize implants with sufficient stability.

Introduction Diabetes mellitus (DM) negatively affects fracture repair by inhibiting endochondral ossification, chondrogenesis, callus formation, and angiogenesis. We previously reported that transcutaneous CO2 application accelerates fracture repair by promoting endochondral ossification and angiogenesis. The present study aimed to determine whether CO2 treatment would promote fracture repair in cases with type I DM.Research design and methods A closed femoral shaft fracture was induced in female rats with streptozotocin-induced type I DM. CO2 treatment was performed five times a week for the CO2 group. Sham treatment, where CO2 was replaced with air, was performed for the control group. Radiographic, histologic, genetic, and biomechanical measurements were taken at several time points.Results Radiographic assessment demonstrated that fracture repair was induced in the CO2 group. Histologically, accelerated endochondral ossification and capillary formation were observed in the CO2 group. Immunohistochemical assessment indicated that early postfracture proliferation of chondrocytes in callus was enhanced in the CO2 group. Genetic assessment results suggested that cartilage and bone formation, angiogenesis, and vasodilation were upregulated in the CO2 group. Biomechanical assessment revealed enhanced mechanical strength in the CO2 group.Conclusions Our findings suggest that CO2 treatment accelerates fracture repair in type I DM rats. CO2 treatment could be an effective strategy for delayed fracture repair due to DM.

INTRODUCTION:Surgical site infection is one of the most severe complications of surgical treatments. However, the optimal procedure to prevent such infections remains uninvestigated. Ultraviolet radiation C (UVC) with a short wavelength has a high bactericidal effect; however, it is cytotoxic. Nonetheless, given that UVC with a wavelength of 222 nm reaches only the stratum corneum, it does not affect the skin cells. This study aimed to investigate the safety of 222-nm UVC irradiation and to examine its skin sterilization effect in healthy volunteers. METHODS:This trial was conducted on 20 healthy volunteers. The back of the subject was irradiated with 222-nm UVC at 50-500 mJ/cm2, and the induced erythema (redness of skin) was evaluated. Subsequently, the back was irradiated with a maximum amount of UVC not causing erythema, and the skin swabs before and after the irradiation were cultured. The number of colonies formed after 24 hours was measured. In addition, cyclobutene pyrimidine dimer (CPD) as an indicator of DNA damage was measured using skin tissues of the nonirradiated and irradiated regions. RESULTS:All subjects experienced no erythema at all doses. The back of the subject was irradiated at 500 mJ/cm2, and the number of bacterial colonies in the skin swab culture was significantly decreased by 222-nm UVC irradiation. The CPD amount produced in the irradiated region was slightly but significantly higher than that of the non-irradiated region. CONCLUSION:A 222-nm UVC at 500 mJ/cm2 was a safe irradiation dose and possessed bactericidal effects. In the future, 222-nm UVC irradiation is expected to contribute to the prevention of perioperative infection.

Curved periacetabular osteotomy (CPO) is used for the treatment of dysplastic hips. Previous studies have reported satisfying outcomes and low rate of severe complications associated with this procedure; however, no case of postoperative sciatic nerve palsy has been reported. In this study, we describe a case of postoperative sciatic nerve palsy following CPO due to nerve strangulation by scar tissue without direct injury. A female patient had severe buttock pain and posterior leg numbness after she underwent left-side CPO. Postoperative magnetic resonance imaging showed that the sciatic nerve was strangulated by the surrounding soft tissue. There was no bone fragment, active infection, bone necrosis, tumor, or spine disease. Therefore, we diagnosed nerve palsy by soft tissue strangulation, and revision surgery was indicated. During revision surgery, the sciatic nerve was observed to be strangulated by the scarring soft tissue, and the nerve had no mobility. After detachment, the pain and numbness disappeared. Direct injury of the sciatic nerve should not be caused by CPO; however, there is a possibility of postoperative sciatic nerve palsy due to the scarring soft tissue. Early diagnosis and appropriate treatment are important for optimal postoperative clinical outcomes.

A 14-year-old girl experienced acute left buttock pain during a sprint. At the local hospital, she was diagnosed with an avulsion fracture of the left ischial tuberosity. She was kept for observation for about 10 months; however, the buttock pain persisted, and the bone fragments did not unite. She was referred to our hospital approximately 11 months after the injury. Plain radiography revealed an increased transposition of the bone fragment, from 12 mm immediately after the injury to 23 mm. Twelve months after the injury, she underwent osteosynthesis using two cannulated cancellous screws and three suture anchors. Following postoperative rehabilitation, the power in her left hamstring recovered, and she was able to run at full speed and returned to athletics 9 months after the surgery. The operative indications for avulsion fractures of the ischial tuberosity are unclear. Careful follow-up is required as the rate of nonunion after conservative treatment tends to be high. This needs to be identified in order to provide timely treatment that allows for early return to sport. Although she had significant chronic pain and muscle weakness, the surgery successfully treated the fracture, and her muscle power recovered, leading to her return to sports.

Abstract 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

Background: Data of vitamin D sufficiency in Asian patients with osteoporotic fragility hip fractures are limited. This study aimed to obtain data from the Japanese population. Methods: Patients aged 60 years or older with hip fractures were prospectively enrolled. Serum 25-hydroxyvitamin D (25(OH)D) levels were measured. Levels were compared between patients receiving and not receiving treatment for osteoporosis, those with and without previous contralateral hip fractures, and those with femoral neck versus trochanteric fractures. Sex-based differences were also assessed. The serum levels in patients younger than 60 years with extremity fractures were assessed, and differences between elderly and younger patients were evaluated. The individual correlation between 25(OH)D levels and the ultraviolet (UV) index and age was analyzed in elderly patients with hip fractures. Results: The data of 360 patients (aged 84.7 ± 8.2 years), comprising 80 men and 280 women, were analyzed. The mean 25(OH)D level was 16.5 ± 7.2 ng/mL. The prevalence of vitamin D insufficiency (25(OH)D

ABSTRACT Improving patient health‐related quality of life (HRQOL) and prevention of bone fracture are important components of the treatment of osteoporosis. Our aim in this study was to evaluate the effect of denosumab treatment in improving HRQOL among patients with osteoporosis. Our analysis was based on 332 patients with osteoporosis, followed for 24 months. All patients received denosumab (60 mg) subcutaneously every 6 months. Bone mineral density (BMD) was assessed at the distal radius, with serum concentration of calcium, phosphate, P1NP, and TRACP5b also measured. HRQOL assessment included pain (visual analogue scale [VAS]) and the EQ‐5D questionnaire. A multivariate analysis was performed to identify the possible confounders associated with deterioration in the EQ‐5D utility score in response to denosumab treatment. Denosumab treatment yielded a 3.4% increase in BMD at 24 months. Serum levels of TRACP5b and P1NP decreased significantly, from baseline, at 6 months, with no effect on calcium and phosphate levels. Pain VAS and EQ‐5D utility score improved significantly, from baseline, at 6 months, with the EQ‐5D utility score correlating with the BMD at all time points of measurement over the 24‐month period of observation. Knee osteoarthritis and multiple comorbidities were significantly associated with a worse HRQOL in response to denosumab treatment. Denosumab treatment increased BMD, with improvements in BMD correlating with improved HRQOL, supporting a possible benefit of using denosumab for the treatment of osteoporosis. © 2019 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.

Purpose: To assess the accuracy of cup orientation and learning curve of the disposable accelerometer-based portable navigation system for total hip arthroplasty (THA) in the supine position. Methods: A total of 75 patients who underwent THA through the anterolateral supine approach (ALS) with an accelerometer-based portable navigation system for the supine position (HipAlign ® ) between July 2017 and October 2018 were analyzed in this study. We compared the intraoperative cup angles using navigation records with the postoperative angles using postoperative computed tomography (CT) data. All patients were categorized into the following groups according to the course of three discrete, sequential operative time periods: 1–25 (initial group), 26–50 (intermediate group), and 51–75 (recent group). We compared the accuracy of cup inclination and anteversion among the three groups. The time required for navigation and the operative time of all patients were measured. Results: The average absolute error in measurement (postoperative CT-navigation record) was 2.6° ± 2.7° (inclination) and 2.8° ± 2.7° (anteversion). There were no significant differences among the three groups. The average time required for navigation and the operative time were 365.1 ± 90.3 s and 76.1 ± 1.6 min, respectively. The required time for HipAlign ® navigation and operative time were constant in most patients, except for those of the initial five cases. Conclusion: The accelerometer-based portable navigation system provides good accuracy of cup orientation, has a short learning curve, and requires a minimal surgical time for THA in supine position.

Purpose: The factors affecting anterior tibial subluxation (ATS) have not yet been well examined. To assess the factors affecting ATS in anterior cruciate ligament (ACL)-deficient knees. Methods: One hundred twenty-four patients with unilateral ACL injuries were included. True lateral views of the ACL-deficient knee and contralateral normal knee were obtained during maximum extension using fluoroscopy under general anesthesia, and ATS was calculated as the side-to-side difference in the tibial position relative to the femur. Patients were divided into four groups according to the time from injury to surgery. To identify the factors affecting ATS, the following possible factors were assessed: (1) the time from injury to surgery, (2) presence of a medial meniscal injury, and (3) posterior tibial slope angle. Results: There was a positive correlation between the ATS ratio and the time from injury to surgery ( r = 0.52). The ratio of the presence of a medial meniscus injury was significantly higher in patients who underwent anterior tibial subluxation reconstruction (ACL-R) more than 12 months after an injury than in other patients who underwent ACL-R within 12 months after an injury. The ATS ratio was significantly higher in patients with a medial meniscus injury than in those without a medial meniscus injury (5.6% vs. 4.1%). Conclusions: Our results suggested that ACL-R should be performed within 6 months after injury if surgeons prefer to avoid an increase in ATS in maximum knee extension and at the latest within 12 months to avoid medial meniscal injury at the time of ACL-R.

Although the definition of atypical femoral fracture (AFF) excludes periprosthetic femoral fracture (PFF), the number of reports about PFF with characteristics of AFF is increasing. We present the case of such a fracture in this report. An 87-year-old woman who underwent bipolar hip arthroplasty for a femoral neck fracture 38 months prior reported left thigh pain with no history of trauma. Radiographs showed a simple transverse fracture at the level of the stem distal end with features of AFF: periosteal thickening of the lateral cortex, a medial spike, and a noncomminuted fracture. She presented other features resembling AFF: history of bisphosphonate use, prodromal symptoms, no associated trauma, and lateral bowing of the contralateral femur. The fracture showed nonunion after the initial osteosynthesis, and a revision surgery of the arthroplasty and osteosynthesis was performed. Nine months after the surgery, bony union was achieved and she regained the ability to walk. It is supposed that the fracture was influenced by a stress force related to implants and lateral bowing concentrating on the fracture site as a mechanical factor in addition to bisphosphonates as a biological factor. It would be important to recognize that AFF could occur at the peri-implant location, and early detection and treatment are essential.

Background and objectives: Internal fixation is one of the most effective methods for the treatment of proximal femur fractures. The migration of implants after the operation can seriously affect the reduction of treatment and even cause complications. Traditional diagnosis methods can not directly measure the extent of displacement. Methods: Based on the analysis of Hansson pins, this paper proposes a measurement method based on three-dimensional matching, which uses computerized tomography (CT) images of different periods of patients after the operation to analyze the implants’ migration in three-dimensional space with the characteristics of fast speed and intuitive results. Results and conclusions: The measurement results show that the method proposed in this paper has more minor errors, more flexible coordinate system conversion, and more explicit displacement analysis than the traditional method of manually finding references in CT images and measuring displacement.

Femoral neck fractures have a high incidence in the geriatric population and are associated with high mortality and disability rates. With the minimally invasive nature, internal fixation is widely used as a treatment option to stabilize femoral neck fractures. The fixation effectiveness and stability of the implant is an essential guide for the surgeon. However, there is no long-term reliable evaluation method to quantify the implant’s fixation effect without affecting the patient’s behavior and synthesizing long-term treatment data. For the femur’s symmetrical structure, this study used 3D convolutional networks for biomedical image segmentation (3D-UNet) to segment the injured femur as a mask, aligned computerized tomography (CT) scans of the patient at different times after surgery and quantified the displacement in the specified direction using the generated 3D point cloud. In the experimental part, we used 10 groups containing two CT images scanned at the one-year interval after surgery. By comparing manual segmentation of femur and segmentation of femur as a mask using neural network, the mask obtained by segmentation using the 3D-UNet network with symmetric structure fully meets the requirements of image registration. The data obtained from the 3D point cloud calculation is within the error tolerance, and the calculated displacement of the implant can be visualized in 3D space.

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.

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.

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.

Purpose. To evaluate the rate of venous thromboembolism (VTE) after complex lower-limb fracture surgery without pharmacological prophylaxis. Methods. Between July 2005 and April 2009, 11 men and 6 women (mean age, 45 years) underwent temporary external fixation followed by internal fixation for a total of 3 femoral and 20 tibial fractures. Patients were screened for VTE using contrast-enhanced computed tomography (CT) when the D-dimer value was beyond normal range. Between May 2009 and December 2012, 18 men and 4 women (mean age, 45 years) underwent temporary external fixation followed by internal fixation for a total of 8 femoral and 20 tibial fractures. Patients were routinely screened for deep vein thrombosis (DVT) using ultrasonography and for pulmonary embolism (PE) using contrast-enhanced CT (in high-risk patients with multiple injuries or pelvic and acetabular fractures). In both groups, pharmacological prophylaxis was not used; only mechanical prophylaxis was used. Results. The 2 groups were comparable in terms of age, sex, and proportion of bilateral external fixation, open fracture, and associated injury, except that the duration of external fixation was longer in the early group (29.8±28.0 vs. 11.6±4.0 days, p=0.001). Of the 17 patients in the early group, 5 developed VTEs (3 DVTs and 2 PEs) at a mean of 13.6 (range, 6–20) days after injury; 2 of whom developed VTE during the external fixation period. Of the 22 patients in the later period, 10 developed VTEs (10 DVTs and 4 PEs) at a mean of 13 (range, 5–33) days after injury; 7 of whom developed VTE during the external fixation period. Conclusion. The rate of VTE was high in patients undergoing complex lower-limb fracture surgery without pharmacological prophylaxis.

We report a case of chronic calcaneal osteomyelitis in a diabetic patient who was successfully treated with radical debridement and gentamycin-impregnated calcium phosphate cement. At 1.5-year follow-up, the patient could walk without any assistance. Calcium phosphate cement is an effective local antibiotic delivery system and a biocompatible material for filling the debrided space to facilitate bone formation.

Purpose. To review the outcomes of 102 consecutive patients who underwent fixation for nonunion of extremities. Methods. Medical records of 71 men and 31 women aged 16 to 82 (mean, 45; standard deviation [SD], 19) years who underwent fixation for nonunion of the upper (n=31) and lower (n=71) extremities were reviewed. The nonunion types included oligotrophic (n=47), hypertrophic (n=22), atrophic (n=17), defect (n=12), and comminuted (n=4). 13 of the nonunions were infected. 10 patients had concomitant injuries of the brain (n=2), abdomen (n=5), chest (n=1), and spine (n=2). 43 patients were smokers, and 19 had diabetes mellitus. 80 patients had had previous surgery, and 3 had undergone previous radiotherapy. The mean time from injury to nonunion surgery was 19 (SD, 25.6; range, 6–180) months. Outcome measures included bone union, ability to return to original work, pain, gait, and loss of range of motion. Results. The mean follow-up period was 26.6 (SD, 19.9; range, 8–121) months. 100 patients achieved bone union. 83 of them achieved bone union after a single surgery in a mean of 5.6 (SD, 2.9) months. The remaining 17 patients underwent multiple surgeries, 13 of whom had infected nonunions. Two patients did not achieve bone union. Of 64 patients who had work, 47 returned to their original work and 17 did not. Outcome was unsatisfactory in 5 patients who had persistent pain and/or no improvement in gait. Conclusion. Bone union is not necessarily associated with adequate recovery of function.