Clinical Results of Carpal Tunnel Release Using Ultrasound Guidance in Over 100 Patients at Two to Six Years.

Purpose: The purpose of this study was to determine the clinical results of carpal tunnel release using ultrasound guidance (CTR-US) at a minimum of 2 years postprocedure. Methods: The study consisted of 102 patients (162 hands) treated with CTR-US by the same physician between June 2017 and October 2020 for whom minimum 2-year follow-up data were available. Questionnaires were sent to gather long-term information, with additional phone calls for clarification if needed. Outcomes included Boston Carpal Tunnel Questionnaire symptom severity (BCTQ-SSS) and functional status (BCTQ-FSS) scores; Quick Disabilities of the Arm, Shoulder, and Hand (QuickDASH) scores; global satisfaction scores; and subsequent surgeries. Results: The 102 patients included 68 females and 34 males with a mean age of 56.9 years at the time of surgery. Fifty-five (53.9%) patients had simultaneous bilateral procedures, 42 (41.2%) had unilateral procedures, and 5 (4.9%) had staged bilateral procedures. Significant improvements in BCTQ-SSS, BCTQ-FSS, and QuickDASH scores persisted at a mean final follow-up of 46 months (range 2-6 years). At final follow-up, 91.2% of patients reported satisfaction with the procedure. No outcomes were significantly different between those treated with simultaneous bilateral versus unilateral procedures. No revision surgeries were reported. Conclusions: CTR-US is a safe and effective procedure that results in significant improvements that persist up to 6 years postprocedure. Long-term results of simultaneous bilateral and unilateral procedures are similar. Type of study/level of evidence: Therapeutic IV.

Lumbar Discectomy With Bone-Anchored Annular Closure Device in Patients With Large Annular Defects: One-Year Results.

BACKGROUND: Reherniation rates following lumbar discectomy are low for most patients; however, patients with a large defect in the annulus fibrosis have a significantly higher risk of recurrence. Previous results from a randomized controlled trial (RCT) demonstrated that the implantation of a bone-anchored annular closure device (ACD) during discectomy surgery lowered the risk of symptomatic reherniation and reoperation over one year with fewer serious adverse events (SAEs) compared to discectomy alone. OBJECTIVE: The objective of this prospective, post-market, historically controlled study was to evaluate the use of an ACD during discectomy, and to confirm the results of the RCT that was used to establish regulatory approval in the United States. METHODS: In this post-market study, all patients (N = 55) received discectomy surgery with a bone-anchored ACD. The comparison population was patients enrolled in the RCT study who had discectomy with an ACD (N = 262) or discectomy alone (N = 272). All other eligibility criteria, surgical technique, device characteristics, and follow-up methodology were comparable between studies. Endpoints included rate of symptomatic reherniation or reoperation, SAEs, and patient-reported measures of disability, pain, and quality of life. RESULTS: Fifty-five patients received ACD implants at 12 sites between May 2020 and February 2021. In the previous RCT, 272 control patients had discectomy surgery alone (RCT-Control), and 262 patients had discectomy surgery with an ACD implant (RCT-ACD). Baseline characteristics across groups were typical of the overall population undergoing lumbar discectomy. The proportion of patients who experienced reherniation and/or reoperation was significantly lower in the ACD group compared to RCT-ACD and RCT-Control groups (p < 0.05). In the ACD study, the one-year rate of symptomatic reherniation was 3.7%, compared to 8.5% in the RCT-ACD group and 17.0% in the RCT-Control group. In the ACD group, the risk of reoperation was 5.5%, compared to 6.5% in the RCT-ACD group and 12.5% in the RCT-Control group. There were no device-related SAEs or device integrity failures in the ACD, and there were clinically meaningful improvements in patient-reported measures of disability, pain, and quality of life. CONCLUSION: In this post-market study of bone-anchored ACD in patients with large annular defects, rates of symptomatic reherniation, reoperation, and SAEs were all low. Compared to the RCT, the post-market ACD study demonstrated lower rates of reherniation and/or reoperation and measures of back pain one-year post-surgery.

The effect of expandable versus static lordotic interbody implants in minimally invasive spine surgery: patient reported outcomes, sagittal alignment, and restoration of disc height and foraminal height.

Background: Pain and disability due to age-related spinal disorders are increasing due to a more active population placing greater demands on their musculoskeletal system. For patients requiring surgery, spinal fusion is typically indicated. Interbody fusion cages improve fusion rates and restore lordosis, disc height, and foraminal height. Static cages are offered in multiple conformations to account for anatomic variability; however, they have issues related to implant subsidence and loss of lordosis. Expandable cages were developed to address these drawbacks. Methods: Patients treated with either static or expandable transforaminal lumbar interbody fusion devices (ProLift® Expandable Spacer System) for the treatment of spondylolisthesis, degenerative disc disease, spinal stenosis, disc herniation, or degenerative scoliosis at L4-L5 or L5-S1 were chosen from retrospective data. Outcomes included radiographic and spinopelvic changes, patient-reported outcomes, and incidence of non-union and revision surgery. Results: One hundred patients were included (Static: 50; Expandable: 50). Demographics between groups were similar, with some differences in comorbidities and spinal disease diagnosis. Radiographically, changes in disc height, foraminal height, and lordosis were significantly improved in the Expandable group up to 2 years (P<0.001). Improvements in patient reported outcomes were more favorable in the Expandable group. Conclusions: In patients who underwent transforaminal lumbar spinal fusion via minimally invasive surgery, the Expandable device group demonstrated significantly improved radiographic and patient reported outcomes compared to a static cage over 2 years.

Cost-effectiveness of 10-kHz spinal cord stimulation therapy compared with conventional medical management over the first 12 months of therapy for patients with nonsurgical back pain: randomized controlled trial.

OBJECTIVE: This analysis evaluated if spinal cord stimulation (SCS) at 10 kHz plus conventional medical management (CMM) is cost-effective compared with CMM alone for the treatment of nonsurgical refractory back pain (NSRBP). METHODS: NSRBP subjects were randomized 1:1 into the 10-kHz SCS (n = 83) or CMM (n = 76) group. Outcomes assessed at 6 months included EQ-5D 5-level (EQ-5D-5L), medication usage, and healthcare utilization (HCU). There was an optional crossover at 6 months and follow-up to 12 months. The incremental cost-effectiveness ratio (ICER) was calculated with cost including all HCU and medications except for the initial device and implant procedure, and cost-effectiveness was analyzed based on a willingness-to-pay threshold of < $50,000 per quality-adjusted life-year. RESULTS: Treatment with 10-kHz SCS resulted in a significant improvement in quality of life (QOL) over CMM (EQ-5D-5L index score change of 0.201 vs -0.042, p < 0.001) at a lower cost, based on reduced frequency of HCU resulting in an ICER of -$4964 at 12 months. The ICER was -$8620 comparing the 6 months on CMM with postcrossover on 10-kHz SCS. CONCLUSIONS: Treatment with 10-kHz SCS provides higher QOL at a lower average cost per patient compared with CMM. Assuming an average reimbursement for device and procedure, 10-kHz SCS therapy is predicted to be cost-effective for the treatment of NSRBP compared with CMM within 2.1 years.

Role of oxidative metabolism in osseointegration during spinal fusion.

Spinal fusion is a commonly performed orthopedic surgery. Autologous bone graft obtained from the iliac crest is frequently employed to perform spinal fusion. Osteogenic bone marrow stromal (a.k.a. mesenchymal stem) cells (BMSCs) are believed to be responsible for new bone formation and development of the bridging bone during spinal fusion, as these cells are located in both the graft and at the site of fusion. Our previous work revealed the importance of mitochondrial oxidative metabolism in osteogenic differentiation of BMSCs. Our objective here was to determine the impact of BMSC oxidative metabolism on osseointegration of the graft during spinal fusion. The first part of the study was focused on correlating oxidative metabolism in bone graft BMSCs to radiographic outcomes of spinal fusion in human patients. The second part of the study was focused on mechanistically proving the role of BMSC oxidative metabolism in osseointegration during spinal fusion using a genetic mouse model. Patients' iliac crest-derived graft BMSCs were identified by surface markers. Mitochondrial oxidative function was detected in BMSCs with the potentiometric probe, CMXRos. Spinal fusion radiographic outcomes, determined by the Lenke grade, were correlated to CMXRos signal in BMSCs. A genetic model of high oxidative metabolism, cyclophilin D knockout (CypD KO), was used to perform spinal fusion in mice. Graft osseointegration in mice was assessed with micro-computed tomography. Our study revealed that higher CMXRos signal in patients' BMSCs correlated with a higher Lenke grade. Mice with higher oxidative metabolism (CypD KO) had greater mineralization of the spinal fusion bridge, as compared to the control mice. We therefore conclude that higher oxidative metabolism in BMSCs correlates with better spinal fusion outcomes in both human patients and in a mouse model. Altogether, our study suggests that promoting oxidative metabolism in osteogenic cells could improve spinal fusion outcomes for patients.

Lactate Dehydrogenase Inhibition With Oxamate Exerts Bone Anabolic Effect.

Cellular bioenergetics is a promising new therapeutic target in aging, cancer, and diabetes because these pathologies are characterized by a shift from oxidative to glycolytic metabolism. We have previously reported such glycolytic shift in aged bone as a major contributor to bone loss in mice. We and others also showed the importance of oxidative phosphorylation (OxPhos) for osteoblast differentiation. It is therefore reasonable to propose that stimulation of OxPhos will have bone anabolic effect. One strategy widely used in cancer research to stimulate OxPhos is inhibition of glycolysis. In this work, we aimed to evaluate the safety and efficacy of pharmacological inhibition of glycolysis to stimulate OxPhos and promote osteoblast bone-forming function and bone anabolism. We tested a range of glycolytic inhibitors including 2-deoxyglucose, dichloroacetate, 3-bromopyruvate, and oxamate. Of all the studied inhibitors, only a lactate dehydrogenase (LDH) inhibitor, oxamate, did not show any toxicity in either undifferentiated osteoprogenitors or osteoinduced cells in vitro. Oxamate stimulated both OxPhos and osteoblast differentiation in osteoprogenitors. In vivo, oxamate improved bone mineral density, cortical bone architecture, and bone biomechanical strength in both young and aged C57BL/6J male mice. Oxamate also increased bone formation by osteoblasts without affecting bone resorption. In sum, our work provided a proof of concept for the use of anti-glycolytic strategies in bone and identified a small molecule LDH inhibitor, oxamate, as a safe and efficient bone anabolic agent. © 2020 American Society for Bone and Mineral Research (ASBMR).

Inhibition of the mitochondrial permeability transition improves bone fracture repair.

Bone fracture is accompanied by trauma, mechanical stresses, and inflammation - conditions known to induce the mitochondrial permeability transition. This phenomenon occurs due to opening of the mitochondrial permeability transition pore (MPTP) promoted by cyclophilin D (CypD). MPTP opening leads to more inflammation, cell death and potentially to disruption of fracture repair. Here we performed a proof-of-concept study and tested a hypothesis that protecting mitochondria from MPTP opening via inhibition of CypD improves fracture repair. First, our in vitro experiments indicated pro-osteogenic and anti-inflammatory effects in osteoprogenitors upon CypD knock-out or pharmacological inhibition. Using a bone fracture model in mice, we observed that bone formation and biomechanical properties of repaired bones were significantly increased in CypD knock-out mice or wild type mice treated with a CypD inhibitor, NIM811, when compared to controls. These effects were evident in young male but not female mice, however in older (13 month-old) female mice bone formation was also increased during fracture repair. In contrast to global CypD knock-out, mesenchymal lineage-specific (Prx1-Cre driven) CypD deletion did not result in improved fracture repair. Our findings implicate MPTP in bone fracture and suggest systemic CypD inhibition as a modality to promote fracture repair.

Cyclophilin D Knock-Out Mice Show Enhanced Resistance to Osteoporosis and to Metabolic Changes Observed in Aging Bone.

Pathogenic factors associated with aging, such as oxidative stress and hormone depletion converge on mitochondria and impair their function via opening of the mitochondrial permeability transition pore (MPTP). The MPTP is a large non-selective pore regulated by cyclophilin D (CypD) that disrupts mitochondrial membrane integrity. MPTP involvement has been firmly established in degenerative processes in heart, brain, and muscle. Bone has high energy demands and is therefore expected to be highly sensitive to mitochondrial dysfunction. Despite this, the role of mitochondria and the MPTP in bone maintenance and bone pathology has not been elucidated. Our goal was to determine whether mitochondria are impaired in aging bone and to see if protecting mitochondria from MPTP opening via CypD deletion protects against bone loss. We found that bone mass, strength, and formation progressively decline over the course of 18 months in C57BL/6J mice. Using metabolomics and electron microscopy, we determined that oxidative metabolism is impaired in aging bone leading to a glycolytic shift, imbalance in nucleotides, and decreased NAD+/NADH ratio. Mitochondria in osteocytes appear swollen which is a major marker of MPTP opening. CypD deletion by CypD knockout mouse model (CypD KO) protects against bone loss in 13- and 18-month-old mice and prevents decline in bone formation and mitochondrial changes observed in wild type C57BL/6J mice. Together, these data demonstrate that mitochondria are impaired in aging bone and that CypD deletion protects against this impairment to prevent bone loss. This implicates CypD-regulated MPTP and mitochondrial dysfunction in the impairment of bone cells and in aging-related bone loss. Our findings suggest mitochondrial metabolism as a new target for bone therapeutics and inhibition of CypD as a novel strategy against bone loss.

Energy Metabolism in Mesenchymal Stem Cells During Osteogenic Differentiation.

There is emerging interest in stem cell energy metabolism and its effect on differentiation. Bioenergetic changes in differentiating bone marrow mesenchymal stem cells (MSCs) are poorly understood and were the focus of our study. Using bioenergetic profiling and transcriptomics, we have established that MSCs activate the mitochondrial process of oxidative phosphorylation (OxPhos) during osteogenic differentiation, but they maintain levels of glycolysis similar to undifferentiated cells. Consistent with their glycolytic phenotype, undifferentiated MSCs have high levels of hypoxia-inducible factor 1 (HIF-1). Osteogenically induced MSCs downregulate HIF-1 and this downregulation is required for activation of OxPhos. In summary, our work provides important insights on MSC bioenergetics and proposes a HIF-based mechanism of regulation of mitochondrial OxPhos in MSCs.

In vivo model to measure bone repair efficacy of nanoparticle-based drug delivery.

Bone repair required for successful arthroplasty can be compromised in patients with comorbid conditions, such as osteoporosis, diabetes mellitus, and chronic kidney disease. Biological compounds have been proposed to promote bone health and repair. The authors have designed a new animal model for testing bone promoting compounds in the in vivo environment. For initial validation of this model, they used a synthetic agonist of a nuclear receptor, liver X receptor, which has been postulated to play a regulatory role in modulating bone growth. A distal femoral unicortical osteotomy was surgically created on skeletally mature C57Bl/6 male and female mice. A nanoparticle carrier delivery system was used to directly introduce N,N-dimethyl-3ß-hydroxycholenamide into the osteotomy. At 35 days post-procedure, the femora were harvested and specimens were obtained for histologic processing and qualitative analysis. The results indicate that the carrier nanoparticles entered the osteotomy defect. Results also indicate that bone repair occurred, although significant differences between groups were not detected in the current study. This study validates the mouse model for testing bone repair promoting compounds. This model can be combined with transgenic or other mouse models to simulate problematic bone repair environments, can be used with a variety of drug carriers, and can test many types of interventional compounds to evaluate potential orthopedic therapeutic applications.