Age-Related Low Bone Mineral Density in C57BL/6 Mice Is Reflective of Aberrant Bone Morphogenetic Protein-2 Signaling Observed in Human Patients Diagnosed with Osteoporosis.

Osteoporosis (OP) is a bone disorder characterized by decreased bone mineral density (BMD). Bone Morphogenetic Protein-2 (BMP-2) injections are used to promote bone formation in OP patients. However, patients are unresponsive to BMP-2 while displaying an upregulation of BMP Receptor Type 1a (BMPRIa) and protein kinase CK2α (CK2α). A synthetically produced peptide named casein kinase 2.3 (CK2.3) utilizes the BMP-signaling pathway as it enhances osteogenesis of primary osteoblasts isolated from OP patients, whereas BMP-2 does not. Although shown in OP patients, there is currently no reliable mouse model to study BMP-2 and CK2.3 signaling. In this publication, we show that BMPRIa was required for CK2.3-mediated osteogenesis in C2C12 cells with a CRISPR-Cas9-mediated gene knockout for BMPRIa. We utilized the C57BL/6 (B6) mouse strain as an aging-model to study aberrant BMP-2 signaling, demonstrating that, like OP patients, in 15 and 20-month mice, BMP-2 did not increase bone growth and displayed upregulated BMPRIa and CK2α protein expression. Furthermore, CK2.3 enhanced osteogenesis and decreased osteoclastogenesis in all age groups, whereas BMP-2 only increased mineralization in 6-month mice while increasing osteoclast formation in all age groups. These data demonstrated that aging B6 mice were a reliable model and mimicked data obtained from OP patients.

Aberrant BMP2 Signaling in Patients Diagnosed with Osteoporosis.

The most common bone disease in humans is osteoporosis (OP). Current therapeutics targeting OP have several negative side effects. Bone morphogenetic protein 2 (BMP2) is a potent growth factor that is known to activate both osteoblasts and osteoclasts. It completes these actions through both SMAD-dependent and SMAD-independent signaling. A novel interaction between the BMP type Ia receptor (BMPRIa) and casein kinase II (CK2) was discovered, and several CK2 phosphorylation sites were identified. A corresponding blocking peptide (named CK2.3) was designed to further elucidate the phosphorylation site's function. Previously, CK2.3 demonstrated an increased osteoblast activity and decreased osteoclast activity in a variety of animal models, cell lines, and isolated human osteoblasts. It is hypothesized that CK2.3 completes these actions through the BMP signaling pathway. Furthermore, it was recently discovered that BMP2 did not elicit an osteogenic response in osteoblasts from patients diagnosed with OP, while CK2.3 did. In this study, we explore where in the BMP pathway the signaling disparity or defect lies in those diagnosed with OP. We found that osteoblasts isolated from patients diagnosed with OP did not activate SMAD or ERK signaling after BMP2 stimulation. When OP osteoblasts were stimulated with BMP2, both BMPRIa and CK2 expression significantly decreased. This indicates a major disparity within the BMP signaling pathway in patients diagnosed with osteoporosis.

CK2.3, a Mimetic Peptide of the BMP Type I Receptor, Increases Activity in Osteoblasts over BMP2.

Bone is one of the most important organs in the human body. It provides structure, function, and protection for other vital organs; therefore, bone maintenance and homeostasis are critical processes. As humans age, their bone mineral density decreases, which leads to diseases like osteoporosis. This disease affects one in two women and one in five men aged 50 and over. As the aging population increases, the interest and significance of studying this debilitating bone disease becomes more relevant. Current therapeutic products for osteoporosis have many side effects and can be taken for a limited number of years. Most therapeutic products only focus on decreasing bone resorption, not increasing bone formation. Bone morphogenetic protein 2 is an essential growth factor that drives osteoblast differentiation and activity and is essential for bone formation. However, usage in the clinic is unsuccessful due to several side effects. Recently, a signaling disparity in bone marrow stromal cells within the bone morphogenetic protein pathway that led to decreased bone morphogenetic protein 2 responsiveness was identified in patients diagnosed with osteoporosis. However, it is unclear how other cell populations, especially osteoblasts, which are key players in bone remodeling, are affected and whether the bone morphogenetic protein pathway is affected during osteoporosis. Our research group designed a novel peptide, casein kinase 2.3, that acts downstream of the bone morphogenetic receptor type Ia and increases bone mineralization in murine cells and primary bovine osteoblasts. The aim of the study presented here was to compare the responsiveness of osteoblasts to bone morphogenetic protein 2 and casein kinase 2.3, especially in patients diagnosed with osteoporosis. Mature osteoblasts were extracted from patients diagnosed with osteoporosis or osteoarthritis from Christiana Care Hospital in Newark, Delaware. They were stimulated with either bone morphogenetic protein 2 or casein kinase 2.3, and their effect on osteoblast activity was determined. The osteoporotic patients showed no mineralization response to bone morphogenetic protein 2 stimulation, while the osteoarthritis patients significantly responded to bone morphogenetic protein 2 stimulation. Furthermore, markers for osteoblast activity were increased by casein kinase 2.3, which was in sharp contrast to bone morphogenetic protein 2. This further supports a major bone morphogenetic protein signaling disparity in both the elderly and those suffering with osteoporosis. Both patient types did significantly respond to casein kinase 2.3. Further analysis of the bone morphogenetic protein pathway could lead to new therapeutic products for osteoporosis.

Energy Impairments in Older Adults With Low Back Pain and Radiculopathy: A Matched Case-Control Study.

OBJECTIVES: To investigate the impact that the presence of chronic low back pain with radiculopathy (CLBPR) may have on (1) energy efficiency and (2) energy capacity among community-dwelling older adults. DESIGN: Matched case-control study. SETTING: Clinical research laboratory. PARTICIPANTS: Included in the analysis were community-dwelling older adults (N=38, 60-85 years) with and without CLBPR. Participants were matched between-groups on age (±5 years), sex, and diabetic status. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Energy cost of walking at self-selected speed (ie, energy efficiency) and peak volume of oxygen consumed (ie, energy capacity). RESULTS: Older adults with CLBPR had a higher energy cost of walking at self-selected speed (P=.009) and lower peak volume of oxygen consumed while walking (P=.050), compared to those without pain. CONCLUSIONS: Older adults with CLBPR may benefit from specific rehabilitative interventions that target these potentially modifiable energetic outcomes, thereby reducing the risk of mobility decline. Future studies should identify which mechanisms specifically contribute to diminished energy efficiency and capacity among older adults with CLBPR.

Asymptomatic Patient With Incarcerated Gravid Uterus Diagnosed in the Third Trimester: A Case Report of a Rare Potential Obstetric Emergency.

Incarcerated gravid uterus (IGU) is a rare condition that occurs when a retropositioned gravid uterus becomes entrapped within the pelvic cavity. Most patients present around the 17th week of pregnancy with symptoms such as pelvic fullness, urinary incontinence, abdominal pain, constipation, and vaginal bleeding. Rarely, patients are asymptomatic throughout pregnancy, leaving IGU undiagnosed and untreated. Here, we present an asymptomatic 26-year-old female who presented at 30 weeks of gestation with severe intrauterine growth retardation (IUGR) on serial obstetric ultrasounds. Further evaluation with ultrasound and MRI revealed an incarcerated uterus. This was complicated by severe fetal IUGR, abnormal biophysical profile, and oligohydramnios. This case highlights the importance of early diagnosis and treatment of IGU in order to prevent complications associated with the condition. Clinicians should be aware that, although uncommon, patients with IGU may be asymptomatic and that diagnosis should depend primarily on imaging findings rather than symptoms.

Reducing Surgical Complications in Spine Patients Through a Medication Management Support Program.

STUDY DESIGN: A hospital-wide medication management program was implemented to ensure that high-risk patients would systematically pause antiplatelet and anticoagulant medications. We analyzed complications before and during the implementation of this program. OBJECTIVE: The goal of the study was to determine if a medication management support program was effective for reducing perioperative complications, including hemorrhage, myocardial infarction, stroke, pulmonary embolism, and deep vein thrombosis. DATA AND METHODS: Using data from the National Surgical Quality Improvement Program database, we examined the presence of 5 complications before and during the implementation of a medication management support program. There were 9732 patients in the clinic population who underwent elective spine surgery between 2011 and 2020 and were included in this analysis. Of those 9732 patients, 7205 had surgery before the introduction of the program, whereas 2527 had surgery at some point after the program was introduced. We conducted a series of Pearson's χ 2 tests to determine the relative frequencies of the complications before and during the program. RESULTS: Results showed that during the implementation of the program, patients were relatively less likely to experience hemorrhage (3.16% vs. 1.11%; P <0.001). The reductions in thrombotic complications were clinically significant: myocardial infarction (0.12% vs. 0.00%), stroke (0.10% vs. 0.04%), pulmonary embolism (0.33% vs. 0.28%), and deep vein thrombosis (0.36% vs. 0.28%). These P values ranged from P =0.08 for myocardial infarction to P =0.67 for pulmonary embolism. CONCLUSIONS: The use of this medication management support program appears effective for reducing the need for blood transfusions and thrombotic complications. While promising, the results should be interpreted with caution as we do not know whether this type of program will be effective for other hospital systems.

Outcomes of 2-Level Versus 3- or 4-Level Anterior Cervical Discectomy and Fusion Using a Biomimetic Surface Titanium Cage: Multicenter Experience.

OBJECTIVE: Interbody cages for spinal fusions are primarily constructed from polyetheretherketone or titanium compositions. However, these crude macroscopic materials pose limitations for improving the rates of bony fusions. The authors aimed to compare the fusion rates and postoperative complications in patients who underwent 2-level or 3-or 4-level anterior cervical discectomy and fusion (ACDF) performed with the use of a novel biomimetic surface titanium cage. METHODS: A retrospective multicenter study was conducted that included all patients who underwent multilevel ACDF with this cage between January 2017 and April 2021. Patient demographics and procedure-related, radiographic, and postoperative complication data were collected. RESULTS: A total of 124 patients were identified; 69 (55.6%) had a 3-or 4-level fusion and 55 (44.4%) had a 2-level fusion. The demographics of the 2 groups differed significantly only in terms of age (P = 0.01). At 3 months, a significantly higher solid fusion rate was found for 2-level fusions than 3-or 4-level fusions (83.7% vs. 56.3%, P = 0.004); however, significance was lost at 6-months (98.2% vs. 88.4%, respectively; P = 0.08). No patients required posterior supplemental fixation. Transient dysphagia was the only postoperative complication that was significantly increased in the 3-or 4-level fusion group compared to the 2-level group (27.5% vs. 9.1%, P = 0.02). CONCLUSIONS: Radiographic and clinical outcomes were equivalent in 3-or 4-level and 2-level ACDFs in which these biomimetic surface titanium cages were used. Furthermore, the use of this technology led to high fusion rates with no requirement for posterior supplemental fusions.

Bone morphogenetic protein in spine surgery: current and future uses.

The clinical use of bone morphogenetic protein (BMP) in spinal fusion surgery has recently become controversial. After its approval by the US FDA in July 2002, BMP was adopted by many spine surgeons as a replacement for the more traditional iliac crest bone graft to avoid the complications associated with bone graft harvest. However, as broad clinical use escalated, reports increased of potentially serious complications associated with BMP. Controversy continues, particularly regarding the safety of BMP and whether it should routinely replace iliac crest bone graft for spinal fusion surgery.

Differentiation of Cells Isolated from Human Femoral Heads into Functional Osteoclasts.

Proper formation of the skeleton during development is crucial for the mobility of humans and the maintenance of essential organs. The production of bone is regulated by osteoblasts and osteoclasts. An imbalance of these cells can lead to a decrease in bone mineral density, which leads to fractures. While many studies are emerging to understand the role of osteoblasts, less studies are present about the role of osteoclasts. This present study utilized bone marrow cells isolated directly from the bone marrow of femoral heads obtained from osteoarthritic (OA) patients after undergoing hip replacement surgery. Here, we used tartrate resistant acid phosphatase (TRAP) staining, Cathepsin K, and nuclei to identity osteoclasts and their functionality after stimulation with macrophage-colony stimulation factor (M-CSF) and receptor activator of nuclear factor kappa-ß ligand (RANKL). Our data demonstrated that isolated cells can be differentiated into functional osteoclasts, as indicated by the 92% and 83% of cells that stained positive for TRAP and Cathepsin K, respectively. Furthermore, isolated cells remain viable and terminally differentiate into osteoclasts when stimulated with RANKL. These data demonstrate that cells isolated from human femoral heads can be differentiated into osteoclasts to study bone disorders during development and adulthood.

Is there a difference between simultaneous or staged decompressions for combined cervical and lumbar stenosis?

STUDY DESIGN: We evaluated 43 patients diagnosed with tandem spinal stenosis (TSS) from 1999 to 2005 in an academic hospital. OBJECTIVE: The purpose of this study is to compare outcomes after simultaneous decompression of the cervical and lumbar spine versus staged operations. SUMMARY OF BACKGROUND DATA: TSS is a rare degenerative disease affecting multiple spinal levels with limited research describing operative management. METHODS: Of our patients, 21 underwent simultaneous decompression of both the cervical and lumbar spine and 22 underwent staged decompression of the cervical spine followed by the lumbar spine at a later date. Medical records were reviewed for patient demographics, type and duration of symptoms, operative time, combined blood loss, cervical myelopathy modified Japan Orthopaedic Association Score, Oswestry Disability Index (ODI), major and minor complications, and average length of follow up. Each category was evaluated by Pearson correlations and unpaired Student t tests. RESULTS: With a mean follow-up of 7 years, both groups improved in JOA and ODI without a significant difference between the 2 operative groups in terms of major or minor complications, JOA, or ODI. Independent of the surgical algorithm, age above 68 years, estimated blood loss ≥400 mL, and operative time ≥150 minutes significantly increased the number of complications. CONCLUSIONS: These results indicate that TSS can be effectively managed by either surgical intervention, simultaneous, or staged decompressions. However, patient age, blood loss, and operative time do significantly impact outcomes. Therefore, operative management should be tailored to the patient's age and the option which will limit blood loss and operative time, whether that is by simultaneous or staged procedures.

Effect of phytic acid and ethylenediaminetetraacetic acid on penetration depth of bioceramic and resin sealers.

This study assessed influence of 1% phytic acid and 17% ethylenediaminetetraacetic acid (EDTA) on the dentinal tubules penetration of EndoSequence BC bioceramic-based and AH Plus resin-based sealers using confocal laser scanning microscopy (CLSM). Forty single-rooted mandibular premolars were divided randomly into four groups (n = 10). Group 1 received final irrigation with 1% phytic acid solution and canals sealed by AH Plus sealer, Group 2: 1% phytic acid solution and EndoSequence BC sealer, Group 3: 17% EDTA solution and AH Plus sealer and Group 4: 17% EDTA solution and EndoSequence BC sealer. Specimens were horizontally sectioned 2, 4 and 6 mm from the apex. Average maximum depth of sealer penetration was examined using CLSM. Group three showed the deepest sealer penetration at all three levels which was significantly higher than all other groups (P ˂ 0.05). Deep sealer penetration is achievable with AH Plus and EDTA. Phytic acid groups have moderate tubular penetration ability.

Two-year radiostereometric analysis evaluation of femoral head penetration in a challenging population of young total hip arthroplasty patients.

This prospective, randomized protocol evaluated femoral head penetration after total hip arthroplasty in a young population. Forty-five patients randomly received either a cross-linked or conventional ultrahigh-molecular-weight polyethylene (UHMWPE) liner in a noncemented hemispheric cup (Trilogy, Zimmer, Warsaw, Ind) with a 28-mm femoral head. Radiostereometric analysis film pairs, Harris hip, UCLA, SF-12, and Western Ontario and McMaster Universities scores were obtained through 2 years. Median femoral head penetration was less among cross-linked compared to conventional liners as follows: 0.06 mm (0.04-0.08 mm) vs 0.08 mm (0.02-0.19 mm) at 6 months, 0.07 mm (-0.14 to 0.16 mm) vs 0.11 mm (0.01-0.27 mm) at 1 year, and 0.065 mm (-0.04 to 0.193 mm) vs 0.169 mm (0.09-0.22 mm) at 2 years. Clinical outcomes were similar between the groups. Highly cross-linked UHMWPE demonstrated 55% less femoral head penetration compared to conventional polyethylene at 2 years. Despite improvements in the manufacturing process and sterilization of conventional UHMWPE, the femoral head penetration rate is unchanged from historical standards.

Pain Provocation and the Energy Cost of Walking: A Matched Comparison Study of Older Adults With and Without Chronic Low Back Pain With Radiculopathy.

BACKGROUND AND PURPOSE: Chronic low back pain with radiculopathy (CLBPR) is common among older adults and can lead to walking difficulty. Energy cost of walking strongly predicts changes in walking speed, which is predictive of mortality in older adults. The purposes of this study were to examine (1) the impact of pain provocation on the energy cost of walking and (2) the relationship between pain intensity and change in energy cost of walking. METHODS: Older adults (60-85 years) with (n = 20) and without (n = 20) CLBPR were matched on age, sex, and diabetes presence/absence. Energy cost of walking was measured with a portable metabolic gas analyzer, as participants walked for 20 minutes or less. Energy cost and pain measurements occurred during early and late stages of walking. Percent change in energy cost was calculated. Participants were grouped by their pain response during walking: increased pain (n = 13); consistent pain (n = 7); no pain, matched to individuals with increased pain (n = 13); and no pain, matched to individuals with consistent pain (n = 7). We examined the within-groups change in energy cost for all groups, as well as the relationship between late-stage pain intensity and percent change of energy cost for individuals whose pain increased. RESULTS AND DISCUSSION: Within the increased pain group, energy cost of walking significantly increased from early to late stages (median change = 0.003 mL/kg/m, P = .006), and late-stage pain intensity explained 41.2% (p = 0.040) of the variance in percent change. Since pain appears to be linked to energy cost, effective pain management with walking may be an important factor in preventing mobility decline. CONCLUSIONS: Among older adults with CLBPR, pain provocation drives increases in the energy cost of walking. Because high energy cost of walking is predictive of mobility decline, clinicians may focus on effective pain management strategies during walking, which may potentially decrease the risk of mobility decline.

The effect of an orthopedic trauma room on after-hours surgery at a level one trauma center.

PURPOSE: The purpose of this study is to examine the effect of establishing a dedicated operating room for unscheduled orthopedic cases and to evaluate a group of patients with isolated femur fractures. The frequency of after-hours surgery and the impact of patients who present with acute orthopedic injuries are reviewed. METHODS: A retrospective review of all orthopedic cases from the operating room scheduling system at a level-one trauma center was undertaken from October 2003 to September 2005. Before October 2004, unscheduled cases were placed on a shared add-on list, and no special priority was given to orthopedic cases. Additionally, a subset of adult patients with isolated femoral shaft fractures was identified to evaluate time from admission to surgery, operative time, frequency of transfer of care between surgeons, and total length of hospital stay. RESULTS: The number of orthopedic cases was 1799 in fiscal year 2004 (FY04) and 2046 in FY05, an increase of 14%. Overall, the hospital experienced an increase in level-one trauma activations from 1450 in FY04 to 1580 in FY05 (8.2%), and an increase in the number operative trauma cases from 447 to 494 (9.5%). Cases after 7:00 pm declined from 197 in FY04 to 165 in FY05, a decrease of 16%. Cases between midnight and 7:00 am declined from 63 in FY04 to 35 in FY05, a decrease of 44%. For the subset of femur fracture patients, transfer of care to another operating surgeon occurred 4.5 times more frequently. The median delay between admission and surgery increased from 5.7 hours to 10.9 hours. Median case duration increased from 106 to 127 minutes. CONCLUSIONS: It is possible to dramatically decrease the occurrence of after-hours orthopedic surgery in a level-one trauma center through the use of a dedicated room for unscheduled orthopedic trauma cases. Benefits include less frequent activation of after-hours operating room resources, fewer disruptions to the OR schedule and office hours, and more frequent fracture care by orthopedic traumatologists. The impact of a longer delay between admission and surgical treatment and more frequent transfer of care between surgeons deserves further evaluation.

A left knee wound complication by non-Hodgkins lymphoma in bilateral total knee arthroplasties.

A 70-year-old woman with a history of bilateral primary knee osteoarthritis presented with a left knee wound complication, a non-Hodgkins lymphoma, after bilateral total knee arthroplasties. After exploring several etiologies, the evidence in this unusual case suggests a coincidental preexisting lymphoma.

Brown-Séquard Syndrome Caused by Blunt Cervical Trauma with Radiographic Correlation.

Brown-Séquard syndrome, while uncommon, is a neurological condition that classically results from the hemisection of the spinal cord as a result of a penetrating injury to the spinal cord. We present a reported case of blunt trauma causing a high-energy cervical burst fracture/dislocation with a significant cord signal change producing Brown-Séquard syndrome. In this case, the burst fracture at the level of C5 obtained from the motor vehicle accident led to the damage of the left-sided lateral spinal thalamic tract, descending lateral cortical spinal tracts, and ascending dorsal column. This is a unique case of blunt nonpenetrating trauma leading to a high-energy cervical burst fracture/dislocation causing significant cord signal change on T2-weighted magnetic resonance imaging (MRI). These physical changes produced symptoms of neurologic impairment commonly seen in those patients with Brown-Séquard syndrome.

Bow Hunter's Syndrome in a Patient with a Right Hypoplastic Vertebral Artery and a Dynamically Compressible Left Vertebral Artery.

This is a case report of a 48-year-old man with multiple transient ischemic attacks and a known hypoplastic right vertebral artery (VA) who presented after a syncopal event while turning his head to the left. The objective of this study is to demonstrate the necessity of proper diagnosis and management of cerebrovascular pathology including imaging and surgical intervention in patients with known anatomical anomalies. This study was conducted at Massachusetts, United States of America. Our patient's history was significant for a hypoplastic right VA and a stenotic segment of the right VA at the C3-C4 junction. There was also degeneration of the C3-C4 facet on the left, with osteophyte formation compressing the VA, and a fusion of the C2-C3 segment. Imaging demonstrated obliteration of the left VA flow with head rotation to the left and subsequent reconstitution of flow in the neutral position. After consultation, the patient decided to proceed with surgical management with an anterior cervical discectomy and fusion at the level of C3-C4. Symptoms of vertebrobasilar insufficiency including syncopal episodes resolved after treatment. VA anomalies, although uncommon, are important to understand. Our patient presented with an anomalous right VA, as well as severe degenerative changes to the C2/C3 vertebrae that contributed to the development of Bow Hunter's syndrome. It is essential that proper monitoring and follow-up has to be carried out in patients with abnormal cerebral vasculature to minimize the occurrence of Bow Hunter's syndrome.

Does medial tenderness predict deep deltoid ligament incompetence in supination-external rotation type ankle fractures?

OBJECTIVE: To identify whether medial tenderness is a predictor of deep deltoid ligament incompetence in supination-external rotation ankle fractures. DESIGN: All Weber B lateral malleolar fractures with normal medial clear space over a 9 month period were prospectively included in the study. Fracture patterns not consistent with a supination-external rotation mechanism were excluded. SETTING: High-volume tertiary care referral center and Level I trauma center. PATIENTS/PARTICIPANTS: Fifty-five skeletally mature patients with a Weber B lateral malleolar fracture and normal medial clear space presenting to our institution were included. INTERVENTION: All study patients had ankle anteroposterior, lateral, and mortise radiographs. Each patient was seen and evaluated by an orthopedic specialist and the mechanism of injury was recorded. Each patient was assessed for tenderness to palpation in the region of the deltoid ligament and then had an external rotation stress mortise radiograph. MAIN OUTCOME MEASURE: Correlating medial tenderness with deep deltoid competence as measured by stress radiographs. RESULTS: Thirteen patients (23.6%) were tender medially and had a positive external rotation stress radiograph. Thirteen patients (23.6%) were tender medially and had a negative external rotation stress radiograph. Nineteen patients (34.5%) were nontender medially and had a negative external rotation stress radiograph. Ten patients (18.2%) were nontender medially and had a positive external rotation stress radiograph. We calculated a chi statistic of 2.37 as well as the associated P value of 0.12. Medial tenderness as a measure of deep deltoid ligament incompetence had a sensitivity of 57%, a specificity of 59%, a positive predictive value of 50%, a negative predictive value of 66%, and an accuracy of 42%. CONCLUSION: There was no statistical significance between the presence of medial tenderness and deep deltoid ligament incompetence. There is a 25% chance of the fracture in question with medial tenderness having a positive external rotation stress and a 25% chance the fracture with no medial tenderness having a positive stress test. Medial tenderness in a Weber B lateral ankle fracture with a normal clear space on standard plain radiographs does not ensure the presence of a positive external rotation stress test.