Abdominal Aortic Calcification is Associated with Degeneration of The Paraspinal Muscles - A Retrospective cross-sectional Study.

STUDY DESIGN: Retrospective cohort study. OBJECTIVE: To analyze the relationship of abdominal aortic calcification (AAC) and a reduction in the cross-sectional area (CSA) and the fatty infiltration (FI) of the paravertebral muscles in patients undergoing lumbar fusion surgery. BACKGROUND: Both AAC and paraspinal muscle degeneration have been shown to be associated with poorer outcomes after surgical treatment of degenerative diseases of the lumbar spine. However, there is a lack of data on the association between AAC and paraspinal muscle changes in patients undergoing spine surgery. METHODS: We retrospectively analyzed patients undergoing lumbar fusion for degenerative spinal pathologies. Muscular and spinal degeneration were measured on magnetic resonance imaging (MRI). AAC was classified on lateral lumbar radiographs. The association of AAC and paraspinal muscle composition was assessed by a multivariate regression analysis adjusted for age, sex, body mass index (BMI), comorbidities, and lumbar degeneration. RESULTS: A total of 301 patients was included. Patients with AAC showed significantly higher degrees of intervertebral disc and facet joint degeneration as well as higher total endplate scores at the L3/4 level. The univariable regression analysis showed a significant positive correlation between the degree of AAC and the FI of the erector spinae (b=0.530, P<0.001) and multifidus (b=0.730, P<0.001). The multivariable regression analysis showed a significant positive correlation between the degree of AAC and the FI of the erector spinae (b=0.270, P=0.006) and a significant negative correlation between the degree of AAC and the CSA of the psoas muscle (b=-0.260, P=0.003). CONCLUSION: This study demonstrates a significant and independent association between AAC and degeneration of the erector spinae and the psoas muscles in patients undergoing lumbar fusion. As both AAC and degeneration of paraspinal muscles impact postoperative outcomes negatively, preoperative assessment of AAC may aid in identifying patients at higher risk after lumbar surgery.

The relationship between paraspinal muscle atrophy and degenerative lumbar spondylolisthesis at the L4/5 level.

BACKGROUND/CONTEXT: Degenerative lumbar spondylolisthesis (DLS) is a prevalent spinal condition that can result in significant disability. DLS is thought to result from a combination of disc and facet joint degeneration, as well as various biological, biomechanical, and behavioral factors. One hypothesis is the progressive degeneration of segmental stabilizers, notably the paraspinal muscles, contributes to a vicious cycle of increasing slippage. PURPOSE: To examine the correlation between paraspinal muscle status on MRI and severity of slippage in patients with symptomatic DLS. STUDY DESIGN/SETTING: Retrospective cross-sectional study at an academic tertiary care center. PATIENT SAMPLE: Patients who underwent surgery for DLS at the L4/5 level between 2016-2018 were included. Those with multilevel DLS or insufficient imaging were excluded. OUTCOME MEASURES: The percentage of relative slippage (RS) at the L4/5 level evaluated on standing lateral radiographs. Muscle morphology measurements including functional cross-sectional area (fCSA), body height normalized functional cross-sectional area (HI) of Psoas, erector spinae (ES) and multifidus muscle (MF) and fatty infiltration (FI) of ES and MF were measured on axial MR. Disc degeneration and facet joint arthritis were classified according to Pfirrmann and Weishaupt, respectively. METHODS: Descriptive and comparative statistics, univariable and multivariable linear regression models were utilized to examine the associations between RS and muscle parameters, adjusting for confounders sex, age, BMI, segmental degeneration, and back pain severity and symptom duration. RESULTS: The study analyzed 138 out of 183 patients screened for eligibility. The median age of all patients was 69.5 years (IQR 62 to 73), average BMI was 29.1 (SD±5.1) and average preoperative ODI was 46.4 (SD±16.3). Patients with Meyerding-Grade 2 (M2, N=25) exhibited higher Pfirrmann scores, lower MFfCSA and MFHI, and lower BMI, but significantly more fatty infiltration in the MF and ES muscles compared to those with Meyerding Grade 1 (M1). Univariable linear regression showed that each cm2 decrease in MFfCSA was associated with a 0.9%-point increase in RS (95% CI -1.4 to - 0.4, p<.001), and each cm2/m2 decrease in MFHI was associated with an increase in slippage by 2.2%-points (95% CI -3.7 to -0.7, p=.004). Each 1%-point rise in ESFI and MFFI corresponded to 0.17%- (95% CI 0.05-0.3, p=.01) and 0.20%-point (95% CI 0.1-0.3 p<.001) increases in relative slippage, respectively. Notably, after adjusting for confounders, each cm2 increase in PsoasfCSA and cm2/m2 in PsoasHI was associated with an increase in relative slippage by 0.3% (95% CI 0.1-0.6, p=.004) and 1.1%-points (95% CI 0.4-1.7, p=.001). While MFfCSA tended to be negatively associated with slippage, this did not reach statistical significance (p=.105). However, each 1%-point increase in MFFI and ESFI corresponded to increases of 0.15% points (95% CI 0.05-0.24, p=.002) and 0.14% points (95% CI 0.01-0.27, p=.03) in relative slippage, respectively. CONCLUSION: This study found a significant association between paraspinal muscle status and severity of slippage in DLS. Whereas higher degeneration of the ES and MF correlate with a higher degree of slippage, the opposite was found for the psoas. These findings suggest that progressive muscular imbalance between posterior and anterior paraspinal muscles could contribute to the progression of slippage in DLS.

Increased ß2-adrenergic signaling promotes fracture healing through callus neovascularization in mice.

Traumatic brain injury (TBI) leads to skeletal changes, including bone loss in the unfractured skeleton, and paradoxically accelerates healing of bone fractures; however, the mechanisms remain unclear. TBI is associated with a hyperadrenergic state characterized by increased norepinephrine release. Here, we identified the ß2-adrenergic receptor (ADRB2) as a mediator of skeletal changes in response to increased norepinephrine. In a murine model of femoral osteotomy combined with cortical impact brain injury, TBI was associated with ADRB2-dependent enhanced fracture healing compared with osteotomy alone. In the unfractured 12-week-old mouse skeleton, ADRB2 was required for TBI-induced decrease in bone formation and increased bone resorption. Adult 30-week-old mice had higher bone concentrations of norepinephrine, and ADRB2 expression was associated with decreased bone volume in the unfractured skeleton and better fracture healing in the injured skeleton. Norepinephrine stimulated expression of vascular endothelial growth factor A and calcitonin gene-related peptide-α (αCGRP) in periosteal cells through ADRB2, promoting formation of osteogenic type-H vessels in the fracture callus. Both ADRB2 and αCGRP were required for the beneficial effect of TBI on bone repair. Adult mice deficient in ADRB2 without TBI developed fracture nonunion despite high bone formation in uninjured bone. Blocking ADRB2 with propranolol impaired fracture healing in mice, whereas the ADRB2 agonist formoterol promoted fracture healing by regulating callus neovascularization. A retrospective cohort analysis of 72 patients with long bone fractures indicated improved callus formation in 36 patients treated with intravenous norepinephrine. These findings suggest that ADRB2 is a potential therapeutic target for promoting bone healing.

Asymmetrical atrophy of the paraspinal muscles in patients undergoing unilateral lumbar medial branch radiofrequency neurotomy.

ABSTRACT: Lumbar medial branch radiofrequency neurotomy (RFN), a common treatment for chronic low back pain due to facet joint osteoarthritis (FJOA), may amplify paraspinal muscle atrophy due to denervation. This study aimed to investigate the asymmetry of paraspinal muscle morphology change in patients undergoing unilateral lumbar medial branch RFN. Data from patients who underwent RFN between March 2016 and October 2021 were retrospectively analyzed. Lumbar foramina stenosis (LFS), FJOA, and fatty infiltration (FI) functional cross-sectional area (fCSA) of the paraspinal muscles were assessed on preinterventional and minimum 2-year postinterventional MRI. Wilcoxon signed-rank tests compared measurements between sides. A total of 51 levels of 24 patients were included in the analysis, with 102 sides compared. Baseline MRI measurements did not differ significantly between the RFN side and the contralateral side. The RFN side had a higher increase in multifidus FI (+4.2% [0.3-7.8] vs +2.0% [-2.2 to 6.2], P = 0.005) and a higher decrease in multifidus fCSA (-60.9 mm2 [-116.0 to 10.8] vs -19.6 mm2 [-80.3 to 44.8], P = 0.003) compared with the contralateral side. The change in erector spinae FI and fCSA did not differ between sides. The RFN side had a higher increase in multifidus muscle atrophy compared with the contralateral side. The absence of significant preinterventional degenerative asymmetry and the specificity of the effect to the multifidus muscle suggest a link to RFN. These findings highlight the importance of considering the long-term effects of lumbar medial branch RFN on paraspinal muscle health.

Patient satisfaction after elective implant removal of the lower extremity - a retrospective cohort study.

PURPOSE: The topic of elective implant removal (IR) in healed fractures of the lower extremity remains controversial, particularly when unspecific symptoms of discomfort, which cannot be quantified, are the primary indication. This study aims to assess indications and outcomes of elective IR of the lower extremity, focusing on unspecific symptoms of discomfort and patient satisfaction postoperatively. MATERIALS AND METHODS: The retrospective cohort study was conducted at a single level I academic trauma center. We included patients who underwent elective IR for healed fractures of the ankle, foot, patella, and proximal tibia from 2016 to 2021. All patients were followed-up for a minimum of 6 weeks after IR. Our outcomes of interest were patient satisfaction, complications, and alleviation of complaints. RESULTS: A total of 167 patients were included in the study. Unspecific symptoms of discomfort were the most common reason for IR in all investigated anatomical regions of the lower extremity (47.9%), followed by pain (43.1%) and limited range of motion (4.2%). 4.8% of patients experienced a combination of pain and range of motion limitation. Among all patients, 47.9% reported subjective improvement after IR. IRs based on unspecific symptoms of discomfort were significantly less likely to show alleviation of complaints after IR (27.5%, OR 0.19, p ≤ 0.01). Patients who reported limited range of motion (OR 1.7, p = 0.41) or pain (OR 6.0, p = 0) were significantly more likely to be satisfied after IR. Patients who reported sensitivity to cold weather also showed a decrease of complaints after IR (OR 3.6, p = 0.03). Major complications occurred in 2.1% of cases. The minor complication rate was 8.4% (predominantly impaired wound healing). Smoking patients showed a significantly higher risk of complications after IR (OR 5.2, p = 0.006). Persistent pain postoperatively was detected in 14.7%. CONCLUSION: When elective IR for consolidated fractures of the lower extremity is primarily motivated by patients' subjective symptoms of discomfort, the risk for postoperative dissatisfaction significantly increases. Objective symptoms on the other hand are associated with higher satisfaction after IR. While the procedure is generally safe, minor complications such as wound healing disorders can occur, especially in smokers. Patient education and well-documented informed consent are critical.

Increased beta2-adrenergic signaling is a targetable stimulus essential for bone healing by promoting callus neovascularization.

Traumatic brain injury (TBI) is associated with a hyperadrenergic state and paradoxically causes systemic bone loss while accelerating fracture healing. Here, we identify the beta2-adrenergic receptor (Adrb2) as a central mediator of these skeletal manifestations. While the negative effects of TBI on the unfractured skeleton can be explained by the established impact of Adrb2 signaling on bone formation, Adrb2 promotes neovascularization of the fracture callus under conditions of high sympathetic tone, including TBI and advanced age. Mechanistically, norepinephrine stimulates the expression of Vegfa and Cgrp primarily in periosteal cells via Adrb2, both of which synergistically promote the formation of osteogenic type-H vessels in the fracture callus. Accordingly, the beneficial effect of TBI on bone repair is abolished in mice lacking Adrb2 or Cgrp, and aged Adrb2-deficient mice without TBI develop fracture nonunions despite high bone formation in uninjured bone. Pharmacologically, the Adrb2 antagonist propranolol impairs, and the agonist formoterol promotes fracture healing in aged mice by regulating callus neovascularization. Clinically, intravenous beta-adrenergic sympathomimetics are associated with improved callus formation in trauma patients with long bone fractures. Thus, Adrb2 is a novel target for promoting bone healing, and widely used beta-blockers may cause fracture nonunion under conditions of increased sympathetic tone.

Procalcitonin is expressed in osteoblasts and limits bone resorption through inhibition of macrophage migration during intermittent PTH treatment.

Intermittent injections of parathyroid hormone (iPTH) are applied clinically to stimulate bone formation by osteoblasts, although continuous elevation of parathyroid hormone (PTH) primarily results in increased bone resorption. Here, we identified Calca, encoding the sepsis biomarker procalcitonin (ProCT), as a novel target gene of PTH in murine osteoblasts that inhibits osteoclast formation. During iPTH treatment, mice lacking ProCT develop increased bone resorption with excessive osteoclast formation in both the long bones and axial skeleton. Mechanistically, ProCT inhibits the expression of key mediators involved in the recruitment of macrophages, representing osteoclast precursors. Accordingly, ProCT arrests macrophage migration and causes inhibition of early but not late osteoclastogenesis. In conclusion, our results reveal a potential role of osteoblast-derived ProCT in the bone microenvironment that is required to limit bone resorption during iPTH.

Future Perspectives in Spinal Cord Repair: Brain as Saviour? TSCI with Concurrent TBI: Pathophysiological Interaction and Impact on MSC Treatment.

Traumatic spinal cord injury (TSCI), commonly caused by high energy trauma in young active patients, is frequently accompanied by traumatic brain injury (TBI). Although combined trauma results in inferior clinical outcomes and a higher mortality rate, the understanding of the pathophysiological interaction of co-occurring TSCI and TBI remains limited. This review provides a detailed overview of the local and systemic alterations due to TSCI and TBI, which severely affect the autonomic and sensory nervous system, immune response, the blood-brain and spinal cord barrier, local perfusion, endocrine homeostasis, posttraumatic metabolism, and circadian rhythm. Because currently developed mesenchymal stem cell (MSC)-based therapeutic strategies for TSCI provide only mild benefit, this review raises awareness of the impact of TSCI-TBI interaction on TSCI pathophysiology and MSC treatment. Therefore, we propose that unravelling the underlying pathophysiology of TSCI with concomitant TBI will reveal promising pharmacological targets and therapeutic strategies for regenerative therapies, further improving MSC therapy.

Mice Lacking the Calcitonin Receptor Do Not Display Improved Bone Healing.

Despite significant advances in surgical techniques, treatment options for impaired bone healing are still limited. Inadequate bone regeneration is not only associated with pain, prolonged immobilization and often multiple revision surgeries, but also with high socioeconomic costs, underlining the importance of a detailed understanding of the bone healing process. In this regard, we previously showed that mice lacking the calcitonin receptor (CTR) display increased bone formation mediated through the increased osteoclastic secretion of sphingosine-1-phosphate (S1P), an osteoanabolic molecule promoting osteoblast function. Although strong evidence is now available for the crucial role of osteoclast-to-osteoblast coupling in normal bone hemostasis, the relevance of this paracrine crosstalk during bone regeneration is unknown. Therefore, our study was designed to test whether increased osteoclast-to-osteoblast coupling, as observed in CTR-deficient mice, may positively affect bone repair. In a standardized femoral osteotomy model, global CTR-deficient mice displayed no alteration in radiologic callus parameters. Likewise, static histomorphometry demonstrated moderate impairment of callus microstructure and normal osseous bridging of osteotomy ends. In conclusion, bone regeneration is not accelerated in CTR-deficient mice, and contrary to its osteoanabolic action in normal bone turnover, osteoclast-to-osteoblast coupling specifically involving the CTR-S1P axis, may only be of minor relevance during bone healing.

Effects of CGRP receptor antagonism on glucose and bone metabolism in mice with diet-induced obesity.

The neuropeptide calcitonin gene-related peptide (CGRP) and its receptor, calcitonin receptor-like receptor (CLR) complexing with receptor activity-modifiying protein 1 (RAMP1), have been shown to be crucially involved in the pathogenesis of migraine. However, CGRP also plays a pivotal role in regulating bone turnover and was suggested to contribute to the development of the metabolic syndrome. Therefore, our study was designed to characterize the effects of CGRP antagonism on bone and glucose metabolism in a murine model of diet-induced obesity (DIO). A subcutaneous pellet releasing the CGRP receptor antagonist BIBN 4096 (BIBN; olcegepant) was implanted in WT mice with DIO. Metabolic effects were assessed through body- and organ-weights, oral glucose tolerance (oGT), serum lipids, and gene-expression studies. Bone turnover was assessed through histomorphometry of non-decalcified bone sections and analyses of bone turnover markers in serum samples. BIBN treatment did not alter body weight gain or the levels of serum lipids including triacylglycerol and cholesterol during DIO. BIBN led to a moderate improvement of oGT which was accompanied by an increased expression of stearoyl-CoA desaturase in the liver. In skeletal tissue, BIBN treatment resulted in reduced bone volume. This was explained by decreased parameters of bone formation whereas bone resorption was not affected. Our results indicate that inhibition of CGRP signaling only moderately affects glucose metabolism during DIO but significantly impairs bone formation. As novel agents blocking CGRP or its receptor are currently introduced clinically for the treatment of migraine disorders, their potential negative impact on bone metabolism requires further clinical studies.

Validation of reference genes for expression analysis in a murine trauma model combining traumatic brain injury and femoral fracture.

Systemic and local posttraumatic responses are often monitored on mRNA expression level using quantitative real-time PCR (qRT-PCR), which requires normalisation to adjust for confounding sources of variability. Normalisation requests reference (housekeeping) genes stable throughout time and divergent experimental conditions in the tissue of interest, which are crucial for a reliable and reproducible gene expression analysis. Although previous animal studies analysed reference genes following isolated trauma, this multiple-trauma gene expression analysis provides a notable study analysing reference genes in primarily affected (i.e. bone/fracture callus and hypothalamus) and secondarily affected organs (i.e. white adipose tissue, liver, muscle and spleen), following experimental long bone fracture and traumatic brain injury. We considered tissue-specific and commonly used top-ranked reference candidates from different functional groups that were evaluated applying the established expression stability analysis tools NormFinder, GeNorm, BestKeeper and RefFinder. In conclusion, reference gene expression in primary organs is highly time point as well as tissue-specific, and therefore requires careful evaluation for qRT-PCR analysis. Furthermore, the general application of Ppia, particularly in combination with a second reference gene, is strongly recommended for the analysis of systemic effects in the case of indirect trauma affecting secondary organs through local and systemic pathophysiological responses.

The neuropeptide calcitonin gene-related peptide alpha is essential for bone healing.

BACKGROUND: Impaired fracture healing represents an ongoing clinical challenge, as treatment options remain limited. Calcitonin gene-related peptide (CGRP), a neuropeptide targeted by emerging anti-migraine drugs, is also expressed in sensory nerve fibres innervating bone tissue. METHOD: Bone healing following a femoral osteotomy stabilized with an external fixator was analysed over 21 days in αCGRP-deficient and WT mice. Bone regeneration was evaluated by serum analysis, µCT analysis, histomorphometry and genome-wide expression analysis. Bone-marrow-derived osteoblasts and osteoclasts, as well as the CGRP antagonist olcegepant were employed for mechanistic studies. FINDINGS: WT mice with a femoral fracture display increased CGRP serum levels. αCGRP mRNA expression after skeletal injury is exclusively induced in callus tissue, but not in other organs. On protein level, CGRP and its receptor, calcitonin receptor-like receptor (CRLR) complexing with RAMP1, are differentially expressed in the callus during bone regeneration. On the other hand, αCGRP-deficient mice display profoundly impaired bone regeneration characterised by a striking reduction in the number of bone-forming osteoblasts and a high rate of incomplete callus bridging and non-union. As assessed by genome-wide expression analysis, CGRP induces the expression of specific genes linked to ossification, bone remodeling and adipogenesis. This suggests that CGRP receptor-dependent PPARγ signaling plays a central role in fracture healing. INTERPRETATION: This study demonstrates an essential role of αCGRP in orchestrating callus formation and identifies CGRP receptor agonism as a potential approach to stimulate bone regeneration. Moreover, as novel agents blocking CGRP or its receptor CRLR are currently introduced clinically for the treatment of migraine disorders, their potential negative impact on bone regeneration warrants clinical investigation. FUNDING: This work was funded by grants from the Else-Kröner-Fresenius-Stiftung (EKFS), the Deutsche Forschungsgemeinschaft (DFG), and the Berlin Institute of Health (BIH).