Pharmacological Probes to Validate Biomarkers for Analgesic Drug Development.

There is an urgent need for analgesics with improved efficacy, especially in neuropathic and other chronic pain conditions. Unfortunately, in recent decades, many candidate analgesics have failed in clinical phase II or III trials despite promising preclinical results. Translational assessment tools to verify engagement of pharmacological targets and actions on compartments of the nociceptive system are missing in both rodents and humans. Through the Innovative Medicines Initiative of the European Union and EFPIA, a consortium of researchers from academia and the pharmaceutical industry was established to identify and validate a set of functional biomarkers to assess drug-induced effects on nociceptive processing at peripheral, spinal and supraspinal levels using electrophysiological and functional neuroimaging techniques. Here, we report the results of a systematic literature search for pharmacological probes that allow for validation of these biomarkers. Of 26 candidate substances, only 7 met the inclusion criteria: evidence for nociceptive system modulation, tolerability, availability in oral form for human use and absence of active metabolites. Based on pharmacokinetic characteristics, three were selected for a set of crossover studies in rodents and healthy humans. All currently available probes act on more than one compartment of the nociceptive system. Once validated, biomarkers of nociceptive signal processing, combined with a pharmacometric modelling, will enable a more rational approach to selecting dose ranges and verifying target engagement. Combined with advances in classification of chronic pain conditions, these biomarkers are expected to accelerate analgesic drug development.

Oral acetaminophen-induced spinal 5-hydroxytriyptamine release produces analgesic effects in the rat formalin test.

The mechanism by which acetaminophen produces its analgesic effects is not fully understood. One possible mechanism is the activation of the spinal 5-hydroxytryptamine (5-HT) receptor, although direct evidence of spinal 5-HT release has not yet been reported. N-arachidonoylphenolamine (AM404), a metabolite of acetaminophen, is believed to be the key substance that contributes to the analgesic effects of acetaminophen. In this study, we examined whether acetaminophen and AM404 induce spinal 5-HT release and the mechanism through which spinal 5-HT receptor activation exerts analgesic effects in a rat formalin test in an inflammatory pain model. Spinal 5-HT release was examined by intrathecal microdialysis in conscious and freely moving rats. Acetaminophen was administered orally, and AM404 was administered intracerebroventricularly. In rat formalin tests, oral acetaminophen and intracerebroventricular AM404 induced significant spinal 5-HT release and produced analgesic effects. The analgesic effect of oral acetaminophen was partially antagonized by intrathecal administration of WAY100135 (a 5-HT1A receptor antagonist) and SB269970 (a 5-HT7 receptor antagonist). In contrast, the analgesic effect of intracerebroventricular AM404 was completely antagonized by WAY100135, while SB269970 had no effect. Our data suggest that while oral acetaminophen and intracerebroventricular AM404 activate the spinal 5-HT system, the role of the spinal 5-HT system activated by oral acetaminophen differs from that activated by intracerebroventricular AM404.

Unusual Quadrupedal Locomotion in Rat during Recovery from Lumbar Spinal Blockade of 5-HT7 Receptors.

Coordination of four-limb movements during quadrupedal locomotion is controlled by supraspinal monoaminergic descending pathways, among which serotoninergic ones play a crucial role. Here we investigated the locomotor pattern during recovery from blockade of 5-HT7 or 5-HT2A receptors after intrathecal application of SB269970 or cyproheptadine in adult rats with chronic intrathecal cannula implanted in the lumbar spinal cord. The interlimb coordination was investigated based on electromyographic activity recorded from selected fore- and hindlimb muscles during rat locomotion on a treadmill. In the time of recovery after hindlimb transient paralysis, we noticed a presence of an unusual pattern of quadrupedal locomotion characterized by a doubling of forelimb stepping in relation to unaffected hindlimb stepping (2FL-1HL) after blockade of 5-HT7 receptors but not after blockade of 5-HT2A receptors. The 2FL-1HL pattern, although transient, was observed as a stable form of fore-hindlimb coupling during quadrupedal locomotion. We suggest that modulation of the 5-HT7 receptors on interneurons located in lamina VII with ascending projections to the forelimb spinal network can be responsible for the 2FL-1HL locomotor pattern. In support, our immunohistochemical analysis of the lumbar spinal cord demonstrated the presence of the 5-HT7 immunoreactive cells in the lamina VII, which were rarely 5-HT2A immunoreactive.

Facilitated and Controlled Strontium Ranelate Delivery Using GCS-HA Nanocarriers Embedded into PEGDA Coupled with Decortication Driven Spinal Regeneration.

BACKGROUND AND PURPOSE: Strontium ranelate (SrR) is an oral pharmaceutical agent for osteoporosis. In recent years, numerous unwanted side effects of oral SrR have been revealed. Therefore, its clinical administration and applications are limited. Hereby, this study aims to develop, formulate, and characterize an effective SrR carrier system for spinal bone regeneration. METHODS: Herein, glycol chitosan with hyaluronic acid (HA)-based nanoformulation was used to encapsulate SrR nanoparticles (SrRNPs) through electrostatic interaction. Afterward, the poly(ethylene glycol) diacrylate (PEGDA)-based hydrogels were used to encapsulate pre-synthesized SrRNPs (SrRNPs-H). The scanning electron microscope (SEM), TEM, rheometer, Fourier-transform infrared spectroscopy (FTIR), and dynamic light scattering (DLS) were used to characterize prepared formulations. The rabbit osteoblast and a rat spinal decortication models were used to evaluate and assess the developed formulation biocompatibility and therapeutic efficacy. RESULTS: In vitro and in vivo studies for cytotoxicity and bone regeneration were conducted. The cell viability test showed that SrRNPs exerted no cytotoxic effects in osteoblast in vitro. Furthermore, in vivo analysis for new bone regeneration mechanism was carried out on rat decortication models. Radiographical and histological analysis suggested a higher level of bone regeneration in the SrRNPs-H-implanted groups than in the other experimental groups. CONCLUSION: Local administration of the newly developed formulated SrR could be a promising alternative therapy to enhance bone regeneration in bone-defect sites in future clinical applications.

Clobetasol promotes neuromuscular plasticity in mice after motoneuronal loss via sonic hedgehog signaling, immunomodulation and metabolic rebalancing.

Motoneuronal loss is the main feature of amyotrophic lateral sclerosis, although pathogenesis is extremely complex involving both neural and muscle cells. In order to translationally engage the sonic hedgehog pathway, which is a promising target for neural regeneration, recent studies have reported on the neuroprotective effects of clobetasol, an FDA-approved glucocorticoid, able to activate this pathway via smoothened. Herein we sought to examine functional, cellular, and metabolic effects of clobetasol in a neurotoxic mouse model of spinal motoneuronal loss. We found that clobetasol reduces muscle denervation and motor impairments in part by restoring sonic hedgehog signaling and supporting spinal plasticity. These effects were coupled with reduced pro-inflammatory microglia and reactive astrogliosis, reduced muscle atrophy, and support of mitochondrial integrity and metabolism. Our results suggest that clobetasol stimulates a series of compensatory processes and therefore represents a translational approach for intractable denervating and neurodegenerative disorders.

Teriparatide and Abaloparatide Have a Similar Effect on Bone in Mice.

Three bone anabolic pharmaceuticals are currently approved for treatment of osteoporosis, teriparatide (PTH (1-34)), the parathyroid hormone-related protein analog abaloparatide (ABL), and romosozumab. The present study compared the effect of intermittent PTH (1-34) and ABL on bone tissue directly mole-to-mole in female mice. Forty-seven C57BL/6 mice were randomly allocated to the following groups: Baseline (n = 11), Control (Ctrl) (n = 12), PTH (n = 12), and ABL (n = 12). The mice were injected s.c. with PTH (100 µg/kg), ABL (96 µg/kg), or saline (Ctrl) five days a week for three weeks. To assess the effect of PTH and ABL, the hindlimb bones were analyzed with DXA, µCT, mechanical testing, dynamic bone histomorphometry, and histological quantification of bone cells. In addition, serum calcium concentration was determined. PTH and ABL significantly increased femoral areal bone mineral density (aBMD) (borderline significant p = 0.06 for PTH), femoral mid-diaphyseal bone strength, femoral metaphyseal and epiphyseal and vertebral bone volume fraction (BV/TV), connectivity density, volumetric bone mineral density (vBMD), and bone formation rate (BFR/BS) compared to Ctrl. In addition, ABL also significantly increased mid-diaphyseal cortical thickness and bone area compared to Ctrl. Neither PTH nor ABL significantly increased bone strength at the femoral neck. In conclusion, abaloparatide and PTH have similar bone anabolic properties when compared directly mole-to-mole in mice.

Effects of triangle grass decoction on bone metabolism in rats with chronic kidney disease complicated with mineral and bone abnormalities.

ETHNOPHARMACOLOGICAL RELEVANCE: Triangle grass is a liliaceous Chlorophytum perennial herb of ChlorophytumlaxumR.Br. It is distributed mainly in Guangdong and Guangxi Provinces of China. The initial use of triangle grass was mainly to treat bone pain and swelling caused by a fall injury. Triangle grass tablets (NO. Z20070544) are also used as a preparation in our hospital because of their analgesic, anti-inflammatory, anti-snake venom and microcirculation improvement properties and other pharmacological effects (Mei et al., 2006). Triangle grass tablets have been widely used in our hospital to treat patients with bone pain from chronic kidney disease-mineral and bone disorder (CKD-MBD). However, the effects and mechanism of triangle grass on bone metabolism in chronic kidney disease complicated with mineral and bone abnormalities are unclear. AIM OF THE STUDY: The aim of the present study was to investigate the effects of a triangle grass decoction on bone metabolism in CKD-MBD rats. MATERIALS AND METHODS: CKD-MBD model rats were subjected to 5/6 nephrectomy combined with 0.5 g NaH2PO4/rat. Serum blood urea nitrogen (BUN), creatinine (Cr), phosphorus (P), calcium (Ca), and intact parathyroid hormone (iPTH) levels were measured with an automatic biochemical analyser. Bone mineral density was determined with a Viva CT 40 system. Bone morphogenetic protein 7(BMP-7),runt-related transcription factor 2 (Runx2) and Osterix protein levels were measured by Western blot analysis. Kidney, vertebra and thoracic aorta tissue samples were assessed by histopathology and immunohistochemistry (IHC). RESULTS: The degrees of membrane thickening, necrosis, swelling and cast deposition were significantly reduced in high-dose rats and Low-dose rats. Serum BUN levels were significantly reduced in the Pre-H group (P < 0.05). Hypocalcaemia and hyperphos phataemia were detected in triangle grass (P < 0.05, P < 0.05). In addition, iPTH levels were significantly increased in the Pre-H group (P < 0.05). Alkaline phosphatase (ALP)levels were significantly decreased in the Pre-H group (P < 0.05). The bone mineral density was improved in the Pre-H and Pre-L groups. BMP-7 protein levels were significantly increased in the Pre-H group (P < 0.05). The pathological changes in muscle fibres in the thoracic aorta middle membranes were significantly alleviated in rats in the Pre-H and Pre-L groups. Changes in SM22α and SMα-act in protein levels were significantly attenuated in the Pre-H group (P < 0.05, P < 0.05). Changes in Runx2 and Osterix protein levels were also significantly attenuated in the Pre-H and Pre-L groups (P < 0.05, P < 0.05). CONCLUSIONS: Triangle grass can simultaneously ameliorate vertebral bone loss and abnormal calcification in the thoracic aorta. Triangle grass has a definite effect on bone metabolism disorder in CKD-MBD rats.

Efficacy and safety of intrathecal morphine for pain control after spinal surgery: a systematic review and meta-analysis.

OBJECTIVE: This study aimed to assess the efficacy and safety of intrathecal (IT) morphine for postoperative pain control in adults undergoing spinal surgeries. We searched the electronic databases of PubMed, Embase, and CENTRAL up to 1st January 2021 for randomized controlled trials (RCTs) or controlled clinical trials (CCTs) comparing IT morphine with placebo or other analgesics. Twelve studies were included. Eleven were RCTs and one was a CCT. Our meta-analysis indicated a statistically significant reduction of pain scores with IT morphine at 2 hours, 4 hours, 6 hours, 8 hours, 12 hours, and 24 hours; but no significant difference at 48 hours. Meta-analysis indicated a statistically significant reduction in analgesic consumption with IT morphine as compared to control. Pooled analysis indicated that IT morphine had no statistically significant effect on length of hospital stay. Our analysis indicated no statistically significant difference in the risk of nausea, vomiting, sedation, respiratory depression, headache, and urinary retention between IT morphine and control groups. The incidence of pruritis was significantly increased in the IT morphine group. The certainty of the evidence was judged to be "moderate" for pain scores at 12 hours, 24 hours, and analgesic consumption. To conclude, our review indicates that IT morphine results in significantly better pain control in the first 24 hours after spinal surgery. The risk of pruritis is significantly increased with the use of IT morphine but not for other opioid-related adverse events. Future RCTs should focus on finding the most optimal dose of IT morphine for spinal surgeries.

Anesthetics fragment hippocampal network activity, alter spine dynamics, and affect memory consolidation.

General anesthesia is characterized by reversible loss of consciousness accompanied by transient amnesia. Yet, long-term memory impairment is an undesirable side effect. How different types of general anesthetics (GAs) affect the hippocampus, a brain region central to memory formation and consolidation, is poorly understood. Using extracellular recordings, chronic 2-photon imaging, and behavioral analysis, we monitor the effects of isoflurane (Iso), medetomidine/midazolam/fentanyl (MMF), and ketamine/xylazine (Keta/Xyl) on network activity and structural spine dynamics in the hippocampal CA1 area of adult mice. GAs robustly reduced spiking activity, decorrelated cellular ensembles, albeit with distinct activity signatures, and altered spine dynamics. CA1 network activity under all 3 anesthetics was different to natural sleep. Iso anesthesia most closely resembled unperturbed activity during wakefulness and sleep, and network alterations recovered more readily than with Keta/Xyl and MMF. Correspondingly, memory consolidation was impaired after exposure to Keta/Xyl and MMF, but not Iso. Thus, different anesthetics distinctly alter hippocampal network dynamics, synaptic connectivity, and memory consolidation, with implications for GA strategy appraisal in animal research and clinical settings.

Off-treatment bone mineral density changes in postmenopausal women receiving anastrozole for 5 years: 7-year results from the IBIS-II prevention trial.

BACKGROUND: Anastrozole has been associated with substantial accelerated bone mineral density (BMD) loss during active treatment. METHODS: One thousand four hundred and ten women were included in a BMD substudy and stratified into three strata according to their baseline T-score at spine or femoral neck. The primary objective of this analysis was to investigate whether DXA BMD at the spine and hip changed two years after treatment cessation (between years 5 and 7) in those who did not receive risedronate. RESULTS: Five- and seven-year BMD data were available for a total of 528 women who did not receive risedronate. In women with normal BMD at baseline, an increase in BMD at the lumbar spine after anastrozole withdrawal was observed 1.25% (95% CI 0.73 to 1.77) (P = 0.0004), which was larger than in those on placebo (0.14% (-0.29 to 0.56))). At the hip, BMD remained unchanged between years 5 and 7 for those previously on anastrozole but continued to a decrease in those who had been randomised to placebo (-1.35% (-1.70 to -0.98)). CONCLUSIONS: These are the first results reporting BMD changes after stopping anastrozole in a breast cancer prevention setting. Our results show that the negative effects of anastrozole on BMD in the preventive setting are partially reversible.

Protective effect of gastrodin on peripheral neuropathy induced by anti-tumor treatment with vincristine in rat models.

Cancer is a common disease threatening human health, chemotherapy is widely used in clinical treatment of cancer, but chemotherapy-induced peripheral neuropathy (CIPN) has a relevant impact on life quality of cancer patients. Administration of gastrodin can relieve chronic pain to cancer patients with CIPN and attenuated the inflammatory response by reducing the expression of tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6). However, its exact molecular mechanisms remain unclear. In this study, we established an animal model of CIPN using Walker-256 breast cancer cell and vincristine. We found that the mechanical and thermal pain threshold of rats was decreased with treatment of vincristine. Using gastrodin could restore the mechanical and thermal threshold without interfering anti-tumor effect of vincristine. Gastrodin relieved CIPN by inhibiting activation of spinal microglia through Fractalkine (CX3CL1) and its receptor CX3CR1, then inhibited P38/mitogen-activated protein kinase (MAPK) signaling pathway and reduced the expression of inflammatory factor TNF-α and interleukin-1ß (IL-1ß). Taking together, our study demonstrated that gastrodin is a potential drug for the treatment of CIPN and likely to improve cancer patient's life quality.

TRPV4 and TRPM8 as putative targets for chronic low back pain alleviation.

The purpose of this study is to investigate the presence of nervous fibers and expression of TRP channels in samples harvested during decompressive/fusion spine surgeries from patients affected by chronic low back pain (CLBP). The aim was to understand if members of this family of receptors played a role in detection and processing of painful stimuli, to eventually define them as potential targets for CLBP alleviation. Expression of transient receptor potential (TRP) channels (A1, V1, V2, V4, and M8) was evaluated in samples from different periarticular sites of 6 patients affected by CLBP, at both protein and transcript levels. The capsular connective pathological tissue appeared infiltrated by sensitive unmyelinated nervous fibers. An increase in TRP channel mRNAs and proteins was observed in the pathological capsule compared with tissues collected from the non-symptomatic area in five of the six analyzed patients, independently by the location and number of affected sites. In particular, TRPV4 and TRPM8 were consistently upregulated in pathological tissues. Interestingly, the only patient showing a different pattern of expression also had a different clinical history. TRPV4 and TRPM8 channels may play a role in CLBP and warrant further investigations as possible therapeutic targets.

Punicalagin Exerts Protective Effects against Ankylosing Spondylitis by Regulating NF-κB-TH17/JAK2/STAT3 Signaling and Oxidative Stress.

BACKGROUND: Ankylosing spondylitis (AS) is a chronic inflammatory disease characterized by sacroiliitis and spinal rigidity of the axial joints. The role of oxidative stress and increased proinflammatory cytokines is well documented in AS pathogenesis. Punicalagin (2,3-hexahydroxydiphenoyl-gallagyl-D-glucose), an ellagitannin widely present in pomegranates, is found to exhibit potent anti-inflammatory, antiproliferative, and antioxidative effects. The present study was undertaken to investigate the effects of punicalagin in a rodent model of AS. METHODS: BALB/c mice induced spondylitis were sacrificed 24 h after the last injection of proteoglycan extract. Histological scoring was done to assess the degree of the disease. The expression of JAK2/STAT3 proteins and proteins of the nuclear factor-κB (NF-κB) pathway was determined by immunoblotting. Serum levels of inflammatory mediators-TNF-α, IL-1ß, IL-6, IL-17A, and IL-23-were assessed. Levels of lipid peroxidation and reactive oxygen species (ROS) were quantified. Antioxidant status as a measure of activities of antioxidant enzymes-catalase (CAT), glutathione peroxidase (GPx), and superoxide dismutase (SOD)-was determined. RESULTS: Punicalagin effectively improved antioxidant status and decreased lipid peroxidation, ROS production, and serum levels of inflammatory mediators. NF-κB pathway and JAK2/STAT3 signaling were significantly (p < 0.05) downregulated. Punicalagin effectively regulated the production of cytokines by the Th17 cells and the IL-17A/IL-23 axis. CONCLUSION: The observations suggest that punicalagin exerts a protective role in AS via reducing oxidative stress and regulating NF-κB/TH17/JAK2/STAT3 signal. Punicalagin thus could be explored further as a potent candidate compound in the treatment of AS.

Early achievement of ASDAS clinical response is associated with long-term improvements in metrological outcomes in patients with ankylosing spondylitis treated with TNF-α blockers.

The aim of this study was to investigate the relationship between long-term spinal mobility improvements and early disease activity changes or achievement of clinical response criteria in patients with ankylosing spondylitis (AS) treated with tumor necrosis factor (TNF-α) blockers.This retrospective study included 112 patients with AS treated with TNF-α blockers for up to 33 months. The paired t-test was used to compare outcome measures between visits. The correlation between disease activity changes and metrological improvements was analyzed using cumulative probability plots, Spearman correlation coefficient, and canonical correlation. The difference in metrological outcomes between responders and non-responders to clinical response criteria was also examined.Metrological and disease activity outcomes improved most markedly in month 3. All disease activity outcomes and ESR from baseline to month 3 (3-month) were significantly correlated with the Bath Ankylosing Spondylitis Metrology Index (BASMI10) improvements from baseline to month 33 (33-month). The 3-month changes in ankylosing spondylitis disease activity score (ASDAS-CRP) and patient's global assessment showed a significant correlation with the 33-month changes in chest expansion. Only responders according to ASDAS major improvement at month 3 demonstrated significant 33-month improvements in both BASMI10 and chest expansion, compared to non-responders. Responders according to Assessment of Spondylo Arthritis international Society 40 at month 3 showed significant 33-month improvements in BASMI10, but not chest expansion, compared to non-responders.The degree of early changes in disease activity outcomes influenced the extent of long-term metrological improvements in AS treated with TNF-α blockers. Additionally, the achievement of ASDAS- major improvement at month 3 predicted significant metrological improvements throughout long-term TNF-α-blocker therapy.

A synthetic synaptic organizer protein restores glutamatergic neuronal circuits.

Neuronal synapses undergo structural and functional changes throughout life, which are essential for nervous system physiology. However, these changes may also perturb the excitatory-inhibitory neurotransmission balance and trigger neuropsychiatric and neurological disorders. Molecular tools to restore this balance are highly desirable. Here, we designed and characterized CPTX, a synthetic synaptic organizer combining structural elements from cerebellin-1 and neuronal pentraxin-1. CPTX can interact with presynaptic neurexins and postsynaptic AMPA-type ionotropic glutamate receptors and induced the formation of excitatory synapses both in vitro and in vivo. CPTX restored synaptic functions, motor coordination, spatial and contextual memories, and locomotion in mouse models for cerebellar ataxia, Alzheimer's disease, and spinal cord injury, respectively. Thus, CPTX represents a prototype for structure-guided biologics that can efficiently repair or remodel neuronal circuits.

Early changes in bone turnover and inflammatory biomarkers and clinically significant bone mineral density loss over 48 weeks among HIV-infected patients with virological failure of a standard first-line antiretroviral therapy regimen in the SECOND-LINE study.

OBJECTIVES: We assessed whether changes at week 12 in markers of bone turnover, inflammation, and immune activation were associated with clinically important (≥ 5%) bone mineral density (BMD) loss from baseline to week 48 at the proximal femur (hip) and lumbar spine in the SECOND-LINE study. METHODS: We measured concentrations of procollagen type 1 pro-peptide (P1NP), carboxyl-terminal collagen crosslinks (CTX), high-sensitivity C-reactive protein (hs-CRP), D-dimer, interleukin (IL)-6, tumor necrosis factor (TNF), neopterin, and soluble CD14 and 163 at weeks 0, 12, and 48 in 123 SECOND-LINE dual-energy X-ray absorptiometry (DXA) substudy participants. Linear regression was used to compare changes in biomarkers. Predictors of ≥ 5% BMD loss were examined using multivariable regression. RESULTS: The mean age was 38 years, the mean CD4 T-cell count was 252 cells/µL and the mean viral load was 4.2 log HIV-1 RNA copies/mL; 56% of participants were female and 47% were randomized to receive a nucleos(t)ide reverse transcriptase inhibitor [N(t)RTI]-based regimen [91% (53/58) were randomized to receive a tenofovir disoproxil fumarate (TDF)-containing regimen]. Over 48 weeks, 71% in the N(t)RTI arm experienced ≥ 5% hip BMD loss vs. 29% in the raltegravir arm (P = 0.001). Week 12 changes in P1NP and CTX were significantly greater among patients experiencing ≥ 5% hip BMD loss, patients randomized to N(t)RTI, and male patients. Predictors of ≥ 5% hip BMD loss at week 48 were P1NP increase [odds ratio (OR) 5.0; 95% confidence interval (CI) 1.1-27; P < 0.043]; N(t)RTI randomization (OR 6.7; 95% CI 2.0-27.1; P < 0.003), being African, higher baseline CD4 T cell count , and smoking. CONCLUSIONS: In a diverse cohort of viraemic HIV-infected patients, switching to second-line antiretroviral therapy (ART) was associated with clinically significant BMD loss, which was correlated with an early increase in P1NP. Measurement of P1NP may facilitate timely interventions to reduce rapid BMD loss among at-risk patients.

Pamidronate in chronic non-bacterial osteomyelitis: a randomized, double-blinded, placebo-controlled pilot trial.

OBJECTIVE: This is the first randomized double-blinded, placebo-controlled pilot trial to investigate the efficacy of pamidronate in reducing radiological and clinical disease activity in chronic non-bacterial osteomyelitis (CNO). METHOD: Patients received pamidronate or placebo at baseline and weeks 12 and 24. Whole-body magnetic resonance imaging was performed at baseline and weeks 12 and 36, and computed tomography of the anterior chest wall (ACW) at baseline and week 36. Radiological disease activity was systematically scored in the ACW and spine. Patient-reported outcomes [visual analogue scale (VAS) pain, VAS global health, Health Assessment Questionnaire (HAQ), EuroQol-5 Dimensions (EQ-5D), and 36-item Short-Form Health Survey (SF-36)] and biomarkers of bone turnover and inflammation were assessed at baseline and weeks 1, 4, 12, 24, and 36. Data are expressed as median [interquartile range]. RESULTS: Fourteen patients were randomized and 12 were analysed. From baseline to week 36, the radiological disease activity score in the ACW decreased from 5 [4-7] to 2.5 [1-3] in the pamidronate group, but did not change in the placebo group (p = 0.04). From baseline to week 36, VAS pain and VAS global health tended to decrease more in the pamidronate than in the placebo group (p = 0.11, p = 0.08). Physical functioning (HAQ) and health-related quality of life (EQ-5D, SF-36) did not change. Biomarkers of bone turnover decreased only in the pamidronate group (p ≤ 0.02). CONCLUSION: Pamidronate may improve radiological and clinical disease activity in CNO. Methods to score radiological disease activity in adult CNO were suggested. Clinical Trials: NCT02594878.

Erythropoietin Mediated Bone Loss in Mice Is Dose-Dependent and Mostly Irreversible.

Recent studies have demonstrated that erythropoietin (EPO) treatment in mice results in trabecular bone loss. Here, we investigated the dose-response relationship between EPO, hemoglobin (Hgb) and bone loss and examined the reversibility of EPO-induced damage. Increasing doses of EPO over two weeks led to a dose-dependent increase in Hgb in young female mice, accompanied by a disproportionate decrease in trabecular bone mass measured by micro-CT (µCT). Namely, increasing EPO from 24 to 540 IU/week produced a modest 12% rise in Hgb (20.2 ± 1.3 mg/dL vs 22.7 ± 1.3 mg/dL), while trabecular bone volume fraction (BV/TV) in the distal femur decreased dramatically (27 ± 8.5% vs 53 ± 10.2% bone loss). To explore the long-term skeletal effects of EPO, we treated mice for two weeks (540 IU/week) and monitored bone mass changes after treatment cessation. Six weeks post-treatment, there was only a partial recovery of the trabecular microarchitecture in the femur and vertebra. EPO-induced bone loss is therefore dose-dependent and mostly irreversible at doses that offer only a minor advantage in the treatment of anemia. Because patients requiring EPO therapy are often prone to osteoporosis, our data advocate for using the lowest effective EPO dose for the shortest period of time to decrease thromboembolic complications and minimize the adverse skeletal outcome.

Erector spine plane block as postoperative rescue analgesia in thoracic surgery.

OBJECTIVE: Erector spine plane block (ESPB) is a newly defined regional anesthesia technique performed by injection of local anesthetic beneath the erector spine muscle. We tested ESPB as a regional rescue analgesia bedside technique to be performed in the thoracic surgical ward, reporting a 7-patient case series. METHODS: We report our experience in rescue analgesia after thoracic surgery. During the postoperative stay, numeric rating scale (NRS) score >3 and inability to perform physiotherapy or effective cough due to postoperative pain represented the criteria for proposing rescue analgesia with ESPB. NRS at rest and during movements was recorded; blood gas analysis and spirometry were performed to evaluate PaO2/FiO2 (P/F), forced vital capacity (FVC), and forced expiratory volume in 1 second (FEV1) before ESPB execution. After performing the ESPB, static and dynamic NRS, P/F, and FVC and FEV1 were recorded at 40 minutes and 80 minutes. RESULTS: NRS had a reduction at rest and in dynamic assessment. The P/F did not improve but spirometric measures improved. FVC had a relevant improvement only after 80 minutes; FEV1 was increased after 40 minutes. CONCLUSION: The use of ESPB as postoperative rescue analgesia can offer several advantages due to effective rescue analgesia and safety that makes it easy to perform in the thoracic surgical ward or in an outpatient clinic setting.

Radiation therapy combined with bone-modifying agents ameliorates local control of osteolytic bone metastases in breast cancer.

Bone-modifying agents (BMAs) are frequently used for the treatment of bone metastases. Both BMA and radiation therapy (RT) are effective; however, there are few studies that have evaluated the efficacy of the combination treatment. We evaluated the effectiveness of RT + BMA in breast cancer-induced osteolytic bone metastasis as compared to BMA alone. A total of 43 lesions in 25 patients were evaluated. The median follow-up period was 18 (range, 2-90) months. None of the lesions was treated with chemotherapy or molecular targeted drugs during the follow-up period for evaluating the local response. Patients with complete or partial response were considered as responders, while those with stable or progressive disease were considered as non-responders. The rate of response with RT + BMA was significantly higher than that with BMA alone (P = 0.001). The cumulative incidence rate of response at 6 months was 54.4% in the RT + BMA group and 27.5% in the BMA alone group. The median time to response was 4 (range, 2-11) months in the RT + BMA group and 6 (range, 4-16) months in the BMA alone group. The overall survival rate in the responder group (83.1% at 1 year) was significantly higher than that in the non-responder group (37.5% at 1 year) (P = 0.029). In conclusion, RT combined with BMA was found to be more effective than BMA alone for the treatment of osteolytic bone metastasis, which thereby improves the prognosis.