An Integrated Care Approach to Improve Well-Being in Breast Cancer Patients.

BACKGROUND: Breast cancer (BC) treatment has recently been revolutionized by the introduction of newer targeted agents, that helped tailoring therapies around the single patient. Along with increased survival rates, a careful evaluation of diet, lifestyle habits, physical activity, emotional and psychological experiences linked to the treatment journey, is now mandatory. However, a true proposal for an omnicomprehensive and "integrative" approach is still lacking in literature. METHODS: A scientific board of internationally recognized specialists throughout different disciplines designed a shared proposal of holistic approach for BC patients. RESULTS: A narrative review, containing information on BC treatment, endocrinological and diet aspects, physical activity, rehabilitation, integrative medicine, and digital narrative medicine, was developed. CONCLUSIONS: In the context of a patient-centered care, BC treatment cannot be separated from a patient's long-term follow-up and care, and an organized interdisciplinary collaboration is the future in this disease's cure, to make sure that our patients will live longer and better. TRIAL REGISTRATION: NCT05893368: New Model for Integrating Person-based Care (PbC) in the Treatment of Advanced HER2-negative Breast Cancer (PERGIQUAL). Registration date: 29th May 2023.

Neutrophil, lymphocyte count, and neutrophil to lymphocyte ratio predict multimorbidity and mortality-results from the Baltimore Longitudinal Study on Aging follow-up study.

Immunosenescence is the age-related changes in the immune system, namely, progressively higher levels of circulating inflammatory markers, characteristics changes of circulating immune subset cells and altered immune function. The neutrophil to lymphocyte ratio (NL ratio) has been identified as a prognostic indicator for neoplastic disease progression, in predicting chronic degenerative diseases, and as a potential indirect marker of healthy aging. This study aims to examine the longitudinal association of neutrophil, lymphocyte absolute count, and their ratio with longitudinal risk for multimorbidity and mortality. The Baltimore Longitudinal Study of Aging (BLSA) is an open observational cohort study of community-dwelling volunteers that are followed every 1-4 years depending on their age. The sample considered in the study consists of 1769 participants (5090 follow-ups) with completed data for physical examination, health history assessment, and donated a blood sample. The NL ratio increased with age and was associated with a higher risk of mortality, while a lower NL ratio was inversely correlated with multimorbidity. Neutrophils increased with aging and an increase in their absolute number predicted mortality risk. However, the absolute number of lymphocytes was associated with age only in a cross-sectional analysis. In conclusion, this study supports the importance of the NL ratio and absolute neutrophil count as markers of aging health status, and as significant predictors of all-cause mortality and multimorbidity in aging individuals. It remains to be demonstrated whether interventions contrasting these trends in circulating cells may result in improved health outcomes.

Beyond Inflammaging: The Impact of Immune System Aging on Age-Related Muscle Decline, Results From the InCHIANTI Study.

Aging is characterized by chronic low-level inflammation and is associated with geriatric syndromes such as sarcopenia and frailty. Our aim was to evaluate the longitudinal variation of muscle area, muscle quality, and muscle strength, relative to the variation of leukocyte-derived markers, and to assess the presence of a pathway of associations among derived leukocyte ratios, and the components of muscle health. The InCHIANTI is a longitudinal cohort study of aging that began in 1998 with follow-up visits every 3 years. Out of the 1 453 participants enrolled at baseline, this study includes 1 179 participants with complete data. Muscle strength was assessed by hand grip strength test, whereas muscle density and fat area were considered as indirect markers of muscle quality, derived from peripheral quantitative computed tomography of the calf. Muscle area was associated with neutrophil-to-lymphocyte ratio (NL-ratio), age, gender, comorbidities, and body mass index (BMI). Muscle density variation over time was inversely associated with age, comorbidities, and BMI, while being positively associated with monocyte-to-lymphocyte ratio (ML-ratio) and male gender. Fat area was inversely associated with age, interleukine-6 (IL-6), male gender, and NL-ratio, while being positively associated with ML-ratio, comorbidities, and BMI. Handgrip strength decreased with age, IL-6 levels, comorbidities, and NL-ratio, but increased with ML-ratio, being male, and having a higher BMI. In a path-analysis model, ML-ratio positively correlates with muscle mass, density, and strength, while NL-ratio only correlates inversely with muscle mass and density. NL-ratio and ML-ratio are associated with aging and may be implicated in age-related mechanisms that affect body composition and muscle strength. These ratios may represent a link between aging of the immune system and decline of muscle health with aging. However, further studies are needed to identify their usefulness for early detection of sarcopenia, myosteatosis, and frailty in the older adult.

Sclerostin: clinical insights in muscle-bone crosstalk.

Sclerostin, a protein encoded by the sclerostin (SOST) gene, is mostly expressed in osteocytes. First described in the pathogenesis of three disorders, sclerosteosis, van Buchem's disease, and craniodiaphyseal dysplasia, sclerostin has been identified as an important regulator of bone homeostasis, controlling bone formation by osteoblasts through inhibition of the canonical Wnt signaling pathway. Recent studies have highlighted a hypothetical role of sclerostin in myogenesis, thus modulating the interaction between bone and muscle. This narrative review provides an overview of the clinical implications of sclerostin modulation on skeletal muscle mass and function, and bone metabolism. Improving knowledge about muscle-bone crosstalk may represent a turning point in the development of therapeutic strategies for musculoskeletal disorders, particularly osteosarcopenia.

Nutritional and physical activity issues in frailty syndrome during the COVID-19 pandemic.

'Frailty' has been described as 'a state of increased vulnerability of the individual caused by an impairment of homeostasis as a result of endogenous or exogenous stress'. Frail individuals are depicted by a dramatic change in health status following an apparently minor insult and a higher risk of adverse health-related outcomes such as osteoporosis and sarcopenia, falls and disability, and fragility fractures. Frailty is a condition of increasing importance due to the global ageing of the population during the last decades. Central to the pathophysiology of frailty is a mechanism that is partially independent of ageing, but most likely evolves with ageing: the cumulative level of molecular and cellular damage in every subject. Furthermore, an uncorrected nutrition and a sedentary behaviour play a pivotal role in worsening the syndrome. In January 2020, a cluster of a genus of the family Coronaviridae was isolated as the pathogen of the new coronavirus disease (COVID-19). Since then, this infection has spread worldwide causing one of the most dramatic pandemics of the modern era, with more than 500 million confirmed cases all over the world. The clinical spectrum of SARS-CoV-2 severity ranges from asymptomatic conditions to mild symptoms, such as fever, cough, ageusia, anosmia and asthenia, up to most severe conditions, such as acute respiratory distress syndrome (ARDS) and multi-organ failure leading to death. Primary evidence revealed that the elderly frail subjects were more susceptible to the disease in its most intense form and were at greater risk of developing severe COVID-19. Factors contributing to the severity of COVID-19, and the higher mortality rate, are a poor immune system activity and long-standing inflammatory status of the frail subjects compared with the general population. Further recent research also suggested a potential role of sedentary behaviour, metabolic chronic disorders linked to it and uncorrected nutritional status. Thus, the aim of this review was to evaluate the different studies and evidence related to COVID-19 pandemic, both nutritional status and physical activity, and, also, to provide further information on the correct nutritional approach in this peculiar pathological condition.

Osteoporosis in Childhood Cancer Survivors: Physiopathology, Prevention, Therapy and Future Perspectives.

The improvement of chemotherapy, radiotherapy, and surgical interventions, together with hematopoietic stem cell transplantation, increased childhood cancer survival rate in the last decades, reaching 80% in Europe. Nevertheless, anti-cancer treatments are mainly responsible for the onset of long-term side effects in childhood cancer survivors (CCS), including alterations of the endocrine system function and activity. In particular, the most frequent dysfunction in CCS is a metabolic bone disorder characterized by low bone mineral density (BMD) with increased skeletal fragility. BMD loss is also a consequence of a sedentary lifestyle, malnutrition, and cancer itself could affect BMD, thus inducing osteopenia and osteoporosis. In this paper, we provide an overview of possible causes of bone impairment in CCS in order to propose management strategies for early identification and treatment of skeletal fragility in this population.

Efficacy and Effectiveness of Extracorporeal Shockwave Therapy in Patients with Myofascial Pain or Fibromyalgia: A Scoping Review.

Myofascial pain syndrome (MPS) and fibromyalgia (FM) are underestimated painful musculoskeletal conditions that could impact function and quality of life. A consensus about the most appropriate therapeutic approach is still not reached. Considering the long course of the diseases, prolonged assumption of drugs, such as NSAIDs and pain killers, could increase the risk of adverse events, often leading affected patients and physicians to prefer non-pharmacological approaches. Among these, radial and focused extracorporeal shock waves therapies (ESWT) are widely used in the management of painful musculoskeletal conditions, despite the fact that the mechanisms of action in the context of pain modulation should be further clarified. We performed a scoping review on PubMed using Mesh terms for analyzing the current evidence about the efficacy and effectiveness of ESWT for patients with MPS or FM. We included 19 clinical studies (randomized controlled trials and observational studies); 12 used radial ESWT, and 7 used focused ESWT for MPS. Qualitative analysis suggests a beneficial role of ESWT for improving clinical and functional outcomes in people with MPS, whereas no evidence was found for FM. Considering this research gap, we finally suggested a therapeutic protocol for this latter condition according to the most recent diagnostic criteria.

The Rationale for Using Neridronate in Musculoskeletal Disorders: From Metabolic Bone Diseases to Musculoskeletal Pain.

Neridronate or ((6-amino-1-hydroxy-1-phosphonohexyl) phosphonic acid) is an amino-bisphosphonate (BP) synthetized in Italy in 1986. Bisphosphonates are molecules with a P-C-P bond in their structure that allows strong and selectively binding to hydroxyapatite (HAP) as well as osteoclasts inhibition through different mechanisms of action. Neridronate was initially used to treat Paget disease of the bone, demonstrating effectiveness in reducing bone turnover markers as well as pain. The interesting molecular properties of neridronate foster its wide use in several other conditions, such as osteogenesis imperfecta, and osteoporosis. Thanks to the unique safety and efficacy profile, neridronate has been used in secondary osteoporosis due to genetic, rheumatic, and oncological diseases, including in pediatric patients. In the last decade, this drug has also been studied in chronic musculoskeletal pain conditions, such as algodystrophy, demonstrating effectiveness in improving extraskeletal outcomes. This review highlights historical and clinical insights about the use of neridronate for metabolic bone disorders and musculoskeletal pain conditions.

Early Denosumab for the prevention of osteoporotic fractures in breast cancer women undergoing aromatase inhibitors: A case-control retrospective study.

BACKGROUND: Aromatase inhibitors (AIs) might have a detrimental impact on bone health in breast cancer (BC) women. Denosumab has been shown to reduce the risk of fractures, but the appropriate time for starting is yet to be clearly defined. OBJECTIVE: To evaluate the effects of early treatment with Denosumab (⩽ 12 months after starting AIs) compared to a delayed treatment in BC women. METHODS: In this retrospective case-control study, we included medical records of BC post-menopausal women, treated with AIs therapy; they were divided as: study group (starting Denosumab ⩽ 12 months after AIs) and control group (> 12 months). At the baseline (T0) and at 18 months (T1), we evaluated the lumbar spine (LS) Tscore and femoral neck (FN) Tscore. Furthermore, at T1 we assessed the incident fragility fractures. RESULTS: Fifty-nine BC survivors (mean age: 61.5 ± 11.5 years) were included: 28 with Early Denosumab and 31 with Late Denosumab. At T1, the study group did not show any incident hip or vertebral fragility fracture, whereas the Late Denosumab group showed 2 incident hip fractures (6.5%) and 4 (12.9%) vertebral fragility fractures. Early Denosumab showed a significant positive effect on both LS (p= 0.044) and FN (p= 0.024) Tscore variations. CONCLUSION: Taken together, our findings suggest that an early start of Denosumab might be considered for the osteoporosis management in BC women undergoing AIs.

Bone Marrow Edema: Overview of Etiology and Treatment Strategies.

➤: Bone marrow edema (BME) is a nonspecific but relevant finding, usually indicating the presence of an underlying pathology. ➤: The gold standard technique for detecting BME is magnetic resonance imaging (MRI), as it allows for a correct diagnosis to be made, which is extremely important given the heterogeneity of BME-related diseases. ➤: Depending on the severity of painful symptomatology and the MRI evidence, different treatment strategies can be followed: physical modalities, pharmacological options, and surgical therapy.

Complex Regional Pain Syndrome in Athletes: Scoping Review.

Background and Objectives: Complex regional pain syndrome (CRPS) is a chronic condition characterized by disproportionate regional pain, usually affecting distal limbs, that follows trauma or surgery. Athletes may develop CRPS because of exposure to traumatic or overuse injuries. The aim of the present study is to review the available literature about CRPS type 1 in athletes. Materials and Methods: We searched two online databases (PubMed and Web of Science), selecting papers aiming at investigating CRPS type 1 (algodystrophy) in athletes. The analysis of databases was made considering original articles published until 30 June 2021, written in English. Results: Fifteen papers (12 case reports, 3 case series) were selected for a total of 20 clinical cases (15 females, 5 males), aged between 10 and 46 years (mean age 18.4 ± 9.8 standard deviation years). Patients included practiced different types of sport (soccer, athletics, gymnastics, basketball). The most involved anatomical sites were lower limbs, and time to diagnosis ranged from 2 days to 4 years. The most used treatments were pharmacological and physical therapies, but sometimes invasive approaches, as regional nerve, or lumbar sympathetic blocks, were provided. The main assessed outcomes were return to activity and pain. Conclusions: Our review suggests a higher prevalence of CRPS type 1 in younger people and in lower limbs than in general population but confirms the higher prevalence in females. However, the number of studies addressing CRPS in athletes is limited, as well as the number of involved patients, considering that only few and heterogeneous case reports were published about this topic. Moreover, the high prevalence of old studies (only 5 available studies in the last 10 years) might have influenced the choice of both assessment tools and management strategies. Despite these limitations, athletes showing disproportionate pain after sport-related injury should be promptly evaluated and treated through a multidimensional approach to avoid long-term consequences of algodystrophy.

Complex Regional Pain Syndrome Type I Following Non-Orthopedic Surgery: Case Report and Narrative Review.

Complex regional pain syndrome type I (CRPS I)-or algodystrophy-is a rare disease that usually occurs after a traumatic event. It is characterized by typical clinical findings such as severe and disabling pain disproportionate to the injury, functional limitations, as well as sensory and vasomotor alterations. However, some people do not report any injury associated with algodystrophy onset in personal history. We describe the management of an unusual case of CRPS I which occurred during the long-term follow-up of percutaneous transluminal coronary angioplasty (PTCA) and performed a narrative review of algodystrophy in non-orthopedic surgery. A clinical case of a 44-year-old man with a spontaneous onset of CRPS I of the right ankle is presented. He did not refer to history of any memorable significant trigger event. Approximately 5 months before the onset of clinical manifestations, he received a PTCA via the right femoral approach. We suppose an association between CRPS and this procedure and propose a possible pathophysiologic mechanism. The patient was treated with intramuscular neridronate, which resulted in significant pain relief and improved his quality of life. A comprehensive clinical and instrumental evaluation in patients with CRPS is challenging but mandatory for a correct diagnosis. An extensive analysis of patient history is important for identifying any potential trigger event, including non-orthopedic procedures. Bone scan could have a pivotal role for improving diagnostic sensitivity and specificity in CRPS I. Neridronate was a safe and effective therapeutic approach for this patient, confirming the results of the high-quality evidence available.

Natural History of Scoliosis in Children with NF1: An Observation Study.

(1) Background. Scoliosis is the most common musculoskeletal manifestation of Neurofibromatosis type 1 (NF1), and it might be dystrophic (D) or non-dystrophic (ND) depending on the presence of dysplastic changes of the spine. The aim of our study was to describe the characteristics and natural history of patients with NF1 and scoliosis. (2) Methods. We retrospectively reviewed records from patients with NF1 and scoliosis. Scoliosis was classified as D if at least two dystrophic changes were documented at imaging. (3) Results. Of the 438 patients reviewed, 43 fulfilled inclusion criteria; 17 were classified in D group and 26 in ND. The groups did not differ in age and localization of scoliosis curvature. Surgery was needed more often in D group, but the between-group difference was not significant. Male-to-female ratios of 3:1 and 4:1 were reported in surgically treated NF1 patients with ND and D scoliosis, respectively. (4) Conclusions. Our data suggests independently by the presence of dysplastic changes affecting the spine that males with NF1 are more often affected by scoliosis that requires surgery.

The aging spine: the effect of vertebral fragility fracture on sagittal alignment.

Our study investigates the relationship, in the aging population, between vertebral fractures, spinal alignment, and quality of life. Kyphotic fractures were related to more significant disability and impaired spinopelvic alignment. The spinal malalignment was strongly associated with fractures in the thoracolumbar junction vertebrae and the absence of powerful compensatory mechanisms as thoracic hypokyphosis and lower lumbar hyperlordosis. INTRODUCTION: In adult spine deformity (ASD), the sagittal imbalance is defined by the deformity in the sagittal plane that causes the need for greater use of muscle strength to maintain an upright static posture or walking. Fragility vertebral fractures (VF) and ASD are frequent causes of spinal morbidity in the elderly. The prevalence of both ASD and VF increases with aging. Although these two clinical conditions insist on the same population, little is known about the interactions between sagittal imbalance and vertebral fracture (VF) deformity. The aim of our work is to examine the associations between vertebral fractures, sagittal alignment, and their impact on the quality of life scores in elderly patients. METHODS: A retrospective cohort study of 110 patients of both sexes, from a spine surgery waiting list, with at least one VF with ≥ 5° of kyphosis and a full-standing X-ray. INDEPENDENT VARIABLES: the presence of VF with kyphotic deformity ≥ 10°, fracture level, degree of kyphosis (deformity) of the fracture, number of fractures, spinopelvic angular parameters, demographic parameters, and scales of evaluation of the health-related quality of life. RESULTS: A total of 110 patients with mean age 73.8 ± 5.2, of which 70 women (63%) were included in the study. Subjects with at least one VF ≥ 10° presented greater disability and an overall worse sagittal spinal alignment (no VF10° vs VF10°: TPA 21.30 ± 11.5 vs 26.51 ± 12.6, p = 0.041) and more disability (no VF10° vs VF10°: ODI 41.91 ± 16.9 vs 54.67 ± 15.8, p < 0.001) than patients with less degree of vertebral deformity. Significant compensatory mechanisms involved the thoracic area and the lower lumbar region. CONCLUSION: Kyphotic VFs were associated with severe alterations of sagittal spine alignment and perceived disability. Subjects with sagittal imbalance have a greater degree of deformity in the thoracolumbar junction area. Thoracic hypokyphosis and lower lumbar hyperlordosis are effective compensatory mechanisms in case of lumbar or thoracic fracture, respectively.

Transient osteoporosis of the hip and subclinical hypothyroidism: an unusual dangerous duet? Case report and pathogenetic hypothesis.

BACKGROUND: Transient osteoporosis of the hip (TOH) is a rare and temporary clinical condition characterised by bone marrow edema (BME), severe pain, and functional limitation. It commonly occurs in middle-aged men or in women in the last trimester of pregnancy. TOH usually resolves with conservative therapy but may predispose to hip fracture or progression to avascular necrosis (AVN). Etiology is still unclear, although several pathophysiological mechanisms underpinning this condition has been proposed. We describe the management of an unusual case of TOH occurred in a patient with subclinical hypothyroidism. CASE PRESENTATION: A clinical case of a 46-year-old man with severe pain in the left anterior thigh is presented. After a comprehensive clinical and radiological approach, a TOH was diagnosed. Moreover, biochemical assessment suggested the presence of subclinical hypothyroidism. After 3 months of treatment with clodronate, physical therapy and hormone replacement therapy (HRT) a significant improvement of clinical and radiological outcomes was observed. CONCLUSION: Several pathological conditions have been related to development of TOH. In our case, we suggested for the first time a role of subclinical hypothyroidism as novel contributory factor for the onset of this condition, providing pathophysiological mechanisms and a scientific rationale for pharmacological treatment.

Management of hip fracture in the older people: rationale and design of the Italian consensus on the orthogeriatric co-management.

BACKGROUND: Hip fracture (HF) is a burdening health problem in older people. The orthogeriatric approach has been shown to favour functional recovery and reduce mortality, but its implementation in clinical practice cannot rely upon shared management protocols and greatly varies among different healthcare systems. Here, we present the rationale and design of the Italian consensus document on the management of HF in older people. METHODS: A panel of multidisciplinary experts from ten Italian scientific societies involved in the care of HF and including geriatricians, orthopaedics, anaesthesiologists, physiatrists and general practitioners, will join to establish the content validity of a list of statements. A Delphi consensus methodology will be applied to obtain the opinions of the panel and to provide the final recommendations. OBJECTIVES: The document will include indications on the following relevant topics: (1) optimal care path of older subjects with HF; (2) management of comorbidities and pre-operative alteration of physiological parameters; (3) management of selected categories of patients at expected increased risk of adverse outcomes; (4) continuity of care out of hospital; (5) screening and correction of risk factors for HF in older subjects; (6) information and divulgation of shared management strategies. The objective of the consensus will be to inform clinicians, patients, researchers, and health policy makers about the best management strategies for HF in older people and their inherent limitations, thus facilitating communication between stakeholders and promoting the most cost/effective models of care.

Pharmacological Therapy of Osteoporosis: What's New?

Osteoporosis and fragility fractures are relevant health issues because of their impact in terms of morbidity, mortality, and socioeconomic burden. Despite this alarming scenario, both underdiagnosis and undertreatment are common features of osteoporotic patients, particularly those who have already sustained a fragility fracture. Pharmacotherapy of osteoporosis is the main treatment option for these patients because of strong evidence about the efficacy of available drugs targeting bone metabolism. However, several issues can interfere with the effectiveness of anti-osteoporotic drugs in clinical practice, such as lack of awareness of both healthcare providers and patients, poor adherence to therapy, and safety in long-term treatment. Therefore, new therapeutic strategies have been proposed to overcome these problems, such as sequential therapy or emerging molecules mainly targeting the stimulation of bone formation. In particular, abaloparatide has been demonstrated to reduce major nonvertebral fracture risk compared with both placebo and teriparatide, although the European Medicines Agency (EMA) refused the marketing authorization because the benefits of this drug did not outweigh its risks. On the other side, EMA has recently approved romosozumab, a monoclonal antibody directed against sclerostin and the only available therapeutic option targeting Wnt signaling, as both bone-forming and antiresorptive intervention to treat osteoporosis and fragility fractures.

Do Dietary Supplements and Nutraceuticals Have Effects on Dental Implant Osseointegration? A Scoping Review.

Several factors affect dental implant osseointegration, including surgical issues, bone quality and quantity, and host-related factors, such as patients' nutritional status. Many micronutrients might play a key role in dental implant osseointegration by influencing some alveolar bone parameters, such as healing of the alveolus after tooth extraction. This scoping review aims to summarize the role of dietary supplements in optimizing osseointegration after implant insertion surgery. A technical expert panel (TEP) of 11 medical specialists with expertise in oral surgery, bone metabolism, nutrition, and orthopedic surgery performed the review following the PRISMA-ScR (Preferred Reporting Items for Systematic Reviews and Meta-Analyses Extension for Scoping Reviews) model. The TEP identified micronutrients from the "European Union (EU) Register of nutrition and health claims made on foods" that have a relationship with bone and tooth health, and planned a PubMed search, selecting micronutrients previously identified as MeSH (Medical Subject Headings) terms and adding to each of them the words "dental implants" and "osseointegration". The TEP identified 19 studies concerning vitamin D, magnesium, resveratrol, vitamin C, a mixture of calcium, magnesium, zinc, and vitamin D, and synthetic bone mineral. However, several micronutrients are non-authorized by the "EU Register on nutrition and health claims" for improving bone and/or tooth health. Our scoping review suggests a limited role of nutraceuticals in promoting osseointegration of dental implants, although, in some cases, such as for vitamin D deficiency, there is a clear link among their deficit, reduced osseointegration, and early implant failure, thus requiring an adequate supplementation.

Cytoplasmic Interactions between the Glucocorticoid Receptor and HDAC2 Regulate Osteocalcin Expression in VPA-Treated MSCs.

Epigenetic regulation has been considered an important mechanism for influencing stem cell differentiation. In particular, histone deacetylases (HDACs) have been shown to play a role in the osteoblast differentiation of mesenchymal stem cells (MSCs). In this study, the effect of the HDAC inhibitor, valproic acid (VPA), on bone formation in vivo by MSCs was determined. Surprisingly, VPA treatment, unlike other HDAC inhibitors, produced a well-organized lamellar bone tissue when MSCs⁻collagen sponge constructs were implanted subcutaneously into nonobese diabetic/severe combined immunodeficiency (NOD/SCID) mice, although a decrease of osteocalcin (OC) expression was observed. Consequently, we decided to investigate the molecular mechanisms by which VPA exerts such effects on MSCs. We identified the glucocorticoid receptor (GR) as being responsible for that downregulation, and suggested a correlation between GR and HDAC2 inhibition after VPA treatment, as evidenced by HDAC2 knockdown. Furthermore, using co-immunoprecipitation analysis, we showed for the first time in the cytoplasm, binding between GR and HDAC2. Additionally, chromatin immunoprecipitation (ChIP) assays confirmed the role of GR in OC downregulation, showing recruitment of GR to the nGRE element in the OC promoter. In conclusion, our results highlight the existence of a cross-talk between GR and HDAC2, providing a mechanistic explanation for the influence of the HDAC inhibitor (namely VPA) on osteogenic differentiation in MSCs. Our findings open new directions in targeted therapies, and offer new insights into the regulation of MSC fate determination.

Stentoplasty of calcaneal fractures: Surgical technique and early outcomes.

Calcaneus is the most common site of hindfoot fracture, frequently caused by fall from height or high energy trauma. The therapeutic strategy ranged from non-operative to ORIF (Open Reduction Internal Fixation). Indications for percutaneous fixation include soft tissue damage or relative contraindications to open surgery. Minimally invasive percutaneous calcaneoplasty should be an alternative to ORIF aiming to reach a stable reduction, early functional recovery and short hospital stay. The aim of our study was to evaluate the clinical and radiographic outcomes of calcaneus fractures treated with balloon calcaneoplasty (BCP) by using a new generation vertebral augmentation system, VBS™-Vertebral Body Stent-DePuy Synthes. A total of 10 patients treated with VBS™ system were recruited for the study. Nine fractures were caused by a fall from height and one case by traffic accident. The mean follow-up was 8.9 months (range 2.6-23.1). The fractures were categorized according to Sanders and Essex-Lopresti classifications (5: type II, 3: type III and 2: type IV; 9: "joint depression" type and 1 case "tongue" type). Radiographic measurement (Böhler's and Gissane's angles) were evaluated at both pre-operative and immediate postoperative time. The American Orthopaedic Foot and Ankle Society (AOFAS) Ankle-Hindfoot score as well as a subjective evaluation (Visual Analog Scale, VAS) were used for the clinical assessment at the last follow-up. Mean preoperative Böhler's angle was 12.3 ± 8.41° (95% CI 6.3-18.3°), whereas mean preoperative Gissane's angle was 123.66 ± 20.47° (95% CI 109.0-138.3°). At postoperative follow-up mean Böhler's angle increased to 21.51 ± 4.17° (95% CI 18.5-24.5°; p < 0.01), and mean postoperative Gissane's angle was 121.74°±6.82° (95% CI 116.8°-126.6°). Mean AOFAS at the last follow-up was 70.4 ± 17.44 (95% CI 57.9-82.8). Our study demonstrates that percutaneous calcaneoplasty using VBS™ is an effective treatment for calcaneus fracture and capable to implement correction manoeuvre with clinical and radiographic outcomes comparable with other percutaneous stentoplasty.