The challenge of pharmacotherapy for musculoskeletal pain: an overview of unmet needs.

Musculoskeletal disorders are characterized by several impairments, including pain, affecting muscles, bones, joints and adjacent connective tissue, resulting in temporary or permanent functional limitations and disability. Musculoskeletal pain is particularly prevalent worldwide and greatly impacts the quality of life, social participation and economic burden. To date, several issues persist about the classification of musculoskeletal pain and its management strategies and resources. The treatment of musculoskeletal pain conditions is complex and often requires a multimodal approach, including pharmacological and non-pharmacological therapy that might be ineffective in many cases, resulting in poor patient satisfaction and controversial expectations about the potential benefits of available interventions. This manuscript provides an overview of unmet needs in managing musculoskeletal pain, particularly focusing on pharmacotherapeutic pitfalls in this context.

Overview of Cochrane Systematic Reviews for Rehabilitation Interventions in Individuals with Upper Limb Fractures: A Mapping Synthesis.

Background and Objectives. This overview of Cochrane systematic reviews (CSRs) reports on current evidence on the effectiveness of rehabilitation interventions for persons with upper limb fractures (ULFs), and the quality of the evidence. Materials and Methods. Following the inclusion criteria defined by the World Health Organization, all CSRs tagged in the Cochrane Rehabilitation database that were relevant for persons with ULFs were included. A mapping synthesis was used to group outcomes and comparisons of included CSRs, indicating the effect of rehabilitation interventions and the certainty of evidence. Results. A total of three CSRs were included in the evidence map. The certainty of evidence was judged as low to very low. Early occupational and hand therapy, cyclic pneumatic soft tissue compression, and cross-education, when started during immobilization, may improve grip strength and wrist range of motion, with results maintained up to 12 weeks from the cast removal, compared to no intervention. Approaches such as occupational therapy and passive mobilisation, started post-immobilization, are probably safe in terms of secondary complications. However, the overall evidence of rehabilitative interventions related to proximal humeral fractures has been judged insufficient for all the outcomes considered. A paucity of primary studies and CSRs for elbow fractures was noted. Conclusions. This overview provided the effect and the certainty of evidence of rehabilitation interventions available after ULFs using a mapping synthesis. To date, there is a need to further the effectiveness and safety of these interventions for persons with ULFs, improving methodological quality of the research in the field.

Effects of adipose-derived mesenchymal stem cell conditioned medium on human tenocytes exposed to high glucose.

Introduction: Diabetic tendinopathy is a common invalidating and challenging disease that may be treated using stem cells. However, the effects of adipose-derived mesenchymal stem cell conditioned medium (ASC-CM) in diabetic tendinopathy have never been explored. Objectives: The present study evaluated the effects of ASC-CM on morphology, cell viability, structure, and scratch wound closure of human tenocytes (HTNC) exposed to high glucose (HG). Design: Experimental study. Methods: HTNC were exposed to HG (25 mM) for 7, 14 and 21 days with or without ASC-CM for the last 24 h. CM was collected from 4 × 105 ASCs, centrifuged for 10 min at 200 g and sterilized with 0.22 µm syringe filter. Results: At 7 days, HG-HTNC had decreased cell viability [72 ± 2%, p < 0.01 versus normal glucose (NG)] compared to NG-HTNC (90 ± 5%). A further decrement was detected after 14 and 21 days (60 ± 4% and 60 ± 5%, both, p < 0.01 versus NG and p < 0.01 versus HG7). While NG-HTNC evidenced a normal fibroblast cell-like elongated morphology, HG-HTNC showed increased cell roundness. In contrast, HG-HTNC exposed to ASC-CM showed a significant increase in cell viability, an improved cell morphology and higher scratch wound closure at all HG time points. Moreover, the exposure to ASC-CM significantly increased thrombospondin 1 and transforming growth factor beta 1 (TGF-ß1) content in HG-HTNC. The TGF-ß1 elevation was paralleled by higher Collagen I and Vascular Endothelial Growth Factor in HG-HTNC. Conclusion: ASC-CM may restore the natural morphology, cell viability and structure of HTNC, promoting their scratch wound closure through TGF-ß1 increase.

Filamin A cooperates with the androgen receptor in preventing skeletal muscle senescence.

Aging induces a slow and progressive decrease in muscle mass and function, causing sarcopenia. Androgens control muscle trophism and exert important anabolic functions through the binding to the androgen receptor. Therefore, analysis of the androgen receptor-mediated actions in skeletal muscle might provide new hints for a better understanding of sarcopenia pathogenesis. In this study, we report that expression of the androgen receptor in skeletal muscle biopsies from 20 subjects is higher in young, as compared with old subjects. Co-immunoprecipitation experiments reveal that the androgen receptor is complexed with filamin A mainly in young, that in old subjects. Therefore, we have in depth analyzed the role of such complex using C2C12 myoblasts that express a significant amount of the androgen receptor. In these cells, hormone stimulation rapidly triggers the assembly of the androgen receptor/filamin A complex. Such complex prevents the senescence induced by oxidative stress in C2C12 cells, as disruption of the androgen receptor/filamin A complex by Rh-2025u stapled peptide re-establishes the senescent phenotype in C2C12 cells. Simultaneously, androgen stimulation of C2C12 cells rapidly triggers the activation of various signaling effectors, including Rac1, focal adhesion kinase, and mitogen-activated kinases. Androgen receptor blockade by bicalutamide or perturbation of androgen receptor/filamin A complex by Rh-2025u stapled peptide both reverse the hormone activation of signaling effectors. These findings further reinforce the role of the androgen receptor and its extranuclear partners in the rapid hormone signaling that controls the functions of C2C12 cells. Further investigations are needed to promote clinical interventions that might ameliorate muscle cell function as well the clinical outcome of age-related frailty.

Correction: Vassallo et al. Hyaluronic Acid-Based Injective Medical Devices: In Vitro Characterization of Novel Formulations Containing Biofermentative Unsulfated Chondroitin or Extractive Sulfated One with Cyclodextrins. Pharmaceuticals 2023, 16, 1429.

In the original publication [...].

The role of the fracture liaison service in the prevention of atypical femoral fractures.

Osteoporosis and fragility fractures (FFs) are considered critical health problems by the World Health Organization (WHO) because of high morbidity, mortality, and healthcare costs. The occurrence of a FF raises the risk of a subsequent fracture (refracture). The hip is the most common site of fragility refracture, and its onset is associated with a further increase in patient's morbidity, mortality, and socioeconomic burden. Therefore, the prevention of refracture is essential. In this context, fracture liaison service (FLS) demonstrated to be able to reduce FF risk and also improve patients' adherence to anti-osteoporotic treatments, particularly for bisphosphonates (BPs). However, long-term and high adherence to BPs may lead to atypical femoral fractures (AFFs). These latter are tensile side stress fractures of the femur, with high rates of complications, including delayed and non-healing. An effective FLS should be able to prevent both FF and AFF. A comprehensive and interdisciplinary approach, through the involvement and education of a dedicated team of healthcare professionals (i.e. orthopedic, geriatrician, primary care physician, rehabilitation team, and bone nurse) for evaluating both FF and AFF risks might be useful to improve the standard of care.

Apparently isolated CNS involvement in Erdheim-Chester disease: Case report.

We present the case of a 48-year-old-woman with apparently isolated central nervous system Erdheim-Chester disease characterized by brainstem involvement. Erdheim-Chester disease is extremely rare and multisystem impairment should always be sought in the suspicion of such pathology.

Hyaluronic Acid-Based Injective Medical Devices: In Vitro Characterization of Novel Formulations Containing Biofermentative Unsulfated Chondroitin or Extractive Sulfated One with Cyclodextrins.

Currently, chondroitin sulfate (CS) and hyaluronic acid (HA) pharma-grade forms are used for osteoarthritis (OA) management, CS as an oral formulations component, and HA as intra-articular injective medical devices. Recently, unsulfated chondroitin, obtained through biofermentative (BC) manufacturing, has been proposed for thermally stabilized injective preparation with HA. This study aimed to highlight the specific properties of two commercial injective medical devices, one based on HA/BC complexes and the other containing HA, extractive CS, and cyclodextrins, in order to provide valuable information for joint disease treatments. Their biophysical and biomechanical features were assayed; in addition, biological tests were performed on human pathological chondrocytes. Rheological measurements displayed similar behavior, with a slightly higher G' for HA/BC, which also proved superior stability to the hyaluronidase attack. Both samples reduced the expression of specific OA-related biomarkers such as NF-kB, interleukin 6 (IL-6), and metalloprotease-13 (MMP-13). Moreover, HA/BC better ensured chondrocyte phenotype maintenance by up-regulating collagen type 2A1 (COLII) and aggrecan (AGN). Notwithstanding, the similarity of biomolecule components, the manufacturing process, raw materials characteristics, and specific concentration resulted in affecting the biomechanical and, more interestingly, the biochemical properties, suggesting potential better performances of HA/BC in joint disease treatment.

Anti-sclerostin antibodies: a new frontier in fragility fractures treatment.

Bone fragility is the determinant of the increased risk of minimal trauma fracture and must be treated with a multimodal approach that includes pharmacological therapy, physical exercise, and adequate nutrition. Pharmacological therapy, to date based on the administration of antiresorptive drugs, such as bisphosphonates and denosumab, or osteoanabolic drugs, such as teriparatide and abaloparatide, has shown to be effective in reducing the risk of fracture in osteoporotic patients. In the context of the cellular and molecular mechanisms that regulate bone metabolism, the discovery of the Wnt signaling pathway and its role in bone tissue homeostasis has allowed the identification of sclerostin as an inhibitor of osteoblastic activity and simultaneously as a stimulator of osteoclastic activity. Therefore, the use of a monoclonal antibody, romosozumab, against this protein has been tested as a potential drug with a dual action, stimulating bone neo-apposition and inhibiting bone resorption. The efficacy of romosozumab has been demonstrated in numerous clinical trials against both placebo and other drugs commonly used in the treatment of patients affected by osteoporosis. The advantages of this drug lie above all in its rapid action which makes it particularly suitable in clinical situations where it is necessary to improve bone strength very quickly due to the imminent risk of fragility fracture. Clinical studies and guidelines suggest romosozumab as an initial drug in an ideal sequential approach from osteoanabolic to antiresorptive drugs. Some aspects of cardiovascular safety remain to be fully investigated, therefore its use in osteoporotic patients at high cardiovascular risk should be avoided until further data become available.

New insights in lower limb reconstruction strategies.

High Energy Musculoskeletal Traumas (HEMTs) represent a relevant problem for healthcare systems, considering the high social costs, and both the high morbidity and mortality. The poor outcomes associated with HEMT are related to the high incidence of complications, including bone infection, fracture malunion and non-union. The treatment of each of these complications could be extremely difficult. Limb reconstruction often needs multiple procedures, rising some questions on the opportunity in perseverate to try to save the affected limb. In fact, theoretically, amputation may guarantee better function and lower complications. However, amputation is not free of complication, and a high long-term social cost has been reported. A comprehensive literature review was performed to suggest possible ways to optimize the limb preservation surgeries of HEMT's complications in order to ameliorate their management.

Pain and Motor Function in Myotonic Dystrophy Type 1: A Cross-Sectional Study.

Pain is an underestimated finding in myotonic dystrophy type 1 (DM1). We provide a characterization of pain in terms of functional implications through a multidimensional assessment in patients with DM1, focusing on gender differences. We assessed pain through the Brief Pain Inventory (BPI) and its indexes (the Severity Index (SI) and the Interference Index (II)), balance/gait (the Tinetti Performance-Oriented Mobility Assessment (POMA)), functional abilities (the Functional Independence Measure (FIM)), and fatigue (the Fatigue Severity Scale (FSS)). We divided our sample into a mild (<4) and a moderate-severe group (≥4) based on BPI indexes. A between-group analysis was performed. We recruited 23 males and 22 females with DM1. A statistically significant difference was found for the FSS and the BPI-SI ≥ 4, and for all outcomes in the BPI-II ≥ 4 (p ≤ 0.003). In the female group, all outcomes except for the FIM were statistically significantly worse (p ≤ 0.004). Dividing our sample into four groups based on gender and the BPI, a statistically significant difference was found for FSS between the two groups with BPI-II ≥ 4 (with worsen score in the female one) (p < 0.002). Pain in DM1 patients is highly reported and gender related, with increased fatigue and poor balance/gait in the female group.

Bone fragility during the COVID-19 pandemic: the role of macro- and micronutrients.

Bone fragility is the susceptibility to fracture due to poor bone strength. This condition is usually associated with aging, comorbidities, disability, poor quality of life, and increased mortality. International guidelines for the management of patients with bone fragility include a nutritional approach, mainly aiming at optimal protein, calcium, and vitamin D intakes. Several biomechanical features of the skeleton, such as bone mineral density (BMD), trabecular and cortical microarchitecture, seem to be positively influenced by micro- and macronutrient intake. Patients with major fragility fractures are usually poor consumers of dairy products, fruit, and vegetables as well as of nutrients modulating gut microbiota. The COVID-19 pandemic has further aggravated the health status of patients with skeletal fragility, also in terms of unhealthy dietary patterns that might adversely affect bone health. In this narrative review, we discuss the role of macro- and micronutrients in patients with bone fragility during the COVID-19 pandemic.

Unicompartimental knee arthroplasty metallosis treated with uni-on-uni revision: A case report.

BACKGROUND: Metallosis is the result of metallic wear debris in the soft tissues and is associated to both local and systemic inflammatory response. Metallosis has been reported after total hip and total knee arthroplasty (TKA), but rarely after a unicompartimental knee arthroplasty (UKA). In the context of UKA metallosis, surgeons often opt for revision using a TKA. However, in this paper, the authors successfully treated UKA revising the metal back only. CASE SUMMARY: Prior to treat our patient we conducted a literature research through which we identified eleven cases of metallosis after UKA, ten (90.9%) were treated revising using though a TKA. Only one case was managed through a uni-on-uni revision, reporting high knee function. Our patient complained worsening pain and function after a snap occurred at 16 mo after UKA implantation. At 18 mo following surgical debridment and uni-on-uni revision surgery, our patient exhibited a relevant improvement in Oxford Knee Score and a reduction of metal ion levels in the blood. CONCLUSION: Our study highlights that in case of metallosis after UKA, the treatment may be based on surgical debridement and just revising the mobilized components.

Periprosthetic knee infection: treatment options.

Infection is one of the most catastrophic complication following total knee arthroplasty (TKA) and represents the second most common cause of TKA failure. Treatment of a patient with periprosthetic joint infection (PJI) could require often costly and prolonged hospital stays, weeks or months of antibiotic therapy, and multiple surgical procedures. The best management is still highly debating, whereas many treatment options are available. These include suppressive antibiotics, arthroscopic irrigation and debridement, open debridement with insert exchange, single-stage reimplantation and two-stage reimplantation. The choice of the treatment depends on many variables, including integrity of implant, timing of the infection, host factors (age, health, immunologic status), virulence of the infecting organism and wishes of the patient. The aim of this review is to provide a comprehensive understaning of the different options for knee PJIs.

Extracapsular femoral neck fractures treated with total hip arthroplasty: identification of a population with better outcomes.

Background: Femoral neck fractures (FNF) are associated to patient's disability, reduced quality of life and mortality. None of the fixation devices commonly used for extracapsular (EC) FNF (i.e., dynamic hip screws (DHS) and intramedullary nails (IN)) is clearly superior to the other, especially in case of unstable fractures (31.A2 and 31.A3 according to AO/OTA classification). The aim of our study was to identify a sub-population of patients with EC fractures in which better outcomes could be obtainable using total hip arthroplasty (THA). Methods: All patients with EC unstable fractures treated with THA were included in the present study. Demographic data, American Society of Anesthesiologists (ASA) score, hospitalization length, transfusion rate, implant-related complications and mortality rate were collected. Clinical outcomes were evaluated using the Oxford Hip Score (OHS), while patients' general health status through the 12 Item Short Form questionnaires (SF-12). Results: 30 patients (7 male; 23 female) with a mean age of 78.8 years were included. The 1-year mortality rate was 13.3%. The mean OHS was 27.5, while the mean SF-12 were 45.84 for the mental item and 41.6 for the physical one. Age was the only factor associated with the OHS and patients older than 75 years presented a 12- fold higher risk of developing bad outcomes. Conclusions: THA seems to be a viable option for unstable EC fractures, with good clinical outcomes, especially in patients younger than 75 years of age. The mortality rate associated with THA in EC fractures is low and anyway comparable with IN.

Osteosarcopenia and type 2 diabetes mellitus in post-menopausal women: a case-control study.

Background: Osteosarcopenia has been defined as the concomitance of low bone density (osteopenia/osteoporosis) and sarcopenia. Osteoporosis is characterized by alterations in bone microarchitecture and decrease of bone mineral density (BMD), whereas sarcopenia is the progressive decrease of both muscle mass and function that increase the risk of falls. Type 2 diabetes mellitus (T2DM) is associated with poor bone strength and muscle wasting. Objective: The aim of this study is to analyze the association between osteosarcopenia and T2DM in post-menopausal women (PMW). Methods: We performed an age matched case-control study (1:2 ratio), considering as cases PMW affected by T2DM, and PMW without T2DM as control group. For all patients a DXA evaluation to investigate bone density and body composition measures were performed. Moreover, we carried out muscle strength and performance assessments. Outcome measures were femoral neck and lumbar spine BMD T-scores, appendicular lean mass (ALM), handgrip strength and the Short Physical Performance Battery (SPPB). Data from both groups were analyzed and compared. Results: Thirty-six PMW (12 T2DM vs 24 non-T2DM) were recruited. The frequency of osteosarcopenia was significantly higher in the T2DM group compared to controls (50% vs 17%; OR 5.0, 95% CI 1.05 to 23.79, p = 0.043). Handgrip strength was significantly lower in the T2DM group (10.09 ± 4.02 kg vs 18.40 ± 6.83 kg; p = 0.001). Conclusions: Post-menopausal women with T2DM have a 5 times higher risk to have osteosarcopenia compared to non-diabetic ones. Further studies on larger cohorts are required to confirm these findings.

Functioning issues in inpatients affected by COVID-19-related moderate pulmonary impairment: a real-practice observational study.

OBJECTIVE: To investigate the correlations between clinical, functional, and radiological outcomes in inpatients with coronavirus disease 2019 (COVID-19). METHODS: In this observational study, we recruited inpatients affected by moderate COVID-19 disease. The clinical evaluation comprised the Cumulative Illness Rating Scale (CIRS), numerical rating scale (NRS), modified Rankin scale (mRS), and the modified Borg dyspnea scale (mBDS). Respiratory involvement was assessed with computed tomography (CT) and graded with a CT-severity score (CT-SS). We retrospectively assessed functioning using the International Classification of Functioning, Disability and Health (ICF) codes of the Clinical Functioning Information Tool (ClinFIT) COVID-19 in the acute phase. Correlation analysis was performed 1) between clinical, instrumental, and functional parameters and 2) between ICF categories. RESULTS: The data showed statistically significant moderate correlations between CT-SS and the following categories: b152 "emotional functions" and b440 "respiratory functions". CONCLUSION: This is the first study to use the ICF framework in people with a moderate form of COVID-19 in the acute phase. Considering the correlations between some ICF categories and radiological findings, our results support the use of the ClinFIT COVID-19 for a comprehensive assessment of COVID-19 patients.

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.

Age over 50 does not predict results in anterior cruciate ligament reconstruction.

Introduction: Grown in the worldwide population of over 50 of age individuals who remain in good health and continue to engage in sports has led to an increase of anterior cruciate ligament (ACL) tears in this aged population. ACL reconstruction was reserved for young and active athletes, but seems to produce good outcomes also in over 50s. Purpose: To compare the patient-reported functional scores, arthrometric outcomes, and complications of primary ACL reconstruction between older (>50 years) and younger (<50 years) patients. Methods: A systematic review was performed on Pubmed, Scopus, Google Scholar and Cochrane library regarding studies that compared the clinical outcomes of ACLR between patients aged > 50 years and those aged < 50 years. The outcomes evaluated were knee functional outcomes, antero-posterior laxity and complications rate. Results: This study included 5 retrospective cohort studies with a total of 645 patients (357 in the older 50 group and 288 in the younger group). All included studies reported significant improvements in clinical outcomes in both groups after ACL reconstruction. No significant differences were noted in terms of International Knee Documentation Committee (IKDC), Lysholm, Tegner scores and anteroposterior instability between the two groups (p = n.s.). Over 50 cohort seem to have an increased risk for complication rate when compared with the younger cohort (p= 0.0005). Conclusion: ACL reconstruction in patients older than 50 years is a safe procedure with good results that are comparable to those of younger patients. Study design: Systematic review and meta-analysis; Level of evidence, 3.

Fragility Fractures of the Acetabulum: Current Concepts for Improving Patients' Outcomes.

The incidence of fragility fractures of the acetabulum (FFA) is constantly increasing. Generally, these fractures are related to a fall on the greater trochanter involving the anterior column. The management of FFA is extremely difficult considering both patients' comorbidities and poor bone quality. Both non-operative and several operative treatment protocols are available, and the choice among them is still ambiguous. The proposed surgical techniques for FFA [namely open reduction and internal fixation (ORIF), percutaneous fixation and total hip arthroplasty (THA)] are associated with a high complication rate. The treatment with the higher early mortality is the ORIF + THA, while the one with the lowest is the non-operative. However, at longer follow-up, this difference dreadfully change is becoming the opposite. Frequently ORIF, percutaneous fixation, and non-operative treatment need a subsequent re-operation through a THA. This latter could be extremely difficult, because of poor bone quality, acetabular mal union/non-union, bone gaps and hardware retention. However, the outcomes of each of the proposed treatment are mostly poor and controverted; therefore, a comprehensive patient evaluation and an accurate fracture description are required to appropriately manage acetabular fracture in the elderly.