Search Results (124)

Objective: Bone-modifying agents (BMA) are central to the prevention of skeletal-related events (SREs) in patients with cancer bone metastases, yet evidence guiding agent selection in very old patients remains limited. This study aimed to compare the effectiveness and safety of Denosumab versus bisphosphonates in patients aged ≥75 years with solid tumour-related bone metastases using a target trial emulation framework. Methods: We conducted a retrospective cohort study using the TriNetX Global Collaborative Network to emulate a hypothetical randomised trial. Patients aged ≥75 years with solid tumour-related bone metastases initiating Denosumab or bisphosphonates were included. After 1:1 propensity score matching (PSM), 10,662 patients were analysed in each treatment group. The primary outcome was time to first SRE. Secondary outcomes included individual SRE components, all-cause mortality, and safety events. Results: Among 21,324 matched patients (mean age, 75.6 years), bisphosphonate use was associated with a higher risk of SREs compared with Denosumab (hazard ratio [HR], 1.15; 95% CI, 1.06–1.25). The excess risk was driven by pathological fractures (HR, 1.28; 95% CI, 1.10–1.49), whereas other SRE components did not differ significantly. All-cause mortality was higher among bisphosphonate users (HR, 1.41; 95% CI, 1.33–1.49, p < 0.001). Hypocalcaemia occurred more frequently with Denosumab (5.7% vs. 2.4%), while risks of acute kidney injury and end-stage renal disease (ESRD) were similar. Findings were consistent across sensitivity and subgroup analyses. Conclusions: In patients aged ≥75 years with solid tumour-related bone metastases, Denosumab was associated with lower risks of skeletal-related events—particularly pathological fractures—and reduced all-cause mortality compared with bisphosphonates. These results extend randomised trial evidence to a clinically vulnerable population and support Denosumab as a preferred BMA in older adults. Full article

Hormone receptor-positive, human epidermal growth factor receptor 2-negative (HR+/HER2−) early breast cancer (EBC) is the most common breast cancer subtype and encompasses a biologically heterogeneous group of tumours. Endocrine therapy (ET) remains the cornerstone of treatment, but decisions regarding chemotherapy, cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors, and bone-modifying agents must be tailored to tumour biology, clinical stage, and menopausal status. REAL Canadian Breast Cancer Alliance (REAL Alliance), a pan-Canadian group of breast cancer specialists, convened to develop national clinical consensus recommendations for the systemic management of HR+/HER2− EBC. Using a structured consensus process, 28 recommendations were endorsed, spanning neoadjuvant and adjuvant systemic therapy, surgical considerations, and use of bisphosphonates. Key recommendations include the selective use of neoadjuvant chemotherapy for high-risk or locally advanced disease; genomic testing to guide chemotherapy decisions, particularly in postmenopausal patients; ET as the foundation of adjuvant therapy with intensification using CDK4/6 inhibitors in higher-risk patients; and adjuvant bisphosphonates in postmenopausal women to reduce recurrence and improve survival. These consensus recommendations provide practical, evidence-based guidance to support individualized, patient-centred management of HR+/HER2− EBC in the Canadian context. Full article

Pulmonary arterial hypertension (PAH) is a severe, progressive vasculopathy characterized by endothelial dysfunction, medial hypertrophy, and maladaptive vascular and cardiac remodelling that ultimately leads to right-heart failure and premature death. Despite advances in vasodilator therapies targeting endothelin, nitric oxide, and prostacyclin pathways, a substantial proportion of patients fail to achieve or maintain a low-risk profile, highlighting the need for disease-modifying strategies. Dysregulation of transforming growth factor-β (TGF-β) superfamily signalling, with excessive activin and growth differentiation factor activity and impaired bone morphogenetic protein signalling, plays a central role in PAH pathobiology. Sotatercept, a first-in-class activin signalling inhibitor, restores this imbalance by selectively trapping pro-proliferative ligands, thereby addressing a key molecular driver of pulmonary vascular remodelling. Evidence from pivotal phase II and III trials—PULSAR, STELLAR, ZENITH, and HYPERION—demonstrates that sotatercept significantly improves exercise capacity, haemodynamics, and risk status when added to background therapy. This review summarises the molecular mechanisms underlying sotatercept’s therapeutic effects, synthesises the current clinical evidence, and discusses its emerging role as a disease-modifying agent capable of promoting reverse pulmonary vascular remodelling within contemporary PAH management. Full article

Background/Objectives: Osteoarthritis (OA) is a multifactorial degenerative joint disease characterized by synovial inflammation, oxidative stress, and progressive cartilage degeneration. This study investigated whether intra-articular N-acetylcysteine (NAC) attenuates synovial inflammation and oxidative stress and whether these effects translate into structural cartilage protection. Methods: OA was induced in rats by anterior cruciate ligament transection (ACLT). NAC (5 mg/50 µL) was administered intra-articularly once weekly for three weeks post-ACLT. Inflammatory cytokines (IL-1β, IL-6, TNF-α), oxidative stress markers (iNOS, TAS, TOS, OSI), and cartilage degradation markers (MMP-13, COMP, CTX-II) were quantified in synovial fluid and cartilage homogenates using ELISA. Cartilage integrity was evaluated histologically using the modified Mankin scoring system. Results: Compared with controls, NAC significantly reduced synovial IL-1β, IL-6, TNF-α, MMP-13, and iNOS levels and improved the synovial redox profile by increasing TAS and reducing TOS and OSI (all p < 0.05). In contrast, NAC did not significantly alter cartilage homogenate levels of inflammatory cytokines, oxidative stress indices, or degradation markers (COMP, CTX-II, MMP-13). Histological analysis demonstrated persistent cartilage fissuring, hypocellularity, and proteoglycan loss in both groups (p > 0.05). Conclusions: Intra-articular NAC exerts potent anti-inflammatory and antioxidative effects within the synovial compartment but fails to prevent cartilage degeneration in the ACLT model. These findings indicate a compartment-specific therapeutic profile, suggesting that NAC may function as a symptom-modifying agent in synovitis-dominant OA rather than a structure-modifying therapy. Future studies should focus on optimized delivery systems or combination strategies targeting cartilage and subchondral bone to achieve disease modification. Full article

Repairing bone defects with implants is an important topic in the field of regenerative medicine, but bacterial infection presents a significant barrier in clinical practice. Therefore, bone implants with antibacterial functionality are currently in high demand. Fresh seaweed-derived exosomes (EXOs) exhibited promising antibacterial activity against bacteria, indicating their potential as natural antimicrobial agents. Moreover, equipping the exosomal lipid bilayer with bacteria-targeting aptamers (Apt), termed EXOs-Apt, enabled precise bacterial killing, thereby promoting more effective antibacterial functions. In our design, porous polyetheretherketone (PEEK) scaffolds were 3D-printed using the melt deposition manufacturing process. Subsequently, the scaffold surfaces were modified via dopamine self-polymerization, resulting in the formation of a polydopamine (PDA) coating. Then, EXOs-Apt was applied to functionalize PEEK scaffolds with antibacterial activity. Given that EXOs display bactericidal effects while Apt facilitates bacterial capture, we engineered a surface coating platform that incorporates both components to produce a multifunctional scaffold with synergistic antibacterial activity. The results showed that modifying EXOs-Apt on PEEK scaffolds significantly improved their antibacterial performance against Escherichia coli and Staphylococcus aureus. To our knowledge, this is the first study to use EXOs-Apt as antibacterial coatings modified on PEEK scaffolds. This study provides new strategies and ideas for the development of antibacterial PEEK orthopedic implants with promising clinical value for infection-resistant repair of bone defects. Full article

Background/Objectives: Although several studies have reported antibiotic protocols for the prevention of medication-related osteonecrosis of the jaw (MRONJ) in patients receiving antiresorptive and/or antiangiogenic therapy following tooth extraction, it remains unclear which protocol is the most effective. Accordingly, this scoping review analyzed antibiotic use in dental extractions in these patients, focusing on whether antibiotic duration influences MRONJ occurrence. Methods: Two authors independently searched PubMed, Scopus, and Web of Science (2003–2025). Out of the 770 studies screened, 36 were included. Descriptive statistics, a meta-analysis comparing MRONJ incidence in patients treated with high-dose (HD) and low-dose (LD) antiresorptive treatment according to the therapeutic indication and generalized linear mixed models on antibiotic duration were obtained (α = 0.05). Results: Amoxicillin, alone or with clavulanic acid, was the most used antibiotic, and in 8 studies it was combined with metronidazole. Seven studies reported parenteral antibiotic administration. Median antibiotic duration was 1.5 days pre-extraction, 5.5 days post-extraction, and 7 days overall. MRONJ risk was significantly higher in HD than LD patients (95% CI: 1.46–5.43; p = 0.002), and antibiotic duration was positively associated with reduced MRONJ risk in HD patients (β = –0.15, p = 0.026; OR = 0.86, 95% CI: 0.75–0.98). Conclusions: The literature shows heterogeneous antibiotic protocols for MRONJ prevention. The increased MRONJ risk and greater protective effect of antibiotics in HD patients suggest that patient risk profile may be more relevant than the antibiotic regimen. Full article

Osteoporosis is a major global health challenge, causing millions of fragility fractures each year and imposing an escalating socioeconomic burden worldwide. Despite advances with antiresorptive and anabolic therapies, substantial residual fracture risk persists, and targeting aging biology may yield disease modifying benefits beyond current standards of care. Senescent cells secrete senescence-associated secretory phenotype (SASP) factors, which impair osteoblast differentiation and contribute to bone loss. We investigated foretinib, a quinoline-based multi-tyrosine kinase inhibitor, as a potential anti-aging agent in osteoblast lineage cells. Foretinib inhibited doxorubicin-induced senescence in osteoblast progenitors via the p53/p21 and p16 pathways and reduced the expression of osteogenesis-inhibiting SASP factors, including CCL2, interleukin (IL)-1α, IL-1β, and IL-6. As a result, foretinib restored the impaired osteogenic differentiation of aged osteoblasts to near-normal levels in vitro. In ovariectomized, estrogen-deficient mice, foretinib significantly reduced trabecular and cortical bone loss by enhancing in vivo osteoblast differentiation, as shown by histological analysis and micro-computed tomography of femoral bone. These results suggest that foretinib alleviates osteoblast senescence and enhances osteogenic differentiation, supporting its promise as a therapeutic candidate for postmenopausal osteoporosis. Full article

Oligometastatic breast cancer represents an intermediate state between localized and disseminated disease with reasonable potential for clinical cure. Advancements in surgery, radiotherapy, and systemic therapy have improved prognosis. Due to the high prevalence of bone metastases, an increasing number of studies are evaluating new treatment strategies for oligometastatic bone disease. The decision to perform skeletal surgery is complex and depends on optimal patient selection. Major criteria include impending or pathologic long bone fractures, severe neurologic compromise, and an expected survival of over 3 months. Factors associated with improved survival include solitary bone metastases, preserved performance status, adequate surgical margins, absence of pathologic fracture, metachronous metastases, and ER-positivity status. Radiotherapy, especially SBRT, offers effective local control and palliation. Interventional radiology techniques such as percutaneous thermal ablation have also been described as potential treatment alternatives, particularly for fragile patients. Systemic treatment varies according to the tumor subtype. For HR+ and HER2 subtypes, a combination of endocrine therapy with CDK4/6 inhibitors may be considered. HER2+ patients are often treated with HER2-targeted therapies combined with chemotherapy. For triple-negative breast cancer, chemotherapy is the primary treatment. Bone-modifying agents are also recommended to maintain bone strength, prevent skeletal-related events, and reduce the need for additional interventions. Skeletal muscle metastases in breast cancer patients are rare and typically indicate advanced disease with poor prognosis. Treatment options include chemotherapy, radiotherapy, and surgical excision, but should be tailored to the patient’s clinical condition and prognosis. Full article

Background: Medication-related osteonecrosis of the jaw (MRONJ) is a serious adverse effect of bone-modifying agents. The aim of this study was to elucidate the pathogenesis of MRONJ through a comprehensive comparison of bone-metabolism-related factors in sera from patients with MRONJ and healthy controls. Methods: This study was a retrospective cross-sectional biobank analysis in which 31 patients in a non-MRONJ group and 10 patients in an MRONJ group were screened. Serum levels of 13 proteins (i.e., hormones, growth factors, and cytokines) related to bone metabolism were measured by simultaneous multi-parameter analysis using bead-based immunoassays. Results: The MRONJ group displayed suppressed bone metabolism with a background of chronic inflammation. In addition, a significant decrease in the expression of alkaline phosphatase liver/bone/kidney (p < 0.05, effect size of 0.46 (95% CI: 0.08 to 0.73)) and a significant increase (p < 0.05, effect size was −0.42 (95%CI: −0.72 to 0.01)) in the expression of tumor necrosis factor α were observed in the MRONJ group. Conclusions: These results may contribute to a better understanding of the etiology, pathophysiology, and progression of MRONJ. Full article

Viscosupplementation with intra-articular hyaluronic acid (HA) is a key therapeutic option for osteoarthritis (OA), yet the field is hampered by clinical controversies and an outdated classification of available products. This comprehensive review critically analyzes the current landscape, moving from a mechanical to a biological paradigm of HA’s mechanism of action. We argue that the traditional HA product classification based solely on molecular weight is insufficient, as it conflates chemically distinct products. Therefore, we propose a new, two-tiered classification framework: the primary distinction is based on chemical structure, separating linear (non-modified) HA from cross-linked (chemically modified) HA. Linear HA is then sub-classified by molecular weight (Low, Intermediate, and High), while cross-linked HA is defined as a separate category of hydrogels with a ultra-high effective molecular weight. Within this clearer framework, we analyze the central controversy between formulations, highlighting the pivotal emergence of high-concentration, high-molecular-weight (>2 million Dalton) linear HA. These formulations not only challenge the durability rationale for cross-linking by providing year-long efficacy but also possess a superior biological profile for chondroprotection, preserving chondrocyte viability and function. Furthermore, we explore the expanding frontier of combination therapies, where linear HA serves as the ideal physiological scaffold for agents like corticosteroids, PRP and other injectable orthobiologics such as bone marrow aspirate and stromal vascular fraction. Full article

Background/Objectives: Management of cancer treatment-induced bone loss (CTIBL) is essential for preserving quality of life among breast cancer (BC) patients receiving endocrine therapy. However, bone-modifying agents (BMAs) remain underused and delayed. In 2014, IRST launched the first bone health outpatient service in Romagna (the eastern area of the Emilia-Romagna region). A multi-centre, retrospective observational study with propensity score matching (PSM) was conducted to evaluate the impact of the IRST organisational model on bone health. Methods: The PSM matched the Emilia-Romagna patients who underwent BC surgery between 2014 and 2022 and were in follow-up in the Romagna area. Patients were grouped as follows: (1) IRST and (2) other Romagna hospitals (without bone health service, i.e., the control group). The matching was based on age, in situ/invasive cancer, and type of early-stage treatment (hormone treatment vs. chemotherapy). Logistic regression and Cox proportional-hazard models assessed factors associated with bone care treatment initiation and timings, respectively. Results: After PSM, we matched 3112 of the 8021 eligible patients into the two cohorts. IRST patients were 39% more likely to receive BMAs (OR: 1.393; 95% CI: 1.236–1.571) and initiated treatment approximately 12 months earlier. We observed that patients with invasive tumours were 77% more likely to initiate bone therapy than those with in situ tumours (OR: 1.766; 95% CI: 1.237–2.585). The early initiation of bone health therapy was influenced by age (p < 0.001) and neoadjuvant chemotherapy treatment (p < 0.001). Conclusions: The IRST model demonstrates responsiveness to bone health needs in BC patients and may be implemented elsewhere to support integrated CTIBL care. Full article

Background: Ankylosing spondylitis (AS) is a chronic autoinflammatory rheumatic disease mainly affecting the sacroiliac joints and spine, causing altered bone remodeling. Pro-inflammatory cytokines such as TNF-α and IL-17 contribute to bone loss by modulating pathways including Wnt/β-catenin, which is inhibited by proteins like Dickkopf-1 (DKK-1) and sclerostin (SOST). Bone morphogenetic protein-6 (BMP-6) promotes osteoblast differentiation and bone formation. This study evaluated the association between serum levels of DKK-1, SOST, BMP-6, and bone mineral density (BMD) in AS patients treated with anti-TNF agents and conventional synthetic DMARDs (csDMARDs). Methods: A cross-sectional study included 76 AS patients diagnosed by modified New York criteria and 30 healthy donors matched by age and sex. BMD at the lumbar spine and hips was assessed by DXA in all participants. Disease activity (BASDAI) and functional index (BASFI) were measured in AS patients. Serum levels of DKK-1, SOST, BMP-6, TNF-α, and IL-17 were quantified by ELISA in both groups. AS patients were divided into two treatment groups: combined anti-TNFα and csDMARD therapy (n = 38), and only csDMARDs (n = 38). Results: Bone mineral density showed no significant statistical differences between the spine (p = 0.930) and hips (p = 0.876) in AS patients compared to healthy controls. The activity (BASDAI) and functionality (BASFI) scores were similar in both treatment groups (p = 0.161 and p = 0.271, respectively). No significant differences were found in serum levels of DKK-1 (p = 0.815), SOST (p = 0.771), BMP-6 (p = 0.451), or IL-17 (p = 0.335) between combined anti-TNFα and csDMARD therapy versus monotherapy with csDMARD. Conclusions: The combination of anti-TNF bDMARD therapy and csDMARD therapy is not significantly associated with serum levels of DKK-1, SOST, BMP-6, and BMD compared to those treated with csDMARD monotherapy in patients with AS. This study provides novel and clinically relevant evidence on how anti-TNF bDMARDs and csDMARDs differentially affect bone turnover biomarkers and bone health in patients with AS, contributing to a better understanding of therapeutic strategies and guiding future research and clinical decision-making. Full article

Philadelphia-negative myeloproliferative neoplasms (Ph-MPNs) are clonal hematologic malignancies characterized not only by driver mutations such as JAK2V617F, CALR, and MPL but also by a profoundly dysregulated immune microenvironment. Chronic inflammation and immune remodeling sustain malignant hematopoiesis and contribute to disease progression from essential thrombocythemia (ET) and polycythemia vera (PV) to overt myelofibrosis (MF). Pro-inflammatory cytokines and chemokines—including IL-2, IFN-α, IL-23, and TNF-α—drive abnormal T cell polarization, favoring a pathogenic Th17 phenotype. Lymphocyte subset analysis reveals a predominance of exhausted PD-1⁺ T cells, reflecting impaired immune surveillance. Concurrently, alterations in neutrophil apoptosis lead to persistent inflammation and stromal activation. GRO-α (CXCL1) is elevated in ET but reduced in MF, suggesting a subtype-specific role in disease biology. Fibrosis-promoting factors such as TGF-β and IL-13 mediate bone marrow remodeling and megakaryocyte expansion, while VEGF and other angiogenic factors enhance vascular niche alterations, particularly in PV. These immunopathologic features underscore novel therapeutic vulnerabilities. In addition to JAK inhibition, targeted strategies such as CXCR1/2 antagonists, anti-TGF-β agents, and immune checkpoint inhibitors (PD-1/PD-L1 blockade) may offer disease-modifying potential. Understanding the interplay between cytokine signaling and immune cell dysfunction is crucial for developing precision immunotherapies in MPNs. Full article

Rheumatoid arthritis (RA) is a systemic autoimmune disorder characterized by chronic inflammation of the synovial membrane, leading to synovial hyperplasia, infiltration of immune cells, and subsequent cartilage and bone erosion. This progressive joint pathology results in persistent pain and functional impairment. Currently, convenient oral traditional disease-modifying anti-rheumatic drugs (DMARDs) are available, and increasingly precise biologic agents and targeted synthetic DMARDs (tsDMARDs) have been developed, offering promising therapeutic options. However, systemic administration generally fails to achieve therapeutic drug concentrations in the joints owing to poor biodistribution and dose-limiting systemic toxicity. Intra-articular (IA) administration has demonstrated promising potential in addressing these challenges. Among the various strategies employed for IA administration, hydrogels have gained significant attention due to their tunable mechanical properties, biocompatibility, and controlled release capabilities. These unique properties enable hydrogel-based IA delivery systems to simultaneously modulate the inflammatory microenvironment and protect cartilage tissue. This review comprehensively summarizes the histopathological changes and associated cellular and molecular events in RA, while also highlighting the design principles of hydrogels and advanced strategies for hydrogel-based IA administration. By addressing the limitations of conventional treatments, hydrogel-based IA injection holds significant promise for improving RA treatment. Full article

Cellular senescence is a fundamental contributor to numerous dysfunctions and degenerative diseases, including osteoporosis. In genetically modified and preclinical animal models, therapeutic strategies targeting persistent senescent cells have been shown to delay and prevent osteoporosis. Senolytics are a class of drugs or compounds designed to selectively eliminate senescent cells without adversely affecting normal cells. In this review, we focus on the role of senolytic agents in regulating bone metabolism and their potential in the treatment of osteoporosis. We discussed major types of senolytics, such as natural compounds, kinase inhibitors, Bcl-2 family inhibitors, inhibitors of the mouse double minute 2/p53 interaction, heat shock protein 90 inhibitors, p53-binding inhibitors, and histone deacetylase inhibitors. This review also highlights the progress of senolytics in clinical trials. However, clinical results diverge from preclinical evidence. Therefore, senolytics should be critically evaluated as a potential therapeutic strategy for osteoporosis, with further validation required. Full article