Osteogenesis Imperfecta from Historical Nosology to Gene-directed Therapy: A Critical Narrative Review of Mechanism, Evidence and Translational Uncertainty

Dose matters: haploinsufficiency in osteogenesis imperfecta.

Adamantinoma of Bone: A Structured Narrative Review of Clinical Outcomes, Recurrence Patterns, and Metastatic Behaviour

Background/Objective: Adamantinoma is a rare, low-grade malignant primary bone tumour with a predilection for the tibial diaphysis. Despite decades of case series and institutional cohorts, the evidence base remains fragmented, and outcomes are inconsistently reported across studies. To synthesise the best available evidence on clinical outcomes, recurrence patterns, metastatic behaviour, and surgical management of skeletal adamantinoma and to appraise the methodological quality of the contributing literature. Methods: A structured narrative review was conducted searching PubMed (294 records) and Web of Science (397 records) from inception to April 2026, yielding approximately 532 unique records after deduplication. Case series of five or more patients with histologically confirmed skeletal adamantinoma were included. A risk-of-bias critique was applied across five domains to each included study. Results: In total, 17 studies, representing more than 900 reported patient entries with possible cohort overlap, formed the primary evidence base. Local recurrence rates for classic adamantinoma (AD) range from 15% to 31%, with metastatic rates from 10% to 27%, predominantly to the lung. The osteofibrous dysplasia-like subtype (OFD-AD) showed no metastases in any series that reports this subtype separately but carries a locally aggressive recurrence rate of 22–43%. Wide resection with uncontaminated margins is the most consistently protective surgical variable (hazard ratio 0.164; p < 0.001). Late recurrences beyond 15 years are documented in multiple series, supporting prolonged surveillance. An MRI-based model for metastatic risk stratification at diagnosis has been proposed but requires external validation. Conclusions: Adamantinoma is more dangerous over a longtime horizon than its low-grade designation implies. Subtype distinction, margin status, and lifelong surveillance are the cornerstones of management. The evidence base carries predominantly moderate to high risk of bias; all conclusions should be interpreted accordingly. A multinational prospective registry remains the most important unmet research need.

Addressing the urgent need for clinical trials in chronic non-bacterial osteomyelitis.

Chronic non-bacterial osteomyelitis (CNO) is an autoinflammatory bone disease primarily affecting children and adolescents. The condition is characterised by bone pain, hyperostosis, and bone deformities, impacting patients' quality of life. Although CNO is the second most common inflammatory rheumatic disease in childhood, no licensed treatments exist. Clinical trials have been challenged by the absence of validated classification criteria and inclusion and exclusion criteria, a shortage of well-validated tools to measure treatment response, and a small market for commercialisation. Clinical trials are urgently needed to generate evidence and allow licensing of medications. Since 2022, long-standing challenges, previously hindering trial design and delivery in CNO, have been addressed through the development of classification criteria, expert consensus on inclusion and exclusion criteria, and the development of outcome measures. Applying a platform trial design testing treatments against a common comparator promises to deliver several key benefits for patients with CNO, families, and health-care services. This Viewpoint summarises treatments currently used to treat CNO alongside promising future candidates, outlining challenges in trial design and how these have, partly, been overcome.

Massage Therapy in Naturopathic Practice: A Critical Narrative Review of Mechanistic Rationale, Clinical Evidence and Conceptual Coherence

Massage is among the oldest and most widely recognised components of naturopathic physical medicine, yet its position within the discipline has become unsettled. Naturopathic philosophy justifies manual therapy through claims about circulation, elimination, nervous regulation and the stimulation of self-healing capacity, whereas the contemporary evidence base evaluates massage as an isolated modality tested against pain, anxiety and function in narrowly defined populations. This review examines that divergence. Its purpose is to assess how far the mechanistic rationale offered for massage within naturopathy survives critical scrutiny, what the clinical literature can and cannot support, and where the methodological architecture of the field constrains further progress. Literature was identified through scholarly indexes and citation registries accessible during the review, supplemented by backward and forward citation searching, with the final search conducted on 9 June 2026. Four findings dominate the synthesis. Mechanotransduction in skeletal muscle has emerged as the most biologically credible mechanism, supported by human biopsy work and animal models, although the translational distance between molecular signalling and patient-reported benefit remains large. The cortisol hypothesis, long central to naturopathic and popular accounts of massage, is not supported by rigorous between-group analysis and should be retired as a primary explanatory device. Affective touch mediated by C-tactile afferents offers a more coherent account of the affective and analgesic responses observed in practice, though it has rarely been tested using recognisable massage protocols. Clinical benefit is most defensible for short-term pain and anxiety reduction in palliative, perioperative and musculoskeletal contexts, but certainty of evidence is consistently low, effect durability is poorly characterised, and expectancy appears to contribute substantially to observed outcomes. Progress requires adequately dosed, longer trials with credible comparators, standardised intervention reporting, and mechanistic work that connects tissue-level responses to symptoms patients care about. The naturopathic claim for massage remains plausible but is presently underdetermined by evidence.

From FGFR3 Hyperactivation to Disease-Modifying Therapy in Pediatric Achondroplasia: Molecular Mechanisms, Clinical Evidence, and Emerging Treatments

Highlights What are the main findings? FGFR3 hyperactivation disrupts growth-plate signaling and endochondral bone growth. Vosoritide confirms that achondroplasia can be treated with disease-modifying therapy. What are the implications of the main findings? Treatment is shifting toward targeted, mechanism-based therapies. Long-term studies are needed to confirm benefits beyond growth velocity. Abstract Background/Objectives: Achondroplasia is the most common genetic skeletal dysplasia associated with disproportionate short stature and is primarily caused by gain-of-function variants in the fibroblast growth factor receptor 3 (FGFR3) gene. Constitutive FGFR3 activation disrupts growth plate homeostasis and endochondral ossification through complex alterations in chondrocyte proliferation, differentiation, hypertrophy, extracellular matrix organization, and intracellular signaling. The increasing understanding of these mechanisms has enabled the transition from exclusively supportive management toward disease-modifying and precision-based therapeutic strategies. This narrative review aimed to critically synthesize current evidence on the genetic basis, molecular pathogenesis, growth plate abnormalities, and current and emerging targeted therapies in achondroplasia. Methods: A narrative literature review was conducted using PubMed/MEDLINE, Scopus, and Web of Science Core Collection, with Google Scholar used as a supplementary source, together with manual screening of the reference lists of relevant original studies, clinical trials, reviews, consensus documents, and clinical guidelines. The principal literature search covered publications from January 2010 to March 2026, while selected seminal primary studies published before 2010 were included when necessary to document the original identification of pathogenic FGFR3 variants and foundational mechanisms of FGFR3-mediated growth plate regulation. Particular emphasis was placed on FGFR3 variants, receptor activation mechanisms, growth plate dysfunction, intracellular signaling pathways, vosoritide, C-type natriuretic peptide-based therapies, FGFR3 inhibitors, ligand–receptor blockade, drug repurposing, Wnt/β-catenin modulation, and gene-based therapeutic approaches. Results: Achondroplasia is characterized by marked molecular homogeneity, with the recurrent p.Gly380Arg substitution accounting for most cases. Mutant FGFR3 displays sustained activity through partial ligand independence, enhanced receptor dimerization and kinase activation, increased receptor stability, and reduced degradation. Excessive signaling through MAPK/ERK, STAT, PI3K/AKT, IHH/PTHrP, and related pathways impairs chondrocyte proliferation and hypertrophic differentiation, alters extracellular matrix turnover, disrupts primary cilium function, and reduces longitudinal bone growth. Vosoritide provides clinical proof that pharmacological modulation of FGFR3-related signaling can improve growth velocity. Additional therapeutic strategies under clinical or preclinical investigation include long-acting CNP analogues, selective FGFR inhibitors, decoy receptors, RNA aptamers, repurposed drugs, Wnt/DKK1 pathway modulation, and gene- or enhancer-targeted interventions. Conclusions: Achondroplasia is increasingly understood as a disorder of dysregulated growth plate signaling rather than solely a condition of reduced stature. Although vosoritide has established the feasibility of disease-modifying treatment, substantial uncertainty remains regarding final adult height, skeletal proportionality, cranio-spinal development, orthopedic outcomes, and long-term safety. Future progress will depend on mechanistically informed therapeutic combinations, improved biomarkers, advanced cellular and animal models, and long-term clinical and real-world evidence.

The clinical recognition, diagnosis and treatment of osteogenesis imperfecta: a case report and literature review.

Osteogenesis imperfecta (OI) is a rare congenital heterogeneous connective tissue disorder characterized by increased bone fragility, recurrent fractures, skeletal deformities, and short stature. Timely diagnosis and intervention can improve patients' quality of life and enhance their long-term prognosis. This study reports a case of a 26-year-old patient with OI who also had autoimmune diseases. Due to long-term treatment with glucocorticoids for autoimmune diseases, the OI was chronically missed. The typical clinical symptoms, skeletal imaging features, and genetic test results of this patient ultimately confirmed the diagnosis of osteogenesis imperfecta. At the same time, a multidisciplinary comprehensive individualized treatment plan was formulated and implemented for the patient, effectively alleviating clinical symptoms and improving the prognosis of the disease. This study reports a case of an adult patient with OI who also has an autoimmune disease. It emphasizes the need for clinicians to pay attention to the early identification and genetic diagnosis of OI in the context of co-morbidity. Multidisciplinary comprehensive treatment can significantly improve the patient's symptoms, providing a reference for the clinical diagnosis and treatment of rare hereditary bone diseases.