Little is known about the underlying cause contributing to the association between Osteoporosis (OP) and Alzheimer’s disease (AD). This review highlights the emerging role of sclerostin, a protein mainly produced by osteocytes, in the newly discovered crosstalk between bone and brain, with a focus on its potential contribution to the relationship between OP and AD. Circulating sclerostin levels increase with aging and are positively associated with brain amyloid-β burden in older adults. Studies demonstrate that elevated sclerostin can cross the blood-brain barrier, promote amyloid-β peptide deposition, and impair synaptic plasticity by suppressing Wnt/β-catenin signalling, whereas sclerostin inhibition restores neuronal plasticity and attenuates AD pathology. Sclerostin represents a promising target in the bone-brain interaction pathway. Its dual role as a measurable circulating biomarker and a modifiable component offers new opportunities for early risk assessment and therapeutic repurposing. Future longitudinal and interventional studies are essential to confirm the association between sclerostin and risk of AD, and to clarify whether targeting sclerostin can delay the onset of the disease or modify its trajectory.
Osteocytes are the most abundant cells in bone and serve as central skeletal regulators. Recent findings from our and other groups demonstrate that beyond soluble mediators, osteocytes communicate by releasing extracellular vesicles (EVs). This review provides a systematic overview of osteocyte-derived EVs and highlights their importance in diagnostic and therapeutic innovation. Accumulating evidence has linked osteocyte mechanotransduction to EV biogenesis and secretion. Mechanically induced calcium oscillations and signaling pathways impact load-induced EV release. Under normal conditions, osteocyte-derived EVs contribute to local and systemic intercellular communication within experimental models, whereas their direct role in immune-microenvironment remodeling remains insufficiently defined. In pathological states, alterations in osteocyte EV release and cargo composition are associated with both benign diseases and malignancies. Engineered osteocyte-derived EVs and EV-inspired delivery systems are being investigated as cell-free therapeutic platforms for skeletal regeneration. Continued research in osteocyte-derived EVs will deepen understanding of bone communication networks and resolve the principal conceptual and technical challenges.
Pediatric osteoporosis is a heterogeneous group of primary and secondary disorders that creates challenges for orthopaedic surgeons. This review summarizes evidence on conditions commonly encountered in pediatric orthopedic practice, medical management strategies, and perioperative care for children with bone fragility. Diagnostic approaches have been evolving toward integrating fracture characteristics, skeletal risk factors, and bone mineral density (BMD). A single low-trauma vertebral compression fracture is now sufficient for diagnosis of osteoporosis in children regardless of BMD. Intravenous bisphosphonates remain first-line therapy, with recent meta-analyses confirming consistent BMD gains and, observationally, a reduction in fracture risk. Bisphosphonates are generally given to children who have sustained low-trauma vertebral fractures and considered for other children with recurrent long bone fractures with low BMD. Early intervention with bisphosphonates may also be warranted for children with high-risk diseases, such as Duchenne’s Muscular Dystrophy (DMD). Biologic agents are emerging in clinical trials and select specialized use, but further research is needed to understand their role in pediatric osteoporosis. Denosumab carries a substantial risk for rebound hypercalcemia in children with osteogenesis imperfecta (OI), limiting its use to selected indications. Preliminary reporting from a large trial of anti-sclerostin therapy in children with osteogenesis imperfecta suggests significant BMD increases while fracture-reduction endpoints were not met, underscoring the limitations of BMD as a surrogate in pediatric bone fragility trials. Providing optimal care for this unique group of patients requires multidisciplinary coordination amongst orthopaedic surgeons, endocrinologists, geneticists, and rehabilitation specialists. Evidence-based management includes preoperative bone health evaluation, procedure-specific modifications in fragile bone, nutritional optimization, and coordinated bisphosphonate timing.
Weight loss is recommended for obesity management, but it also increases bone turnover and reduces bone mineral density (BMD) and bone quality (microarchitecture, geometry, and strength). This review examines mechanisms and the multiple factors that influence skeletal responses to caloric restriction. Bone loss during weight loss likely reflects multiple interacting mechanisms, including alterations in endocrine signaling, impaired calcium absorption, reduced mechanical loading, and alterations in the gut microbiota. The extent of bone loss is further influenced by age, sex, initial body weight, nutrient intake, and method of weight loss, with greater loss in older and lean adults, and after severe caloric restriction, such as with incretin mimetics or bariatric surgery. Current evidence emphasizes the importance of adequate nutrient intake (e.g., calcium, protein, etc.) and exercise as countermeasures to attenuate bone loss. Emerging evidence also suggests that additional countermeasures, including osteoporosis medications and other lifestyle interventions, may affect weight-loss-induced bone loss, and randomized trials are needed. Weight-loss-induced bone loss is multifactorial, involving endocrine, metabolic, nutritional, mechanical, and gut microbiota-mediated mechanisms that remain incompletely understood. These mechanisms influencing skeletal responses to weight loss can inform targeted strategies to preserve bone health and reduce fracture risk during obesity management.
Aging disrupts skeletal homeostasis, resulting in impaired fracture healing, increased risk of nonunion, and reduced regenerative capacity. These deficits are associated with dysregulated inflammation, impaired angiogenesis, and reduced osteogenesis, while current treatments remain limited in aged populations. This review examines emerging regenerative approaches that target both vascular and osteogenic dysfunction during skeletal repair. Recent studies have emphasized the importance of angiogenic-osteogenic coupling in successful bone repair. Endothelial progenitor cells (EPCs) promote neovascularization, improve vascular function, and support osteogenesis, while EPC-derived extracellular vesicles (EV), particularly exosomes, enhance intercellular communication, angiogenesis, and tissue repair with fewer limitations than cell-based therapies. In addition, signal transducer and activator of transcription 3 (STAT3) has been identified as a key regulator of osteoblast function, angiogenesis, and bone remodeling, making it an attractive molecular target for enhancing skeletal regeneration. EPC-based therapies, exosome-mediated interventions, and modulation of STAT3 signaling are promising strategies to enhance skeletal regeneration by addressing both vascular dysfunction and impaired osteogenesis. Continued investigation into the mechanisms, safety, and translational potential of these approaches will be critical for advancing regenerative therapies for age-related skeletal disorders.
