Omega-3 polyunsaturated fatty acids (ω-3 PUFAs, n-3 PUFAs), including eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), and alpha-linolenic acid (ALA), are essential polyunsaturated fats primarily obtained from fatty fish and plant-based sources. Compelling evidence from preclinical and epidemiological studies consistently suggests beneficial effects of ω-3 PUFAs on bone health and healthy aging processes. However, clinical trials have yielded mixed results, with some failing to replicate these benefits seen in preclinical models. This contraindication is mainly due to challenges such as low bioavailability, potential adverse effects with higher doses, and susceptibility to oxidation of ω-3 fatty acids, hindering their clinical effectiveness. This review comprehensively discusses recent findings from a clinical perspective, along with preclinical and epidemiological studies, emphasizing the role of ω-3 PUFAs in promoting bone health and supporting healthy aging. Additionally, it explores strategies to improve ω-3 PUFA efficacy, including nanoparticle encapsulation and incorporation of specialized pro-resolving mediators (SPM) derived from DHA and EPA, to mitigate oxidation and enhance solubility, thereby improving therapeutic potential. By consolidating evidence from various studies, this review underscores current insights and future directions in leveraging ω-3 PUFAs for therapeutic applications.

Conjugated linoleic acid (CLA) is a bioactive compound known for its anti-inflammatory, anti-carcinogenic, and metabolic effects, with growing interest in its role in supporting bone health. Preclinical studies, particularly those involving the t10c12 isomer, have shown that CLA can enhance bone mineral density (BMD) by enhancing bone formation and reducing bone resorption, indicating its potential as a therapeutic agent to improve bone health. However, clinical trials have yielded inconsistent results, underscoring the difficulty in translating animal model successes to human applications. A major challenge is CLA’s low water solubility, poor absorption, and limited bioavailability, which restrict its therapeutic effectiveness. To address these issues, nanoparticle-based delivery systems have been proposed to improve its solubility, stability, and resistance to oxidative damage, thereby enhancing its bioactivity. Recent studies also suggest that electrical stimulation can stimulate bone regeneration by promoting bone cell proliferation, differentiation, and adherence to scaffolds. This review explores the combined use of CLA supplementation and electrical stimulation as a novel approach to improving bone health, particularly in osteoporosis management. By integrating CLA’s biological effects with the regenerative potential of electrical stimulation, this multimodal strategy offers a promising method for enhancing bone restoration, with significant implications for clinical applications in bone health.

Omega-3 polyunsaturated fatty acids (ω-3 PUFAs, n-3 PUFAs), including eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), and alpha-linolenic acid (ALA), are essential polyunsatu-rated fats primarily obtained from fatty fish and plant-based sources. Compelling evidence from preclinical and epidemiological studies consistently suggests beneficial effects of ω-3 PUFAs on bone health and healthy aging processes. However, clinical trials have yielded mixed results, with some failing to replicate these benefits seen in preclinical models. This contraindication is mainly due to challenges such as low bioavailability, potential adverse effects with higher doses, and susceptibility to oxidation of ω-3 fatty acids, hindering their clinical effectiveness. This review provides an in-depth analysis of recent findings, focusing on clinical perspectives and encom-passing all relevant published studies to date, including preclinical and epidemiological research, with an emphasis on the role of omega-3 fatty acids in promoting bone health and supporting healthy aging. Additionally, it explores strategies to improve ω-3 PUFA efficacy, including na-noparticle encapsulation and incorporation of specialized pro-resolving mediators (SPM) derived from DHA and EPA, to mitigate oxidation and enhance solubility, thereby improving therapeutic potential. By consolidating evidence from various studies, this review underscores current in-sights and future directions in leveraging ω-3 PUFAs for therapeutic applications.

Transcriptomic technologies have revolutionized our understanding of skeletal biology by shifting research from descriptive cellular characterization to a systems-level analysis of bone homeostasis and pathology. The rapid evolution of bulk RNA sequencing (bulk RNA-seq), single-cell RNA sequencing (scRNA-seq), spatial transcriptomics, and integrative multi-omics approaches has enabled unprecedented resolution of the molecular and cellular complexity of the skeletal microenvironment. Bone remodeling is a tightly regulated process driven by coordinated interactions among bone marrow-derived mesenchymal stem/stromal cells (BMSCs), osteoblasts, osteoclasts, osteocytes, immune cells, and other bone microenvironment components. This narrative review summarizes recent advances in bulk RNA-seq, scRNA-seq, spatial transcriptomics, and emerging multi-omics approaches that have transformed the study of bone development, remodeling, and disease. We discuss how transcriptomic analyses have revealed the heterogeneity of BMSCs and osteoblasts, elucidated the molecular mechanisms regulating osteoclast differentiation, and identified transcriptional changes associated with osteoclast dysregulation in metabolic, inflammatory, and age-related bone disorders. We further evaluate the limitations of bulk and scRNA-seq, including technical biases, loss of spatial information, and computational challenges. Finally, we highlight how spatial transcriptomics and integrative multi-omics approaches are overcoming these limitations by combining transcriptional, spatial, epigenetic, proteomic, and metabolomic data to provide a comprehensive understanding of skeletal biology, accelerate biomarker discovery, identify novel therapeutic targets, and advance precision medicine for bone diseases.