<p>Osteoporosis is a metabolic disorder of the bones that is identified by progressive structural degradation, decreased bone density, and raised the risk of fractures, which ultimately impacting the quality of life of patients. Its complex pathogenesis involves bone breakdown, reduced bone formation, and insufficient vascularization. Traditional treatments struggle to comprehensively tackle this multifaceted challenge. The existing therapies are non-specific and offer limited efficacy and also have shown adverse effects when used for long term. Therefore, the quest for therapeutic medications devoid of adverse effects is an essential and pressing need. The disease’s rising global incidence highlights the need for more effective treatments, prompting ongoing research into novel targets and therapies. There is a growing enthusiasm for small interfering RNA (siRNA) nanotherapeutics, indicating a promising future for these interdisciplinary approach-based modalities that integrate the fundamental principles of molecular biology, precision medicine, and nanotechnology. These therapies are limited by certain challenges viz., cell membrane permeability, degradation by nucleases, off target effects, endosomal escape etc. Extensive research on development of nanocarrier armor has helped overcome the delivery challenges of siRNA. These advancements offer targeted gene silencing of specific molecular mechanisms involved in bone remodeling and fracture, thereby providing a ray of hope for osteoporosis treatment. This review explores the role of signaling pathways, challenges of existing conventional therapies and potential therapeutic avenues for advanced therapies with special emphasis on siRNA delivery in the osteoporosis treatment.</p> Graphical Abstract <p></p>