Pathophysiology and Molecular Signalling in Osteoporosis: Linking Risk Factors to Bone Loss.

Osteoporosis is a prevalent skeletal disorder characterised by progressive reduction in bone mass, microarchitectural deterioration, and increased fracture susceptibility. In India, approximately one-third of the elderly population is affected by bone-related disorders, and the global burden of osteoporosis continues to rise. Despite its significant impact on morbidity, mortality, and quality of life, current diagnostic approaches and therapeutic strategies remain suboptimal due to limitations such as prolonged treatment duration, poor patient adherence, low oral bioavailability of first-line therapies, and potential cardiovascular risks associated with some anti-resorptive agents. Given these challenges, there is an urgent need to develop safer and more effective preventive and therapeutic interventions. However, rational drug design and targeted therapies require a comprehensive understanding of osteoporosis pathophysiology. In this review, we provide an integrated overview of normal bone remodelling, key cellular players, and the mechanisms underlying impaired bone homeostasis in osteoporosis. We discuss the roles of osteoblasts, osteoclasts, and their progenitor cells, along with critical regulatory factors governing their differentiation and function. Later, we have discussed the core mechanisms and pathways involved in the pathophysiology of osteoporosis, including the RANKL-OPG axis, Wnt/β-catenin signalling, Parathyroid hormone (PTH)/PTH1R (cAMP/PKA vs. sustained Ca2+/PKC) signalling, TGF-β/BMP-SMAD signalling, etc. Furthermore, we summarise the major risk factors, including ageing, sex hormones, nutritional deficiencies, lifestyle factors, and comorbidities and delineate their mechanistic links to bone loss. This comprehensive synthesis aims to enhance understanding of osteoporosis pathogenesis and to facilitate the identification of novel molecular targets for improved therapeutic strategies.