**4.1 Pathophysiology of AIs-induced bone loss**

The hypoestrogenic state brought on by AIs accelerates bone loss at the areas with high levels of trabecularity (vertebral body) and significantly increases bone resorption. In fact, a lack of estrogen alters the dynamic equilibrium between the osteoblasts and osteoclasts activities. Tumor necrosis factor (TNF) and receptor activator of nuclear factor-kB ligand (RANKL), which serve as the main mediators for osteoclast activation and maturation, are more likely to be secreted by T cells as a result of this situation. The equilibrium between RANKL and osteoprotegerin (OPG), a soluble RANKL decoy receptor that blocks the binding of RANK to RANKL and inhibits the osteoclast activity, actually maintains the proper functioning of osteoblasts and osteoclasts [22–28].

Finally, the pathologic bone remodeling seen following AIs therapy may be caused by genetic variations of the RANK/RANKL/OPG pathway. The RANKL/OPG ratio was shown to be altered as a result of the rs7984870 SNP in the RANKL gene, which had detrimental effects on bone health. Despite the fact that Exemestane (Aromasin) appeared to have a bone-sparing impact in preclinical investigations, which is likely due to its androgenic nature, bone loss was documented for all AIs in clinical trials, which largely evaluated these medication's effectiveness in breast cancer. According to some reports, the rate of bone loss following AIs therapy is two times higher than in postmenopausal women in good health [25]. This data led investigators to propose that several pathophysiological mechanisms, such as those influencing bone geometry, bone microstructure, other aspects of bone quality, may be responsible for bone fragility in women who have received AIs treatment.
