Nrf2 Activation as a Therapeutic Target for Flavonoids in Aging-Related Osteoporosis

Biological aging is a substantial change that leads to different diseases, including osteoporosis (OP), a condition involved in loss of bone density, deterioration of bone structure, and increased fracture risk. In old people, there is a natural decline in bone mineral density (BMD), exacerbated by hormonal changes, particularly during menopause, and it continues in the early postmenopausal years. During this transition time, hormonal alterations are linked to elevated oxidative stress (OS) and decreased antioxidant defenses, leading to a significant increase in OP. Aging is significantly associated with an abnormal ratio of oxidant/antioxidant and modified nuclear factor erythroid-derived two related factor2 (Nrf2)/Kelch-like ECH-associated protein 1 (Keap1) pathway. OS adversely affects bone health by promoting osteoclastic (bone resorbing) activity and impairing osteoblastic (bone-forming cells). Nrf2 is critical in controlling OS and various cellular processes. The expression of Nrf2 is linked to multiple age-related diseases, including OP, and Nrf2 deficiency leads to unbalanced bone formation/resorption and a consequent decline in bone mass. Various drugs are available for treating OP; however, long-term uses of these medicines are implicated in diverse illnesses such as cancer, cardiovascular, and stroke. At the same time, multiple categories of natural products, in particular flavonoids, were proposed as safe alternatives with antioxidant activity and substantial anti-osteoporotic effects.