Primary Osteoporosis Induced by Androgen and Estrogen Deficiency: The Molecular and Cellular Perspective on Pathophysiological Mechanisms and Treatments

Primary osteoporosis is closely linked to hormone deficiency, which disrupts the balance of bone remodeling. It affects postmenopausal women but also significantly impacts older men. Estrogen can promote the production of osteoprotegerin, a decoy receptor for RANKL, thereby preventing RANKL from activating osteoclasts. Furthermore, estrogen promotes osteoblast survival and function via activation of the Wnt signaling pathway. Likewise, androgens play a critical role in bone metabolism, primarily through their conversion to estrogen in men. Estrogen deficiency accelerates bone resorption through a rise in pro-inflammatory cytokines (IL-1, IL-6, TNF-α) and RANKL, which promote osteoclastogenesis. In the classic genomic pathway, estrogen binds to estrogen receptors in the cytoplasm, forming a complex that migrates to the nucleus and binds to estrogen response elements on DNA, regulating gene transcription. Androgens can be defined as high-affinity ligands for the androgen receptor; their combination can serve as a ligand-inducible transcription factor. Hormone replacement therapy has shown promise but comes with associated risks and side effects. In contrast, the non-genomic pathway involves rapid signaling cascades initiated at the cell membrane, influencing cellular functions without directly altering gene expression. Therefore, the ligand-independent actions and rapid signaling pathways of estrogen and androgen receptors can be harnessed to develop new drugs that provide bone protection without the side effects of traditional hormone therapies. To manage primary osteoporosis, other pharmacological treatments (bisphosphonates, teriparatide, RANKL inhibitors, sclerostin inhibitors, SERMs, and calcitonin salmon) can ameliorate osteoporosis and improve BMD via actions on different pathways. Non-pharmacological treatments include nutritional support and exercise, as well as the dietary intake of antioxidants and natural products. The current study reviews the processes of bone remodeling, hormone actions, hormone receptor status, and therapeutic targets of primary osteoporosis. However, many detailed cellular and molecular mechanisms underlying primary osteoporosis seem complicated and unexplored and warrant further investigation.