Department of Medical Education, Taipei Tzu-Chi Hospital, The Buddhist Tzu-Chi Medical Foundation, New Taipei City 231, Taiwan.
Department of Physical Medicine and Rehabilitation, Mackay Memorial Hospital, Taipei 104, Taiwan.
Int J Mol Sci. 2024 Nov 12;25(22):12139. doi: 10.3390/ijms252212139.
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.
原发性骨质疏松症与激素缺乏密切相关，后者破坏了骨重建的平衡。它不仅影响绝经后妇女，而且对老年男性也有显著影响。雌激素可以促进骨保护素的产生，骨保护素是 RANKL 的诱饵受体，从而防止 RANKL 激活破骨细胞。此外，雌激素通过激活 Wnt 信号通路促进成骨细胞的存活和功能。同样，雄激素在骨代谢中起着关键作用，主要通过在男性中转化为雌激素。雌激素缺乏会通过促炎细胞因子（IL-1、IL-6、TNF-α）和 RANKL 的增加加速骨吸收，从而促进破骨细胞的生成。在经典的基因组途径中，雌激素与细胞质中的雌激素受体结合，形成一个复合物，迁移到细胞核并与 DNA 上的雌激素反应元件结合，调节基因转录。雄激素可以被定义为雄激素受体的高亲和力配体；它们的结合可以作为配体诱导的转录因子。激素替代疗法已显示出前景，但也存在相关风险和副作用。相比之下，非基因组途径涉及细胞膜起始的快速信号级联，影响细胞功能而不直接改变基因表达。因此，可以利用雌激素和雄激素受体的非配体依赖性作用和快速信号通路来开发新的药物，这些药物可以提供骨保护而没有传统激素治疗的副作用。为了治疗原发性骨质疏松症，其他药物治疗（双膦酸盐、特立帕肽、RANKL 抑制剂、硬化素抑制剂、选择性雌激素受体调节剂和降钙素鲑鱼）可以通过作用于不同的途径改善骨质疏松症和提高 BMD。非药物治疗包括营养支持和运动，以及抗氧化剂和天然产物的饮食摄入。本研究综述了原发性骨质疏松症的骨重建过程、激素作用、激素受体状态和治疗靶点。然而，原发性骨质疏松症的许多详细的细胞和分子机制似乎很复杂，尚未得到充分探索，需要进一步研究。
