Geriatric Unit, Department of Internal Medicine and Specialties, University of Palermo, Viale F. Scaduto 6/c, 90144, Palermo, Italy.
Biogerontology. 2011 Oct;12(5):397-408. doi: 10.1007/s10522-011-9344-5. Epub 2011 Jun 22.
Fragility fractures, a major public health concern, are expected to further increase due to aging of the world populations because age remains a cardinal, independent determinant of fracture risk. With aging the balance between bone formation and resorption during the remodeling process becomes negative, with increased resorption and reduced formation. Bisphosphonates (BPs) are widely prescribed anti-resorptive agents that inhibit osteoclasts attachment to bone matrix and enhance osteoclast apoptosis. BPs can be divided into nitrogen-containing (N-BPs) and non-nitrogen-containing BPs (non-N-BPs). Both classes induce apoptosis but they evoke it differently. Several studies have examined the molecular mechanisms underlying BPs' effects on osteoclasts and bone remodeling. N-BPs (alendronate, risedronate, zoledronate) inhibit the intracellular mevalonate pathway and protein isoprenylation, via the enzyme farnesyl pyrophosphate synthase. N-BPs act by competition, binding to the natural substrate-binding site of the enzyme. The less potent non-N-BPs (etidronate, clodronate), do not inhibit the mevalonate pathway and protein isoprenylation, but are metabolized intracellularly to metabolites, which are cytotoxic analogs of ATP. N-BPs represent the first choice treatment for diseases associated with excessive bone resorption, such as fragility fractures (due to postmenopausal-, male, glucocorticoid- and transplant-induced osteoporosis), Paget's disease of bone, and bone metastasis. Better understanding of BPs' effects on osteoblasts/osteocytes (e.g., preventing apoptosis) and differential distribution may further help explain anti-fracture benefit and bone quality effects. Lower affinity BPs (e.g., risedronate) may allow better access to osteocyte network. Effects of BPs on bone senescence, cancer cells apoptosis and prevention of cardiovascular calcifications may open new avenues for biogerontological research.
脆性骨折是一个主要的公共卫生问题，由于世界人口老龄化，预计这一问题将进一步加剧，因为年龄仍然是骨折风险的一个主要独立决定因素。随着年龄的增长，在重塑过程中骨形成和吸收之间的平衡变得消极，吸收增加，形成减少。双膦酸盐（BPs）是广泛应用的抗吸收剂，可抑制破骨细胞附着在骨基质上，并促进破骨细胞凋亡。BPs 可分为含氮（N-BPs）和不含氮（非 N-BPs）两类。两类药物都能诱导细胞凋亡，但诱导方式不同。有几项研究检查了 BPs 对破骨细胞和骨重塑的作用的分子机制。N-BPs（阿仑膦酸盐、利塞膦酸盐、唑来膦酸盐）通过抑制法呢基焦磷酸合酶抑制细胞内甲羟戊酸途径和蛋白质异戊烯化。N-BPs 通过竞争结合酶的天然底物结合位点起作用。作用较弱的非 N-BPs（依替膦酸盐、氯膦酸盐）不抑制甲羟戊酸途径和蛋白质异戊烯化，但在细胞内代谢为细胞毒性的 ATP 类似物。N-BPs 是治疗与过度骨吸收相关疾病的首选药物，如脆性骨折（由于绝经后、男性、糖皮质激素和移植引起的骨质疏松症）、骨关节炎、Pagets 病和骨转移。更好地了解 BPs 对成骨细胞/成骨细胞的影响（例如，预防细胞凋亡）和差异分布可能有助于进一步解释抗骨折益处和骨质量效应。亲和力较低的 BPs（如利塞膦酸盐）可能允许更好地进入骨细胞网络。BPs 对骨衰老、癌细胞凋亡和预防心血管钙化的作用可能为生物老年学研究开辟新途径。
