Weinstein Robert S, Jia Dan, Powers Cara C, Stewart Scott A, Jilka Robert L, Parfitt A Michael, Manolagas Stavros C
Center for Osteoporosis and Metabolic Bone Diseases, Department of Internal Medicine, Central Arkansas Veterans Healthcare System, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205-7199, USA.
Endocrinology. 2004 Apr;145(4):1980-7. doi: 10.1210/en.2003-1133. Epub 2004 Jan 8.
Hypogonadism has been implicated as a contributing factor in glucocorticoid-induced osteoporosis, but evidence for this is limited. Hypogonadism and glucocorticoid excess both cause bone loss, but the cellular mechanisms responsible are distinct. Loss of gonadal steroids causes an increase in bone remodeling by up-regulating osteoblastogenesis and osteoclastogenesis. Glucocorticoid excess, conversely, suppresses remodeling by down-regulating osteoblastogenesis and osteoclastogenesis. Nonetheless, both conditions increase osteoblast apoptosis and decrease osteoclast apoptosis, and both cause bone loss due to an undersupply of osteoblasts relative to the need for cavity repair. To investigate their interactions, we compared the effects of orchidectomy, glucocorticoid excess, or both combined in mice. After 28 d, serum unbound testosterone concentration and seminal vesicle weight were not diminished when prednisolone was administered alone. Vertebral bone mineral density and compression strength decreased to the same extent in animals receiving prednisolone or after orchidectomy, but the changes were not additive. Orchidectomy induced the expected up-regulation of osteoblast and osteoclast progenitors, but these changes were prevented in orchidectomized mice simultaneously receiving glucocorticoids. Likewise, the increase in cancellous osteoid, osteoblasts, osteoclasts, bone formation, and activation frequency caused by orchidectomy were prevented by prednisolone. The prevalence of osteoblast apoptosis increased in the mice receiving prednisolone or after orchidectomy, but the increases were not additive. These data demonstrate that hypogonadism does not occur in or contribute to glucocorticoid-induced osteoporosis and that the adverse skeletal effects of glucocorticoid excess override those of orchidectomy.
性腺功能减退被认为是糖皮质激素诱导的骨质疏松症的一个促成因素，但这方面的证据有限。性腺功能减退和糖皮质激素过量都会导致骨质流失，但相关的细胞机制是不同的。性腺类固醇的缺乏通过上调成骨细胞生成和破骨细胞生成导致骨重塑增加。相反，糖皮质激素过量通过下调成骨细胞生成和破骨细胞生成来抑制重塑。尽管如此，这两种情况都会增加成骨细胞凋亡并减少破骨细胞凋亡，并且由于相对于空洞修复需求而言成骨细胞供应不足，两者都会导致骨质流失。为了研究它们之间的相互作用，我们比较了去势、糖皮质激素过量或两者联合对小鼠的影响。28天后，单独给予泼尼松龙时，血清游离睾酮浓度和精囊重量并未降低。接受泼尼松龙的动物或去势后的动物，其椎骨骨密度和抗压强度下降程度相同，但这些变化并非相加性的。去势诱导了预期的成骨细胞和破骨细胞祖细胞的上调，但在同时接受糖皮质激素的去势小鼠中，这些变化被阻止了。同样，泼尼松龙阻止了去势引起的松质骨类骨质、成骨细胞、破骨细胞、骨形成和激活频率的增加。接受泼尼松龙的小鼠或去势后的小鼠中，成骨细胞凋亡的发生率增加，但增加并非相加性的。这些数据表明，糖皮质激素诱导的骨质疏松症中不会发生性腺功能减退，也不会导致性腺功能减退，并且糖皮质激素过量对骨骼的不良影响超过了去势的影响。
