Department of Biomedical Engineering, Center for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute, Troy, NY 12180, USA.
Osteoporos Int. 2009 Jun;20(6):887-94. doi: 10.1007/s00198-008-0754-4. Epub 2008 Oct 11.
One year of high-dose bisphosphonate (BPs) therapy in dogs allowed the increased accumulation of advanced glycation end-products (AGEs) and reduced postyield work-to-fracture of the cortical bone matrix. The increased accumulation of AGEs in these tissues may help explain altered bone matrix quality due to the administration of BPs in animal models
Non-enzymatic glycation (NEG) is a posttranslational modification of the organic matrix that results in the formation of advanced glycation end-products (AGEs). In bone, the accumulation of AGEs play an important role in determining fracture resistance, and elevated levels of AGEs have been shown to adversely affect the bone's propensity to brittle fracture. It was thus hypothesized that the suppression of tissue turnover in cortical bone due to the administration of bisphosphonates would cause increased accumulation of AGEs and result in a more brittle bone matrix.
Using a canine animal model (n = 12), we administered daily doses of a saline vehicle (VEH), alendronate (ALN 0.20, 1.00 mg/kg) or risedronate (RIS 0.10, 0.50 mg/kg). After a 1-year treatment, the mechanical properties, intracortical bone turnover, and the degree of nonenzymatic cross-linking of the organic matrix were measured from the tibial cortical bone tissue of these animals.
There was a significant accumulation of AGEs at high treatment doses (+49 to + 86%; p < 0.001), but not at doses equivalent to those used for the treatment of postmenopausal osteoporosis, compared to vehicle. Likewise, postyield work-to-fracture of the tissue was significantly reduced at these high doses (-28% to -51%; p < 0.001) compared to VEH. AGE accumulation inversely correlated with postyield work-to-fracture (r (2) = 0.45; p < 0.001), suggesting that increased AGEs may contribute to a more brittle bone matrix.
High doses of bisphosphonates result in the accumulation of AGEs and a reduction in energy absorption of cortical bone. The increased accumulation of AGEs in these tissues may help explain altered bone matrix quality due to the administration of BPs in animal models.
在狗中进行为期一年的高剂量双膦酸盐（BPs）治疗会导致晚期糖基化终产物（AGEs）的积累增加，并降低皮质骨基质的屈服后断裂功。这些组织中 AGEs 的积累增加可能有助于解释由于在动物模型中使用 BPs 而导致的骨基质质量改变。
非酶糖基化（NEG）是有机基质的一种翻译后修饰，导致晚期糖基化终产物（AGEs）的形成。在骨骼中，AGEs 的积累在决定抗断裂能力方面起着重要作用，并且已经表明升高的 AGEs 水平会不利地影响骨骼的脆性断裂倾向。因此，假设由于双膦酸盐的给药导致皮质骨组织的周转率下降会导致 AGEs 的积累增加，并导致更脆弱的骨基质。
使用犬动物模型（n = 12），我们给予每日剂量的生理盐水载体（VEH）、阿仑膦酸盐（ALN 0.20、1.00 mg/kg）或利塞膦酸盐（RIS 0.10、0.50 mg/kg）。经过 1 年的治疗后，从这些动物的胫骨皮质骨组织中测量机械性能、皮质内骨转换和有机基质的非酶交联程度。
与载体相比，高治疗剂量（+49 至+86%；p < 0.001）时 AGEs 大量积累，但在与用于治疗绝经后骨质疏松症等效的剂量时没有积累。同样，与 VEH 相比，这些高剂量时的屈服后断裂功显著降低（-28%至-51%；p < 0.001）。AGE 积累与屈服后断裂功呈负相关（r²=0.45；p < 0.001），表明 AGEs 的增加可能导致骨基质更脆弱。
高剂量的双膦酸盐会导致 AGEs 的积累和皮质骨能量吸收的减少。这些组织中 AGEs 的积累增加可能有助于解释由于在动物模型中使用 BPs 而导致的骨基质质量改变。
