Emerzian Shannon R, Chow Jarred, Behzad Ramina, Unal Mustafa, Brooks Daniel J, Wu I-Hsien, Gauthier John, Jangolla Surya Vishva Teja, Yu Marc Gregory, Shah Hetal S, King George L, Johannesdottir Fjola, Karim Lamya, Yu Elaine W, Bouxsein Mary L
Center for Advanced Orthopedic Studies, Department of Orthopedic Surgery, Beth Israel Deaconess Medical Center, Boston, MA 02215, United States.
Harvard Medical School, Boston, MA 02115, United States.
J Bone Miner Res. 2024 Dec 31;40(1):87-99. doi: 10.1093/jbmr/zjae184.
Type 1 diabetes (T1D) is associated with an increased risk of hip fracture beyond what can be explained by reduced bone mineral density, possibly due to changes in bone material from accumulation of advanced glycation end-products (AGEs) and altered matrix composition, though data from human cortical bone in T1D are limited. The objective of this study was to evaluate cortical bone material behavior in T1D by examining specimens from cadaveric femora from older adults with long-duration T1D (≥50 yr; n = 20) and age- and sex-matched nondiabetic controls (n = 14). Cortical bone was assessed by mechanical testing (4-point bending, cyclic reference point indentation, impact microindentation), AGE quantification [total fluorescent AGEs, pentosidine, carboxymethyl lysine (CML)], and matrix composition via Raman spectroscopy. Cortical bone from older adults with T1D had diminished postyield toughness to fracture (-30%, p = .036), elevated levels of AGEs (pentosidine, +17%, p = .039), lower mineral crystallinity (-1.4%, p = .010), greater proline hydroxylation (+1.9%, p = .009), and reduced glycosaminoglycan (GAG) content (-1.3%, p < .03) compared to nondiabetics. In multiple regression models to predict cortical bone toughness, cortical tissue mineral density, CML, and Raman spectroscopic measures of enzymatic collagen crosslinks and GAG content remained highly significant predictors of toughness, while diabetic status was no longer significant (adjusted R2 > 0.60, p < .001). Thus, the impairment of cortical bone to absorb energy following long-duration T1D is well explained by AGE accumulation and modifications to the bone matrix. These results provide novel insight into the pathogenesis of skeletal fragility in individuals with T1D.
1型糖尿病（T1D）与髋部骨折风险增加相关，这种风险增加超出了骨矿物质密度降低所能解释的范围，这可能是由于晚期糖基化终产物（AGEs）积累导致的骨材料变化以及基质组成改变所致，不过来自T1D患者人类皮质骨的数据有限。本研究的目的是通过检查长期患T1D（≥50岁；n = 20）的老年人以及年龄和性别匹配的非糖尿病对照者（n = 14）的尸体股骨标本，来评估T1D患者皮质骨材料的行为。通过机械测试（四点弯曲、循环参考点压痕、冲击微压痕）、AGE定量[总荧光AGEs、戊糖苷、羧甲基赖氨酸（CML）]以及通过拉曼光谱分析基质组成来评估皮质骨。与非糖尿病患者相比，长期患T1D的老年人的皮质骨屈服后骨折韧性降低（-30%，p = 0.036），AGEs水平升高（戊糖苷，+17%，p = 0.039），矿物质结晶度降低（-1.4%，p = 0.010），脯氨酸羟化程度更高（+1.9%，p = 0.009），糖胺聚糖（GAG）含量降低（-1.3%，p < 0.03）。在预测皮质骨韧性的多元回归模型中，皮质组织矿物质密度、CML以及酶促胶原交联和GAG含量的拉曼光谱测量值仍然是韧性的高度显著预测指标，而糖尿病状态不再显著（调整后R2>0.60，p < 0.001）。因此，长期患T1D后皮质骨吸收能量的受损情况可以很好地用AGE积累和骨基质改变来解释。这些结果为T1D患者骨骼脆性的发病机制提供了新的见解。
