Department of Orthopaedic Surgery, Jikei University School of Medicine 3-25-8, Nishi-Shinbashi, Minato-ku, Tokyo 105-8461, Japan.
Bone. 2010 Apr;46(4):1170-9. doi: 10.1016/j.bone.2009.12.008. Epub 2009 Dec 22.
Both bone density and quality are important determinants of bone strength. Bone quality is prescribed by matrix characteristic including collagen cross-linking and bone structural characteristics and is important in reinforcement of bone strength. We investigated the effects of alfacalcidol (ALF), a prodrug of calcitriol, and alendronate (ALN), a bisphosphanate, on the mechanical properties and content of enzymatic cross-links in femoral bone using a fracture repair rat model. Forty 3-month-old female Wistar-Imamichi rats were randomized into 4 groups: SHAM (sham-operated+vehicle), OVX (ovariectomy+vehicle), ALF (ovariectomy+ALF, 0.1 microg/kg/d, p.o.) and ALN (ovariectomy+ALN, 10 microg/kg/d, s.c.). Treatment began immediately after SHAM or OVX surgery. Three weeks later, all animals underwent transverse osteotomies at the midshaft of the left femur. Treatment was continued and rats were sacrificed at 12 weeks post-fracture for evaluation by X-ray radiography, micro-CT, pQCT, biomechanical testing and bone histomorphometry. In the ALN group, no new cortical shell appeared and the callus diameter was significantly larger than in the OVX group (p<0.05). Stiffness of fractured callus in the ALF group, but not in the ALN group, was significantly higher than in the OVX group. Young's modulus in the ALN group was significantly decreased compared to the OVX group. Moreover, micro-CT analysis showed that ALN treatment increased the lowly mineralized bone in the callus by, resulting in the highest content of woven bone area and lowest content of lamellar bone. The total amount of enzymatic cross-links in both the ALF and ALN groups was significantly higher than in the OVX control group. Of particular interest, the Pyr-to-Dpyr ratio was significantly decreased by ALF administration, suggesting that ALF but not ALN normalized the enzymatic cross-link patterns in fractured bone to the control level. In conclusion, ALN and ALF treatment increased bone strength via the distinctive effect on bone mass and quality. ALN formed larger calluses and increased enzymatic cross-links despite delayed woven bone remodeling into lamellar bone, whereas ALF treatment induced lamellar bone formation coincided with increasing in the enzymatic cross-linking and normalizing the cross-link pattern in callus to native bone pattern.
骨密度和质量都是骨强度的重要决定因素。骨质量由基质特征决定，包括胶原交联和骨结构特征，对增强骨强度很重要。我们使用骨折修复大鼠模型研究了活性维生素 D 制剂（骨化三醇前体药物）阿尔法骨化醇（ALF）和双膦酸盐阿仑膦酸钠（ALN）对股骨力学性能和酶交联含量的影响。40 只 3 月龄雌性 Wistar-Imamichi 大鼠随机分为 4 组：SHAM（假手术+载体）、OVX（卵巢切除术+载体）、ALF（卵巢切除术+ALF，0.1μg/kg/d，口服）和 ALN（卵巢切除术+ALN，10μg/kg/d，皮下注射）。治疗在 SHAM 或 OVX 手术后立即开始。3 周后，所有动物均在左股骨中段行横向截骨术。继续治疗，骨折后 12 周处死大鼠，进行 X 射线放射照相、微 CT、pQCT、生物力学测试和骨组织形态计量学评估。在 ALN 组，无新皮质壳出现，骨痂直径明显大于 OVX 组（p<0.05）。ALF 组骨折骨痂的刚度显著高于 OVX 组（p<0.05）。与 OVX 组相比，ALN 组的杨氏模量显著降低。此外，微 CT 分析显示，ALN 治疗增加了骨痂中低矿化骨的含量，导致编织骨面积最高，板层骨含量最低。ALF 和 ALN 组的总酶交联含量均显著高于 OVX 对照组。特别有趣的是，ALF 给药后 Pyr-to-Dpyr 比值显著降低，表明 ALF 而非 ALN 使骨折骨的酶交联模式正常化至对照水平。总之，ALN 和 ALF 治疗通过对骨量和质量的独特作用增加了骨强度。ALN 形成较大的骨痂并增加酶交联，尽管编织骨向板层骨的重塑延迟，但 ALF 治疗诱导板层骨形成，同时增加酶交联并使骨痂中的交联模式正常化至天然骨模式。
