NYPH-Weill Cornell Medical Center, New York, NY, USA.
Osteoporos Int. 2012 Mar;23(3):1141-50. doi: 10.1007/s00198-011-1742-7. Epub 2011 Sep 8.
We report a direct comparison of receptor activator of nuclear factor kappa B ligand (RANKL) inhibition (RANK-Fc) with bisphosphonate treatment (alendronate, ALN) from infancy through early adulthood in a mouse model of osteogenesis imperfecta. Both ALN and RANK-Fc decreased fracture incidence to the same degree with increases in metaphyseal bone volume via increased number of thinner trabeculae.
The potential therapeutic benefit of RANKL inhibitors in osteogenesis imperfecta (OI) is under investigation. We report a direct comparison of RANKL inhibition (RANK-Fc) with bisphosphonate treatment (ALN) from infancy through early adulthood in a model of OI, the oim/oim mouse.
Two-week-old oim/oim, oim/+, and wildtype (+/+) mice were treated with RANK-Fc 1.5 mg/kg twice per week, ALN 0.21 mg/kg/week or saline (n = 12-20 per group) for 12 weeks.
ALN and RANK-Fc both decreased fracture incidence (9.0 ± 3.0 saline 4.4 ± 2.7 ALN, 4.3 ± 3.0 RANK-Fc fractures per mouse). Serum TRACP-5b activity decreased to 65% after 1 month in all treated mice, but increased sacrifice with RANK-Fc to 130-200% at sacrifice. Metaphyseal density was significantly increased with ALN in +/+ and oim/oim mice (p < 0.05) and tended to increase with RANK-Fc in +/+ mice. No changes in oim/oim femur biomechanical parameters occurred with treatment. Both ALN and RANK-Fc significantly increased trabecular number (3.73 ± 0.77 1/mm for oim/oim saline vs 7.93 ± 0.67 ALN and 7.34 ± 1.38 RANK-Fc) and decreased trabecular thickness (0.045 mm ± 0.003 for oim/oim saline vs 0.034 ± 0.003 ALN and 0.032 ± 0.002 RANK-Fc) and separation in all genotypes (0.28 ± 0.08 mm for oim/oim saline vs 0.12 ± 0.010 ALN and 13 ± 0.03 RANK-Fc)., with significant increase in bone volume fraction (BVF) with ALN, and a trend towards increased BVF in RANK-Fc.
Treatment of oim/oim mice with either a bisphosphonate or a RANK-Fc causes similar decreases in fracture incidence with increases in metaphyseal bone volume via increased number of thinner trabeculae.
报告核因子 κB 配体（RANKL）抑制剂（RANK-Fc）与双膦酸盐（阿仑膦酸盐，ALN）在成骨不全症（OI）小鼠模型中从婴儿期到成年早期的直接比较。ALN 和 RANK-Fc 通过增加更细的小梁数量，将骺板骨量增加到相同程度，从而降低骨折发生率。
RANKL 抑制剂在成骨不全症（OI）中的潜在治疗益处正在研究中。我们报告了 RANKL 抑制剂（RANK-Fc）与双膦酸盐（ALN）在 OI 模型，oim/oim 小鼠中的直接比较。
2 周龄的 oim/oim、oim/+ 和野生型（+/+）小鼠接受 RANK-Fc 1.5mg/kg，每周两次，ALN 0.21mg/kg/周或生理盐水（每组 12-20 只）治疗 12 周。
ALN 和 RANK-Fc 均降低骨折发生率（oim/oim 组为 9.0±3.0 生理盐水组为 4.4±2.7 ALN 组为 4.3±3.0 骨折/只）。所有治疗小鼠的血清 TRACP-5b 活性在 1 个月后均降至 65%，但在 RANK-Fc 组中，在处死时增加至 130-200%。ALN 在+/+和 oim/oim 小鼠中均显著增加骺板密度（p<0.05），并在+/+小鼠中趋于增加 RANK-Fc。治疗后 oim/oim 股骨生物力学参数无变化。ALN 和 RANK-Fc 均显著增加小梁数量（oim/oim 生理盐水组为 3.73±0.77 1/mm，ALN 组为 7.93±0.67，RANK-Fc 组为 7.34±1.38），降低小梁厚度（oim/oim 生理盐水组为 0.045mm±0.003，ALN 组为 0.034±0.003，RANK-Fc 组为 0.032±0.002）和分离（oim/oim 生理盐水组为 0.28±0.08mm，ALN 组为 0.12±0.010，RANK-Fc 组为 13±0.03），ALN 增加骨体积分数（BVF），RANK-Fc 有增加 BVF 的趋势。
在 oim/oim 小鼠中，用双膦酸盐或 RANK-Fc 治疗可通过增加更细的小梁数量，使骺板骨量增加相同程度，从而降低骨折发生率。
