Lindahl K, Kindmark A, Rubin C-J, Malmgren B, Grigelioniene G, Söderhäll S, Ljunggren Ö, Åström E
Department of Medical Sciences, Uppsala University, Uppsala, Sweden.
Department of Medical Sciences, Uppsala University, Uppsala, Sweden; Science for Life Laboratory, Department of Medical Sciences, Uppsala University Hospital, Uppsala, Sweden.
Bone. 2016 Jun;87:11-8. doi: 10.1016/j.bone.2016.02.015. Epub 2016 Mar 5.
Osteogenesis imperfecta (OI) is an inherited heterogeneous bone fragility disorder, usually caused by collagen I mutations. It is well established that bisphosphonate treatment increases lumbar spine (LS) bone mineral density (BMD), as well as improves vertebral geometry in severe OI; however, fracture reduction has been difficult to prove, pharmacogenetic studies are scarce, and it is not known at which age, or severity of disease, treatment should be initiated.
COL1A1 and COL1A2 were analyzed in 79 children with OI (type I n=33, type III n=25 and type IV n=21) treated with Pamidronate. Data on LS BMD, height, and radiologically confirmed non-vertebral and vertebral fractures were collected prior to, and at several time points during treatment.
An increase in LS BMD Z-score was observed for all types of OI, and a negative correlation to Δ LS BMD was observed for both age and LS BMD Z-score at treatment initiation. Supine height Z-scores were not affected by Pamidronate treatment, The fracture rate was reduced for all OI types at all time points during treatment (overall p<0.0003, <0.0001 and 0.0003 for all OI types I, III and IV respectively). The reduced fracture rate was maintained for types I and IV, while an additional decrease was observed over time for type III. The fracture rate was reduced also in individuals with continued low BMD after >4yrs Pamidronate. Twice as many boys as girls with OI type I were treated with Pamidronate, and the fracture rate the year prior treatment was 2.2 times higher for boys (p=0.0236). Greater Δ LS BMD, but smaller Δ fracture numbers were observed on Pamidronate for helical glycine mutations in COL1A1 vs. COL1A2. Vertebral compression fractures did not progress in any individual during treatment; however, they did not improve in 9%, and these individuals were all >11years of age at treatment initiation (p<0.0001).
Pamidronate treatment in children with all types of OI increased LS BMD, decreased fracture rate, and improved vertebral compression fractures. Fracture reduction was prompt and maintained during treatment, irrespective of age at treatment initiation and collagen I mutation type.
成骨不全症（OI）是一种遗传性的异质性骨脆性疾病，通常由I型胶原蛋白突变引起。已证实双膦酸盐治疗可增加腰椎（LS）骨矿物质密度（BMD），并改善重度OI患者的椎体形态；然而，骨折减少情况难以证实，药物遗传学研究稀缺，且尚不清楚应在哪个年龄或疾病严重程度开始治疗。
对79例接受帕米膦酸盐治疗的OI患儿（I型n = 33，III型n = 25，IV型n = 21）进行COL1A1和COL1A2分析。在治疗前及治疗期间的多个时间点收集LS BMD、身高以及经放射学证实的非椎体和椎体骨折的数据。
所有类型的OI患者LS BMD Z值均升高，治疗开始时的年龄和LS BMD Z值与ΔLS BMD呈负相关。仰卧位身高Z值不受帕米膦酸盐治疗的影响。治疗期间所有时间点所有OI类型的骨折率均降低（所有OI类型I、III和IV的总体p < 0.0003、< 0.0001和0.0003）。I型和IV型骨折率降低得以维持，而III型随时间推移额外降低。帕米膦酸盐治疗超过4年后仍有持续低BMD的个体骨折率也降低。接受帕米膦酸盐治疗的I型OI男孩数量是女孩的两倍，治疗前一年男孩的骨折率是女孩的2.2倍（p = 0.0236）。与COL1A2相比，COL1A1螺旋甘氨酸突变患者接受帕米膦酸盐治疗时观察到更大的ΔLS BMD，但骨折数减少幅度较小。治疗期间任何个体的椎体压缩骨折均未进展；然而，9%的个体未改善，这些个体治疗开始时均>11岁（p < 0.0001）。
所有类型OI患儿接受帕米膦酸盐治疗可增加LS BMD，降低骨折率，并改善椎体压缩骨折。骨折减少迅速且在治疗期间得以维持，与治疗开始时的年龄和I型胶原蛋白突变类型无关。
