Hoyer-Kuhn Heike, Netzer Christian, Koerber Friederike, Schoenau Eckhard, Semler Oliver
Orphanet J Rare Dis. 2014 Sep 26;9:145. doi: 10.1186/s13023-014-0145-1.
Osteogenesis imperfecta (OI) is a hereditary disease causing reduced bone mass, increased fracture rate, long bone deformities and vertebral compressions. Additional non skeletal findings are caused by impaired collagen function and include hyperlaxity of joints and blue sclera. Most OI cases are caused by dominant mutations in COL1A1/2 affecting bone formation. During the last years, recessive forms of OI have been identified, mostly affecting posttranslational modification of collagen. In 2011, mutations in SERPINF1 were identified as the molecular cause of OI type VI, and thereby a novel pathophysiology of the disease was elucidated. The subgroup of patients with OI type VI are affected by an increased bone resorption, leading to the same symptoms as observed in patients with an impaired bone formation. Severely affected children are currently treated with intravenous bisphosphonates regardless of the underlying mutation and pathophysiology. Patients with OI type VI are known to have a poor response to such a bisphosphonate treatment.
Deciphering the genetic cause of OI type VI in our 4 patients (three children and one adolescent) led to an immediate translational approach in the form of a treatment with the monoclonal RANKL antibody Denosumab (1 mg/kg body weight every 12 weeks).
Short-term biochemical response to this treatment was reported previously. We now present the results after 2 years of treatment and demonstrate a long term benefit as well as an increase of bone mineral density, a normalization of vertebral shape, an increase of mobility, and a reduced fracture rate.
This report presents the first two-year data of denosumab treatment in patients with Osteogenesis imperfecta type VI and in Osteogenesis imperfecta in general as an effective and apparently safe treatment option.
成骨不全症（OI）是一种遗传性疾病，可导致骨量减少、骨折率增加、长骨畸形和椎体压缩。其他非骨骼表现是由胶原蛋白功能受损引起的，包括关节过度松弛和巩膜发蓝。大多数OI病例是由影响骨形成的COL1A1/2显性突变引起的。在过去几年中，已发现隐性形式的OI，主要影响胶原蛋白的翻译后修饰。2011年，SERPINF1突变被确定为VI型OI的分子病因，从而阐明了该疾病的一种新的病理生理学。VI型OI患者亚组受到骨吸收增加的影响，导致与骨形成受损患者观察到的相同症状。目前，无论潜在的突变和病理生理学如何，严重受影响的儿童都接受静脉注射双膦酸盐治疗。已知VI型OI患者对这种双膦酸盐治疗反应不佳。
对我们的4例患者（3名儿童和1名青少年）进行VI型OI的基因病因分析，导致了一种直接的转化方法，即采用单克隆RANKL抗体地诺单抗（每12周1mg/kg体重）进行治疗。
此前已报道了该治疗的短期生化反应。我们现在展示了2年治疗后的结果，证明了长期益处以及骨矿物质密度增加、椎体形状正常化、活动能力增加和骨折率降低。
本报告展示了地诺单抗治疗VI型成骨不全症患者以及一般成骨不全症患者的首份两年数据，表明其是一种有效且明显安全的治疗选择。
