Severe Skeletal Toxicity From Protracted Etidronate Therapy for Generalized Arterial Calcification of Infancy
Severe Skeletal Toxicity From Protracted Etidronate Therapy for Generalized Arterial Calcification of Infancy
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DOI：
10.1002/jbmr.1752
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发表时间：
2013-02-01
影响因子：
6.2
通讯作者：
Whyte, Michael P.
中科院分区：
文献类型：
--
作者：
Otero, Jesse E.;Gottesman, Gary S.;Whyte, Michael P.
婴儿泛发性动脉钙化（AC）是一种常染色体隐性遗传疾病，其特征是动脉弹性纤维内羟基磷灰石沉积。未经治疗，大约85%的GACI患者在6个月大时死于心脏缺血和充血性心力衰竭。第一代双膦酸盐依替膦酸盐（EHDP;乙烷-1-羟基-1，1-二膦酸，也称为1-羟基亚乙基双膦酸盐）抑制骨吸收，并可通过阻断矿化来模拟内源性无机焦磷酸盐。用EHDP治疗GACI，AC可能在治疗停止后消退而不会复发。佝偻病不是GACI的早期特征，但获得性低磷血症或长期EHDP治疗可导致佝偻病。我们报告一个7岁的男孩与GACI提到深刻的，获得性，骨骼疾病。AC在婴儿期EHDP治疗5个月后消失，但GACI相关的关节钙化进展。他接受EHDP，200 mg/天口服，并有吞咽困难、弥漫性阿片类药物控制疼痛、斜头、面部畸形、关节钙化、挛缩，并坐轮椅。矿物质稳态的生化参数基本正常。血清骨钙素低，脑肌酸激酶和抗酒石酸酸性磷酸酶5 b（TRAP-5 b）亚型升高，如骨硬化症。骨骼影像学检查结果类似于儿科低磷酸酶症伴全颅骨结合、长骨弯曲、骺板增宽以及干骺端骨质增生、杯状和磨损以及射线可透性“舌”。骨硬化症的影像学特征包括骨质疏松和股骨锥形瓶畸形。停止EHDP后，他迅速改善，包括显著的骨骼愈合和关节钙化减少。在长期EHDP治疗的GACI中，可发生严重但迅速可逆的骨骼矿化抑制和关节附近的反常钙化。虽然EHDP治疗是挽救生命的GACI，监测毒性是至关重要的。(C)2013年美国骨与矿物质研究学会。
Generalized arterial calcification (AC) of infancy (GACI) is an autosomal recessive disorder that features hydroxyapatite deposition within arterial elastic fibers. Untreated, approximately 85% of GACI patients die by 6 months of age from cardiac ischemia and congestive heart failure. The first-generation bisphosphonate etidronate (EHDP; ethane-1-hydroxy-1,1-diphosphonic acid, also known as 1-hydroxyethylidene-bisphosphonate) inhibits bone resorption and can mimic endogenous inorganic pyrophosphate by blocking mineralization. With EHDP therapy for GACI, AC may resolve without recurrence upon treatment cessation. Skeletal disease is not an early characteristic of GACI, but rickets can appear from acquired hypophosphatemia or prolonged EHDP therapy. We report a 7-year-old boy with GACI referred for profound, acquired, skeletal disease. AC was gone after 5 months of EHDP therapy during infancy, but GACI-related joint calcifications progressed. He was receiving EHDP, 200 mg/day orally, and had odynodysphagia, diffuse opioid-controlled pain, plagiocephaly, facial dysmorphism, joint calcifications, contractures, and was wheelchair bound. Biochemical parameters of mineral homeostasis were essentially normal. Serum osteocalcin was low and the brain isoform of creatine kinase and tartrate-resistant acid phosphatase 5b (TRAP-5b) were elevated as in osteopetrosis. Skeletal radiographic findings resembled pediatric hypophosphatasia with pancranial synostosis, long-bone bowing, widened physes, as well as metaphyseal osteosclerosis, cupping and fraying, and "tongues" of radiolucency. Radiographic features of osteopetrosis included osteosclerosis and femoral Erlenmeyer flask deformity. After stopping EHDP, he improved rapidly, including remarkable skeletal healing and decreased joint calcifications. Profound, but rapidly reversible, inhibition of skeletal mineralization with paradoxical calcifications near joints can occur in GACI from protracted EHDP therapy. Although EHDP treatment is lifesaving in GACI, surveillance for toxicity is crucial. (C) 2013 American Society for Bone and Mineral Research.