Division of Adolescent/Young Adult Medicine, Boston Children's Hospital, Boston, MA, USA.
Department of Radiology, Boston Children's Hospital, Boston, MA, USA.
Bone. 2019 Aug;125:103-111. doi: 10.1016/j.bone.2019.05.008. Epub 2019 May 8.
Children with Hutchinson-Gilford progeria syndrome (HGPS), a rare premature aging disease, exhibit extraskeletal calcifications detected by radiographic analysis and on physical examination. The aim of this study was to describe the natural history and pathophysiology of these abnormal calcifications in HGPS, and to determine whether medications and/or supplements tested in clinical trials alter their development.
Children from two successive clinical trials administering 1) lonafarnib (n = 26) and 2) lonafarnib + pravastatin + zoledronic acid (n = 37) were studied at baseline (pre-therapy), one year on therapy, and at end-of-therapy (3.3-4.3 years after the baseline visit). Calcium supplementation (oral calcium carbonate) was administered during the first year of the second trial and was subsequently discontinued. Information on calcifications was obtained from physical examinations, radiographs, and serum and urinary biochemical measures. The mineral content of two skin-derived calcifications was determined by x-ray diffraction.
Extraskeletal calcifications were detected radiographically in 12/39 (31%) patients at baseline. The odds of exhibiting calcifications increased with age (p = 0.045). The odds were unaffected by receipt of lonafarnib, pravastatin, and zoledronate therapies. However, administration of calcium carbonate supplementation, in conjunction with all three therapeutic agents, significantly increased the odds of developing calcifications (p = 0.009), with the odds plateauing after the supplement's discontinuation. Composition analysis of calcinosis cutis showed hydroxyapatite similar to bone. Although serum calcium, phosphorus, and parathyroid hormone (PTH) were within normal limits at baseline and on-therapy, PTH increased significantly after lonafarnib initiation (p < 0.001). Both the urinary calcium/creatinine ratio and tubular reabsorption of phosphate (TRP) were elevated at baseline in 22/39 (56%) and 31/37 (84%) evaluable patients, respectively, with no significant changes while on-therapy. The mean calcium × phosphorus product (Ca × Pi) was within normal limits, but plasma magnesium decreased over both clinical trials. Fibroblast growth factor 23 (FGF23) was lower compared to age-matched controls (p = 0.03).
Extraskeletal calcifications increased with age in children with HGPS and were composed of hydroxyapatite. The urinary calcium/creatinine ratio and TRP were elevated for age while FGF23 was decreased. Magnesium decreased and PTH increased after lonafarnib therapy which may alter the ability to mobilize calcium. These findings demonstrate that children with HGPS with normal renal function and an unremarkable Ca × Pi develop extraskeletal calcifications by an unidentified mechanism that may involve decreased plasma magnesium and FGF23. Calcium carbonate accelerated their development and is, therefore, not recommended for routine supplementation in these children.
儿童患有哈钦森-吉尔福德早衰综合征（HGPS），这是一种罕见的过早衰老疾病，通过放射分析和体格检查可检测到骨骼外钙化。本研究旨在描述 HGPS 中这些异常钙化的自然史和病理生理学，并确定临床试验中测试的药物和/或补充剂是否会改变其发展。
对连续两项临床试验中的儿童进行研究，分别给予 1） lonafarnib（n=26）和 2） lonafarnib+pravastatin+zoledronic acid（n=37）。在基线（治疗前）、治疗一年和治疗结束时（基线后 3.3-4.3 年）进行研究。在第二项试验的第一年期间给予钙补充剂（碳酸钙口服），随后停止。通过体格检查、射线照相和血清和尿液生化测量来获取钙化信息。通过 X 射线衍射确定两块皮肤衍生钙化的矿物质含量。
基线时，12/39（31%）名患者在放射影像学上检测到骨骼外钙化。出现钙化的几率随年龄增长而增加（p=0.045）。接受 lonafarnib、pravastatin 和 zoledronate 治疗不会影响几率。然而，钙补充剂的给药，与所有三种治疗药物联合使用，显著增加了发生钙化的几率（p=0.009），在补充剂停止使用后，几率趋于平稳。皮肤钙化的成分分析显示羟磷灰石类似于骨骼。尽管基线和治疗期间血清钙、磷和甲状旁腺激素（PTH）均在正常范围内，但 lonafarnib 开始后 PTH 显著升高（p<0.001）。在可评估的 39 名患者中的 22 名（56%）和 37 名中的 31 名（84%）基线时，尿钙/肌酐比值和磷重吸收率（TRP）均升高，而在治疗期间无明显变化。钙×磷乘积（Ca×Pi）在正常范围内，但两个临床试验期间血浆镁均降低。成纤维细胞生长因子 23（FGF23）与年龄匹配的对照组相比降低（p=0.03）。
HGPS 儿童的骨骼外钙化随年龄增长而增加，其组成部分为羟磷灰石。与年龄相比，尿钙/肌酐比值和 TRP 升高，而 FGF23 降低。 lonafarnib 治疗后镁减少，PTH 升高，这可能改变钙动员能力。这些发现表明，肾功能正常且 Ca×Pi 无异常的 HGPS 儿童会通过未知机制发生骨骼外钙化，这可能涉及血浆镁和 FGF23 减少。碳酸钙加速了它们的发展，因此不建议在这些儿童中常规补充。
