Göteborg Pediatric Growth Research Center, Department of Pediatrics, Institute of Clinical Sciences, The Sahlgrenska Academy at the University of Gothenburg, SE-416 85 Göteborg, Sweden.
Department of Physiology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, SE-405 30 Göteborg, Sweden.
Bone. 2018 Nov;116:144-153. doi: 10.1016/j.bone.2018.07.023. Epub 2018 Jul 30.
Growth hormone (GH) regulates both longitudinal growth and bone acquisition in children, and has profound metabolic effects. The aim was to investigate the association between proteomic biomarkers, body fat, nutrition and bone formation markers, and longitudinal growth in response to GH during the first year of treatment. The degree to which changes in these factors could explain variations in GH-dependent longitudinal growth and bone mineralization was also assessed.
The individualized GH dose trial included 128 short prepubertal children with either normal (non-GH-deficient) or reduced levels of GH secretion (GH-deficient) (mean age ± SD, 8.6 ± 2.6 years; 90 boys), i.e., with a broad range of GH-secretion and GH-responsiveness, receiving GH treatment (mean 43 μg/kg/day). Blood samples were taken and dual-energy X-ray absorptiometry (DXA) measured at baseline and 1 year of treatment. Step-wise multiple regression models were constructed including three steps with different independent variables added at each step to explain the variance in outcome variables (height, bone mineral content (BMC) and bone mineral density (BMD). Independent variables included in Step I were previously identified proteomic markers related to GH treatment response, bone formation markers (intact PINP, bone-specific alkaline phosphatase and osteocalcin), variables at treatment start (GH dose mU/kg/day, GH maximum secretion, and difference between child's current and mid-parental height). Step II explored the added influence of body composition data (body mass index or DXA). Step III explored the added influence of serum nutritional markers and hormones.
Step I variables explained 71% of the variation in first year height gain, median (minimum-maximum) 0.8 (0.24-1.67); and the proportion explained rose to 73% following inclusion of step II variables and 75% following step III. Corresponding values for total body BMC were 58%, 78%, and 80%, respectively. Proportions fell by approximately 20% when BMC was adjusted for height; 33%, 57%, and 57% for steps I, II, and III, respectively. Corresponding values for total body BMD were 29%, 39%, and 45%, respectively.
For total BMC, as much as 80% of the variation during the first year of GH treatment could be explained by proteomic biomarkers, body fat, nutrition and bone formation markers, whereas for height-adjusted BMC 57% could be explained. The inclusion of information about either body composition (fat/lean mass) or nutritional markers contributed with approximately 20%. The variation in height gain could be explained to 75%. Hence, information of fat or nutrition markers was needed for explaining the variation in bone acquisition to the same magnitude as explaining the variation in height response.
生长激素（GH）不仅调节儿童的纵向生长和骨量获得，还具有深远的代谢作用。本研究旨在探讨蛋白质组生物标志物、体脂、营养和骨形成标志物与 GH 治疗第一年的纵向生长和骨矿化之间的相关性。还评估了这些因素的变化在多大程度上可以解释 GH 依赖性纵向生长和骨矿化的变化。
个体化 GH 剂量试验纳入了 128 名青春期前的矮身材儿童，他们要么有正常（非 GH 缺乏）的 GH 分泌水平（GH 缺乏）（平均年龄 ± 标准差，8.6 ± 2.6 岁；90 名男孩），即 GH 分泌和 GH 反应性广泛，接受 GH 治疗（平均 43μg/kg/天）。在基线和治疗 1 年时采集血样并进行双能 X 线吸收法（DXA）测量。逐步多元回归模型构建了三个步骤，每个步骤都添加了不同的自变量来解释因变量（身高、骨矿物质含量（BMC）和骨矿物质密度（BMD）的变化。步骤 I 中纳入的自变量是与 GH 治疗反应相关的先前确定的蛋白质组生物标志物、骨形成标志物（完整 PINP、骨特异性碱性磷酸酶和骨钙素）和治疗开始时的变量（GH 剂量 mU/kg/天、GH 最大分泌量以及儿童当前身高与中亲身高之间的差异）。步骤 II 探讨了身体成分数据（体重指数或 DXA）的附加影响。步骤 III 探讨了血清营养标志物和激素的附加影响。
步骤 I 变量解释了第一年身高增长的 71%，中位数（最小值-最大值）为 0.8（0.24-1.67）；纳入步骤 II 变量后，解释比例上升至 73%，纳入步骤 III 变量后上升至 75%。相应的全身 BMC 比例分别为 58%、78%和 80%。当 BMC 按身高调整时，比例下降约 20%；分别为步骤 I、II 和 III 的 33%、57%和 57%。相应的全身 BMD 比例分别为 29%、39%和 45%。
对于全身 BMC，多达 80%的 GH 治疗第一年的变化可以用蛋白质组生物标志物、体脂、营养和骨形成标志物来解释，而对于身高调整后的 BMC 则可以解释 57%。身体成分（脂肪/瘦肉量）或营养标志物的信息增加了约 20%。身高增长的变化可以解释为 75%。因此，解释骨量获得变化所需的信息与解释身高反应变化所需的信息相同。
