Grinspoon S K, Baum H B, Peterson S, Klibanski A
Neuroendocrine Unit, Massachusetts General Hospital, Boston 02114, USA.
J Clin Invest. 1995 Aug;96(2):900-6. doi: 10.1172/JCI118137.
Insulin-like growth factor-I (IGF-I) is a nutritionally dependent bone trophic hormone which stimulates osteoblast function and collagen synthesis in vivo and in vitro. We hypothesized that in the fasting state, IGF-I levels would decline significantly and would establish a model in which we could investigate the effects of IGF-I administration on bone turnover. We therefore studied 14 normal women ages 19-33 (mean, 24 +/- 4 [SD] years) during a complete 10-d fast. After 4 d of fasting, subjects were randomized to receive rhIGF-I or placebo subcutaneously twice a day for 6 d. Bone turnover was assessed using specific markers of formation (osteocalcin and type I procollagen carboxyl-terminal propeptide [PICP]) and resorption (pyridinoline, deoxypyridinoline, type I collagen crosslinked N-telopeptide [N-telopeptide] and hydroxyproline). Serum levels of PICP and osteocalcin decreased from 143 +/- 52 to 60 +/- 28 ng/ml (P = 0.001) and from 7.6 +/- 5.4 to 4.2 +/- 3.1 ng/ml (P = 0.001) respectively with 4 d of fasting. Urinary excretion of pyridinoline and deoxypyridinoline decreased from 96 +/- 63 to 47 +/- 38 nmol/mmol creatinine (P < 0.05) and from 28 +/- 17 to 14 +/- 11 nmol/mmol creatinine (P < 0.05) respectively. Mean IGF-I levels decreased from 310 +/- 81 to 186 +/- 78 ng/ml (P = 0.001). In the second part of the experimental protocol, serum osteocalcin and PICP levels increased 5- and 3-fold, respectively with rhIGF-I administration and were significantly elevated compared with the placebo group at the end of treatment (20.9 +/- 17.3 vs. 5.9 +/- 6.4 ng/ml for osteocalcin [P < 0.05] and 188 +/- 45 vs. 110 +/- 37 ng/ml for PICP [P < 0.05]). In contrast, all four markers of bone resorption, including urinary pyridinoline, deoxypyridinoline, N-telopeptide and hydroxyproline were unchanged with rhIGF-I administration. This report is the first to demonstrate that bone turnover falls rapidly with acute caloric deprivation in normal women. RhIGF-I administration uncouples bone formation in this setting by significantly increasing bone formation, but not resorption. These data suggest a novel use of rhIGF-I to selectively stimulate bone formation in states of undernutrition and low bone turnover.
胰岛素样生长因子-I（IGF-I）是一种营养依赖性骨营养激素，可在体内和体外刺激成骨细胞功能和胶原蛋白合成。我们假设在禁食状态下，IGF-I水平会显著下降，并建立一个模型，用于研究给予IGF-I对骨转换的影响。因此，我们对14名年龄在19 - 33岁（平均24±4[标准差]岁）的正常女性进行了为期10天的完全禁食研究。禁食4天后，受试者被随机分为两组，每天皮下注射两次重组人IGF-I（rhIGF-I）或安慰剂，共6天。使用骨形成（骨钙素和I型前胶原羧基末端前肽[PICP]）和骨吸收（吡啶啉、脱氧吡啶啉、I型胶原交联N-末端肽[N-末端肽]和羟脯氨酸）的特异性标志物评估骨转换。禁食4天时，血清PICP和骨钙素水平分别从143±52降至60±28 ng/ml（P = 0.001）和从7.6±5.4降至4.2±3.1 ng/ml（P = 0.001）。尿吡啶啉和脱氧吡啶啉排泄量分别从96±63降至47±38 nmol/mmol肌酐（P < 0.05）和从28±17降至14±11 nmol/mmol肌酐（P < 0.05）。平均IGF-I水平从310±81降至186±78 ng/ml（P = 0.001）。在实验方案的第二部分，给予rhIGF-I后，血清骨钙素和PICP水平分别升高了5倍和3倍，且在治疗结束时与安慰剂组相比显著升高（骨钙素为20.9±17.3 vs. 5.9±6.4 ng/ml[P < 0.05]，PICP为188±45 vs. 110±37 ng/ml[P < 0.05]）。相比之下，给予rhIGF-I后，所有四种骨吸收标志物，包括尿吡啶啉、脱氧吡啶啉、N-末端肽和羟脯氨酸均未改变。本报告首次证明，正常女性急性热量剥夺时骨转换迅速下降。在这种情况下，给予rhIGF-I通过显著增加骨形成但不增加骨吸收来使骨形成与骨吸收解偶联。这些数据表明rhIGF-I在营养不足和低骨转换状态下选择性刺激骨形成方面有新的用途。
