Ghiron L J, Thompson J L, Holloway L, Hintz R L, Butterfield G E, Hoffman A R, Marcus R
Aging Study Unit, VA Medical Center, Palo Alto, California, USA.
J Bone Miner Res. 1995 Dec;10(12):1844-52. doi: 10.1002/jbmr.5650101203.
We evaluated the effects of recombinant insulin-like growth factor-I (IGF-I) and growth hormone (GH) on calciotropic hormones and bone turnover markers in 16 healthy elderly women 71.9 +/- 1.3 years of age (mean +/- SEM). Subjects consumed a fixed diet providing 1000 mg of calcium and 0.9 g/kg of protein for 10 days before starting baseline 24-h urine and blood collections. Specimens were collected for 6 consecutive days before initiating subcutaneous injections of GH (25 micrograms/kg/day, n = 5) and IGF-I at 60 micrograms/kg b.i.d. (high-dose, n = 5) or at 15 micrograms/kg b.i.d. (low-dose, n = 6) for 28 days. Resorption markers included urine hydroxyproline (OHP), total pyridinolines (PYD), and N-telopeptide; formation markers include osteocalcin, skeletal alkaline phosphatase (sALP), and type I procollagen carboxy-terminal extension peptide (CICP). For each subject, baseline daily turnover markers varied substantially (DV = 16-22%). With GH and high-dose IGF-I, resorption and formation markers increased progressively to maximum levels at day 21. For GH, the increase in day 21 PYD, N-telopeptide, osteocalcin, and CICP was 143, 111, 53, and 81%, respectively (p < 0.96-0.02). For high-dose IGF-I, these increases were 108, 81, 77, and 111% (p < 0.02-0.002). However, with low-dose IGF-I no change was observed in resorption markers while osteocalcin and CICP increased progressively (day 21, % increases = 88 +/- 51, 36 +/- 14). Twenty-four hour urine collections during the last days of baseline and of study drug were taken as six 4 h aliquots. When deoxyPYD was measured on these samples in the low-dose IGF-I group, a significant increase was observed only on the 0800-1200 h aliquot. Serum phosphorus concentrations increased with GH (21.2 +/- 3.3%) and high-dose IGF-I (8.8 +/- 3.6%) by day 21 but actually decreased by day 28 (-9.7 +/- 2.7, p < 0.02) with low-dose IGF-I. Urinary phosphorus excretion decreased with high-dose IGF-I only. Twenty-four hour calcium excretion increased with all treatments. These results indicate that both GH and high-dose IGF-I activate remodeling osteons. By contrast, low-dose IGF-I may directly increase osteoblastic function with only a minimal increase in bone resorption and may therefore provide a useful means to increase bone mass. The results also suggest some of the GH action on renal phosphorus handling represents a direct action of GH on the nephron which does not involve the intermediacy of IGF-I. Finally, even under controlled conditions bone turnover markers exhibit substantial daily variation so that a very large treatment effect will be required for these markers to have clinical utility.
我们评估了重组胰岛素样生长因子-I（IGF-I）和生长激素（GH）对16名71.9±1.3岁（均值±标准误）健康老年女性钙调节激素和骨转换标志物的影响。在开始基线24小时尿液和血液采集前，受试者食用固定饮食10天，该饮食提供1000毫克钙和0.9克/千克蛋白质。在开始皮下注射GH（25微克/千克/天，n = 5）和IGF-I（高剂量组60微克/千克，每日两次，n = 5；低剂量组15微克/千克，每日两次，n = 6）共28天之前，连续6天采集样本。吸收标志物包括尿羟脯氨酸（OHP）、总吡啶啉（PYD）和N-端肽；形成标志物包括骨钙素、骨特异性碱性磷酸酶（sALP）和I型前胶原羧基末端延长肽（CICP）。对于每位受试者，基线每日转换标志物差异很大（变异系数 = 16 - 22%）。使用GH和高剂量IGF-I时，吸收和形成标志物在第21天逐渐增加至最高水平。对于GH，第21天PYD、N-端肽、骨钙素和CICP的增加分别为143%、111%、53%和81%（p < 0.96 - 0.02）。对于高剂量IGF-I，这些增加分别为108%、81%、77%和111%（p < 0.02 - 0.002）。然而，使用低剂量IGF-I时，吸收标志物未观察到变化，而骨钙素和CICP逐渐增加（第21天，增加百分比 = 88±51，36±14）。在基线期和研究药物期的最后几天，24小时尿液采集分为6个4小时的等分样本。在低剂量IGF-I组对这些样本测量脱氧PYD时，仅在0800 - 1200小时的等分样本中观察到显著增加。血清磷浓度在第21天时随着GH（21.2±3.3%）和高剂量IGF-I（8.8±3.6%）升高，但在第28天时使用低剂量IGF-I时实际下降（-9.7±2.7，p < 0.02）。尿磷排泄仅在高剂量IGF-I时减少。所有治疗均使24小时钙排泄增加。这些结果表明，GH和高剂量IGF-I均激活重塑骨单位。相比之下，低剂量IGF-I可能仅在骨吸收仅有最小增加的情况下直接增加成骨细胞功能，因此可能是增加骨量的有用方法。结果还表明，GH对肾脏磷处理的某些作用代表了GH对肾单位的直接作用，这不涉及IGF-I的介导。最后，即使在受控条件下，骨转换标志物也表现出很大的每日变化，因此这些标志物要具有临床实用性将需要非常大的治疗效果。
