Tankó László B, Bagger Yu Z, Alexandersen Peter, Devogelaer Jean-Pierre, Reginster Jean-Yves, Chick Rosalind, Olson Melvin, Benmammar Hakim, Mindeholm Linda, Azria Moise, Christiansen Claus
Center for Clinical and Basic Research, Ballerup, Denmark.
J Bone Miner Res. 2004 Sep;19(9):1531-8. doi: 10.1359/JBMR.040715. Epub 2004 Jul 26.
Oral administration of calcitonin could improve compliance to long-term treatment. Efficacy and safety of a novel oral formulation was assessed on 277 postmenopausal women. The results show (1) effective enteral absorption, (2) marked inhibition of bone resorption with minimal alteration of formation, and (3) reproducibility of responses over 3 months.
We have recently introduced an Eligen technology-based oral formulation of salmon calcitonin (sCT) that effectively delivers the hormone to the circulation. The efficacy and safety during longer-term administration, however, has not been investigated in the target population.
This was a multicenter, randomized, double-blind, placebo-controlled, dose-ranging clinical trial including 277 healthy postmenopausal women 55-85 years of age. Women received treatment with either daily (0.15, 0.4, 1.0, or 2.5 mg) or intermittent doses (1.0 mg, every other day) of sCT combined with the delivery agent (8-[N-2-hydroxi-5-chloro-benzoyl]-amino-caprylic acid, 200 mg) or placebo for 3 months. All participants received 1,000 mg calcium plus 400 IU vitamin D daily throughout the study. Efficacy parameters were the acute and/or pre-dose changes in serum and urinary C-terminal telopeptide of type I collagen (CTx), N-mid osteocalcin (OC), bone-specific alkaline phosphatase (BSALP), calcium, and parathyroid hormone (PTH) measured by established immunoassays.
After the first dose, sCT evoked dose-dependent decreases in serum CTx (-60.8% to -81.8% from baseline) compared with placebo, reaching nadirs 2-3 h after drug intake, after which, gradual increases were observed. The simultaneous acute changes in OC were statistically nonsignificant. Area under the curve (AUC) of serum CTx responses at months 1 and 3 showed strong correlation with those at baseline (both r = 0.78, p < 0.001). At month 3, the placebo-corrected changes in the pre-dose value of serum and urinary CTx were significant only in the 1.0-mg dose group (-18.9% and -20.5%, respectively, p < 0.05). The placebo-corrected change in OC was -8.6 (p = 0.09), whereas the change in BSALP was -7.3 (p = 0.02). The oral formulation was well tolerated, with mild to moderate gastrointestinal and skin manifestations apparent mainly in the high-dose groups.
The results of this 3-month trial show that the novel Eligen technology-based oral formulation of sCT has potential to become a safe and effective treatment for postmenopausal bone loss. Future trials are needed to assess the impact of long-term administration on changes in BMD and fracture risk.
口服降钙素可提高长期治疗的依从性。对277名绝经后女性评估了一种新型口服制剂的疗效和安全性。结果显示：（1）有效的肠道吸收；（2）显著抑制骨吸收，对骨形成的影响最小；（3）3个月内反应具有可重复性。
我们最近推出了一种基于Eligen技术的鲑鱼降钙素（sCT）口服制剂，该制剂能有效地将激素输送到循环系统。然而，在目标人群中尚未对长期给药期间的疗效和安全性进行研究。
这是一项多中心、随机、双盲、安慰剂对照、剂量范围临床试验，纳入277名55 - 85岁的健康绝经后女性。女性接受每日（0.15、0.4、1.0或2.5毫克）或间歇剂量（1.0毫克，隔日一次）的sCT联合递送剂（8 - [N - 2 - 羟基 - 5 - 氯 - 苯甲酰基] - 氨基 - 辛酸，200毫克）或安慰剂治疗3个月。在整个研究过程中，所有参与者每天接受1000毫克钙加400国际单位维生素D。疗效参数是通过既定免疫测定法测量的血清和尿I型胶原C末端肽（CTx）、N - 中段骨钙素（OC）、骨特异性碱性磷酸酶（BSALP）、钙和甲状旁腺激素（PTH）的急性和/或给药前变化。
首次给药后，与安慰剂相比，sCT引起血清CTx剂量依赖性降低（从基线降低 - 60.8%至 - 81.8%），在服药后2 - 3小时达到最低点，之后观察到逐渐升高。OC的同时急性变化在统计学上无显著意义。第1个月和第3个月血清CTx反应的曲线下面积（AUC）与基线时的AUC显示出强相关性（两者r = 0.78，p < 0.001）。在第3个月，血清和尿CTx给药前值的安慰剂校正变化仅在1.0毫克剂量组有显著意义（分别为 - 18.9%和 - 20.5%，p < 0.05）。OC的安慰剂校正变化为 - 8.6（p = 0.09），而BSALP的变化为 - 7.3（p = 0.02）。口服制剂耐受性良好，轻度至中度胃肠道和皮肤表现主要在高剂量组明显。
这项为期3个月的试验结果表明，基于新型Eligen技术的sCT口服制剂有可能成为绝经后骨质流失的安全有效治疗方法。需要进一步的试验来评估长期给药对骨密度变化和骨折风险的影响。
