二甲双胍、罗格列酮和胰岛素对 2 型糖尿病患者骨代谢的影响。

Effects of metformin, rosiglitazone and insulin on bone metabolism in patients with type 2 diabetes.

机构信息

Clinical Pharmacology and Pharmacy, Department of Public Health, University of Southern Denmark, Odense, Denmark; Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, USA.

Department of Clinical Biochemistry and Pharmacology, Odense University Hospital, Odense, Denmark.

出版信息

Bone. 2018 Jul;112:35-41. doi: 10.1016/j.bone.2018.04.004. Epub 2018 Apr 12.

DOI:10.1016/j.bone.2018.04.004

PMID:29654849

Abstract

BACKGROUND

Fracture risk is increased in individuals with type 2 diabetes (T2D). The pathophysiological mechanisms accentuating fracture risk in T2D are convoluted, incorporating factors such as hyperglycaemia, insulinopenia, and antidiabetic drugs. The objectives of this study were to assess whether different insulin regimens, metformin and rosiglitazone influence bone metabolism. We explored if the concentration of metformin and rosiglitazone in blood or improved glycaemic control altered bone turnover.

METHODS

Two-year clinical trial designed to investigate effects of antidiabetic treatment in 371 T2D patients. Participants were randomized to short or long-acting human insulin (non-blinded) and then further randomized to metformin + placebo, rosiglitazone + placebo, metformin + rosiglitazone or placebo + placebo (blinded). Fasting bone turnover markers (BTM) representing bone resorption (CTX) and formation (PINP) including HbA1c were measured at baseline and after 3, 12 and 24 months. Trough steady-state plasma concentrations of metformin and rosiglitazone were measured after 3, 6 and 9 months of treatment. Associations between treatments and BTMs during the follow-up of the trial were analysed in mixed-effects models that included adjustments for age, gender, BMI, renal function and repeated measures of HbA1c.

RESULTS

BTMs increased from baseline to month 12 and remained higher at month 24, with CTX and PINP increasing 28.5% and 23.0% (all: p < 0.001), respectively. Allocation of insulin regimens was not associated with different levels of BTMs. Metformin and metformin + rosiglitazone but not rosiglitazone alone were associated with lower bone formation (PINP). Neither metformin nor rosiglitazone plasma concentrations was associated with BTMs. HbA1c was inversely associated with CTX but not P1NP.

CONCLUSIONS

The choice of insulin treatment is not influencing BTMs, metformin treatment may decrease BTMs, and improvement of glycaemic control may influence bone resorption activity.

摘要

背景

2 型糖尿病（T2D）患者的骨折风险增加。加重 T2D 骨折风险的病理生理机制很复杂，包括高血糖、胰岛素缺乏和抗糖尿病药物等因素。本研究的目的是评估不同的胰岛素方案、二甲双胍和罗格列酮是否会影响骨代谢。我们探讨了二甲双胍和罗格列酮的血药浓度或改善血糖控制是否改变了骨转换。

方法

这是一项为期两年的临床试验，旨在研究抗糖尿病治疗对 371 例 T2D 患者的影响。参与者被随机分配接受短效或长效人胰岛素（非盲法），然后进一步随机分配接受二甲双胍+安慰剂、罗格列酮+安慰剂、二甲双胍+罗格列酮或安慰剂+安慰剂（盲法）。在基线和 3、12 和 24 个月时测量空腹骨转换标志物（BTM），代表骨吸收（CTX）和形成（PINP），包括 HbA1c。在治疗 3、6 和 9 个月时测量二甲双胍和罗格列酮的稳态血浆浓度。在试验随访期间，使用混合效应模型分析治疗与 BTM 之间的关系，模型中包括年龄、性别、BMI、肾功能和 HbA1c 的重复测量的调整。

结果

BTM 从基线到 12 个月增加，并在 24 个月时仍保持较高水平，CTX 和 PINP 分别增加 28.5%和 23.0%（均<0.001）。胰岛素方案的分配与 BTM 水平无差异。二甲双胍和二甲双胍+罗格列酮，但不是罗格列酮单独治疗，与较低的骨形成（PINP）相关。二甲双胍和罗格列酮的血浆浓度均与 BTM 无关。HbA1c 与 CTX 呈负相关，但与 P1NP 无关。