周期联合应用不同剂量经皮雌二醇与口服孕激素7年预防绝经早期妇女骨丢失的效果比较

Effects of 7-year cyclic percutaneous estradiol combined with oral progestogen on bone loss in early postmenopausal women

目的比较经皮雌二醇0.75mg及1.5mg两种剂量长期周期联合不同孕激素,预防绝经早期妇女骨丢失的效果。方法 7年的前瞻性随机开放平行组设计试验研究。雌激素为经皮17-β雌二醇(E_2)凝胶,口服孕激素为微粉化天然黄体酮(MP)与甲羟孕酮(MPA)。60名绝经早期(1～5年)妇女随机分为4组:Gl:E2 1.5mg/d+MP100mg/d;G2:E2 1.5mg/d+MPA 2mg/d;G3:E2 0.75mg/d+MP 100mg/d;G4:E_20.75mg/d+MPA 2mg/d。每周期连用25天,停药5天进入下一周期。主要观察指标包括QCT法腰椎L_(1-4)骨密度(每2年),DXA法L_(2-4)、股骨颈Neck骨密度(每0.5～1年),单光子吸收法右前臂桡骨远端1/3处骨矿盐含量(RBMC)及骨密度(RBMD)(每年),以及日记记录阴道出血、骨折情况及不良反应等。其中L_(1-4)、RBMC及RBMD随访了4年,其余指标均随访7年。组间基线比较应用方差分析,变化率是通过完成例数自身前后数值比较计算得到。治疗后各观察指标不同时点的重复测量数据,运用重复测量分析法,所有重复测量的趋势及组间差异分析均通过调整基线水平去除其影响。结果 (1)用药后,研究对象各部位骨密度均有增加。各部位骨密度较基线水平的变化率依次为L_(1-4)>L_(2-4)>Neck>RBMD。(2)L_(1-4)在用药2年时达到峰值,比基线增加4.2%～8.3%(P=0.04);L_(2-4)逐渐增加,至第7年增加5.9%～11.7%(P<0.0001);Neck逐渐增加,第7年时增加4.3%～4.6%(P=0.004);RMBC逐渐增加,至第4年增加14.3%～22.1%(P<0.0001);RBMD在第2～3年达到峰值,增加0.6%～3.2%(P=0.059)。各指标随时间变化趋势均组间无显著差异。(3)按雌激素剂量进行并组后,1.5mg E2组RBMC显著高于0.75mg组(P=0.03),在L_(1-4)、NECK、RBMD等指标上改善较0.75mg组略大,但两组间差异无统计意义(P为0.15～0.90)。(4)按孕激素进行并组后,联合MP组在L_(2-4)、NECK、RBMC、RBMD等方面的改善较MPA组略大,但组间差异均无统计学意义(P为0.27～0.98)。(5)用药期间各组不规则出血周期的发生率分别为,G1:8.5%,G2:32.27%,G3:7.46%,G4:14.86%,组间差异有统计学意义(P<0.002)。(6)用药期间骨折发生降低。(7)用药期间无严重不良反应发生。结论 0.75mg及1.5mg两种经皮雌二醇剂量长期周期联合不同孕激素均可预防绝经早期妇女骨丢失,且其对松质骨骨密度的改善优于皮质骨。1.5mg E_2对RBMC的改善作用优于0.75mg。联合MP(100mg/d)和联合MPA(2mg/d)对骨密度的影响无显著差异。在不良反应方面,1.5mgE_2阴道不规则出血率高于0.75mg组,MP(100mg/d)在避免阴道不规则出血方面优于MPA(2mg/d)。临床应用应个体化。

Objective To compare the long-term effects of treatment with cyclic percutaneous estradiol （1.5mg/d or 0. 75mg/d） combined with two kinds of oral progestogen on bone loss in early postmenopausal women. Methods A 7-year open, randomized, parallel-group clinical trial was designed. The percutaneous 17J3-estradiol （E2 ） gel was used in a cyclic regimen combined with micronized progesterone （MP） or medroxyprogesterone acetate （MPA） for 7 years. 60 early postmenopansal women were randomly assigned into 4 groups ： G1 ： E2 1.5 ＋ MP100 ; G2 ： E2 1.5 ＋ MPA 2 ; G3 ： E2 0. 75 ＋ MP 100 ; G4 ： E20. 75 ＋ MPA 2 （ all doses in rag/d）. All were given for 25 d/month, and 5 days free. Main measurements included bone mineral density （BMD） of L1.4 by quantitative computed tomography （every 2 years for 4 years）, BMD of L2.4 and neck of femur （Neck） by dual energy X-ray absorptiometry （ every 0. 5 - 1 year for 7 years）, radius bone mineral content （RBMC） and BMD of right radius （RBMD） by single photon absorptiometry （ev- ery year for 4 years）. The vaginal bleeding, fracture, adverse effects were also recorded. Results （ 1 ） The BMD of all sites increased after treatment. The order of the percentage change of BMD in various parts from high to low in turns was L1.4, L24, Neck, RBMD. （2） L1.4 increased to its peak （ ＋ 4.2%- ＋ 8. 3% ） at the 2nd year （P = 0.04） ; L2-4 increased gradually （ ＋5.9% ~ ＋ 11.7% at the 7th year） （P 〈0. 0001 ） ; Neck increased gradually （ ＋4. 3% ~ ＋4.6% at the 7th year ） （ P = 0. 004） ; RMBC increased gradually in 4 years （ ＋ 14. 3 % ~ ＋ 22. 1% ） （ P 〈 0. 0001 ） ; RBMD increased to its peak at the first 2 -3 years （ ＋0. 6% - ＋3.2% ） （P =0. 059）. There was no significant between-group difference in the change of each indicator. （3） Compared with the groups with E2 0. 75mg/d, the groups with E2 1.5mg/d had more percentage change in RBMC （P =0. 03） and L~.4, Neck and RBMD （P =0. 15 ~0. 90）. （4） Compared with the groups with MPA, the groups with MP had more percentage change in L1.4, Neck, RBMC and RBMD （P =0. 27 -0. 98）. （5） The occurrence of unscheduled vaginal bleeding in G1, G2, G3, G4 were 8.5%, 32. 27%, 7, 46% and 14. 86%, respectively （P 〈0. 002）. （6） There were few fractures during the study. （7） There was no se- rious adverse effect during the treatment. Conclusion Both 0.75mg and 1.5mg percutaneous estradiol combined with different progestogen can prevent bone loss in early postmenopausal women. HT had more effect on trabecular BMD than cortical BMD. The effect of 1.5mg E2 on the change of RBMC was better than 0. 75mg E2. There was no difference in the effect on BMD between E2 combined with MP and with MPA. The vaginal bleeding rate was low in the group with 0. 75mg E2, and when E2 combined with 100 mg MP. We should consider individualized HT in clinical practice.