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连续雌二醇联合间歇性诺孕酯对绝经后女性骨密度和骨转换的影响。

The effect of continuous oestradiol with intermittent norgestimate on bone mineral density and bone turnover in post-menopausal women.

作者信息

Arrenbrecht Stefan, Caubel Patrick, Garnero Patrick, Felsenberg Dieter

机构信息

R.W. Johnson Pharmaceutical Research Institute, Raritan, NJ, USA.

出版信息

Maturitas. 2004 Jul 15;48(3):197-207. doi: 10.1016/j.maturitas.2003.08.013.

Abstract

OBJECTIVE

To assess in post-menopausal women the efficacy and tolerability of a continuous oestradiol/intermittent norgestimate HRT regimen to prevent and to reverse post-menopausal loss of bone mineral density (BMD) and to determine the effects on serum bone turnover markers markers.

METHODS

A 1-year, multicentre, international, placebo-controlled, randomised, double-blind clinical trial was conducted in 146 post-menopausal women with an intact uterus in order to assess the effect on bone loss of continuous oral 17beta-oestradiol (1 mg per day) combined with norgestimate (90 microg per day), for 3 consecutive days out of every 6-day treatment period (E2/iNGM). During a second year extension, all women agreeing to continue were on the E2/iNGM regimen. BMD was assessed prior to treatment and after 1 and 2 years or at the end of treatment in women stopping participation prematurely after at least 6 months of treatment. Serum bone turnover markers were determined prior to and at 1 year of treatment Adverse events were collected at three-monthly intervals during clinic visits over the treatment period.

RESULTS

BMD in the lumbar spine, the primary endpoint, was evaluable in 117 subjects completing >6 months of treatment. BMD increased on average by 2.4% in women on the intermittent progestin regimen. It decreased by 1.4% in placebo treated women. The change from baseline and the difference between active and placebo treatment (Delta placebo) were highly significant (P < 0.0001). On E2/iNGM, also the BMD in the total hip increased (+1.49%, Delta placebo 3.73%, P < 0.0001). The serum markers for bone formation osteocalcin and type I collagen N-propeptide were significantly reduced compared to baseline by 31 and 44%, respectively and the bone resorption marker C-terminal crosslinked telopeptide of type I collagen by 59%. Minor increases (<10%) of markers in the placebo group were not significant. During a second year extension of the trial, all subjects were on active treatment. Subjects on placebo who lost (median+/-CI 95%) 0.66% (-2.3 to +0.5) of spine BMD during the first year now gained 4.41% (2.7-7.6). They also gained 1.6% (0.1-0.3.6) in the total hip. Subjects continuously on oestradiol/intermittent norgestimate (E2/iNGM) gained an additional 5.7% (2.3-13.5) in the lumbar spine and +0.1% (-0.6 to +2.2) at the total hip. Side effects reported by women on the intermittent progestin regimen significantly in excess over reports from the placebo group were uterine bleeding, abdominal and breast pain, but not headache. Back pain and weight gain was reported by significantly fewer women on active treatment compared to placebo.

CONCLUSION

The continuous oestradiol/intermittent norgestimate HRT regimen is well tolerated, reduces bone turnover and prevents post-menopausal bone loss in healthy post-menopausal women.

摘要

目的

评估连续雌二醇/间歇诺孕酯激素替代疗法(HRT)方案在绝经后女性中预防和逆转绝经后骨矿物质密度(BMD)丢失的疗效及耐受性,并确定其对血清骨转换标志物的影响。

方法

对146名子宫完整的绝经后女性进行了一项为期1年的多中心、国际、安慰剂对照、随机、双盲临床试验,以评估连续口服17β-雌二醇(每日1毫克)联合诺孕酯(每6天治疗周期中连续3天每日90微克)(E2/iNGM)对骨质流失的影响。在第二年的延长期,所有同意继续治疗的女性均采用E2/iNGM方案。在治疗前、治疗1年和2年后或在至少接受6个月治疗后提前退出研究的女性治疗结束时评估BMD。在治疗前和治疗1年时测定血清骨转换标志物。在治疗期间的门诊就诊时,每3个月收集一次不良事件。

结果

117名完成>6个月治疗的受试者可评估腰椎BMD这一主要终点。接受间歇孕激素方案治疗的女性BMD平均增加2.4%。安慰剂治疗的女性BMD下降了1.4%。与基线的变化以及活性药物与安慰剂治疗之间的差异(Delta安慰剂)非常显著(P<0.0001)。在E2/iNGM方案治疗下,全髋BMD也增加了(+1.49%,Delta安慰剂3.73%,P<0.0001)。与基线相比,骨形成标志物骨钙素和I型胶原N-端前肽分别显著降低了31%和44%,骨吸收标志物I型胶原C-端交联端肽降低了59%。安慰剂组标志物的轻微升高(<10%)无显著意义。在试验的第二年延长期,所有受试者均接受活性药物治疗。第一年脊柱BMD下降(中位数±95%CI)0.66%(-2.3至+0.5)的安慰剂组受试者现在增加了4.41%(2.7-7.6)。全髋也增加了1.6%(0.1-0.36)。持续接受雌二醇/间歇诺孕酯(E2/iNGM)治疗的受试者腰椎又增加了5.7%(2.3-13.5),全髋增加了+0.1%(-0.6至+2.2)。接受间歇孕激素方案治疗的女性报告的副作用明显多于安慰剂组,包括子宫出血、腹痛和乳房疼痛,但不包括头痛。与安慰剂相比,接受活性药物治疗的女性报告背痛和体重增加的明显较少。

结论

连续雌二醇/间歇诺孕酯HRT方案耐受性良好,可降低骨转换,预防健康绝经后女性的绝经后骨质流失。

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