Effects of specific post-menopausal hormone therapies on bone mineral density in post-menopausal women: a meta-analysis

Martina Dören1,4, Jan-Åke Nilsson2 and Olof Johnell3

1 Free University of Berlin, Clinical Research Center of Women’s Health, Klingsorst 109a, D-12203 Berlin, Germany, 2 Department of Medicine, University of Lund and 3 Department of Orthopaedics, Malmö University Hospital, University of Lund, S-20502 Malmö, Sweden

4 To whom correspondence should be addressed. e-mail: martina.doeren{at}medizin.fu-berlin.de


    Abstract
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
BACKGROUND: Long-term post-menopausal hormone therapy (pHT) was often regarded as first-line therapy to prevent fractures in post-menopausal women, a recommendation under scrutiny given the benefit–risk profile of the Women’s Health Initiative results of the estrogen–progestin combination. Apart from controlled clinical studies providing data with fractures as an end point, measures of lumbar and hip bone mineral density (BMD) may be used to assess bone-related effects of pHT. The objective of this study was to conduct a systematic review of 2-year trials, published between 1990 and December 2002, and assessing changes in BMD by any estrogen including ethinyl estradiol, any estrogen plus any progestin, or tibolone. METHODS: We searched MEDLINE, EMBASE and systematic reviews. Thirty-nine randomized, prospective, controlled 2-year trials were analysed in pre-specified groups according to the profile of the compounds. RESULTS: Virtually all pHT regimens at least maintain BMD at the lumbar spine and the hip compared with baseline; there is no apparent difference between the various estrogenic compounds. Tibolone, a synthetic progestin, appears to be as effective as any estrogen. Most trials were conducted in early post-menopausal women, fewer in women with hysterectomy and/or bilateral oophorectomy. CONCLUSIONS: The size of impact on BMD does not appear to differ between tibolone and any estrogen compound studied.

Key words: bone mineral density/estrogen replacement therapy/post-menopausal hormone therapy/prevention of post-menopausal osteoporosis/tibolone


    Introduction
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Until recently, prevention of fractures was one generally accepted major indication for long-term post-menopausal hormone therapy (pHT) (World Health Organization, 1994Go; American Association of Clinical Endocrinologists, 1998Go; Genant et al., 1999Go; National Institute of Health, 2001Go). [pHT is used instead of the term hormonal replacement therapy (HRT) acknowledging the fact that not all compounds used constitute a replacement as they partly differ from endogenous estradiol and progesterone.] The Women’s Health Initiative (WHI) Randomized Controlled Trial showed a nominal significant reduction for vertebral, hip and combined fractures in women using a specific estrogen and progestin combination (Writing Group for the Women’s Health Initiative Investigators, 2002Go). The absolute numbers of fractures was relatively low in the sample of 16 608 women, one-third of whom were younger than 60 years of age. However, this is the largest controlled clinical pHT trial with the secondary end points of hip and other fractures respectively.

Apart from the WHI study, in the absence of other adequately powered, randomized, prospective, controlled, clinical trials with estrogens, measures of bone mineral density (BMD) have been widely used to make inferences about the bone-related benefits of pHT. However, the optimal time to start treatment and its duration are still not well defined today, in spite of the benefit–risk profile of the WHI study (Writing Group for the Women’s Health Initiative Investigators, 2002Go). One treatment concept suggested that short-term pHT treatment in the early menopause may decrease the future risk of fracture (Johnell et al., 2001Go), an assumption supported by one controlled clinical trial (Greendale et al., 2002Go) and the WHI study.

Two recent meta-analyses assessing the impact of estrogens for fracture prevention prior to the WHI study utilized the surrogate end point BMD. Results were conflicting; one study indicated that the use of pHT is associated with a reduction of non-vertebral fractures, in particular in women with uptake of pHT before the age of 60 (Torgerson and Bell-Syer, 2001Go). However, one of the results of this analysis, suggesting an attenuation of efficacy of pHT in women below the age of 60, has been questioned due to methodological issues (Altmann, 2001Go). The latest meta-analysis (Wells et al., 2002Go) with a considerably different selection of included studies compared with the analysis of Torgerson and Bell-Syer (2001Go) concluded that the trend towards a reduced incidence in (non-)vertebral fractures in pHT users was non-significant.

Compounds classified as pHT may include estrogens and synthetic steroids such as tibolone. The latter is a derivative of the progestin norethyndrone, which also exhibits androgenic and estrogenic effects (Tax et al., 1987Go). It is the only pHT compound used without a concomitant estrogen. Thus, we analysed the effects of various pre-classified pHT regimens, accounting for type of compounds, dose and route of administration, on BMD in women with permanent estrogen deficiency.


    Methods
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 Introduction
 Methods
 Results
 Discussion
 References
 
The prime sources for this report were MEDLINE and EMBASE databases searched for trials published between 1990 and December 2002. We used both free text searching and MeSH headings to retrieve randomized controlled clinical trials involving post-menopausal or ovariectomized women with use of any estrogen or progestin for prevention of osteoporosis. Search terms included ‘bone and bones’, ‘bone mineral density’, ‘bone mass’ ‘bone mineral content’, ‘densitometry’, ‘fracture’, ‘hormone replacement therapy’, ‘estrogen replacement therapy’ (including specific generic terms of approved medications), ‘tibolone’, ‘menopause’, ‘post-menopause’ and ‘osteoporosis’. Further searches in combination with these terms were conducted to retrieve studies using estradiol compounds, non-human estrogens, estriol and any progestin including natural progesterone. The list of references of each original paper and of known reviews of osteoporosis in women were reviewed potentially to identify articles missed by the computerized search.

The eligibility criteria for inclusion in this review were: (i) randomized, prospective, clinical trials of post-menopausal and/or ovariectomized women involving at least 60 women for the purpose of prevention of post-menopausal osteoporosis; (ii) use of any estrogen or any estrogen plus any progestin or use of a progestin only, irrespective of concomitant use of calcium supplements or dietary counselling regarding calcium or vitamin D intake; (iii) a control group randomized to either a placebo and/or calcium or no treatment; (iv) reported changes in BMD of the lumbar spine and/or the hip; (v) a study duration of >=2 years; and (vi) any trial published in English. We excluded abstracts as we doubted whether the information that had to be extracted would be fully available in all abstracts. The lower limit of 60 study patients was chosen allowing for detection of a 2% difference in BMD with a power of 80%.

We included all studies irrespective of prior fracture history of study participants; sometimes fracture status was not reported. We retrieved 122 studies, 39 of which fulfilled our criteria (Table I). Thus, a majority had to be excluded, primarily because of the short lengths of the trials or the small sample size. Self-selection of control groups or inclusion of active treatments only were other reasons for exclusions, as were apparent double publications and the inability to extract data for the size of baseline study groups. Studies included women across the broad age range of 40–76 years; the majority included women between 50 and 60 years. Two authors (M.D. and O.J.) selected and extracted the studies, and bias was minimized by double-checking both literature searches and data extraction.


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Table I. Description of eligible trials (n = 39)
 
We had to acknowledge substantial variation in methods used for the assessment of bone mineral. The majority of studies used DEXA (dual-energy X-ray absorptiometry). Studies with dual-photon absorptiometry (DPA) and one with single-energy quantitative computed tomography (QCT) were included. We did not include studies using roentgenograms, metacarpal measurements or ultrasound as these methods (roentgenograms etc.) would probably increase the heterogeneity of the results and further diminish the aim to assess a uniform outcome. The terms ‘post-menopause’ and ‘menopause’ were accepted as stated or apparent in the individual studies. However, the definition of the (post-)menopause varied. Several studies recruited women with both natural and surgical menopause. Additionally, several trials included hysterectomized women with unknown age of menopause, defined as definite termination of menstruation due to permanent loss of ovarian function. Not all studies explicitly stated whether hysterectomized and/or women with bilateral ovariectomy were included; none provided information as to whether women with unilateral ovariectomy were included. Thus, heterogenous study populations across a wide age range were included.

Hormonal therapies were subdivided a priori into groups, acknowledging differences in composition, pharmacodynamics, pharmacokinetics and route of administration. Thus, we differentiated between conjugated equine estrogens (CEEs; Table II); estradiol, estradiol valerate, esterified estrogens (which largely contains estrone sulphate), estrone sulphate and estriol (Table III); transdermal estradiol (almost exclusively matrix and reservoir patches; Table IV); tibolone (Table V); and ethinyl estradiol (Table VI). All groups contained approved, different doses of the various compounds.


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Table II. BMD trials—conjugated equine estrogens
 

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Table III. BMD trials—oral estradiol, estradiol valerate, esterified estrogens, estrone sulphate, estriol
 

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Table IV. 2-year-BMD trials—transdermal estradiol
 

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Table V. 2-year-BMD trial—tibolone
 

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Table VI. 2-year-BMD trial—ethinyl estradiol (Speroff et al., 1996)
 
Overall, 48 different HRT regimes (44 regimens excluding tibolone) were included, taking into account dose and route of administration of estrogens and progestins, without considering further additions to pHT trial regimens (i.e. addition of calcium supplementations). Oral pHT regimens were predominant. One study each investigated ethinyl estradiol and estriol, respectively (Speroff et al., 1996Go; Itoi et al., 1997Go). Progestins, administered together with estrogens except for tibolone, included medroxyprogesterone acetate, levonorgestrel, cyproterone acetate, norethisterone (norethindrone) acetate and norgestrel. Cyclic use of a progestin denotes any daily use for 10–14 days per treatment month or cycle (28 days), and long-cycle therapy indicates any use of a progestin for an interval every 3 months (only one study). The majority of studies were primary prevention trials. Women were recruited within hospital-based out-patient centres or via centres using population-based recruitment. Most studies were conducted in Caucasian populations.

Statistical analysis
Our prime objective was to compare the changes of BMD in the treatment and control groups. It was not possible to determine a uniform outcome, as the methodology of bone mineral assessment varied. The effect size was defined as the mean change of a given BMD assessment at the end of the study compared with baseline of each study, adjusted for the changes in the control groups. We based the analyses on published figures and, in a few cases, on best estimates (M.Dören and O.Johnell) derived from published graphs. Only in some more recent trials was it explicitly stated whether the statistics were based on an intention-to-treat analysis or on the study sample of adherent women. We selected the statistics based on the intention-to-treat-analysis where this information was provided. The effect size, i.e. changes of lumbar and femoral BMD, for the different studies was combined using meta-analysis (random-effects model; Snedecor and Cochrane, 1989Go). The analyses were conducted in three separate models: studies unweighted for the number of study participants; weighted for sample sizes; and weighted for the ratio of sample size/drop-outs respectively. Mean, minimum and maximum of BMD changes, and confidence intervals were calculated for five HRT groups (Table VII). The confidence intervals for the combined effect sizes within each of the five groups were calculated based on the t-distribution. Overall, 77 comparisons between treatment groups were performed from data of the 39 studies. We used analysis of variance (ANOVA) for the comparison of effect sizes among the HRT groups. The relationship between BMD changes and the mean age of the study participants was estimated using Spearman rank order correlations.


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Table VII. 2-year BMD changes—lumbar spinea
 

    Results
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Most clinical trials for prevention of post-menopausal osteoporosis were conducted in early post-menopausal women with preservation of both ovaries, fewer in women with hysterectomy and/or bilateral oophorectomy (Table I). Our analyses suggest two major findings. First, there is no apparent difference between the various oral and non-oral estrogen compounds given the pre-specified classifications. Virtually all HRT regimens are associated with at least maintenance or gain of BMD at the lumbar spine and the hip within the study period of 2 years (Tables IIVI). The relative change of lumbar BMD did not vary across all groups. Thus, there appears to be no difference whether CEEs, oral or non-oral estradiol preparations, ethinyl estradiol or tibolone are used (Table VII; there were too few data to extract the analogous information for femoral neck or total hip BMD). The mean effect size did not change if the largest single trial with a compound not generally recommended for prevention of post-menopausal bone loss (ethinyl estradiol) was excluded (Speroff et al., 1996Go). There was little difference in terms of changes of BMD between the different models adjusted and non-adjusted for sample size and drop-outs. Due to small sample sizes per defined estrogen compound, dose and route of administration, it was not possible to analyse further the relationship between various doses of a given compound and the impact on lumbar and femoral BMD. Additionally, due to the variety of progestins (tibolone excluded), statistical power was also insufficient to assess their potential different effects on BMD when given together with a specific estrogen. Our results suggest a trend towards an inverse correlation between age and BMD changes after 2 years; however, this was not significant (P = 0.0962). Secondly, tibolone appears to be as effective as regimens containing any estrogen (ANOVA P = 0.944, not significant). Thus, there is no difference between any estrogen group and the tibolone group regarding BMD changes after 2 years.


    Discussion
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 Introduction
 Methods
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The finding that all estrogens, irrespective of the mode of administration, are effective in maintaining BMD agrees with major results of previous meta-analyses and structured reviews (Hailey et al., 1998Go; Henry et al., 1998Go; Macedo et al., 1998Go; O’Connell et al., 1998Go; Marcus et al., 2002Go; Wells et al., 2002Go). Effects appear to be greater at the lumbar spine compared with the hip. Essentially, methodological problems of pHT trials for primary fracture prevention are also reflected by the results of our analyses: compared with placebo or no treatment, various estrogen formulations with and without a progestin co-administered in a sequential and continuous combined fashion are effective in preserving BMD, but there is little information on their comparative effectiveness (Henry et al., 1998Go; Macedo et al., 1998Go), information which could be provided by more trials with direct comparison of regimens.

Our results suggest for the first time that tibolone is as suitable as any estrogen to prevent bone loss. Previous assessments including one meta-analysis did not differentiate between the various estrogens and tibolone, and allocated tibolone to the estrogen group (O’Connell et al., 1998Go), or did not consider this steroid for the analysis (Torgerson and Bell-Syer, 2001Go), or excluded tibolone studies, although ‘progestational hormones’ was a pre-defined search term (Wells et al., 2002Go). Clinical and preclinical data show that tibolone inhibits bone loss similarly to estrogens (Moore, 1999Go; Modelska and Cummings, 2002Go). It has been suggested that the lack of regular withdrawal bleedings (Dören et al., 1999Go) may be important for long-term adherence, an important clinical issue beyond the scope of our analysis.

However, our results have several limitations. We could not analyse the impact of different estrogen doses sufficiently given the combination of a wide range of compounds, routes of administration and the large variety of progestins (44 pHT regimens excluding tibolone). Additionally, we cannot provide further insight as to whether the trend that advanced age may be associated with attenuated effects of pHT, a result consistent with the analysis of Torgerson and Bell-Syer (2001Go), could be due to the paucity of data available for older women, potentially lower adherence to pHT in this age group, or other factors we did not study. As we did not re-analyse individual data of each study, we do not know how the obvious heterogeneity of studies may have interfered with our major results. Our report is limited further by the fact that we did not address the issue of publication bias by additional statistical methods such as funnel plots. The latter method was applied in the two meta-analyses; publication bias was suggested by Torgerson and Bell-Syer (2001Go), but not by Wells et al. (2002Go).

The finding that BMD can be maintained with the use of estrogens within the first 5–10 years after menopause was the rationale to advocate the administration of estrogens until old age. This concept is being challenged by the profile of results of the WHI study (Fletcher and Colditz, 2002Go; Hays et al., 2003Go; Solomon and Dluhy, 2003Go). There is limited evidence that long-term pHT may be not necessary for bone protection given the results of a 4-year-follow-up investigation of the 3-year Post-menopausal Estrogen/Progestin Interventions (PEPI) trial. These results suggest that bone loss after discontinuation of pHT is not accelerated and that BMD after ~3 years of treatment does not change (Greendale et al, 2002Go). Whether certain regimes such as long-term, low dose continuous combined therapy are a promising alternative for elderly women (Delmas, 1999Go) presently is unknown. In the light of the WHI study, this concept may be questioned.

The WHI initiated an in-depth discussion of the risks and benefits of pHT, including combinations of other estrogens and other progestins (Fletcher and Colditz, 2002Go; Nelson et al., 2002Go; Neves-e-Castro et al., 2002Go). The aspect of our meta-analysis suggesting equal effectiveness of tibolone when compared with estrogens in terms of BMD changes may also add to this discussion. At present, data from rigorous trials regarding the relative risks of this compound for breast and other cancers, and cardiovascular disease end points, are not available for tibolone in order to allow for any comprehensive risk–benefit assessment.

In conclusion, all oral and non-oral, human and non-human estrogens appear to exert similar effects on BMD. The size of impact on BMD does not appear to differ between tibolone and any estrogen.


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Submitted on December 13, 2002; accepted on April 25, 2003.