1 Free University of Berlin, Clinical Research Center of Womens 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
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Abstract |
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Key words: bone mineral density/estrogen replacement therapy/post-menopausal hormone therapy/prevention of post-menopausal osteoporosis/tibolone
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Introduction |
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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 benefitrisk profile of the WHI study (Writing Group for the Womens Health Initiative Investigators, 2002). One treatment concept suggested that short-term pHT treatment in the early menopause may decrease the future risk of fracture (Johnell et al., 2001
), an assumption supported by one controlled clinical trial (Greendale et al., 2002
) 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, 2001). 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, 2001
). The latest meta-analysis (Wells et al., 2002
) with a considerably different selection of included studies compared with the analysis of Torgerson and Bell-Syer (2001
) 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., 1987). 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.
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Methods |
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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 4076 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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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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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, 1989). 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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Results |
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Discussion |
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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 (OConnell et al., 1998), or did not consider this steroid for the analysis (Torgerson and Bell-Syer, 2001
), or excluded tibolone studies, although progestational hormones was a pre-defined search term (Wells et al., 2002
). Clinical and preclinical data show that tibolone inhibits bone loss similarly to estrogens (Moore, 1999
; Modelska and Cummings, 2002
). It has been suggested that the lack of regular withdrawal bleedings (Dören et al., 1999
) 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 (2001), 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 (2001
), but not by Wells et al. (2002
).
The finding that BMD can be maintained with the use of estrogens within the first 510 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, 2002; Hays et al., 2003
; Solomon and Dluhy, 2003
). 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, 2002
). Whether certain regimes such as long-term, low dose continuous combined therapy are a promising alternative for elderly women (Delmas, 1999
) 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, 2002; Nelson et al., 2002
; Neves-e-Castro et al., 2002
). 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 riskbenefit 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.