Original research articleA 3-year double-blind, randomized, controlled study on the influence of two oral contraceptives containing either 20 μg or 30 μg ethinylestradiol in combination with levonorgestrel on bone mineral density
Introduction
Since the introduction of combined oral contraceptives (COCs) in the early 1960s, considerable efforts have been made to reduce the dose of the hormonal components in order to minimize the risk of adverse events. These efforts attempted to reduce the hormone content, particularly the ethinylestradiol (EE) content, according to the principle: as little as possible, but as much as necessary. In the 1990s, two new 20-μg EE preparations were introduced, one containing the progestogen gestodene [1], [2] and the other desogestrel [3]. Both were dose-reduced variations of well-established 30-μg EE preparations. The preparation tested in this study (20 μg EE, 100 μg LNG) was also derived from an oral contraceptive containing 30 μg EE combined with 150 μg LNG [4]. In this new preparation, which has already been proven safe and effective in three large Phase III studies [5], [6], [7], the dose of both EE and LNG were reduced by one third.
Although a considerable number of studies have been published so far, the question of whether or not COCs have an impact on bone mineral density (BMD) remains controversial. Possible reasons for this nonuniform picture are:
- 1.
The majority of publications report retrospective data and/or do not specify the EE dose, the type of progestogen and the duration of treatment.
- 2.
The study populations of prospective studies are different with respect to age, parity, lactational status, physical activity, smoking habit, etc.
- 3.
The BMD measurement techniques and the regions of interest were different.
- 4.
Not all prospective studies included a randomized control group.
- 5.
The majority of studies provide results during treatment with OCs containing ≥30 μg EE.
Our literature search revealed a total of five prospective studies looking for an effect of 20-μg EE combined COCs. Two noncontrolled studies [8], [9] showed a slight but statistically insignificant BMD increase after 1 and 2 years of treatment, respectively. Audran et al. [10] reported a statistically significant increase in BMD of two COCs containing 20 and 30–40 μg EE after a 1-year treatment period. Nappi et al. [11] compared 15 μg EE and 20 μg EE preparations with untreated controls over 12 months. He found neither any change over time nor any differences between the preparations. On the other hand, Polatti et al. [12] provided data of a prospective, open, but nonrandomized study on women taking a 20-μg EE COC compared with women not using hormonal contraceptives. While COC users exhibited no significant change, the nonusers experienced a significant increase (7.8%) in BMD after 5 years.
This is the first study to provide double-blind, randomized, controlled data on the influence of two oral contraceptives containing either 20 μg or 30 μg EE on BMD.
Section snippets
Materials and methods
The study was performed as a prospective, double-blind, randomized, parallel-group study at one center in Germany (Clinic Benjamin Franklin Free University, Center of Muscle and Bone Research, Berlin, Germany) from October 1997 to August 2001.
We compared the dose-reduced investigational preparation containing 20 μg EE and 100 μg LNG (20/100; Schering AG, Berlin, Germany) with the reference containing 30 μg EE and 150 μg LNG (30/150; Schering AG). The study lasted 36 cycles. The study protocol
Results
We screened a total of 104 women and randomized 100 of them. Eighty-eight subjects (44 in each group) started medication and provided data for the safety evaluation. Thirty-five subjects (20/100: n = 18; 30/150: n = 17) prematurely discontinued the study due to various reasons (due to adverse events: n = 9; withdrawal of consent: n = 3; lost to follow-up: n = 15; due to other not treatment-related reasons: n = 8). Major protocol violations like violation of inclusion/exclusion criteria were
Discussion
In this first double-blind, randomized, controlled study, we evaluated the impact of two COCs on BMD and metabolic bone parameters. We compared one dose-reduced preparation containing 20 μg EE and 100 μg LNG with a reference containing 30 μg EE and 150 μg LNG.
While much of data on preparations with ≥30 μg EE are available, results for the modern low-dose OC containing 20 μg EE are still relatively scarce. Additionally, the majority of publications with ≥30 μg EE COCs are based on retrospective
Conclusion
In conclusion, BMD did not change during the 3-year observation period. Thus, both trial preparations containing either 20 or 30 μg EE in combination with LNG were capable of maintaining BMD in young fertile women. There is no reason to assume that the EE dose reduction had any negative impact on BMD. Because there were no differences in BMDs between the treatment groups, it can be assumed that dosages even lower than 20 μg EE might be sufficient for bone protection. Biochemical markers
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