A 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

doi:10.1016/j.contraception.2003.10.002

Contraception

Volume 69, Issue 3, March 2004, Pages 179-187

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Abstract

In this first prospective, double-blind, randomized, parallel-group study we evaluated the influence of two combined oral contraceptives on bone mineral density (BMD) and metabolic bone parameters. One dose-reduced preparation contained 20 μg ethinylestradiol (EE) in combination with 100 μg levonorgestrel (LNG) (20/100) was compared with the reference preparation which contained 30 μg EE in combination with 150 μg LNG (30/150). Data from 48 volunteers aged 20–35 years were obtained over an observation period of 36 treatment cycles. The direction of the change (increase or decrease) in all investigated bone-related variables was similar in both treatment groups. As compared to baseline, bone mineral density decreased by 0.4% in the 20/100 group and by 0.8% in the 30/150 group after 36 treatment cycles. These changes were not significantly different between the two treatment groups (p = 0.902). For bone-specific alkaline phosphatase, we measured a mean increase of 55.4% (20/100 group) and of 113.2% (30/150 group) after 36 treatment cycles. The two treatments did not differ statistically significantly (p = 0.522). With respect to cross-linked N-telopeptides (NTx), we detected a decrease of the mean NTx urine concentrations of 21.1% (20/100) and of 13.4% (30/150). These changes also did not significantly differ between the two treatments (p = 0.613). Both study treatments were safe and well-tolerated by all volunteers participating in the study. 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 BMD between the treatment groups, it can be assumed that even lower dosages than 20 μg EE might be sufficient for bone protection. Biochemical markers provided evidence for a reduced bone resorption.

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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Bone metabolic marker concentrations across the menstrual cycle and phases of combined oral contraceptive use
2021, Bone
Citation Excerpt :
PINP has only been studied across a COC cycle on one other occasion, where there was a 21% reduction in PINP concentrations between the PFI and day 18–21 pill consumption [18]. Data from the previous study, however, may not be applicable to the general population as the participants had chronic posterior pain and had only used COCs for two months, both of which may have affected responses [19,35]. This is the first study to assess P1NP across an COC cycle in a healthy population and has shown that there was no significant difference in bone formation concentrations between phases.
There is a need to further understand the impact of the menstrual cycle and phase of combined oral contraceptive (COC) use on the pre-analytical variability of markers of bone metabolism in order to improve standardisation procedures for clinical practice and research. The aim of this study was to assess bone metabolism marker concentrations across the menstrual cycle and phases of COC use. Carboxy-terminal cross-linking telopeptide of type I collagen (β-CTX), procollagen type 1 N propeptide (P1NP) and Bone alkaline phosphatase (Bone ALP) concentrations were assessed in eumenorrheic women (n = 14) during the early follicular, ovulatory and mid-luteal phases of the menstrual cycle and in COC (Microgynon®) (n = 14) users on day 2–3 of pill consumption (PC1), day 15–16 pill consumption (PC2) and day 3–4 of the pill free interval (PFI). β-CTX was significantly (−16%) lower at PC2 compared to PC1 (P = 0.015) in COC users and was not affected by menstrual cycle phase (P > 0.05). P1NP and Bone ALP were not significantly different across either menstrual cycle phase or phase of COC use (all P > 0.05). There was no difference in pooled bone marker concentrations between eumenorrheic women and COC users (P > 0.05). In contrast to some previous studies, this study showed that bone marker concentrations do not significantly fluctuate across the menstrual cycle. Furthermore, bone resorption markers are significantly affected by phase of COC use, although bone formation markers do not significantly vary by COC phase. Therefore, the phase of COC use should be considered in clinical practice and research when assessing markers of bone metabolism as this can impact circulating concentrations of bone metabolic markers yet is not currently considered in existing guidelines for best practice.
Comparison of long-term use of combined oral contraceptive after gonadotropin-releasing hormone agonist plus add-back therapy versus dienogest to prevent recurrence of ovarian endometrioma after surgery
2019, European Journal of Obstetrics and Gynecology and Reproductive Biology
Citation Excerpt :
However, when followed by long-term COC, BMD did not deteriorate at 12 and 24 months, and actually improved from 6 months. This finding is consistent with randomized studies reporting that COCs do not exert any clinically significant effect on BMD in the general population [22–25]. Meanwhile, lumbar spine BMD significantly decreased during the first 6 months of DNG treatment (-2.3%), consistent with previous Asian studies reporting BMD decrease from -1.7% to -2.8% within a year of DNG use [15,26].
The aim of this study was to compare long-term use of combined oral contraceptive (COC) after gonadotropin-releasing hormone (GnRH) agonist plus add-back therapy with dienogest (DNG) treatment as medical treatments after surgery for ovarian endometrioma.
This prospective cohort study analyzed 52 reproductive-aged women who underwent surgery for ovarian endometrioma and received postoperative medical treatment with either COC after GnRH agonist (n = 20) or DNG (n = 32) for 24 months. Changes in quality-of-life (QOL) and bone mineral density (BMD) were compared according to treatment. In addition, recurrence of pain and lesions were compared.
Baseline characteristics did not differ in demographic profiles and factors associated with endometriosis or QOL. During 24 months of treatment, no differences in any component of QOL were found between the two groups. BMD at the lumbar spine significantly decreased after the first 6 months of treatment in both COC after GnRH agonist (−3.5%) and DNG (−2.3%) groups, but the groups did not differ statistically. After 6 months, further decrease in BMD was not observed until 24 months in both groups. In addition, no cases of pain or endometrioma recurrence were found.
Our results suggest that long-term use of COC after GnRH agonist plus add-back therapy is comparable to dienogest as a long-term postoperative medical treatment for endometriosis.
The Efficacy of Postoperative Cyclic Oral Contraceptives after Gonadotropin-Releasing Hormone Agonist Therapy to Prevent Endometrioma Recurrence in Adolescents
2017, Journal of Pediatric and Adolescent Gynecology
Citation Excerpt :
Therefore, there has been some concern regarding the long-term use of OCs on BMD during the adolescent period. However, despite the controversial effect of long-term OC use on BMD during the adolescent period, several randomized and large cohort studies have shown no significant difference in BMD between OC users and control participants.31–38 Our findings also suggest that there is no detrimental effect on BMD related to long-term OC use in adolescents with endometriosis.
Young age is a possible risk factor of endometriosis recurrence after surgery. However, the efficacy of postoperative medical treatment has not been well addressed in adolescents. The purpose of this study was to evaluate whether postoperative medical treatment is as effective in adolescents as it is in adults in the prevention of endometrioma recurrence.
A retrospective cohort study.
Samsung Medical Center, Seoul, Korea.
This study included 176 reproductive-aged women who underwent conservative laparoscopic surgery for pathology-confirmed endometrioma. Women were classified into 2 groups according to age: adolescents (20 years of age and younger, n = 34; group I) and reproductive-aged women (aged 25-35 years, n = 142; group II).
The same surgeon performed all of the surgeries for uniformity. Postoperatively, patients were treated monthly with a gonadotropin-releasing hormone agonist depot for 3-6 months, followed by cyclic oral contraceptives.
Endometrioma recurrence was determined using ultrasonography. The recurrence rate of endometrioma was compared between the 2 groups.
During the treatment period (median, 41.0 months; range, 6-159 months), recurrence was noted in 8 cases (4.5%). After adjusting for confounders (which were statistically different between the groups), the cumulative proportion of recurrent endometriomas after 60 months was comparable between the 2 groups (5.3% in group I and 8.5% in group II).
Long-term postoperative medical treatment with cyclic oral contraceptives after a gonadotropin-releasing hormone agonist can be as effective in adolescents as it is in adults in the prevention of endometrioma recurrence.
Bone mineral density: reference values and correlates for Bangladeshi women aged 16–65 years
2015, Journal of Orthopaedic Science
Background Studies examining the reference values of bone mineral density (BMD) and their patterns at different ages are largely based on data generated from developed countries. The objective of this study was to estimate reference values of BMD, along with their correlates, for women living in urban and suburban areas of Bangladesh.Methods Dual-energy X-ray absorptiometry scans were performed on 500 women 16–65 years of age. Reference values at the lumbar spine (LS) and femoral neck (FN) were estimated after adjusting for height and weight. In addition, multiple linear regression analysis was used to examine correlates of BMD at the LS and FN.
Results Mean BMD was highest at the LS and FN in women 16–19 (1.001–1.007 g/cm2) and 16–22 years of age (0.880–0.888 g/cm2), respectively, and gradually declined with increasing age thereafter. BMD decreased at an annual rate of 0.0027 g/cm² at the LS and 0.0046 g/cm² at the FN among women aged 16–45 years. For women 46–65 years of age, the respective figures were 0.0073 and 0.0083 g/cm². In both age groups, body weight was positively associated with BMD at both sites, and with height only at the LS. In addition, years of pill use was positively associated with BMD at the LS among women aged 16–45 years.BMD levels at both sites began to decline during the early twenties among Bangladeshi women.
Conclusions Age-specific BMD data generated in this study could be useful for interpreting bone densitometry data among women in Bangladesh and other South Asian countries.
Hormonal contraception and bone metabolism: A systematic review
2012, Contraception
Citation Excerpt :
Data on COCs use and fracture risk are summarized in Table 1. All randomized controlled studies [72–78] on the effects of COCs on bone used surrogate markers (BMD and bone turnover markers) as end points and not fractures. Indeed, the studies generally had sufficient duration to detect changes in BMD, not to detect a variation in fracture incidence.
Although a large amount of studies in the literature evaluated the effects of hormonal contraception on bone, many questions remained still unclear, such as the effect of these therapies on fracture risk.
We performed a systematic search of the published studies from January 1975 through January 2012 on the effects of hormonal contraceptives on bone metabolism. We analyzed the overall effect on bone mineral density (BMD) and on fracture risk of combined oral contraceptives (COCs), progestogen-only contraceptives, transdermal contraceptives and vaginal ring.
COC therapy does not seem to exert any significant effect on BMD in the general population. In adolescents, the effects of COCs on BMD seem to be mainly determined by estrogen dose. The use of COCs in perimenopausal women seems to reduce bone demineralization and may significantly increase BMD even at a 20-mcg dose. Use of depot medroxyprogesterone acetate is associated with a decrease in BMD, although this decrease seems to be partially reversible after discontinuation. Data on other progestogen-only contraceptives, transdermal patch and vaginal ring are still limited, although it seems that these contraceptive methods do not exert any influence on BMD.
Hormonal contraceptives do not seem to exert any significant effect on bone in the general population. However, other randomized controlled trials are needed to evaluate the effects on fracture risk since the data available are derived from studies having the effects on BMD as the primary end point, and BMD may not accurately reflect the real fracture risk.
Impact of combined and progestogen-only contraceptives on bone mineral density
2009, Revue du Rhumatisme (Edition Francaise)

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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

Abstract

Introduction

Section snippets

Materials and methods

Results

Discussion

Conclusion

Contraception

Contraception

Contraception

Contraception

Contraception

Contraception

Contraception

Obstet Gynecol

J Pediatr

Fertil Steril

Am J Med

A three-year clinical investigation into efficacy, cycle control and tolerability of a new low-dose monophasic oral contraceptive containing gestodene

Gynecol Endocrinol

German trial of an oral contraceptive containing 0.150 mg desogestrel plus 0.020 mg ethinylestadiol

Acta Obstet Gynecol Scand

Reference values for trabecular and cortical vertebral bone density in single and dual-energy quantitative computed tomography

Eur J Radiol

Original research article
A 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