Short-term variations in bone remodeling markers of an oral contraception formulation containing 3 mg of drospirenone plus 30 μg of ethinyl estradiol: Observational study in young postadolescent women

doi:10.1016/j.contraception.2004.04.004

Contraception

Volume 70, Issue 4, October 2004, Pages 293-298

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Abstract

The clinical study of treated subjects and nontreated controls was made in healthy eumenorrheic young postadolescent women volunteers in the Department of Obstetrics and Gynaecology at Cagliari University, to investigate whether an oral contraceptive (OC) containing drospirenone (3 mg) plus ethinyl estradiol (30 μg) (DRSP+EE) can affect bone metabolism. Control group (n = 26) and OC group (n = 28) women did not differ in age, body mass index, waist-to-hip ratio and main outcome measures [urinary levels of deoxypyridinoline and pyridinoline, serum levels of osteocalcin, bone specific alkaline phosphatase (bSAP), total testosterone (total-T), sex hormone-binding globulin (SHBG), progesterone and bone mineral density (BMD) at the heel]. The control group was studied at the luteal phase (LP) during both the first and the sixth menstrual cycle; the OC group was studied during the first cycle at the LP, and on days 16–18 of the sixth cycle of DRSP+EE treatment. At the sixth cycle, in the control group, the main outcome measures did not change compared to baseline. In the OC group, deoxypyridinoline, pyridinoline, osteocalcin, bSAP, total-T and progesterone levels were reduced, whereas SHBG levels were increased. The BMD was unchanged compared to baseline. The results suggest that 6-month DRSP+EE treatment decreases bone turnover.

Introduction

The bone mineral density (BMD) is reduced in women with low ovarian estrogen levels due to hypothalamic amenorrhea [1], [2], [3] or to premature ovarian failure [4] or to GnRHa- chronic treatment [5]. However, low ovarian estrogen levels due to use of oral contraceptives (OCs) containing estrogen-progestin formulations do not seem to cause impairment to bone metabolism in young postadolescent women [6], even when formulations with low [7], [8], very low [7], [9], [10] or ultra-low doses [10] of ethinyl estradiol (EE) are used.

On the contrary, some studies concur to show that contraceptive treatment with only progestagen compounds derived from 17-OH progesterone [11], but not from 19-nor testosterone [11], [12], [13], could impair bone health. Therefore, the effect of an OC on the bone could depend not only on EE content, but also on the pharmacological properties of the progestin compound [11]. The residual androgenic affinity of synthetic 19-nor-testosterone derivatives could protect bone health through a direct effect on androgen osteoblast receptors [14], [15]. It is also known that the androgenic activity of these steroids could increase androgenic availability because they counteract the stimulatory effect of EE on hepatic sex hormone-binding globulin (SHBG) secretion [16], [17]. Furthermore, it has been shown that 19-nor-testosterone derivatives exert estrogenic effect through the estrogen receptors [18].

Drospirenone (DRSP) is a 17-α-spirolactone derivative with pharmacological properties that uniquely combine progestogenic, antimineralcorticoid and antiandrogenic activity but without estrogenic and androgenic activity [19], [20], [21]. The OC containing 3 mg DRSP plus 30 μg EE (DRSP+EE) proved to provide effective oral contraception, excellent cycle control and good tolerability, mainly because DRSP counteracts water retention related to EE and improves psychological symptoms with a global positive effect on the woman's well-being [22]. A recent study by our group [23] suggests that DRSP+EE could also improve anxiety, and other psychological symptoms in a population of healthy women without psychological diseases and without premenstrual symptoms.

Even though it has been shown that the addition of spironolactone to different OCs treatments does not impair bone turnover [24], no studies have been published up to now on the role of DRSP+EE on bone metabolism. This study aimed to assess whether variations of BMD and biochemical markers of bone formation and bone resorption occur during a 6-month treatment with DRSP+EE in young postadolescent women.

Section snippets

Subjects

The subjects included in the study were recruited from women who presented to the Department of Obstetrics and Gynaecology of the University of Cagliari asking for contraception. Subjects included in the study did not have contraindications to OC intake in accordance with the World Health Organization guidelines [25]. They did not have past or present bone diseases, disorders of bone metabolism, thyroid diseases, disorders of lipid or glucose metabolism, renal, hepatic or urinary diseases or a

Results

Two women in the control group did not complete the study for personal reasons, whereas no woman in the OC group abandoned the study. Therefore, all results are reported as mean ± SD for 26 subjects in control group and 28 subjects in the OC group.

Discussion

The study was conducted on a selected population of young women in whom the main factors affecting variability of bone remodeling markers were excluded [26], [27], [28], [29], [30], [31] and variability in urinary PYR and D-PYR measurements was minimized and standardized by applying the recommendations of Vesper et al. [30]. It can be assumed that the bone markers evaluated here provide a dynamic picture of the bone turnover rate [35] in a population of young postadolescent women.

bSAP plays an

Acknowledgements

The authors thank Franca Fadda and Kate Jenkins for typing and revising the manuscript, and midwives Amalia Loi and Francesca Melis for their work with study participants.

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Despite significantly different reproductive hormone profiles, with eumenorrheic participants displaying significantly higher 17-β-oestradiol concentrations compared to COC users, there were no differences in β-CTX, P1NP or Bone ALP concentrations between groups. This is in contrast to some studies where COC use was shown to reduce bone marker concentrations [18,37–42], although it does agree with other studies that have shown no differences between eumenorrheic women and COC users [35,43–45]. The between-group comparisons in the current study were conducted using mean values from three different phases of the menstrual cycle and COC cycle, and, therefore, may be more representative of bone (re)modelling marker concentrations compared to previous research, which used measurements from one time point only.
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.
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Despite the increasing use of COC therapy in younger women, investigators have failed to definitively answer the basic question, i.e. are COCs helpful or harmful to bone? COCs suppress bone turnover markers, including those of bone formation [16–20], and some studies suggest a deleterious impact of COCs on bone mineral density (BMD) in younger compared to older women [10,21]. Interpreting reports of effects of COCs on bone is complicated by varied study designs and populations studied, lack of randomized, controlled trials (RCTs), and the rapidly-evolving nature of contraceptive therapies [10,22].
Bone growth, development, and remodeling are modulated by numerous circulating hormones. Throughout the lifespan, the extent to which each of the hormones impacts bone differs. Understanding the independent and combined impact of these hormones on controlling bone remodeling allows for the development of more informed decision making regarding pharmacology, specifically the use of hormonal medication, at all ages. Endocrine control of bone health in women is largely dictated by the growth hormone (GH)/insulin-like growth factor-1 (IGF-1) axis and the hypothalamic-pituitary-ovarian (HPO) axis. Growth hormone, secreted from the pituitary gland, stimulates cells in almost every tissue to secrete IGF-1, although the majority of circulating IGF-1 is produced hepatically. Indeed, systemic IGF-1 concentrations have been found to be correlated with bone mineral density (BMD) in both pre- and post-menopausal women and is often used as a marker of bone formation. Sex steroids produced by the ovaries, namely estradiol, mediate bone resorption through binding to estrogen receptors on osteoclasts and osteoblasts. Specifically, by increasing osteoclast apoptosis and decreasing osteoblast apoptosis, adequate estrogen levels prevent excessive bone resorption, which helps to explain the rapid decline in bone mass that occurs with the menopausal decrease in estrogen production. Though there are documented correlations between endogenous estrogen concentrations and GH/IGF-1 dynamics, this relationship changes across the lifespan as sex-steroid dynamics fluctuate and, possibly, as tissue responsiveness to GH stimulation decreases. Aside from the known role of endogenous sex steroids on bone health, the impact of exogenous estrogen administration is of interest, as exogenous formulations further modulate GH and IGF-1 production. However, the effect and extent of GH and IGF-1 modulation seems to be largely dependent on age at administration and route of administration. Specifically, premenopausal women using combined oral contraceptive therapy (COC), post-menopausal women taking oral hormone therapy (HT), and both pre- and post-menopausal women using a transdermal form of estrogen therapy (COC or HT) demonstrate disparate GH/IGF-1 responses to exogenous estrogen. This review serves to summarize what is currently known regarding the influence of exogenous estrogen administration across the lifespan on the GH/IGF-1 axis and implications for bone health.
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However, these trials have also measured markers of bone turnover among women treated with COCs, finding an increase in markers of bone formation and a reduction in markers of resorption, even for COCs containing 20 or 15 mcg EE [73,75,76]. Data derived from longitudinal, nonrandomized studies are in agreement with these results [89–94]. In particular, Castelo-Branco et al. [93] performed a longitudinal nonrandomized study on 67 women treated with a COC containing 35 mcg EE and 2 mg cyproterone acetate or 30 mcg EE and 150 mg desogestrel for 2 years.
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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.
Effect of Combined Oral Contraceptive Use on Bone Mineral Density in Adolescent Females
2012, Journal of Reproduction and Contraception
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After 24 months of Marvelon use, as compared with baseline, the mean BMD in lumbar spine and femoral neck were decreased by 0.30% and 0.61%, respectively. While in the nonusers group, the mean BMD were increased by 1.88% and 1.10%, respectively. Lumbar spine and femoral neck BMD in women who used Marvelon were not significantly different compared with the subjects who used nonhormonal contraception (P>0.05).
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For 24 months of treatment, lumbar spine and femoral neck BMD values in women who used ethinylestradiol/desogestrel and ethinylestradiol/cyproterone acetate were not significantly different compared with the baseline and the values of subjects in nonuser (P>0.05).
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Original research articleShort-term variations in bone remodeling markers of an oral contraception formulation containing 3 mg of drospirenone plus 30 μg of ethinyl estradiol: Observational study in young postadolescent women

Abstract

Introduction

Section snippets

Subjects

Results

Discussion

Acknowledgements

Eur J Obstet Gynecol Reprod Biol

Fertil Steril

Fertil Steril

Bone

Contraception

Contraception

Contraception

Obstet Gynecol

Contraception

J Pediatr

Bone

FEBS Lett

Contraception

Contraception

Contraception

Fertil Steril

Bone

Bone

Fertil Steril

Metabolism

Bone

Original research article
Short-term variations in bone remodeling markers of an oral contraception formulation containing 3 mg of drospirenone plus 30 μg of ethinyl estradiol: Observational study in young postadolescent women