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The Journal of Clinical Endocrinology & Metabolism Vol. 88, No. 8 3651-3656
Copyright © 2003 by The Endocrine Society

Effects of a Triphasic Combination Oral Contraceptive Containing Norgestimate/Ethinyl Estradiol on Biochemical Markers of Bone Metabolism in Young Women with Osteopenia Secondary to Hypothalamic Amenorrhea

S. K. Grinspoon, A. J. Friedman, K. K. Miller, J. Lippman, W. H. Olson and M. P. Warren

Neuroendocrine Unit, Massachusetts General Hospital (S.K.G., K.K.M.), Boston, Massachusetts 02114-2696; Ortho-McNeil Pharmaceutical, Inc. (A.J.F., W.H.O.), Raritan, New Jersey 08869-0602; Ethicon (J.L.), Somerville, New Jersey 08876; and Center for Menopause, Hormonal Disorders and Women’s Health (M.P.W.), New York, New York 10022

Address all correspondence and requests for reprints to: Steven Grinspoon, M.D., Massachusetts General Hospital, Neuroendocrine Unit, Bul 457b, 55 Fruit Street, Boston, Massachusetts 02114-2696. E-mail: Sgrinspoon{at}partners.org.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
This multicenter, double-blind, placebo-controlled, randomized study of 45 patients evaluated the short-term effects of an oral contraceptive [Ortho Tri-Cyclen, 180–250 µg of norgestimate (NGM) and 35 µg of ethinyl estradiol (EE)] on biochemical markers of bone resorption, formation, and osteoprotegerin in young women (mean age ± SD, 26.5 ± 6.3 yr) with hypothalamic amenorrhea and osteopenia. Body fat, endocrine, and cognitive function were evaluated as secondary endpoints. Biomarkers of bone metabolism were measured at baseline and after three cycles of NGM/EE or placebo. There were significant decreases in mean values of N-telopeptide [mean (SD), -13.4 (13.4) vs. 1.2 (23.8) nmol bone collagen equivalents (BCE)/mmol creatinine (Cr); P = 0.001] and deoxypyridinoline [-1.2 (2.9) vs. -0.5 (1.5) nmol deoxypyridinoline/mmol Cr; P = 0.021] as well as significant decreases in bone specific alkaline phosphatase [-5.1 (3.5) vs. 0.4 (3.1) ng/ml; P < 0.001], osteocalcin [-5.9 (3.6) vs. -2.9 (3.7); P = 0.016], and procollagen of type I propeptide [-35.2 (44.6) vs. -0.2 (30.0) ng/ml; P = 0.025], but not osteoprotegerin [0.39 (1.46) vs. -0.2 (0.49) pmol/liter; P = 0.397] in the NGM/EE vs. placebo group. There were no significant differences between groups with respect to changes in cognitive function, mood, body weight, body mass index, body fat, percentage of body fat, and all endocrine levels except FSH, [-3.7 (3.8) vs. -0.6 (2.1) IU/liter; P < 0.001, NGM/EE vs. placebo]. No serious adverse events were reported in either group. These results suggest that NGM/EE decreases bone turnover in osteopenic premenopausal women with hypothalamic amenorrhea. Further studies are needed to determine whether estrogen will increase bone density in this population.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
HYPOTHALAMIC AMENORRHEA (HA) and other forms of secondary amenorrhea associated with hypoestrogenemia may affect the attainment of peak bone mass in young women (1, 2, 3). Bone mineral density (BMD) in patients with HA is significantly lower than that of normal controls and is negatively correlated with age (2) and duration of amenorrhea (3). Furthermore, markers of bone turnover are significantly elevated in this population (4) in whom the risk of developing osteoporosis and, possibly, fractures later in life may be increased (5).

Estrogen plays an important role in promoting bone mass in adolescents and young adults and in maintaining bone mass in adult women (6, 7, 8). Although oral contraceptives (OC) are sometimes used as estrogen replacement for women with HA, limited studies have been performed in this patient population with varying results (9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20), perhaps due to differences in study design, selection criteria, outcome measures, and the type and dose of OC preparation used (21, 22). Therefore a multicenter, double-blind, randomized, placebo-controlled short-term study was conducted to determine the effects of an OC (Ortho Tri-Cyclen, Ortho-McNeil Pharmaceutical, Raritan, NJ) on bone metabolism and other endocrine parameters in osteopenic women with HA. In contrast to prior studies, subjects with anorexia nervosa (5, 23, 24, 25) and other medical conditions known to affect bone were excluded to allow for the determination of estrogen effects in a homogeneous population of premenopausal women with estrogen deficiency.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Study design

This was a multicenter, double-blind, randomized, parallel group, placebo-controlled study with the primary objective of evaluating the effects of a triphasic, combination OC containing norgestimate (NGM) and ethinyl estradiol (EE) for three 28-d cycles on urinary and serum biochemical markers of bone metabolism in young women with osteopenia and HA. Secondary objectives were to evaluate the effects of NGM/EE on endocrine function, body composition, cognitive function, and mood.

Subjects

Women between 18 and 40 yr of age were eligible for study inclusion if they demonstrated laboratory values consistent with HA (see paragraph below) and one of the following menstrual patterns: 1) no menses in the previous 3 months and no more than two menses in the previous 12 months; or 2) a previous diagnosis of HA and no spontaneous menses in the previous 3 months and, if hormone-induced menses had occurred during the previous 12 months, a total duration of hormonal therapy of less than 6 months in the previous year. In addition, the subjects were required to have a posteroanterior total lumbar (L1–L4) spine BMD no greater than 0.937 g/cm2 (>=1 SD less than young adult normal), and a body mass index (BMI) between 16 and 24 kg/m2.

Women with any disorder for which steroid hormonal therapy is contraindicated were not eligible for study enrollment. Also excluded were women with any significant coexisting medical condition that could contribute to osteopenia (e.g. untreated hyperthyroidism) or those with unknown or suspected malignant breast disease, hypertension, or a history of severe migraines. Subjects between the ages of 35 and 40 yr were required to be nonsmokers, whereas those between the ages of 18 and 34 yr were permitted to smoke 10 cigarettes or less per day. Other exclusion criteria included a prolactin level of at least 30 ng/ml, an FSH level of at least 40 mIU/ml, a testosterone level of at least 56 ng/dl, a LH/FSH level of at least 2.5, and a LH level of at least 11 mIU/ml (if verified on repeat). Women with marked hirsutism, anorexia nervosa, or a recent history (<12 months) of alcohol/substance abuse were excluded from the study, as were those who were currently using any medications that could affect OC metabolism (e.g. antibiotics, anticonvulsants, barbiturates), those who had used systemic steroids or diuretics for more than 5 d during the past 3 months, or those who had used estrogen within 3 months of the study. Women who were currently pregnant or nursing were also ineligible, and all study participants were required to use a reliable, nonhormonal method of birth control during the course of the study. Subjects were recruited from community advertisements.

The study protocol and amendments were reviewed by an independent institutional review board. The study was conducted in compliance with the Declaration of Helsinki and the International Conference on Harmonization. Each subject (or a legally authorized representative) was required to sign an informed consent form after the nature of the study had been fully explained.

Treatment

The study participants were randomized in strict sequential order, at each study site, to treatment with NGM/EE or placebo for three consecutive 28-d cycles. The dosing schedule for the active treatment group was as follows: d 1–7 (180 µg NGM/35 µg EE), d 8–14 (215 µg NGM/35 µg EE), d 15–21 (250 µg NGM/35 µg EE), and d 22–28 (inactive tablets). Subjects randomized to the placebo treatment group received placebo tablets identically color matched and packaged to that of the active treatment group. Subjects received a once daily multivitamin [Centrum Multivitamins (400 IU Vitamin D), Wyeth-Ayerst, Inc., Madison, NJ) and were instructed not to take any additional hormonal or nutritional supplements.

Assessments

Eligibility for study inclusion was confirmed during a screening visit, at which time a posteroanterior total lumbar spine (L1–L4) and total hip (nondominant) dual-energy x-ray absorptiometry (DXA) was performed. Synarc, Inc. (Bedford, MA) validated the instruments used for the DXA scans, trained the technicians at each study site, and verified the scans. Each study site was required to use the same DXA instrument and mode of scanning, and whenever possible the same DXA technician was to be used throughout the course of the study. Quality control was performed daily at each site by the use of a standard spine phantom. In addition to standard laboratory tests including a complete blood count, electrolyte and liver function tests, an endocrine panel (FSH, LH, prolactin, testosterone), thyroid panel (T3RIA, T4, TSH, T3 resin uptake), and 24-h urine free cortisol were performed at the screening visit. All testing was performed at a central laboratory (Esoterix, formerly Endocrine Sciences, Calabasas Hills, CA).

Bone markers, endocrine, body composition, neurocognitive, and quality of life (QOL) testing were performed at the baseline visit. Bone turnover markers and endocrine parameters were performed by a central laboratory (Esoterix). Assays were performed as follows: deoxypyridinoline (DPYR) in urine, by competitive enzyme immunoassay (normal range, 3.0–7.4 nmol DPYR/mmol Cr); N-telopeptide (NTX) in urine, second morning void, by ELISA (normal range, 10–65 nmol BCE/mmol Cr); bone specific alkaline phosphatase (BSAP) in serum, by immunoradiometric assay (normal range, 2–24 ng/ml); osteocalcin in serum, by RIA (normal range, 2–22 ng/ml); procollagen of type I propeptide (PICP) in serum, by an enzyme-linked immunosorbent procedure (normal range, 69–147 ng/ml); dehydroepiandrosterone sulfate (DHEAS, normal range, 76–255 µg/dl, ages 21–30 yr; 48–247 µg/dl, ages 31–40 yr); estradiol (normal range, 3–10 ng/dl); and IGF-I (normal range, 87–368 ng/ml, ages 21–30 yr; 106–368 ng/ml, ages 31–40 yr). Osteoprotegerin (OPG; standard range, 0–30 pmol/liter) was measured by enzyme immunoassay (American Laboratory Products Company, Wyndham, NH) at the Massachusetts General Hospital. The subjects’ body fat was measured via the use of calipers. QOL and mood were assessed by the Medical Outcomes Study (MOS) 36-item Short Form Health Survey (SF-36) and the Profile of Mood States (POMS) test. Cognitive function testing was conducted by a neuropsychologist at a separate site and included the Wechsler Memory Scale-Revised (WMS-R), Complex Figure Copy and Immediate Recall, STROOP Color and Word Test, Embedded Figures, Paired Associates, and Digit Cancellation.

Testing procedures performed at the baseline visit were repeated at the cycle 3 or early termination visit.

All subjects were questioned regarding possible adverse events (AEs) during a 6-wk interim visit and during the cycle 3 or early termination visit. These were documented on the case report form. Safety was also assessed based on the findings of a physical examination (including vital signs) and laboratory tests (complete blood count, electrolytes, and liver function tests) performed at the screening and cycle 3 or early termination visit.

Statistical methods and analyses

The primary outcome variables in the study were changes in the levels of the biochemical markers of bone resorption (NTX and DPYR) from the baseline visit to the cycle 3 (or early termination) visit. Secondary outcome variables included changes from admission visit to cycle 3 in markers of bone formation, OPG, cognitive function parameters, POMS, QOL variables, and other variables relevant to bone loss (e.g. body weight, BMI, body fat, and endocrine levels). Analyses were performed in an evaluable-for-efficacy population (all randomized subjects who completed three cycles of the study medication) and an intent-to-treat (ITT) population (all randomized subjects who took at least one dose of the study medication and had a cycle 3 or early termination visit). Results of the ITT analysis are included when they differ from those in the evaluable-for-efficacy population. A population consisting of all randomized subjects who took at least one dose of the study medication was identified for a safety analysis.

To assess the statistical significance of treatment differences, analysis of covariance was used, adjusting for admission values and study center. Because of lack of normality, the Wilcoxon rank-sum test was used to assess the statistical significance of changes in all cognitive function and POMS scores. All statistical tests were two-tailed at the P = 0.05 level of significance.

The number and percentage of subjects reporting AEs were classified by body system and preferred term using a modified World Health Organization Adverse Reaction Terms (WHOART) and by treatment group. AEs were further summarized according to severity and relationship to the study medication.

The sample size estimation was based on the assumption that the treatment difference in NTX values would be at least 15 nM BCE/nM Cr at month 3, with a SD value of 20 nM BCE/nM Cr (18, 23). It was estimated that 30 subjects per treatment group would be adequate to detect such a treatment difference, with 80% power in a two-sided test at a 5% significance level. To account for uncertainty, the planned sample size was 76 women (38 per treatment group). Enrollment was ended after 45 subjects because of slower than anticipated recruitment. A post hoc power analysis demonstrated 60% power for a two-sided t test, conducted at the 5% significance level assuming a difference in the mean change of 14.6 nmol BCE/mmol Cr and a SD value for the change in NTX of 19.57 nmol BCE/mmol Cr (pooled SD).


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
This study was conducted from June 22, 1998, until September 22, 2000. During this time, 132 subjects were screened, and 45 subjects were enrolled at six sites (see Acknowledgments), 25 of whom were randomized to treatment with NGM/EE and 20 to treatment with placebo. Among the 25 women receiving NGM/EE, three discontinued due to an AE (see Safety Analysis), two because of personal choice and one because of a protocol violation. None of the subjects randomized to placebo discontinued prematurely. Thus, 19 (76%) subjects in the NGM/EE group and 20 (100%) subjects in the placebo group completed the study and composed the evaluable-for-efficacy population.

As shown in Table 1Go, the demographic and baseline characteristics of the evaluable-for-efficacy subjects in the NGM/EE and placebo groups were similar. An enrollment exception was made for one 17-yr-old subject who met all the other study criteria. There were no notable differences between the two treatment groups with respect to mean age, race, weight, height, BMI, or BMD.


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  		TABLE 1. Demographic and baseline characteristics of the evaluable-for-efficacy population

 
Table 2Go presents an overview of the subjects’ gynecological history. Across treatment groups, the mean age of menarche was 13.3–13.4 yr, and the mean duration from the women’s last menstrual period to the screening visit was approximately 18–20 months. Slightly more than half of the subjects had been amenorrheic (i.e. no spontaneous periods) during the past year, and nearly two thirds had not used hormonal therapy in the previous 12 months.


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  		TABLE 2. Gynecological history of the evaluable-for-efficacy population

 
In the evaluable-for-efficacy population, 100% of subjects in both the NGM/EE and placebo-treatment groups were compliant with study medication (i.e. took more than 85% of the study medication during the first 21 d of each cycle as determined by pill count).

Table 3Go displays the changes from baseline to cycle 3 in the biomarkers of bone metabolism in the evaluable-for-efficacy population. Changes in urinary levels of NTX and DPYR, markers of bone resorption, were statistically significantly different between groups. The mean percentage changes in NTX were -25.3% and +13.0% in the NGM/EE and placebo groups, respectively. At baseline, mean urinary NTX and DPYR concentrations were at the upper end of the established normal reference range for premenopausal women (see Subjects and Methods) and increased above the normal range in 21 and 30% of the entire group, respectively. There were also significant differences between the NGM/EE and placebo groups with respect to the changes from baseline to cycle 3 in all three biomarkers of bone formation in the evaluable-for-efficacy population (Table 3Go). The change in OPG was not significantly different between the groups (Table 3Go). Results for NTX and DPYR remained significant (P < 0.025), applying a Bonferroni correction in the evaluable-for-efficacy analysis. Statistically significant changes between treatment groups were observed for NTX, BSAP, and PICP in the ITT analysis.


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  		TABLE 3. Change from baseline to cycle 3 in biochemical markers of bone resorption (NTX and DPYR), bone formation (BSAP, osteocalcin, and PICP) and OPG in the evaluable-for-efficacy population

 
Changes in markers of bone formation, but not resorption were well correlated (osteocalcin vs. BSAP, r = 0.56, P = 0.0003; osteocalcin vs. PICP, r = 0.43, P = 0.006; BSAP vs. PICP, r = 0.57, P = 0.0002). In addition, the change in OPG correlated with the change in PICP (r = -0.38; P = 0.045) among the entire study group.

Changes in estradiol, testosterone, DHEAS, LH, or IGF-I levels were not significant between the groups (Table 4Go). However, the changes in FSH were statistically significant between the treatments groups. Changes in body weight, BMI, body fat, and percentage body fat were not statistically significant between the treatment groups.


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  		TABLE 4. Change from baseline to cycle 3 in endocrine parameters in the evaluable-for-efficacy population

 
Changes in cognitive function tests POMS or the SF-36 were not significant between the groups in the evaluable for efficacy analysis, although there were significant differences between groups that favored placebo with respect to changes in three QOL variables (i.e. vitality, social functioning, and mental health) in the ITT analysis.

A total of 44 subjects were included in the evaluable-for-safety population, 24 in the NGM/EE group and 20 in the placebo group. The mean number of days on therapy for subjects in the safety population was 74.6 d (range, 6–91 d) in the NGM/EE group and 84.3 d (range, 81–89 d) in the placebo group. Of the 24 women in the NGM/EE group, 14 (58.3%) reported one or more AE, whereas five (25%) of the 20 subjects in the placebo group reported AEs. Four (16.7%) patients in the NGM/EE group reported AEs that were considered to be probably treatment-related, including headache, nausea, anxiety, depression, and acne (Table 5Go). Two (10%) patients in the placebo group reported AEs that were considered to be probably treatment-related, including abdominal pain and flatulence. No AEs were considered to be certainly related to treatment in either group. Only one subject in the NGM/EE group reported two AEs (anxiety and depression) judged to be of marked severity, whereas none of the placebo-treated subjects reported AEs of marked severity. Three subjects in the NGM/EE group withdrew from the study because of treatment-related AEs: two subjects due to depression and one subject as a result of anxiety and depression. None of the women in the placebo group withdrew due to an AE. No AEs related to chemistry or hematology safety assessments were reported.


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  		TABLE 5. Number (%) of subjects reporting AEs considered to be probably or certainly1 treatment-related

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
Women with HA experience significant bone loss. OC therapy is often recommended to restore menstrual function in such patients. However, the effects of OC administration on bone metabolism have not been definitively established in this population. To assess the effects of OCs on bone metabolism and related parameters, we performed a multicenter, double-blind, placebo-controlled, 3-month study of an OC containing 180–250 µg of NGM and 35 µg of EE.

HA is a clinical model for estrogen deficiency in young women. The subjects in this trial were selected on the basis of their age (18–40 yr), with strict criteria applied for the diagnosis of HA and osteopenia (see inclusion criteria). Bone mineral accrual may vary with estrogen status and age, but bone density, age of menarche, hormonal and bone turnover parameters were equivalent at baseline in the treatment groups. The women were also selected on the basis of their current medical status (e.g. women were to be excluded if they had any significant coexisting condition that could contribute to osteopenia, including anorexia nervosa), and hormonal use (e.g. women were also excluded if they had used any oral hormonal therapy within 3 months of screening). FSH levels were within normal limits and similar at baseline in the treatment groups, but were reduced with OC estrogen, demonstrating intact feedback inhibition in this population.

Markers of bone resorption (NTX and DPYR) at the baseline visit were at the upper end of the normal range and frankly elevated in a significant number of subjects suggesting that bone resorption was generally increased, as anticipated, in this estrogen-deficient population. In contrast, reduced markers of bone turnover have been reported in other populations with HA and undernutrition (26, 27, 28). In this study, patients with HA treated with NGM/EE demonstrated significant reductions in the urinary biomarkers of bone resorption, NTX and DPYR, when compared with placebo-treated controls. Three months was chosen as a sufficient period of time to see changes in bone resorption in response to estrogen/progestin (29). In addition to the prominent changes in markers of bone resorption, there were significant decreases in the serum markers of bone formation (BSAP, osteocalcin, PICP) in the NGM/EE group as compared with the placebo group, suggesting a coupling of formation and resorption markers in response to estrogen in this population. Biochemical markers of bone resorption and formation are useful surrogate measures for assessing changes in bone metabolism and response to therapy (30, 31, 32, 33). Therefore, the significant decreases in the levels of biomarkers in the osteopenic patients treated with NGM/EE compared with placebo in our study reflect a decrease in the rate of bone turnover, which may attenuate bone loss in this population.

In this study, OPG, the decoy receptor of receptor activator of nuclear factor {kappa}B ligand (RANKL), was measured to determine whether increasing OPG is a potential mechanism by which NGM/EE decreased bone resorption in our population. Circulating OPG concentrations have been shown in some studies to increase with age in women, perhaps as a homeostatic mechanism to limit bone loss associated with estrogen deficiency (34). In contrast, estrogen has been shown to increase OPG from marrow stromal and osteoblast cells, and to increase OPG in men (35, 36). Among postmenopausal women, a weakly positive association has been shown between OPG and serum estradiol (37). However, the effects of estrogen administration on OPG in estrogen-deficient premenopausal women are not known. In this study, OPG did not change significantly between the treatment groups. The change in OPG was not significantly associated with the change in NTX or other markers of resorption, but was negatively correlated with the change in PICP. Although these data from a relatively small group of patients do not definitively rule out a modest effect of NGM/EE on OPG, these data are the first to suggest that such a mechanism seems unlikely to explain the robust effects of NGM/EE on bone resorption in this population. Taken together, the data suggest that NGM/EE administration may affect bone resorption through mechanisms other than OPG, and further studies are needed in this regard.

IGF-I may be an important determinant of bone turnover and BMD in young estrogen-deficient women (38). In contrast to prior studies demonstrating a reduction in IGF-I in response to oral estrogen administration in postmenopausal women (39, 40), we showed no such effect of OC administration on serum levels of IGF-I in young premenopausal women in this study.

Four subjects (16.7%) receiving NGM/EE reported AEs, compared with two subjects (10.0%) receiving placebo. No serious AEs were reported. In the ITT population, subjects receiving NGM/EE reported decreases in three QOL parameters, including mental health, although no differences were seen in the evaluable-for-efficacy population. It is possible that the addition of sex steroids to young women with prolonged hypogonadotropic hypogonadism may explain these findings in this short-term study.

The results of this study show that NGM/EE is effective in decreasing bone turnover in osteopenic premenopausal women with HA. These results were determined in a rigorous, placebo-controlled clinical trial conducted specifically to evaluate the effects of an OC on bone metabolism in a select population of estrogen-deficient, premenopausal osteopenic women. The effect of OC to decrease markers of turnover does not appear to be mediated through changes in OPG or other hormones such as IGF-I. Further studies are necessary to determine the long-term effects of OCs on bone density in this population and to determine the mechanism of estrogen action on bone turnover in this setting.


   Acknowledgments
 
Sites participating in this study were as follows: Massachusetts General Hospital (Boston, MA), Columbia Presbyterian Medical Center (New York, NY), Southwest Clinical Research Center (Albuquerque, NM), University of Pittsburgh School of Medicine (Pittsburgh, PA), Center for Health Studies (Cleveland, OH), and Center for Women’s Health and Sports Medicine (Philadelphia, PA).


   Footnotes
 
Abbreviations: AE, Adverse event; BCE, bone collagen equivalents; BMD, bone mineral density; BMI, body mass index; BSAP, bone specific alkaline phosphatase; Cr, creatinine; DHEAS, dehydroepiandrosterone sulfate; DPYR, deoxypyridinoline; DXA, dual-energy x-ray absorptiometry; EE, ethinyl estradiol; HA, hypothalamic amenorrhea; ITT, intent-to-treat; NGM, norgestimate; NTX, N-telopeptide; OC, oral contraceptive(s); OPG, osteoprotegerin; PICP, procollagen of type I propeptide; POMS, Profile of Mood States; QOL, quality of life.

Received January 6, 2003.

Accepted April 10, 2003.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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