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ORIGINAL RESEARCH |
From the Departments of Obstetrics and Gynecology and Preventive Medicine and Community Health, University of Texas Medical Branch, Galveston, Texas; and Wilford Hall Medical Center, San Antonio, Texas.
Address reprint requests to: Abbey B. Berenson, MD, Department of Obstetrics and Gynecology, University of Texas Medical Branch, 301 University Boulevard, Route 0587, Galveston, TX 77555-0587; E-mail: abberens{at}utmb.edu.
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ABSTRACT |
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METHODS: Data from 155 women were analyzed. Depot medroxyprogesterone acetate was administered to 33 women; 63 women who chose oral contraception were randomly assigned to receive either a norethindrone-containing pill (n = 28) or a desogestrel-containing pill (n = 35). Fifty-nine women who did not use hormonal contraception served as controls. Lumbar spine BMD was determined using dual-energy x-ray absorptiometry at baseline and after 12 months of contraceptive use. We analyzed method-related percent change in BMD while controlling for body mass index, calcium intake, exercise, and smoking. We had approximately 90% power to detect a 2.5% difference between any two groups.
RESULTS: Users of DMPA experienced a mean BMD loss of 2.74% over 12 months compared with controls who sustained a 0.37% loss (P = .01). Users of OCs generally demonstrated a gain (2.33% for norethindrone-containing pills, 0.33% for desogestrel-containing pills), which was different from controls among users of norethindrone-containing pills (P = .01), but not among users of desogestrel-containing pills (P = .99). Observed changes in BMD among DMPA users differed from women who used either type of pill (P < .002).
CONCLUSION: Depot medroxyprogesterone acetate has an adverse effect on BMD, in comparison with OCs or non-hormonal methods, when used for 12 months. Results must be interpreted cautiously until it is determined whether these effects endure or are reversible.
Recent studies have suggested that use of depot medroxyprogesterone acetate (DMPA) during the reproductive years may cause or accelerate bone loss. In a cross-sectional study, Cundy et al noted that DMPA users had a lumbar spine bone mineral density (BMD) that was 7.2% lower than that of matched controls.1 Cromer et al noted a 3.1% reduction in lumbar BMD among eight adolescents who used DMPA for 2 years,2 and Scholes et al observed an adverse relationship between DMPA use and BMD among young women.3 Several other investigations outside of the United States have associated use of DMPA with decreased bone density in the lumbar spine,4,5 as well as several regions of the hip (Ward’s triangle, trochanter, femoral neck),5 and the distal forearm.6 However, no prospective study has been published, comparing adult DMPA users with women using no hormonal contraception, which controlled for demographic and behavioral factors believed to affect BMD. Thus, the independent effects of DMPA use on BMD among adult women remain unclear.
Similarly, it is not clear whether use of birth control pills during the reproductive years affects BMD. Some studies have shown that use of oral contraceptives (OC) has a beneficial effect on BMD,7–9 whereas others report no effect.10,11 Findings from these studies are difficult to interpret for several reasons. First, some studies included users of pills containing 50–100 µg of ethinyl estradiol (E2),12,13 formulations that are currently unavailable or rarely prescribed. Others combined users of different pill formulations or failed to specify the pill formulation.7–11 Studies are also limited by small sample sizes2,14 and minimal consideration of behavioral confounders.9,14 Finally, many studies on OCs did not include a control group.9,15,16
The purpose of this study was to assess the independent effect of DMPA and two different types of OC on BMD among women 18–33 years of age compared with those not using hormonal contraception over a 12-month interval.
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MATERIALS AND METHODS |
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After obtaining informed, written consent, each subject was allowed to select the type of contraception that she would use for the duration of the study. Women who preferred injectable contraception received 150 mg of DMPA every 3 months, whereas those who chose oral contraception were randomly assigned to receive either pills containing 0.035 mg of ethinyl E2 and 1.0 mg of norethindrone or pills containing 0.030 mg of ethinyl E2 and 0.15 mg of desogestrel. Pills were referred to by the color names "green" (the desogestrel formulation) or "red" (the norethindrone formulation) and were de-identified by a research assistant who eliminated package labeling. Randomization was carried out through the use of a random numbers table, which assigned the next eligible patient who chose to use OCs to either the "green" or the "red" formulation. Women who did not wish to use hormonal birth control were recruited to serve as controls. Controls were frequency matched on age and race/ethnicity to the entire sample of hormonal contraceptive users.
At the initial visit, height and weight were measured from which body mass index (BMI) was calculated as weight in kilograms divided by the square of the height in meters. Demographic information and medical history were recorded. Cigarette use was recorded as a dichotomous variable: yes (smoked occasionally, regularly in the past, or regularly now) or no (never smoked, smoked only once or twice in the past). Whether or not the individual engaged in weight-bearing and/or high-impact exercise as part of a regular exercise program was recorded as a dichotomous variable (yes/no). To determine calcium consumption, trained research personnel assisted women with recalling and recording all foods and beverages consumed during the 24 hours before the baseline study visit. Appropriate cues and prompts were given to help women with recall, and writing assistance was provided as necessary. Calcium intake was computed using Menu Mizar 3.0 for Windows (Menu Systems, Ruffs Dale, PA).
Bone mineral density of the anterior-posterior lumbar spine (L1–L4) was determined using dual-energy x-ray absorptiometry at baseline and after 12 months of contraceptive use. All baseline scans were performed within 2 months of initiation of hormonal contraception. Follow-up scans were performed on all women between 10 and 14 months after the baseline scan. In addition, follow-up scans for hormonal contraceptive users were performed within 2 months of their 1-year anniversary of initiating contraception. Bone mineral density measurement was performed using a single machine at each study site. Scans at UTMB were performed using a Hologic QDR 1000-W (Hologic, Waltham, MA) bone densitometer, whereas those at WHMC were obtained with a Lunar DPX (Lunar, Madison, WI). Direct comparison of measured BMD values between the two sites was limited by the use of machines from different manufacturers. However, experts have shown strong correlations across Hologic and Lunar machines when percentage change in BMD is used in longitudinal studies as a measure of lumbar spine BMD changes.17
Short-term precision was evaluated to examine the reproducibility of BMD outcomes. To estimate precision, 20 subjects at UTMB and 10 at WHMC were randomly selected to undergo two consecutive scans at their 12-month visit, with an approximate interscan interval of 10–20 minutes. The coefficient of variation was computed as the root-mean-square averages of standard deviations (SD) of the repeated measurements.18 In vivo precision was less than 1% for the only technician at WHMC and 1.2% for the primary technician at UTMB.
Continuous variables are expressed as means ± SD. Group comparisons for these variables were conducted using analysis of variance or independent group t tests. Group differences in categorical variables were analyzed using 
2 or Fisher exact test. A two-sided significance level of .05 was used to determine statistical significance. Separate analyses were conducted at each site on the actual BMD values (g/cm2) to estimate mean changes from baseline and conduct group comparisons using analysis of covariance (ANCOVA). Our primary outcome was change in BMD over the follow-up interval, which was computed as the mean percent change from baseline using the formula: (follow-up BMD - baseline BMD)/baseline BMD x 100. An ANCOVA was performed on percent change BMD, controlling for pertinent behavioral (smoking, calcium intake, weight-bearing exercise) and demographic (race/ethnicity, age, BMI) factors related to BMD. Group mean percent changes in lumbar spine BMD, adjusted for covariates, and Bonferroni adjusted 95% confidence intervals for group comparisons were estimated using ANCOVA. Bonferroni-adjusted P values from these models are presented for pairwise comparisons of groups.
A post-hoc power analysis using observed mean differences and SDs demonstrated that this study had greater than 90% power to detect differences between the DMPA and pill groups, and between the norethindrone-containing pill group and the control group. There was 71% power to detect differences between the two pill groups and between DMPA users and controls, and only 30% power to detect the difference between controls and users of desogestrel-containing pills. Power calculations were based on the two-sample t test for unequal n using a two-sided significance level of .05. The estimate for the SD was the average for the two groups being compared (see Table 1
).
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RESULTS |
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There were no significant differences between the four contraceptive groups in their characteristics (Table 2), although women who selected an oral method of birth control were significantly less likely to report smoking cigarettes than those who used DMPA or nonhormonal methods (P = .02).
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). Women using DMPA, on average, experienced a loss in bone density. Using data from UTMB only, the results of the ANCOVA revealed that the loss in BMD among DMPA users was significantly greater than that observed among controls (P = .03). Women using OCs experienced slight gains or no change in BMD at both sites. Bone mineral density changes among users of desogestrel-containing pills compared with users of norethindrone-containing pills did not differ at UTMB (P = .39) or WHMC (P = .95).
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). On average, users of both types of birth control pills demonstrated a gain, with users of norethindrone-containing pills experiencing a 2.33% gain, and users of desogestrel-containing pills demonstrating a 0.33% gain in BMD. Table 5 presents 95% confidence intervals for pairwise differences in percent change in BMD between the contraceptive groups. The gain among users of pills was significantly different from controls for users of norethindrone-containing pills (P = .01), but not for users of desogestrel-containing pills (P = .99). Mean changes in BMD significantly differed between DMPA users and women who used either type of birth control pill (both P < .002).
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DISCUSSION |
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This study compares the effects of two different types of OCs on BMD. Previously, it was not possible to compare the effects of the type of pill on BMD because earlier studies did not specify the type, merged different types, or included only one pill formulation. In contrast, we randomized OC users to a norethindrone-containing or desogestrel-containing pill. A small gain in BMD was noted among users of both types of pills, which was significantly different from controls for norethindrone pills. We did not detect a difference between users of desogestrel pills and controls, which may have been because of insufficient power. In addition, we did not detect a difference between these two pills in their effect on BMD. The lack of a significant difference between the two pill groups in this study suggests that no firm conclusions should be drawn regarding a potential difference between these two types of pills until more data are available.
Because of the difficulty in randomizing women to a particular contraceptive method, we did allow all subjects to select whether they would use injectable, oral, or a nonhormonal method. In the absence of a randomized design, we carefully inspected the data for evidence of bias (because of self-selection) in the composition of the contraceptive groups. Specifically, we examined group-based differences in age, race/ethnicity, weight-bearing exercise habits, calcium intake, cigarette smoking, and BMI. These analyses were conducted univariately using appropriate statistical tests, and multivariably by conducting analyses of variance that included the relevant interaction terms. Although only smoking status significantly differed by method, we included all behavioral and demographic factors as covariates in our final analysis. Our inclusion of multiple covariates and our choice to apply a Bonferroni correction to evaluate pairwise comparisons between contraceptive groups represents a conservative strategy toward detecting method-related effects on BMD. The contraceptive-related differences we observed in BMD remained significant after controlling for behavioral and demographic correlates such as smoking and age, which have been influential in the broader literature on bone density.
Calcium intake data demonstrated that regardless of the type of contraception they used, few women ingested an adequate amount of calcium. In fact, the daily mean calcium intake among all women was 565 mg (SD = 379). Only 7% of women 18–24 years old ingested the recommended daily amount (1200 mg) for women aged 11–24 years, whereas only 12% of women 25–33 years of age met recommendations for their age group (1000 mg/day).22 This is particularly disconcerting considering that most women in our study had healthy habits — 61% reported exercising three times per week or more, and none were obese. Thus, it appears that women of reproductive age may not ingest adequate amounts of calcium, even if they engage in other healthy behaviors. This is especially of concern if their contraception places them at risk of bone loss.
This study has limitations that bear mentioning. Ideally, all women would have been scanned on a single bone densitometer. We minimized this shortcoming by first inspecting the pattern of data within each site as differences between measured BMD and as percent change BMD over the study interval. Only upon observation of consistent patterns at UTMB and WHMC did we merge the data from the two sites and report overall percent change in BMD. We also note that most women in this study were white, and all were within 36% of their ideal body weight and had obtained a high school degree. As most women in the United States do not fit this profile, our findings are not readily applicable to the general population. Furthermore, a 39% method discontinuation rate was observed within the12-month study period. This discontinuation rate is similar, and in many cases, lower, than that found in other published studies. For example, among users of various OC formulations, 12-month discontinuation rates have ranged from nearly 36–66%,23,24 and among users of injectable contraception, 1-year discontinuation rates have ranged from 48–77%.24–28 Acknowledging that high discontinuation rates temper the conclusions that can be drawn in contraceptive studies, we are careful to apply the findings of this research only to women who continued their contraceptive method for a 1-year period. Finally, we collected data over 12 months only. Additional studies are needed to determine the effects of these methods on BMD compared with controls over longer durations of use.
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Footnotes |
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This study was supported by the US Army Medical Research and Material Command under contract No. DAMD17-96-C-6113, and by the National Osteoporosis Foundation.
The views, opinions, and/or findings contained in this report are those of the authors and should not be construed as an official Department of the Army position, policy, or decision unless so designated by other documentation. The investigators adhered to the policies regarding the protection of human subjects as described by 45 CFR 46 and 32 CFR 219 (Protection of Human Subjects).
Presented at the Annual Clinical Meeting of Obstetricians and Gynecologists, San Francisco, California, May 22, 2000.
Received April 2, 2001. Received in revised form June 4, 2001. Accepted June 15, 2001.
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REFERENCES |
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20. Raisz LG. Physiology and pathophysiology of bone remodeling. Clin Chem 1999;45:1353–8.
21. Aedo AR, Landgren BM, Diczfalusy E. Studies on ovarian and adrenal steroids at different phases of the menstrual cycle. III. Steroid and lutropin levels before and after the administration of a single contraceptive dose of depot medroxyprogesterone acetate (DMPA). Contraception 1981;24:117–35.[Medline]
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