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A Randomized Controlled Trial of Estrogen Replacement Therapy in Long-Term Users of Depot Medroxyprogesterone Acetate

Department of Medicine, Faculty of Medicine & Health Science (T.C., R.A., A.H., J.C., G.G., I.R.R.), University of Auckland, and the Family Planning Association (H.R.), 1001 Auckland, New Zealand

Address all correspondence and requests for reprints to: Dr. Tim Cundy, Department of Medicine, Faculty of Medical & Health Sciences, University of Auckland, Private Bag 92019, Auckland, New Zealand. E-mail: t.cundy{at}auckland.ac.nz.

	Abstract

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Long-term use of the injectable contraceptive depot medroxyprogesterone acetate (DMPA, Depo-Provera) is associated with a reduction in bone mineral density (BMD), particularly in the lumbar spine. The cause of DMPA-associated bone loss is not known, but the relative estrogen deficiency induced by DMPA use could be responsible. We have undertaken a randomized, double-blind controlled trial of oral estrogen replacement therapy in 38 premenopausal women (mean age 37) with a minimum 2 yr DMPA use who had a below average baseline lumbar spine BMD (T score 0). Nineteen women were allocated to receive conjugated estrogens (0.625 mg/d orally) and 19 to receive a matching placebo. All continued with regular DMPA injections throughout the study. Areal bone density was measured by dual energy x-ray absorptiometry at the lumbar spine, femoral neck, and total body sites every 6 months for 2 yr; the main outcome measure being the change in areal BMD at the lumbar spine. At baseline, the two groups were well matched for demographic, anthropometric, and biochemical variables, and for BMD. Twenty-seven subjects completed at least 18 months in the study, and 26 the full 2 yr, with similar numbers dropping out from each group (mainly for personal reasons). In the estrogen-treated group, mean lumbar spine BMD increased 1%, whereas in the placebo group it fell 2.6%, over 2 yr. The between group differences were 2.0% at 12 months (P = 0.058), 3.2% at 18 months (P < 0.01), and 3.5% at 24 months (P < 0.002). Differences of lesser statistical magnitude were seen at the femoral neck (between group differences at 2 yr: 2.7%, P = 0.24), Ward’s triangle (5.0%, P = 0.055), greater trochanter (3.6%, P = 0.056), total body (1.3%, P = 0.046), legs (1.3%, P = 0.065), and trunk (2.0%, P = 0.029). There were no major adverse events. These data support the view that the likely cause of DMPA-associated bone loss is estrogen deficiency and demonstrate that it can be arrested by estrogen replacement therapy.

	Introduction

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A REDUCTION IN bone mineral density (BMD) in women with long-term use of the injectable contraceptive depot medroxyprogesterone acetate (DMPA) has been reported in several studies. The deficit in bone density tends to be greatest in women who start DMPA at an early age, and in those whose duration of use exceeds 15 yr (1, 2, 3, 4, 5, 6, 7). The cause of DMPA-associated bone loss is not certain, but the most plausible explanation is that it is a consequence of estrogen deficiency. DMPA suppresses pituitary gonadotropin secretion, and with continued use most women become amenorrheic and typically have plasma estradiol levels comparable to those in the early follicular phase or postmenopausal range (8, 9). However, other explanations have been advanced: that smoking (common in DMPA users) could account for the bone loss, or that DMPA itself has direct effects on bone. In this study, we have tested the hypothesis that DMPA-associated bone loss can be prevented by estrogen replacement therapy. In a double-blind, randomized controlled trial of 2-yr duration, we have examined the effects of estrogen on BMD in long-term DMPA users who had below average baseline spinal BMD.

	Subjects and Methods

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Women aged 45 yr or less who were long-term (2 yr) users of DMPA were recruited from Family Planning Clinics in the Auckland region. A screening test of the lumbar spine BMD was made and women with an areal BMD at or below the young adult average (1.200 g/cm², T score O) were invited to participate in the study. Subjects known to have metabolic bone disease or taking drugs (other than DMPA) that can affect bone density were excluded from the study, as were those with elevated basal plasma FSH values (>20 U/liter) indicating menopause. Forty-one subjects fulfilling the BMD criterion were identified. Of these, three women were ineligible because they had high FSH levels. The remaining 38 subjects were randomized to take either conjugated estrogens 0.625 mg (Premarin, Wyeth-Ayerst, Collegeville, PA; n = 19) or matching placebo (n = 19) orally, once daily for 2 yr. All subjects continued with 12 weekly injections of DMPA 150 mg (Depo-Provera, Pharmacia \|[amp ]\| Upjohn, Piscataway, NJ) throughout the study. None of the subjects took calcium or vitamin D supplements during the study.

Subjects were seen at 6-month intervals during the study at which times adverse events and side effects were assessed and bone density measurements were made. Specific inquiry was made regarding breast tenderness (rated as follows: 0, none; 1, mild; 2, moderate; 3, severe) and vaginal bleeding. Adherence to therapy was assessed by counting returned tablets. Biochemical measurements were made at baseline, 6 months and 24 months (study end). The measurements included plasma calcium and phosphate and markers of bone turnover. Plasma total alkaline phosphatase activity was used as a marker of bone formation, and the fasting urine N-telopeptide/creatinine ratio (Osteomark NTx assay, Ostex International, Inc., Seattle, WA) as a marker of bone resorption. Plasma estradiol was measured by a sensitive RIA. The normal ranges in premenopausal women (follicular phase) are 90–200 pmol/liter and in postmenopausal women less than 100 pmol/liter.

Areal BMD (g/cm²⁾ was measured by dual energy x-ray absorptiometry (Lunar Corp., Madison, WI) at the lumbar spine, femur, and the total body sites. Regional analysis of the total body scan (trunk and leg regions) are also reported. Coefficients of variation for repeated measures in our laboratory are 1.0% for the lumbar spine, 1.4% for the femoral neck, and 0.5% for the total body BMD. The change in lumbar spine BMD was the primary outcome measure. The results were analyzed by intention to treat. Mean values were compared by paired or unpaired t test, as appropriate, and proportions were compared by the ² test. A mixed models approach to repeated measures (SAS Institute Inc., Cary, NC; version 8.0) was employed to test for differences between the treatment arms over time. Significant main and interaction effects were further investigated using Tukey’s method, to preserve an overall 5% significance level. Values for missing at random data (<<10%) were imputed using maximum likelihood estimation. Marginal least squares means are presented. All tests were two tailed.

All subjects gave written informed consent. The study was approved by the Auckland Research Ethics Committee.

	Results

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Thirty-eight women were randomized in to the study. Baseline data are given in Table 1. There were no significant differences between the groups in any demographic variable, or in initial bone density measurements. The mean T-score for the lumbar spine BMD was -1.04 (SD 0.81) in the group allocated to receive conjugated estrogens, and -0.74 (0.61) in the group allocated to receive placebo. There was no significant correlation between baseline lumbar spine BMD and plasma estradiol (r = 0.136, P = 0.43). The dropout rate early in the study was high, with eight subjects not reaching the first follow-up at 6 months (four from the placebo group) and a further three subjects (2 from the placebo group) dropping out between 6 and 12 months. Only one of these subjects discontinued participation for a medical reason—breast tenderness—and she was from the placebo group. Of the 27 subjects completing 18 months or more (13 from the control group), adherence to therapy exceeded 85% in 20 subjects. No follow-up bone density measurements were made on subjects dropping out from the study.

View larger version (13K): [in this window] [in a new window]   Figure 1. Changes in areal BMD recorded every 6 months at the lumbar spine BMD in subjects assigned to conjugated estrogens (closed symbols) or to placebo (open symbols). The results are expressed as the percentage change from the initial measurement. Mean values (with SEM) are illustrated. P values refer to significant intergroup differences (Student’s t test).

View larger version (10K): [in this window] [in a new window]   Figure 2. Individual changes over 2 yr in lumbar spine BMD in subjects assigned to conjugated estrogens (closed symbols) or to placebo (open symbols). The results are expressed both as absolute change (mg/cm2) (left) and percentage change (right). Mean values are indicated.

Adverse events were no more common in the group receiving estrogen than in the group receiving placebo. In particular, breast tenderness rated moderate or severe was reported by 4 of 19 subjects taking conjugated estrogens and in 3 of 19 subjects on placebo. Vaginal bleeding (any episode) was reported by 3 of 19 subjects taking conjugated estrogens and in 2 of 19 subjects on placebo. Neither fracture nor thromboembolism occurred in either group. No pregnancies occurred.

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Studies from many countries have demonstrated that women using long-term DMPA contraception have reduced BMD, particularly in the lumbar spine (1, 2, 3, 4, 5, 6, 7). The likely, but unproven, cause is the estrogen deficiency that DMPA induces, by its indirect inhibition of ovarian function. The current study was undertaken to test the hypothesis that replacing estrogen would attenuate DMPA-associated bone loss. Over 2 yr, long-term DMPA users with spinal BMD below the age-related average allocated to receive conjugated estrogens showed a small increment in areal BMD at the lumbar spine, and no change at the femoral neck or total body sites. In contrast, bone was lost from the lumbar spine and whole body sites in subjects allocated to placebo. The differences between the groups appeared earlier and were greater in magnitude at the lumbar spine than the other sites. This was as expected, and reflects the larger proportion of trabecular bone in the lumbar spine. Trabecular bone has a greater surface area relative to bone volume engaged in bone turnover, and so responds more rapidly to inhibitors of bone resorption such as estrogen. Given the greater imprecision of the femoral measurements compared with the lumbar spine measurements, the study was underpowered to demonstrate clear-cut statistical differences at this site. The lack of relationship between improvement in BMD and the plasma estradiol in the group receiving conjugated estrogens is not surprising, in view of the small number of subjects in the study and the variability in plasma estradiol that can occur during the 12 wk interval between DMPA injections (8, 9).

Our results demonstrate that estrogen replacement therapy arrests DMPA-related bone loss. This is entirely consistent with the idea that DMPA-related bone loss is due to accelerated bone turnover, secondary to estrogen deficiency, but of course it does not prove that this is the sole mechanism. The failure to detect any significant difference in bone turnover markers, and any relationship between these and changes in BMD, probably relates to the small number of subjects in this study, the inherent variation in these indices and the insensitivity of total alkaline phosphatase activity as a marker of bone formation. In a much larger sample of subjects Ott et al. (10) have shown that N-telopeptide excretion, a bone resorption marker, is significantly increased in DMPA users compared with users of combined oral contraceptives. Other data published by our group also point to estrogen deficiency being the likely cause of DMPA-associated bone loss. Long-term premenopausal DMPA users gain bone at the lumbar spine when DMPA is discontinued, and they become estrogen replete (11); long-term users who continue DMPA right through to the menopause lose bone at a slower rate than normal in the early postmenopausal period (12). In other contexts, medroxyprogesterone may not reduce bone density. For example, when given in low dose to premenopausal women with a deficient luteal phase, bone density may increase (13). Similarly, there is some evidence that the addition of low dose medroxyprogesterone may enhance the effects of estrogen replacement therapy on bone density in postmenopausal women (14). In both of these instances, the possible beneficial effects of medroxyprogesterone on bone occurred in the context of sufficiency or replacement of estrogen. In contrast, chronic DMPA use causes estrogen deficiency, an effect that is presumably dominant over any potentially beneficial effect of medroxyprogesterone. Although our results are consistent with the idea that DMPA-associated bone loss is the consequence of estrogen deficiency, they do not conclusively prove it because estrogen can arrest bone loss in other conditions: for example, primary hyperparathyroidism (15).

The drop-out rate from this study was high, with only 26 of 38 subjects (68%), completing the full 2 yr. Adverse events and side effects were uncommon and equally distributed between the two groups and were not the cause of the high drop-out rate. It is probable that one of the reasons why some women like using DMPA for contraception (four injections a year) is that they are not temperamentally inclined to take tablets (such as the oral contraceptive) with the necessary regularity to ensure efficacy. This should be borne in mind when considering estrogen replacement in a woman taking DMPA, or designing further studies of estrogen replacement in DMPA users. The effect of DMPA on BMD does appear to be greater in adolescents than in older women. In the only study in adolescents published to date, DMPA users showed a reduction in areal BMD in the lumbar spine of 1.5% over 2 yr, compared with gains of about 8% in controls and combined oral contraceptive users (2). There are no data as yet to indicate that whether this large and potentially significant deficit is recoverable with estrogen replacement or cessation of DMPA use. It might be anticipated that, in this age group of DMPA users, the adherence to oral estrogen replacement would be even poorer than in adults. Alternative methods of estrogen administration are likely to be necessary.

	Footnotes

 
The study was supported by the Health Research Council of New Zealand.

Abbreviations: BMD, Bone mineral density; DMPA, depot medroxyprogesterone acetate.

Received June 4, 2002.

Accepted September 12, 2002.

	References

Top Abstract Introduction Subjects and Methods Results Discussion References

 

1. Cundy T, Evans M, Roberts H, Wattie D, Ames R, Reid IR 1991 Bone density in women receiving depot medroxyprogesterone acetate contraception. Br Med J 303:13–16 (correction, p. 209)
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8. Jeppsson S, Gershagen S, Johansson EDB, Rannevik G 1982 Serum medroxyprogesterone (MPA), sex hormone binding globulin, gonadal steroids, gonadotrophins and prolactin in women during long term use of depo-MPA as a contraceptive. Acta Endocrinol 99:339–343
9. Clark MK, Sowers M, Levy BT, Tenhundfeld P 2001 Magnitude and variability of sequential estradiol and progesterone concentrations in women using depot medroxyprogesterone acetate for contraception. Fertil Steril 75:871–877[CrossRef][Medline]
10. Ott SM, Scholes D, LaCroix AZ, Ichikawa LE, Yoshida CK, Barlow WE 2001 Effects of contraceptive use on bone biochemical markers in young women. J Clin Endocrinol Metab 86:179–185[Abstract/Free Full Text]
11. Cundy T, Cornish J, Evans MC, Roberts H, Reid IR 1994 Recovery of bone density in women who stop using medroxyprogesterone acetate. Br Med J 308:247–248[Free Full Text]
12. Cundy T, Roberts H, Cornish J, Reid IR 2002 Menopausal bone loss in long term users of depot medroxyprogesterone acetate contraception. Am J Obstet Gynecol 186:978–983[CrossRef][Medline]
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15. Orr-Walker BJ, Evans MC, Clearwater JM, Horne A, Grey AB, Reid IR 2000 Effects of hormone replacement therapy on bone mineral density in postmenopausal women with primary hyperparathyroidism: four-year follow-up and comparison with healthy postmenopausal women. Arch Intern Med 160:2161–2166[Abstract/Free Full Text]

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