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Journal of Clinical Endocrinology & Metabolism , doi:10.1210/jc.2007-2201
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The Journal of Clinical Endocrinology & Metabolism Vol. 93, No. 4 1317-1323
Copyright © 2008 by The Endocrine Society

Effects of Depot Medroxyprogesterone Acetate on Bone Density and Bone Metabolism before and after Peak Bone Mass: A Case-Control Study

Jennifer S. Walsh, Richard Eastell and Nicola F. A. Peel

Academic Unit of Bone Metabolism, Northern General Hospital, University of Sheffield, Sheffield S5 7AU, United Kingdom

Address all correspondence and requests for reprints to: Dr. J. S. Walsh, Academic Unit of Bone Metabolism, Sorby Wing, Northern General Hospital, Herries Road, Sheffield S5 7AU, United Kingdom. E-mail: jenniferwalsh{at}doctors.org.uk.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Introduction: Depot medroxyprogesterone acetate (DMPA; Depo-Provera, Tadworth, UK) contraception is used by more than 9 million women worldwide and has a high usage among teenagers in the United Kingdom and the United States. Previous studies have found that DMPA use is associated with a bone density deficit.

Objectives: This case-control matched study aims to eliminate potential confounding factors, identify whether the effect of DMPA on the skeleton is age specific, and determine the effects of DMPA on hormones and bone turnover.

Design/Participants: We measured bone density, bone turnover, and hormones in individually matched case-control pairs of women: 50 pairs aged 18–25 yr and 50 pairs aged 35–45 yr.

Results: DMPA use was associated with a 5% bone density deficit at the lumbar spine and hip in women who started DMPA use before age 20 yr but not after age 34 yr. Bone turnover was increased in DMPA users in both age groups. DMPA users had lower estradiol and higher IGF-I than controls, and younger DMPA users had higher dehydroepiandrosterone sulfate than controls. In a multiple regression model, estradiol and IGF-I were associated with bone turnover, but addition of DMPA to the model made the association with estradiol nonsignificant.

Conclusions: DMPA use is associated with a bone density deficit at the spine and hip when used before peak bone mass. DMPA acts on the skeleton mainly through estrogen deficiency.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
Depot medroxyprogesterone acetate (DMPA; Depo-Provera, Tadworth, UK) is a long-acting progestogen-only contraceptive, administered by 3-monthly im injection. DMPA is used by more than 9 million women worldwide (1) and has a high usage among teenagers in the United Kingdom and the United States (2). By 1 yr of use, most women become amenorrheic (3), and there has been concern over potential effects on bone. The first report of low bone density in DMPA users was in 1991 by Cundy et al. (4). They described a bone mineral density (BMD) deficit of 7.5% at the lumbar spine and 6.6% at the femoral neck, compared with healthy premenopausal controls. Subsequent work has confirmed an effect of DMPA on the spine and hip. Cross-sectional studies have described BMD deficits ranging from 2.2 to 17% at the proximal femur and 2.5 to 18% at the lumbar spine (5, 6, 7, 8, 9, 10, 11, 12). Prospective studies have demonstrated bone loss in new DMPA users. Bone loss at the lumbar spine and hip is approximately 5.7% after 2 yr and seems to be linear over this time (13, 14). Bone loss is most rapid in the first few years of DMPA use and subsequently decelerates (15). Studies that have examined the forearm have failed to consistently demonstrate an effect of DMPA on BMD when measured by dual-energy x-ray absorptiometry (DXA) or peripheral quantitative computed tomography (pQCT) (16, 17, 18, 19, 20). Only one study has measured BMD at the forearm and axial skeleton (21). DMPA users had lower BMD than controls at the lumbar spine but no difference at the hip or distal forearm, suggesting that there may be a site-specific effect.

Studies focused on adolescents and young women up to age 21 yr found that BMD decreased in new DMPA users at a rate of about 1.5%/yr. Controls gained BMD at about 2%/yr over the period of follow-up, resulting in differences of up to 6.8% after 2 yr (22, 23, 24, 25, 26). These studies show that DMPA use in teenage years results in bone loss at a time when bone growth and mineral accrual should be taking place.

Discontinuation of DMPA is associated with some recovery of BMD, but not all studies demonstrated complete recovery (27, 28, 29, 30, 31, 32). In women aged 18–21 yr, recovery was less complete than in older women. In adolescents discontinuer rates of bone gain were higher than in adult women. Recovery at the hip was slower than at the spine in all age groups.

There is little information available on the endocrine and biochemical effects of DMPA on bone. Estradiol is lower in DMPA users than in controls but higher than in postmenopausal women (4, 5, 6, 18). Studies of bone turnover have produced inconsistent results. Increased bone resorption has been described with N-terminal telopeptide of type I collagen (NTX) 30% higher than controls (33) and increased osteocalcin and deoxypyridinoline with increasing duration of DMPA use (12). Other studies using urine hydroxyproline, serum total alkaline phosphatase, and osteocalcin (4, 17, 33) found no statistically significant differences in these markers. In girls aged 12–18 yr, DMPA use may be associated with decreased bone turnover measured by bone-specific alkaline phosphatase and deoxypyridinoline (34). No changes in PTH or calcium have been found (33).

There are some limitations to the available data. DMPA users (especially in young age groups) are less likely to be educated beyond 16 yr, more likely to have a low calcium intake, be smokers, and become pregnant at a younger age and more frequently than their peers, all of which may have an effect on their bone density (4, 8, 13, 14, 35). Discrepancies are seen when different skeletal sites are measured, and only one study has measured BMD at the spine, hip, and forearm. There is very little information on the effect of DMPA on bone biochemistry. It is unclear whether estrogen deficiency is the sole mechanism through which DMPA acts on bone. Androgens and GHs could be influenced by DMPA, and DMPA as a progestogen could have direct effects on bone.

There are good-quality longitudinal studies of DMPA in actively growing adolescents but none specifically examining women who have reached adult height but not yet attained peak bone mass who may also be a vulnerable group. Subgroup analyses have shown that 18- to 21-yr-old DMPA users have a greater bone deficit than older users, and they also seem to be the slowest to recover BMD after cessation of DMPA. Bone mineral accrual continues beyond the end of longitudinal growth until peak bone mass (peak bone mineral content) is reached during the third decade (36, 37, 38). If late bone development is interrupted, there may be an effect on bone size and peak bone mass that could influence fracture risk, and this has not yet been studied.

This cross-sectional study was designed to eliminate confounding effects of social and lifestyle factors and determine the following: 1) whether DMPA has a greater effect on the skeleton before skeletal maturity, 2) whether there is an effect on bone size, 3) whether the effect of DMPA on the skeleton is site specific, 4) the effect of DMPA on bone turnover, and 5) which hormones mediate the effect of DMPA on bone.


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

Two hundred women were recruited from local general practices and family-planning clinics; 50 DMPA users aged 18–25 yr who commenced use before age 20 yr (to study effects before attainment of peak bone mass), 50 DMPA users aged 35–45 yr who commenced DMPA use after age 34 yr (to study effects after attainment of peak bone mass), and 100 women who had never used DMPA individually matched to DMPA users by source of recruitment, postal code, age, height, body mass index, and smoking habit. DMPA use was of at least 12 months’ duration. All general practitioners and family-planning clinics gave permission for their patients to be approached. Women currently using DMPA (cases) or with no record of DMPA use in the same postal code and age group as cases (controls) were sent a written invitation to participate and then were screened by telephone. Women were excluded if they did not fit the criteria above; were non-Caucasian, pregnant, trying to conceive, or breast feeding; weighed more than 110 kg; had any medical condition or were taking any medication known to affect bone density; or had previous amenorrhea of more than 6 months’ duration. Controls were excluded if they were not having regular menses or were not adequately matched to a DMPA user. The study was approved by the North Sheffield Local Research Ethics Committee and all subjects gave written informed consent.

Women using combined oral contraceptive pills (COCPs) were included in the control group because there is good evidence it has no effect on BMD in estrogen-replete adult women (8, 13, 16, 19, 21, 26), and it is the most prevalent contraceptive choice in young women (39), so to exclude users would result in a biased sample. However, COCP use may be associated with a decrease in markers of bone turnover (40, 41), so COCP users were excluded from the comparison of bone turnover. Hormones were tested for an effect of COCP, and if an effect was present, COCP users were excluded from the analysis.

Methods

Subjects attended for a single visit. Controls were assessed during the follicular phase of the menstrual cycle. A questionnaire was administered by interview, which included medical, family, obstetric and gynaecological history, history of fractures, lifestyle, and calcium intake by food frequency.

BMD was measured at the lumbar spine (anteroposterior and lateral) and hip on the Delphi densitometer (Hologic Inc., Bedford, MA). Bone size and volumetric BMD [bone mineral apparent density (BMAD)] were estimated at the lumbar spine by the Carter method (which uses a scaling factor to correct for increased depth of larger bones) (42) and at the femoral neck by the Kroger method (which approximates the femoral neck to a cylinder) (43). Forearm BMD was measured by DXA on the DTX-200 (Osteometer Meditech A/S, Seattle, WA) and pQCT on the XCT-2000 (Norland Medical Systems, Ft. Atkinson, WI).

Fasting blood was obtained for measurement of aminoterminal propeptide of type I procollagen (PINP), estradiol, SHBG, dehydroepiandrosterone sulfate (DHEAS), IGF-I, and PTH. Samples were left to clot at room temperature for 30 min and then centrifuged and aliquoted. Timed second-morning void urine was obtained for measurement of NTX and creatinine. Samples were stored at –80 C, and samples from case-control pairs were run in the same assay. PINP, estradiol, and PTH were measured on the Elecsys 2010 autoanalyzer (Roche Diagnostics, Lewes, UK), NTX was measured on the Vitros EC1 autoanalyzer (Ortho-Clinical Diagnostics, Amersham, UK), creatinine was measured on the Vitros 250 autoanalyzer (Ortho-Clinical Diagnostics), DHEAS was measured on the Beckman Access 2 autoanalyzer (Beckman Coulter Inc., Fullerton, CA), and SHBG was measured on the Immulite 2000 autoanalyzer (Diagnostic Products Corp., Los Angeles, CA). IGF-I was measured with a manual immunoradiometric assay (Nichols Institute Diagnostics, San Clemente, CA).

Statistics

All statistical analysis was done with SPSS for Windows version 10.0 (SPSS Inc., Chicago, IL). The study was powered at 80% to detect a 0.5 SD difference in lumbar spine BMD with P = 0.05. Data that were not normally distributed were log transformed before analysis. Paired t tests were used to compare areal BMD between DMPA users and controls in each age group. Linear regression was used to calculate expected values for age for areal BMD, bone volume, and BMAD from controls and applied to generate SD scores for age (Z-scores) in DMPA users. One-sample t tests were applied to Z-score values to determine whether they differed significantly from zero. General linear model univariate analysis was used to assess the effect of DMPA use and age on variables. COCP users and their matched cases were excluded from the comparison of bone turnover markers then paired t tests were used to compare the remaining DMPA users with controls. The effect of the oral contraceptive on hormones was assessed by t tests of COCP and nonhormonal contraception controls. If there was no difference, COCP users were included in the analysis. If there was a difference, COCP users were excluded from that analysis.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
To recruit 100 DMPA users, we sent 1115 letters and received 296 responses (27%). Of these, 172 did not fit the inclusion criteria, and 24 declined to participate. To recruit 100 controls, we sent 1719 letters and received 469 responses (27%). Of these, 104 did not fit the inclusion criteria, 255 were not adequately matched to a DMPA user, and 10 declined to participate.

DMPA users and controls were well matched (Table 1Go). Mean duration of DMPA use was 37 months in both age groups.


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  		TABLE 1. Case-control matching

 
Bone density and bone size

In the younger age group, DMPA use was associated with a BMD deficit at the lumbar spine and hip (Fig. 1Go). There was also a significant difference in lateral areal BMD at L2-L3 (4.9%, P = 0.02) between DMPA users and controls. There were no statistically significant differences between DMPA users and controls at the forearm by DXA (Fig. 1Go) or pQCT.


Figure 1
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  		FIG. 1. Lumbar spine, total hip, and distal forearm BMD in patients aged 18–25 yr. Box and whisker plots show median, 25th to 75th centile, and range.

 
In the older age group, there were no significant differences between DMPA users and controls in BMD at the lumbar spine, hip, or forearm by DXA (Fig. 2Go) or the forearm by pQCT.


Figure 2
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  		FIG. 2. Lumbar spine, total hip, and distal forearm BMD in patients aged 35–45 yr. Box and whisker plots show median, 25th to 75th centile, and range.

 
In younger DMPA users, the BMD deficit at the spine was accounted for by a low BMAD, but at the femoral neck, bone volume was low and there was no significant difference in BMAD. In older women, although there was no significant deficit in areal BMD, the same pattern of lower BMAD at the spine and lower bone volume at the femoral neck was observed (Fig. 3Go).


Figure 3
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  		FIG. 3. Z-scores and SEM for areal BMD (aBMD), estimated volume, and BMAD at the lumbar spine and femoral neck in patients aged 18–25 yr (A) and 35–45 yr (B).

 
Within the control group, the bone density in COCP users was not significantly different from nonhormonal contraceptive users, but there was a trend toward lower BMD in COCP users in the younger age group (lumbar spine 1.001 vs. 1.009 g/cm2, total hip 0.979 vs. 1.001 g/cm2).

Bone turnover

Both bone turnover markers were higher in the younger age group and both were higher in DMPA users (Fig. 4Go). There were significant differences between DMPA users and controls when all DMPA users and nonhormonal contraception users were compared using an independent-sample t test and when only the pairs with nonhormonal contraception controls were compared with a paired-sample t test (18–25 yr, n = 14 pairs, 35–45 yr, n = 44 pairs). General linear model univariate analysis showed statistically significant relationships between bone turnover and age and bone turnover and DMPA use (all P < 0.001) but no significant interaction between age and DMPA use on bone turnover. We excluded COCP users from the bone turnover analysis because previous studies had described changes in bone turnover in COCP users. However, an independent-sample t test found no differences between COCP users and controls in our study group.


Figure 4
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  		FIG. 4. Bone turnover in DMPA users and controls: urine NTX (A) and serum PINP (B). Box and whisker plots show median, 25th to 75th centile, and range. COCP users excluded (18–25 yr DMPA, n = 50; controls, n = 14; 35–45 yr DMPA, n = 50, controls n = 44). Cr, Creatinine; CI, confidence interval.

 
Hormones

The hormone results are shown in Table 2Go.


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  		TABLE 2. Hormones in DMPA users and controls with general linear model analysis for effect of DMPA, effect of age, and DMPA/age interaction

 
Estradiol was lower in the younger age group and was lower in DMPA users than in controls. Estradiol in older DMPA users was comparable with controls in the younger age group. SHBG was lower in the younger age group and was lower in DMPA users than in controls. DHEAS was higher in the younger age group, and DMPA use was associated with higher DHEAS in the younger age group but not in the older age group. IGF-I was higher in the younger age group, and higher in DMPA users than in controls. PTH was lower in the younger age group, but there were no differences in PTH between DMPA users and controls in either age group.

Multiple regression analysis using estradiol, IGF-I and DHEAS found that bone turnover markers were most closely associated with IGF-I (NTX, r = 0.3, P = 0.001; PINP, r = 0.43, P < 0.001) and estradiol (NTX, r = –0.17, P = 0.03; PINP, r = –0.14, P = 0.06). When DMPA use was added to the model (NTX, r = 0.19, P = 0.04; PINP, r = 0.22, P = 0.01), it made estradiol nonsignificant (NTX, r = –0.06, P = 0.6; PINP, r = –0.01, P = 0.9), suggesting that DMPA exerts its effect on bone turnover through estradiol. IGF-I remained an independent predictor of bone turnover (NTX, r = 0.29, P = 0.001; PINP, r = 0.22 P < 0.001).


   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
This study demonstrated that when the effects of body size and lifestyle factors are eliminated by close case-control matching, DMPA use is associated with a BMD deficit in Caucasian women. In the younger age group, COCP users had slightly lower BMD than controls using nonhormonal contraception, which may have caused an underestimate in the magnitude of the effect of DMPA. The effect of DMPA on the skeleton is age and site specific, consistent with the existing literature. The age specificity suggests that the immature skeleton is more vulnerable to the effects of DMPA and is reassuring for older users of DMPA. This is the first study to assess the effect of DMPA on bone size. Previous studies have shown that BMD improves on cessation of DMPA use, but recovery was less complete in younger users and less complete at the hip than the lumbar spine. Our finding of smaller femoral neck size in young DMPA users could explain this result. Although BMD may recover, it is not yet known whether effects on bone size will be reversible, and smaller bone size is likely to confer a mechanical disadvantage that could increase future fracture risk.

The site-specific effect is interesting, and previous studies that examined the forearm alone may have been falsely reassuring. If the only mechanism acting were estrogen deficiency, the forearm would be likely to be affected, as is seen in postmenopausal osteoporosis. DMPA itself or the increased IGF-I levels in DMPA users may have a protective effect at the forearm.

Bone turnover was higher in the younger age group, consistent with active bone modeling. Resorption (NTX) and formation (PINP) were increased in DMPA users in both age groups by up to 40%, suggesting that the effects of DMPA on the skeleton are at least partially mediated through increased bone turnover. This increase is less than that seen after menopause or bilateral oophorectomy, when changes of more than 100% have been described (44, 45). During late adolescence and early adulthood, bone turnover should be decreasing as bone modeling is completed, and continued high turnover and remodeling could impair bone mineral accrual.

The higher estradiol in older women may be due to shortening of the follicular phase and premenopausal hyperestrogenism (46) and may be part of the reason why older women are protected from the skeletal effects of DMPA. Estrogen deficiency is likely to be the major mechanism through which DMPA acts on the skeleton, and estrogen replacement has been shown to improve lumbar spine BMD in DMPA users (47, 48). However, SHBG was also reduced in young DMPA users, so the decrease in free estradiol may be small. In the younger age group, DMPA use was associated with higher DHEAS but not in the older age group. There is some evidence to suggest that adrenal androgen synthesis is influenced by ovarian factors, and ovarian-adrenal cross talk mechanisms may explain a rise in DHEAS when gonadotrophins are suppressed in the presence of intact ACTH and normal ovaries (49). DHEAS has been shown to be an important regulator of bone metabolism, both directly through the androgen receptor and indirectly by conversion to other sex steroids, and could play a role in the maintenance of bone mass in estrogen deficiency. DMPA may have an effect on IGF-I, and the higher IGF-I may afford some protection against estrogen deficiency. This could be a direct effect on the GH/IGF-I axis or mediated through changes in sex steroids.

Cross-sectional design is a limitation in any association study, the study was not randomized, and there is likely to be an element of bias in any self-selected group. We cannot be sure that the sample is representative of all DMPA users because not all of the potentially eligible women responded to the invitation letter. However, the close matching of DMPA users and controls reduced bias associated with body size and social and lifestyle differences.

The inclusion of combined oral contraceptive users reduced the number of subjects available for the biochemical analyses, particularly in the younger group. The majority of the available literature and this study failed to identify a significant effect of COCP use on bone density in young women, although in the youngest women, there may be a negative effect that would have reduced, rather than exaggerated, the observed effect of DMPA in this study. The number of COCP users in the study group was representative of the number in all the women who responded to the initial invitation.

Use of DXA for bone size measurement depends on the reliability of the mathematical models used. Although variation in body size causes variation in bone size measurements using fan beam DXA, the accurate matching of individual DMPA users with controls reduced this source of error. Quantitative computed tomography may be a better method of bone size measurement and would provide additional information on cortical and trabecular bone, but on the scanners available to this study, the dose of ionizing radiation would be unsuitable for research involving young women.

A longer duration of DMPA use may have increased the observed effect and may have demonstrated an effect in the older age group. However, previous studies have suggested that the most rapid bone loss occurs in the first 2 yr of DMPA use, and the mean duration of 37 months’ use in this study includes that period.

It is difficult to predict what the long-term effects of DMPA use in young adulthood will be. There is good evidence that the BMD deficit is at least partially reversible, but the discovery of a bone size effect at the hip is a concern for future fracture risk. To prospectively study fracture risk would require a very long follow-up period with large numbers of participants.

However, adolescent specialist practitioners have advised that the benefits of DMPA use outweigh the risk to bone health in adolescents and advocate continued use after assessing the individual’s risks and benefits, addressing modifiable risk factors and considering calcium or estrogen supplementation (50). DMPA is still a useful contraceptive agent for young women, and further work should investigate the reversibility of effects on bone size and address strategies to minimize the effect on bone density and bone size.


   Footnotes
 
This work was supported by a Clinical Research Fellowship from the Arthritis Research Campaign (Grant 13951) and a project grant from the National Osteoporosis Society.

Disclosure Statement: J.S.W. and N.F.A.P. have nothing to declare. R.E. has consulted for and received grants from Unipath.

First Published Online January 29, 2008

Abbreviations: BMAD, Bone mineral apparent density; BMD, bone mineral density; COCP, combined oral contraceptive pill; DHEAS, dehydroepiandrosterone sulfate; DMPA, depot medroxyprogesterone acetate; DXA, dual-energy x-ray absorptiometry; NTX, N-terminal telopeptide of type I collagen; PINP, propeptide of type I procollagen; pQCT, peripheral quantitative computed tomography.

Received October 3, 2007.

Accepted January 23, 2008.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

  1. Kaunitz AM, Rosenfield A 1993 Injectable contraception with depot medroxyprogesterone acetate. Drug 45:854–865
  2. Cromer BA, Berg-Kelly KS, Van Gronigen JP, Seimer BS, Ruusuvaara L 1998 Depot medroxyprogesterone acetate (Depo-Provera) and levonorgestrel (Norplant) use in adolescents among clinicians in northern Europe and the United States. J Adolesc Health 22:74–80
  3. Mainwaring R, Hales HA, Stevenson K, Poulson AM, Jones KP, Peterson CM 1995 Metabolic parameters, bleeding and weight change in women using progestin only contraceptives. Contraception 51:149–153[CrossRef][Medline]
  4. Cundy T, Evans M, Roberts H, Wattie D, Ames R, Reid IRR 1991 Bone density in women receiving depot medroxyprogesterone acetate for contraception. BMJ 303:13–16[Abstract/Free Full Text]
  5. Cundy T, Cornish J, Roberts H, Elder H, Reid IR 1998 Spinal bone density in women using depot medroxyprogesterone acetate contraception. Obstet Gynecol 92:569–573[CrossRef][Medline]
  6. Paiva LC, Pinto-Neto AM, Faundes A 1998 Bone density among long-term users of medroxyprogesterone acetate as a contraceptive. Contraception 58:351–355[CrossRef][Medline]
  7. Gbolade B, Ellis S, Murby B, Randall S, Kirkman R 1998 Bone density in long-term users of depot medroxyprogesterone acetate. Br J Obstet Gynaecol 105:790–794[Medline]
  8. Scholes D, Lacroix AZ, Ott SM, Ichikawa LE, Barlow WE 1999 Bone mineral density in women using depot medroxyprogesterone acetate for contraception. Obstet Gynecol 93:233–238[CrossRef][Medline]
  9. Tang OS, Tang G, Yip P, Li B, Fan S 1999 Long-term depot medroxyprogesterone acetate and bone mineral density. Contraception 59:25–29[CrossRef][Medline]
  10. Ryan PJ, Singh SP, Guillebaud J 2002 Depot medroxyprogesterone and bone mineral density. J Fam Plan Reprod Health Care 28:12–15[CrossRef]
  11. Albertazzi P, Bottazzi M, Steel SA 2006 Bone mineral density and depot medroxyprogesterone acetate. Contraception 73:577–583[CrossRef][Medline]
  12. Shaarawy M, El-Mallah SY, Seoudi S, Hassan M, Mohsen IA 2006 Effects of the long-term use of depot medroxyprogesterone acetate as hormonal contraceptive on bone mineral density and biochemical markers of bone remodelling. Contraception 74:297–302[CrossRef][Medline]
  13. Berenson AB, Radecki Breitkopf C, Grady JJ, Rickert VI, Thomas A 2004 Effects of hormonal contraception on bone mineral density after 24 months of use. Obstet Gynecol 103:899–906[Medline]
  14. Clark MK, Sowers M, Nichols S, Levy B 2004 Bone mineral density changes over two years in first-time users of depot medroxyprogesterone acetate. Fertil Steril 82:1580–1586[CrossRef][Medline]
  15. Tang OS, Tang G, Yip PSF, Li B 2000 Further evaluation on long-term depot medroxyprogesterone acetate use and bone mineral density: a longitudinal cohort study. Contraception 62:161–164[CrossRef][Medline]
  16. Petitti DB, Piaggio G, Mehta S, Cravioto MC, Meirik O 2000 Steroid hormone contraception and bone mineral density: a cross-sectional study in an international population. The WHO Study of Hormonal Contraception and Bone Health. Obstet Gynecol 95:736–744[CrossRef][Medline]
  17. Naessen T, Olsson SE, Gudmundson J 1995 Differential effects on bone density of progestogen-only methods of contraception. Contraception 52:35–39[CrossRef][Medline]
  18. Taneepanichskul S, Intaraprasert S, Theppisai U, Chaturachinda K 1997 Bone mineral density in long-term depot medroxyprogesterone acetate acceptors. Contraception 56:1–3[CrossRef][Medline]
  19. Perrotti M, Bahamondes L, Petta C, Castro S 2001 Forearm bone density in long-term users of oral combined contraceptives and depot medroxyprogesterone acetate. Fertil Steril 76:469–473[CrossRef][Medline]
  20. Merki-Field GS, Neff M, Keller PJ 2000 A prospective study on the effects of depot medroxyprogesterone acetate on trabecular and cortical bone after attainment of peak bone mass. Br J Obstet Gynaecol 107:863–869
  21. Wanichsetakul P, Kamudhamas A, Watanaruangkovit P, Siripakarn Y, Visutakul P 2002 Bone mineral density at various anatomic bone sites in women receiving combined oral contraceptives and depot medroxyprogesterone acetate for contraception. Contraception 65:407–410[CrossRef][Medline]
  22. Cromer BA, Blair JM, Mahan JD, Zibners L, Naumovski Z 1996 A prospective comparison of bone density in girls receiving depot medroxyprogesterone acetate (Depo-Provera), levonorgestrel (Norplant) or oral contraceptives. J Pediatr 129:671–676[CrossRef][Medline]
  23. Busen NH, Britt RB, Rianon N 2003 Bone mineral density in a cohort of adolescent women using depot medroxyprogesterone acetate for one to two years. J Adolesc Health 32:257–259[CrossRef][Medline]
  24. Cromer BA, Stager M, Bonny A, Lazebnik R, Rome E, Ziegler J, Debanne SM 2004 Depot medroxyprogesterone acetate, oral contraceptives and bone mineral density in a cohort of adolescent girls. J Adolesc Health 35:434–441[CrossRef][Medline]
  25. Scholes D, Lacroix AZ, Ichikawa LE, Barlow WE, Ott SM 2004 The association between depot medroxyprogesterone acetate contraception and bone mineral density in adolescent women. Contraception 69:99–104[CrossRef][Medline]
  26. Lara-Torre E, Edwards CP, Perlman S, Hertweck SP 2004 Bone mineral density in adolescent females using depot medroxyprogesterone acetate. J Pediatr Adolesc Gynecol 17:17–21[CrossRef][Medline]
  27. Cundy T, Cornish J, Evans MC, Roberts H, Reid IR 1994 Recovery of bone density in women who stop using medroxyprogesterone acetate. BMJ 308:247–248[Free Full Text]
  28. Scholes D, LaCroix AZ, Ichikawa LE, Barlow WE, Ott SM 2002 Injectable hormonal contraception and bone density: results from a prospective study. Epidemiology 13:581–587[CrossRef][Medline]
  29. Kaunitz AM, Miller PD, Montgomery Rice V, Ross D, McClung MR 2006 Bone mineral density in women aged 25–35 receiving depot medroxyprogesterone acetate: recovery following discontinuation. Contraception 74:90–99[CrossRef][Medline]
  30. Clark MK, Sowers M, Levy B, Nichols S 2006 Bone mineral density loss and recovery during 48 months in first-time users of depot medroxyprogesterone acetate. Fertil Steril 86:1466–1474[CrossRef][Medline]
  31. Hertweck SP, Harel Z, Stager M, Gold MA, Coupey SM, Burkman RT 2006 Evaluation of bone mineral density in adolescents during use of depot medroxyprogesterone acetate intramuscular injection and after discontinuation. Obstet Gynecol 107:51S
  32. Scholes D, LaCroix AZ, Ichikawa LE, Barlow WE, Ott SM 2005 Change in bone mineral density among adolescent women using and discontinuing depot medroxyprogesterone acetate contraception. Arch Pediatr Adolesc Med 159:139–144[Abstract/Free Full Text]
  33. 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]
  34. Rome E, Ziegler J, Secic M, Bonny A, Stager M, Lazebnik R, Cromer BA 2004 Bone biochemical markers in adolescent girls using either depot medroxyprogesterone acetate or an oral contraceptive. J Pediatr Adolesc Gynecol 17:373–377[CrossRef][Medline]
  35. Cromer BA, Smith RD, Blair JM, Dwyer J, Brown RT 1994 A prospective study of adolescents who choose among levonorgestrel implant (Norplant), medroxyprogesterone acetate (Depo-Provera) or the combined oral contraceptive pill as a contraception. Pediatrics 94:687–694[Abstract/Free Full Text]
  36. Recker RR, Davies MK, Hinders SM, Heaney RP, Stegman MR, Kimmel DB 1992 Bone gain in young adult women. JAMA 268:2403–2408[Abstract/Free Full Text]
  37. Parsons TJ, Prentice A, Smith EA, Cole TJ, Compston JE 1996 Bone mineral mass consolidation in young British adults. J Bone Miner Res 11:264–274[Medline]
  38. Henry YM, Fatayerji D, Eastell R 2004 Attainment of peak bone mass at the lumbar spine, femoral neck and radius in men and women: relative contributions of bone size and volumetric bone density. Osteoporosis Int 15:263–273[CrossRef][Medline]
  39. Office for National Statistics 2003 Contraception and sexual health. Her Majesty’s Stationary Office, The Stationary Office, Norwich, UK
  40. Nappi C, Di Spiezio Sardo A, Acunzo G, Bifulco G, Tommaselli GA, Guida M, Di Carlo C 2003 Effects of low-dose and ultra-low-dose combined oral contraceptive use on bone turnover and bone mineral density in young fertile women: a prospective controlled randomized study. Contraception 67:355–359[CrossRef][Medline]
  41. Garnero P, Soray-Rendu E, Delmas PD 1995 Decreased bone turnover in oral contraceptive users. Bone 16:499–503[Medline]
  42. Carter DR, Bouxsein ML, Marcus R 1992 New approaches for interpreting projected bone densitometry data. J Bone Miner Res 7:137–145[Medline]
  43. Kroger H, Kotaniemi A, Vainio P, Alhava E 1992 Bone densitometry of the spine and femur in children by dual-energy x-ray absorptiometry. Bone Miner 17:75–85[CrossRef][Medline]
  44. Peris P, Alvarez L, Monegal A, Guanabens N, Duran M, Pons F, Martinez de Osaba MJ, Echevarria M, Ballesta AM, Munoz-Gomez J 1999 Biochemical markers of bone turnover after surgical menopause and hormone replacement therapy. Bone 25:349–353[Medline]
  45. Seifert-Klaus V, Mueller J, Luppa P, Probst R, Wilker J, Höss C, Treumann T, Kastner C, Ulm K 2002 Bone metabolism during the perimenopausal transition: a prospective study. Maturitas 41:23–33[CrossRef][Medline]
  46. Santoro N, Rosenberg Brown J, Adel T, Skurnick JH 1996 Characterisation of reproductive hormone dynamics in the perimenopause. J Clin Endocrinol Metab 81:1495–1501[Abstract]
  47. Cundy T, Ames R, Horne A, Clearwater J, Roberts H, Gamble G, Reid IR 2003 A randomized controlled trial of estrogen replacement therapy in long-term users of depot medroxyprogesterone acetate. J Clin Endocrinol Metab 88:78–81[Abstract/Free Full Text]
  48. Cromer BA, Lazebnik R, Rome E, Stager M, Bonny A, Ziegler J, Debanne SM 2005 Double-blinded randomized controlled trial of estrogen supplementation in adolescent girls who receive depot medroxyprogesterone acetate for contraception. Am J Obstet Gynecol 192:42–47[CrossRef][Medline]
  49. Doi SAR, Towers PA, Scott CJ, Al-Shoumer KAS 2005 PCOS: an ovarian disorder that leads to dysregulation in the hypothalamic-pituitary-adrenal axis? Eur J Obstet Gynecol 118:4–16[CrossRef]
  50. Cromer BA, Scholes D, Berenson A, Cundy T, Clark MK, Kaunitz AM 2006 Depot medroxyprogesterone acetate and bone mineral density in adolescents—the black box warning: a position paper of the Society for Adolescent Medicine. J Adol Health 39:296–301[CrossRef][Medline]



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S. M. Ott
Reproductive Hormones and Skeletal Health in Young Women
J. Clin. Endocrinol. Metab., April 1, 2008; 93(4): 1175 - 1177.
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