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- Discuss the potential for decreased bone mineral density in using depot-medroxyprogesterone acetate (DMPA) with any woman who is thinking of it as a means of contraception (C).
- Recommend to women that they take 1300 mg of calcium and 400 IU of vitamin D when using DMPA (C).
- Consider prescribing estrogen replacement if DMPA is going to be used for more than 2 years (C).
Strength of recommendation (SOR)
- Good-quality patient-oriented evidence
- Inconsistent or limited-quality patient-oriented evidence
- Consensus, usual practice, opinion, disease-oriented evidence, case series
Among adolescent women who use contraception, the injectable progestin-only depot-medroxyprogesterone acetate (DMPA, Depo-Provera) is second in popularity only to oral contraceptive pills.1 A very real drawback with DMPA, however, is a resultant hypoestrogenic state that has been linked to lowered bone mineral density (BMD).
Although several studies have demonstrated a relationship between DMPA use and lower BMD among adults and adolescents (strength of recommendation [SOR]: B), many of them had small sample sizes and methodological flaws. Moreover, most studies have shown that BMD change is reversible after discontinuation of DMPA.
Experts recommend counseling young women about DMPA’s possible effects on bone. But they caution against limiting its use based on the insufficient research to date (SOR: C). Analysts estimate that the availability of DMPA has contributed significantly to decreased adolescent pregnancy rates in the United States over the last 10 years.2 This article reports on a systematic review of the literature concerning DMPA and BMD.
Reason for concern
A 1991 study by Cundy et al3 was the first to examine the relationship between DMPA and BMD and found that DMPA users had significantly lower BMD than nonusers. DMPA delivers high doses of progestin and inhibits ovulation in most women. Consequently, DMPA can decrease serum estradiol levels. Low serum estradiol levels have also been linked to lower BMD levels in women who are in menopause or who have eating disorders.
Adolescence is a time of bone building. The chief reason for interest in the association between DMPA and decreased BMD is the potential risk of future osteoporosis and osteoporotic fractures for women using DMPA during adolescence. A mature woman’s BMD at any given time is related to her peak bone mass and subsequent rate of decline. Ninety percent of peak bone mass (the highest level of BMD achieved during one’s lifetime) is determined by age 18 in women.4 Between the ages of 18 and 30, women gain the last 10% of their maximum bone density. After age 30, bone resorption outpaces bone formation and women start to lose bone slowly.5 This decline continues until menopause, when women experience a more rapid decline in BMD related to sudden withdrawal of estrogen.
Factors that affect peak BMD. Several factors influence the level of peak bone mass a woman will reach—genetics, race, hormonal milieu, and lifestyle factors.4,5 As for lifestyle, it’s been shown that both anorexia and the female athlete triad cause low estrogen levels, and the resultant loss of BMD may not be recovered.6,7
Pregnancy, too, is known to be a state of increased bone turnover and resorption,8,9 and pregnancy during adolescence may also negatively impact BMD. A small 2002 study compared teenagers who had been pregnant with age-matched controls who had not been pregnant, and found that hip bone density in the adolescent mothers was lower by approximately 10%.10
Use of bone-affecting medications by adolescents is worrisome because they are still building bone at a high rate.
What the literature tells us
Studies of adult women. Studies examining the relationship between DMPA use and BMD have yielded varying results ( TABLE 1 ). Most of them show that using DMPA over a course of 2 years decreases BMD by 5% to 10%. New users have the most significant decreases in BMD, suggesting the decline levels off after 2 years of use (SOR: B).11-13 However, most early studies were cross-sectional and small, and thus had limited power to determine causality. In addition, these trials were not randomized, and they may have suffered from bias because treatment groups were volunteers.
Three recent prospective studies12,14,15 found that bone density losses recover after discontinuation of DMPA. Kaunitz15 followed women for up to 2 years after DMPA discontinuation and found that BMD recovered almost completely (-0.2% at hip and -1.19% at lumbosacral [LS] spine at 2 years). However, only a small number of women were studied post-discontinuation for the full 2 years. Clark12 followed women for up to 18 months after discontinuation and found that those who had used DMPA still had significantly lower BMD (-4.7% at the hip and -2.9% at the spine).
These studies established that bone density decreases with the initiation of DMPA, but none of them addressed the key issue of whether BMD remains at lower levels long term (ie, decades) and thereby increases future fracture risk.
Studies of adolescents. Fewer studies have examined the relationship between DMPA use and BMD in adolescents ( TABLE 2 ). Most available studies have small sample sizes and methodological limitations (high dropout rates, different age criteria, and significant differences in the comparison groups). In this population, DMPA seems to cause a mild decrease in BMD. There are not enough data to evaluate BMD recovery after DMPA discontinuation. Therefore, it is hard to extrapolate the information about BMD in an adolescent to future fracture risk.
One study examined serum estradiol levels and BMD in 22 adolescents ages 15 to 19 years who were new users of DMPA.16 Only 6 participants were still using DMPA at 1 year, and 4 used it throughout the 2 years of the study. The trend over 2 years was toward decreasing BMD. Serum estradiol levels were low, but were not correlated with BMD.
Another related study measured bone biochemical markers in 3 groups: 53 adolescents ages 12 to 18 starting DMPA; 165 adolescents starting oral contraceptive pills; and 152 adolescent women not using hormonal contraception.17 There was no relationship between bone biochemical markers and BMD at either the LS spine or the femoral neck.
TABLE 1
DMPA’s effect on BMD in adult women: What the studies reveal
| AUTHOR (TYPE OF STUDY) | # OF PARTICIPANTS/ POPULATION DESCRIPTION | OUTCOME MEASURE | RESULTS | COMMENTS |
|---|---|---|---|---|
| Gbolade, 199824 (cross-sectional) | N=185 Ages 17-52 (mean 33) Using DMPA for 1-16 years | DEXA of LS spine and femoral neck | Z-score lower at LS spine (P<.001) but not at the femoral neck (P=.25) | No significant association between duration of DMPA use and Z-score |
| Ryan, 200225 (cross-sectional) | N=32 Ages 19-53 Using DMPA >2 years Low serum estradiol level or menopausal symptoms | DEXA of LS spine and femoral neck | Z-scores were lower at both femoral neck (-0.84; 95% confidence interval [CI], -1.17 to -0.52) and LS spine (-0.32; 95% CI, -0.62 to -0.02) | 18 women had osteopenia at LS spine 3 women had osteoporosis at LS spine |
| Petitti, 200026 (cross-sectional) | n=350 (DMPA) n=695 (control) Ages 30-34 Using DMPA ≥2 years Control group: women who never used hormonal contraception | SXA of wrist | BMD was lower for DMPA current users vs nonusers 0.465 vs 0.471 g/cm2 in midshaft ulna (P<.001) 0.369 vs 0.382 g/cm2 in distal radius (P<.001) | Large WHO-sponsored, multinational study Past users of DMPA had bone densities not significantly different from nonusers Large variations in BMD among sites |
| Wanichsetakul, 200227 (cross-sectional) | n=34 (DMPA) n=62 (comparison) Ages 30-34 Using DMPA ≥2 years Comparison groups of women on no steroid contraception in prior 6 months | DEXA of LS spine, distal radius, and femoral neck | BMD at femoral neck and distal radius was not different between DMPA users and controls (P=.335 and P=.398) DMPA users had lower BMD at LS spine (P=.007) | Study conducted in Thailand |
| Beksinska, 200528 (cross-sectional) | n=127 (DMPA) n=161 (comparison) Ages 40-49 Using DMPA ≥1 year | DEXA of radius and ulna | No significant difference in BMD at distal radius (P=.26) or ulna (P=.21) | Higher BMD was associated with higher BMI Higher FSH levels were associated with lower BMD |
| Tang, 200029 (cohort) | N=59 Ages 37-49 Using DMPA for a mean of 10 years | DEXA of LS spine and femoral neck Annual measurements for 3 years | Small annual decreases in BMD at LS spine (-0.44%), femoral neck (-0.4%), and Ward’s triangle (-1.05%) | Duration of DMPA use not related to BMD Decreases in BMD less than projected for age Study conducted in China |
| Scholes, 200213 (cohort) | n=183 (DMPA) n=258 (comparison) Ages 18-39 Comparison group not exposed to DMPA | DEXA of LS spine and proximal femur Measurements every 6 months for 4 years | Total hip and LS spine BMD were lower for DMPA users (P=.002 at LS spine; P<.005 for proximal femur) | New users lost bone faster than longer-term users Women who discontinued DMPA showed increasing BMD levels, which reached levels of nonusers after 30 months 33% dropout rate among both groups at 3 years, 44% of DMPA users discontinued use within first 6 months of the study |
| Cundy, 199411 (cohort) | n=36 (DMPA) n=18 (comparison) Ages 25-51 (mean 41-45) 14 women had used DMPA for ≥3 years and discontinued 22 women were long-term DMPA users Individuals in comparison group were never users of DMPA | DEXA of LS spine and femoral neck Measured twice in each woman | Group I (discontinuers) BMD change at LS spine 3.4% per year (1.6% to 5.2%) and at femoral neck 0.8% per year (-1.8% to 3.4%) Group II (long-term users) BMD change at LS spine -0.2% per year (-2.0% to 1.6%) and at femoral neck -1.1% per year (-2.6% to 0.4%) Group III (nonusers) BMD change at LS spine 0.3% per year (-2.2% to 2.8%) and at femoral neck -1.5% per year (-3.2% to 0.2%) | BMD in LS spine in both groups of DMPA users was 9% lower than control group at baseline |
| Berenson, 200130 (cohort) | n=33 (DMPA) n=59 (comparison) Ages 18-33 New users of DMPA Comparison group not using any hormonal contraception | DEXA at LS spine 2 measurements for each participant 12 months apart | Adjusted percent change in BMD for DMPA users was -2.7% (-4.44% to -1.05%) and in nonusers was -0.37% (-1.98% to 1.25%), P=.01 | 39% dropout rate among both groups |
| Merki-Feld, 200031 (cohort) | N=36 Ages 30-45 Using DMPA ≥6 months | Quantitative CT of radius Measured twice over 12 months | Trabecular bone mass increased 1.6% (P=.8) Cortical bone mass decreased 0.6% (P<.04) | Duration of DMPA use was not associated with BMD change |
| Clark, 200414 (cohort) | n=178 (DMPA) n=145 (comparison) Ages 18-35 New users of DMPA Comparison group not using hormonal contraception | DEXA of LS spine and total hip Measured every 3 months for 2 years | At 24 months, change in BMD in DMPA users was -5.8% (SE=0.096) at hip and -5.7% (SE=0.034) at LS spine Significant difference between DMPA group and comparison group (P=.001) | Dropout rate 22% in both groups over 2 years Duration of use predicted decrease in BMD Among DMPA users, increasing BMI was protective against BMD loss at hip |
| Kaunitz, 200615 (cohort) | n=248 (DMPA) n=360 (comparison) Ages 25-35 New users of DMPA Comparison group not using hormonal contraception | DEXA LS spine, total hip, femoral neck, and trochanter Measured at baseline and every 48 weeks for up to 5 years | Mean decrease in BMD in DMPA users was 5.16% (±3.6) at hip and 5.38% (±3.57) at LS spine At 96 weeks after discontinuation, change was -0.20% at hip and -1.19% at LS spine | Decreases in BMD were linearly associated with duration of use up to 5 years 17% of DMPA group and 33% of comparison group completed entire 5 years of study |
| Clark, 200612 (cohort) | n=178 (DMPA) n=145 (comparison) Ages 18-35 New DMPA users Comparison group not using hormonal contraception | DEXA total hip and LS spine Measured every 3 months for up to 4 years | Mean change in BMD in DMPA users was -7.7% (±0.11) at hip and -6.4% (±0.36) at LS spine DMPA users of 24-36 months had BMD of -4.7% (hip) and -2.9% (spine) compared with baseline 18 months after discontinuation | Most loss was noted first 2 years after initiation of DMPA Most users of DMPA up to 2 years returned to baseline BMD by 3 years 36% dropout rate in both groups after second year of study Only 45% of DMPA group completed 4 years of study |
| BMD, bone mineral density; BMI, body mass index; CT, computed tomography; DEXA, dual-energy x-ray absorptiometry; DMPA, depot- medroxyprogesterone acetate; FSH, follicle-stimulating hormone; LS, lumbosacral; SE, standard error; SXA, single-energy x-ray absorptiometry; WHO, World Health organization. | ||||
TABLE 2
DMPA’s effect on BMD in adolescent women: What the studies reveal
| AUTHOR (TYPE OF STUDY) | # OF PARTICIPANTS/ POPULATION DESCRIPTION | OUTCOME MEASURE | RESULTS | COMMENTS |
|---|---|---|---|---|
| Scholes, 200432 (cross-sectional) | n=81 (DMPA) n=93 (comparison) Ages 14-18 Current users of DMPA, range of 1-13 injections (mean 3) | DEXA proximal femur and LS spine | Neither total hip (P=.1) nor spine (P=.19) BMD was significantly lower in DMPA users | 17 non-DMPA users were taking OCPs DMPA users were more likely to be African American and to have a previous pregnancy |
| Beksinska, 200733 (cohort) | n=115 (DMPA) n=144 (comparison) Ages 15-19 New users of DMPA Comparison group not using hormonal contraception | DEXA of distal radius and ulna | No significant difference in BMD between groups (P=.88) | 51 DMPA users completed the study vs 91 nonusers of hormonal contraception Majority of cohort was African American |
| Cromer, 200434 (cohort) | n=53 (DMPA) n=152 (comparison) Ages 12-18 New users of DMPA Comparison group not using hormonal contraception | DEXA of femoral neck and LS spine Measured at baseline, 6 months, and 12 months | LS spine BMD decreased in DMPA group 1.4% and increased in control group 3.8% (P<.001); femoral neck BMD decreased in DMPA group 2.2% and increased in control group 2.3% (P<.001) | 45% dropout rate by 12 months in the DMPA group |
| Lara-Torre, 200435 (cohort) | n=58 (DMPA) n=19 (comparison) Ages 12-21 New DMPA users Comparison group ages 15-19 not using any hormonal contraception | DEXA of LS spine Measured at baseline and every 6 months for 2 years | DMPA group had significantly more BMD changes than control group at each check: -3.02% at 6 months (P=.014); -3.38% at 12 months (P=.001); -4.81% at 18 months (P<.001); -6.81% at 24 months (P=.01) | DMPA group was more likely to be African American DMPA group had dropout rates of 54% at 12 months and 64% at 24 months |
| Scholes, 200536 (cohort) | n=80 (DMPA) n=90 (comparison) Ages 14-18 Baseline users of DMPA (duration of use from 1 to 13 injections) | DEXA of hip, spine, and whole body Measured at baseline and every 6 months for 24-36 months | Significant BMD decreases in DMPA users at each check vs comparison group in hip and spine (P=.001), but not in whole-body BMD (P=.78) Most discontinuers had regained BMD back to baseline by 12 months | 18.9% of non-DMPA users were taking OCPs 61 participants discontinued DMPA during the study DMPA group more likely to smoke and to have been pregnant |
| BMD, bone mineral density; DEXA, dual-energy x-ray absorptiometry; DMPA, depot-medroxyprogesterone acetate; LS, lumbosacral; OCPs, oral contraceptive pills. | ||||
Can estrogen therapy counteract DMPA’s effect?
If decreased BMD in women taking DMPA is due to low estradiol levels, it is logical that a trial of estradiol supplementation would mitigate the negative effect. Indeed, a bone-protective effect of supplemental estrogen therapy has been found in studies of young women with amenorrhea secondary to the female athlete triad. Similarly, in postmenopausal women with low serum estradiol levels, supplemental estrogen therapy helps maintain BMD.18
Two randomized trials have evaluated the use of supplemental estrogen on the adverse effects of DMPA on bone.19,20 The trial by Cromer et al19 randomized 123 adolescent women ages 12 to 18 to receive either estrogen supplementation or placebo. They found that the participants in the estrogen group had BMD gains vs BMD losses among those in the placebo group over the 2-year period of the study (2.8% vs -1.8% at the LS spine, and 4.7% vs -5.1% at the femoral neck; P<.001 for both). The limitations to this study include a high dropout rate (53 participants had left by 24 months) and incomplete data collection due to early stoppage of the study.
Cundy et al20 studied 38 adult women who had been on DMPA for at least 2 years and had below-average LS spine BMD. Nineteen women were randomized to receive estrogen supplementation and underwent bone density tests every 6 months; 19 women were also in the comparison placebo group. In the estrogen supplementation group, there was significant attenuation of lowering BMD that increased throughout the trial. However, only 26 subjects completed the 2-year study.
Limit DMPA use to 2 years? Experts disagree
The FDA, in 2004, placed a black box warning on DMPA: “Women who use Depo-Provera Contraceptive Injection may lose significant bone mineral density. Bone loss is greater with increasing duration of use and may not be completely reversible. It is unknown if use of Depo-Provera Contraceptive Injection during adolescence or early adulthood, a critical period of bone accretion, will reduce peak bone mass and increase the risk of osteoporotic fracture later in life. Depo-Provera Contraceptive Injection should be used as a long-term birth control method (eg, longer than 2 years) only if other birth-control methods are inadequate.”21 In light of these FDA guidelines, many practitioners have started limiting patients’ use of DMPA to 2 years.
The Society of Adolescent Medicine has produced clinical guidelines for treating adolescents who do well on DMPA for contraception (SOR: C, expert opinion).22 The guidelines recommend, among other things, that physicians:
- continue prescribing DMPA to adolescent girls needing contraception, while providing adequate explanation of benefits and potential risks.
- consider ordering a dual-energy x-ray absorptiometry (DEXA) scan to evaluate a patient’s risk.
- keep in mind that duration of use need not be restricted to 2 years.
- recommend 1300 mg calcium plus 400 IU vitamin D and daily exercise to all adolescents receiving DMPA.
- consider estrogen supplementation in those girls with osteopenia (or those at high risk of osteopenia who have not had a DEXA scan) who are otherwise doing well on DMPA and have no contraindication to estrogen.
The World Health Organization similarly published recommendations stating that no restriction should be placed on the use of DMPA due to bone effects (SOR: C, expert opinion).23
Formulate a reasonable approach
As with any other potentially harmful medication, weigh the risks and benefits of DMPA for the individual patient. It is unclear whether BMD lost during DMPA use completely recovers or even what the time frame for that recovery is. Whether the potential risk for future fracture is increased is unknown, but it certainly is cause for concern. Discuss potential risks with any woman who wants to use DMPA for contraception. Routine calcium and vitamin D supplementation for women using DMPA may be helpful and is unlikely to be harmful.
A search of PubMed, the Cochrane database, and all references from primary reviewed articles was performed in 2007 using the terms depot-medroxyprogesterone acetate, bone mineral density, osteoporosis, osteopenia, injectable contraception, progestin-only contraception, Depo-Provera, and DMPA. Studies qualified for analysis if they contained data about bone density in women who had used some type of progestin-only injectable contraception. All types of studies were included. Excluded were studies that did not use BMD as an outcome measure or that re-analyzed data published elsewhere.
Bone mineral density is traditionally used as a surrogate measure of fracture risk in postmenopausal women. However, most of the women included in the reviewed studies were young and at low risk of fracture. The relationship between bone density in premenopausal women and fracture risk later in life is unclear. There are no available studies relating injectable progestin-only contraception with future osteoporotic fractures.
There is not enough evidence to recommend for or against routine screening of BMD in long-term users of DMPA. Research should evaluate the efficacy of estrogen supplementation in women on prolonged DMPA. Long-term studies could provide more information regarding BMD recovery over several years.
Correspondence
Sarina Schrager, MD, MS, Department of Family Medicine, University of Wisconsin, 777 South Mills Street, Madison, WI 53715; sbschrag@wisc.edu
1. Piccinino LJ, Mosher WK. Trends in contraceptive use in the United States: 1982-1995. Fam Plann Perspect. 1998;30:4-10.
2. Donovan P. Falling teen pregnancy, birthrates. What’s behind the declines? The Guttmacher Report on Public Policy. 1998;1(5).-
3. Cundy T, Evans M, Roberts H. Bone density in women receiving depot medroxyprogesterone acetate for contraception. BMJ. 1991;303:13-16.
4. Soyka LA, Fairfield WP, Klibanski A. Hormonal determinants and disorders of peak bone mass in children. J Clin Endocrinol Metab. 2000;85:3951-3963.
5. Tudor-locke C, McColl RS. Factors related to variation in premenopausal bone mineral status: a health promotion approach. Osteoporos Int. 2000;11:1-24.
6. Bachrach LK, Katzman DK, Litt IF, et al. Recovery from osteopenia in adolescent girls with anorexia nervosa. J Clin Endocrinol Metab. 1991;72:602-606.
7. Miller KK, Lee EE, Lawson Ea, et al. Determinants of skeletal loss and recovery in anorexia nervosa. J Clin Endocrinol Metab. 2006;91:2931-2937.
8. Silva HG, Tortora RP, Farias ML. Increased bone turnover during the third trimester of pregnancy and decreased bone mineral density after parturition in adolescents as compared to age-matched control patients. Gynecol Endocrinol. 2005;21:174-179.
9. Ulrich U, Miller PB, Eyre DR, et al. Bone remodeling and bone mineral density during pregnancy. Arch Gynecol Obstet. 2003;268:309-316.
10. Lloyd T, Beck TJ, Lin HM, et al. Modifiable determinants of bone status in young women. Bone. 2002;30:416-421.
11. Cundy T, Cornish J, Evans MC, et al. Recovery of bone density in women who stop using medroxyprogesterone acetate. BMJ. 1994;308:247-248.
12. Clark MK, Sowers M, Levy B, et al. Bone mineral density loss and recovery during 48 months in first-time users of depot medroxyprogesterone acetate. Fertil Steril. 2006;86:1466-1474.
13. Scholes D, LaCroix A Z, Ichikawa LE, et al. Injectable hormone contraception and bone density: results from a prospective study [erratum appears in Epidemiology.2002;13:749]. Epidemiology. 2002;13:581-587.
14. Clark MK, Sowers MR, Nichols S, et al. Bone mineral density changes over two years in first-time users of depot medroxyprogesterone acetate. Fertil Steril. 2004;82:1580-1586.
15. Kaunitz AM, Miller PD, Rice VM, et al. Bone mineral density in women aged 25-35 years receiving depot medroxyprogesterone acetate: recovery following discontinuation. Contraception. 2006;74:90-99.
16. Busen NH, Britt RB, Rianon N. Bone mineral density in a cohort of adolescent women using depot medroxyprogesterone acetate for one to two years. Adolesc Health. 2003;32:257-259.
17. Rome E, Ziegler J, Secic M, et al. Bone biochemical markers in adolescent girls using either depot medroxyprogesterone acetate or an oral contraceptive [see comment]. J Pediatr Adolesc Gynecol. 2004;17:373-377.
18. Cumming DC. Exercise associated amenorrhea, low bone density, and estrogen replacement therapy. Arch Intern Med. 1996;156:2193-2195.
19. Cromer B, Lazebnik R, Rome E, et al. Double-blinded randomized controlled trial of estrogen supplementation in adolescent girls who receive depot medroxyprogesterone acetate for contraception. Am J Obstet. Gynecol. 2005;192:42-47.
20. Cundy T, Ames R, Horne A, et al. A randomized controlled trial of estrogen replacement therapy in long-term users of depot medroxyprogesterone acetate. J Clin Endocrinol Metab. 2003;88:78-81.
21. U.S. Food and Drug Administration. Black box warning added concerning long-term use of Depo-Provera Contraceptive Injection. 2004. Available at: http://www.fda.gov/bbs/topics/ANSWERS/2004/ANS01325.html. Accessed April 7, 2009.
22. Cromer BA, Scholes D, Berenson A, et al. Depot medroxyprogesterone acetate and bone mineral density in adolescents: the black box warning: a position paper of the Society for Adolescent Medicine. Adolesc Health. 2006;39:296-301.
23. d’Arcanques D. WHO statement on hormonal contraception and bone health. Contraception. 2006;73:443-444.
24. Gbolade B, Ellis S, Murby B, et al. Bone density in long term users of depot medroxyprogesterone acetate. Brit J Obstet Gynaecol. 1998;105:790-794.
25. Ryan PJ, Singh SP, Guillebaud J. Depot medroxyprogesterone and bone mineral density. J Fam Plann Reproduct Health Care. 2002;28:12-15.
26. Petitti DB, Piaggio G, Mehta S, et al. 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. 2000;95:736-744.
27. Wanichsetakul P, Kamudhamas A, Watanaruangkovit P, et al. Bone mineral density at various anatomic bone sites in women receiving combined oral contraceptives and depot-medroxyprogesterone acetate for contraception. Contraception. 2002;65:407-410.
28. Beksinska ME, Smit JA, Kleinschmidt I, et al. Bone mineral density in women aged 40-49 years using depot-medroxyprogesterone acetate, norethisterone enanthate or combined oral contraceptives for contraception. Contraception. 2005;71:170-175.
29. Tang OS, Tang G, YIP PS, et al. Further evaluation on long-term depot-medroxyprogesterone acetate use and bone mineral density: a longitudinal cohort study. Contraception. 2000;62:161-164.
30. Berenson AB, Radecki CM, Grady JJ, et al. A prospective, controlled study of the effects of hormonal contraception on bone mineral density. Obstet Gynecol. 2001;98:576-582.
31. Merki-Feld GS, Neff M, Keller PJ. A prospective study on the effects of depot medroxyprogesterone acetate on trabecular and cortical bone after attainment of peak bone mass. BJOG. 2000;107:863-869.
32. Scholes D, LaCroix AZ, Ichikawa LE, et al. The association between depot medroxyprogesterone acetate contraception and bone mineral density in adolescent women. Contraception. 2004;69:99-104.
33. Beksinska ME, Kleinschmidt I, Smit JA, et al. Bone mineral density in adolescents using norethisterone enanthate, depot-medroxyprogesterone acetate or combined oral contraceptives for contraception. Contraception. 2007;75:438-443.
34. Cromer BA, Stager M, Bonny A, et al. Depot medroxyprogesterone acetate, oral contraceptives and bone mineral density in a cohort of adolescent girls [see comment]. Adolesc Health. 2004;35:434-441.
35. Lara-Torre E, Edwards CP, Perlman S, et al. Bone mineral density in adolescent females using depot medroxyprogesterone acetate. J Pediatr Adolesc Gynecol. 2004;17:17-21.
36. Scholes D, LaCroix AZ, Ichikawa LE, et al. Change in bone mineral density among adolescent women using and discontinuing depot medroxyprogesterone acetate contraception. Arch Pediatr Adolesc Med. 2005;159:139-144.
- Discuss the potential for decreased bone mineral density in using depot-medroxyprogesterone acetate (DMPA) with any woman who is thinking of it as a means of contraception (C).
- Recommend to women that they take 1300 mg of calcium and 400 IU of vitamin D when using DMPA (C).
- Consider prescribing estrogen replacement if DMPA is going to be used for more than 2 years (C).
Strength of recommendation (SOR)
- Good-quality patient-oriented evidence
- Inconsistent or limited-quality patient-oriented evidence
- Consensus, usual practice, opinion, disease-oriented evidence, case series
Among adolescent women who use contraception, the injectable progestin-only depot-medroxyprogesterone acetate (DMPA, Depo-Provera) is second in popularity only to oral contraceptive pills.1 A very real drawback with DMPA, however, is a resultant hypoestrogenic state that has been linked to lowered bone mineral density (BMD).
Although several studies have demonstrated a relationship between DMPA use and lower BMD among adults and adolescents (strength of recommendation [SOR]: B), many of them had small sample sizes and methodological flaws. Moreover, most studies have shown that BMD change is reversible after discontinuation of DMPA.
Experts recommend counseling young women about DMPA’s possible effects on bone. But they caution against limiting its use based on the insufficient research to date (SOR: C). Analysts estimate that the availability of DMPA has contributed significantly to decreased adolescent pregnancy rates in the United States over the last 10 years.2 This article reports on a systematic review of the literature concerning DMPA and BMD.
Reason for concern
A 1991 study by Cundy et al3 was the first to examine the relationship between DMPA and BMD and found that DMPA users had significantly lower BMD than nonusers. DMPA delivers high doses of progestin and inhibits ovulation in most women. Consequently, DMPA can decrease serum estradiol levels. Low serum estradiol levels have also been linked to lower BMD levels in women who are in menopause or who have eating disorders.
Adolescence is a time of bone building. The chief reason for interest in the association between DMPA and decreased BMD is the potential risk of future osteoporosis and osteoporotic fractures for women using DMPA during adolescence. A mature woman’s BMD at any given time is related to her peak bone mass and subsequent rate of decline. Ninety percent of peak bone mass (the highest level of BMD achieved during one’s lifetime) is determined by age 18 in women.4 Between the ages of 18 and 30, women gain the last 10% of their maximum bone density. After age 30, bone resorption outpaces bone formation and women start to lose bone slowly.5 This decline continues until menopause, when women experience a more rapid decline in BMD related to sudden withdrawal of estrogen.
Factors that affect peak BMD. Several factors influence the level of peak bone mass a woman will reach—genetics, race, hormonal milieu, and lifestyle factors.4,5 As for lifestyle, it’s been shown that both anorexia and the female athlete triad cause low estrogen levels, and the resultant loss of BMD may not be recovered.6,7
Pregnancy, too, is known to be a state of increased bone turnover and resorption,8,9 and pregnancy during adolescence may also negatively impact BMD. A small 2002 study compared teenagers who had been pregnant with age-matched controls who had not been pregnant, and found that hip bone density in the adolescent mothers was lower by approximately 10%.10
Use of bone-affecting medications by adolescents is worrisome because they are still building bone at a high rate.
What the literature tells us
Studies of adult women. Studies examining the relationship between DMPA use and BMD have yielded varying results ( TABLE 1 ). Most of them show that using DMPA over a course of 2 years decreases BMD by 5% to 10%. New users have the most significant decreases in BMD, suggesting the decline levels off after 2 years of use (SOR: B).11-13 However, most early studies were cross-sectional and small, and thus had limited power to determine causality. In addition, these trials were not randomized, and they may have suffered from bias because treatment groups were volunteers.
Three recent prospective studies12,14,15 found that bone density losses recover after discontinuation of DMPA. Kaunitz15 followed women for up to 2 years after DMPA discontinuation and found that BMD recovered almost completely (-0.2% at hip and -1.19% at lumbosacral [LS] spine at 2 years). However, only a small number of women were studied post-discontinuation for the full 2 years. Clark12 followed women for up to 18 months after discontinuation and found that those who had used DMPA still had significantly lower BMD (-4.7% at the hip and -2.9% at the spine).
These studies established that bone density decreases with the initiation of DMPA, but none of them addressed the key issue of whether BMD remains at lower levels long term (ie, decades) and thereby increases future fracture risk.
Studies of adolescents. Fewer studies have examined the relationship between DMPA use and BMD in adolescents ( TABLE 2 ). Most available studies have small sample sizes and methodological limitations (high dropout rates, different age criteria, and significant differences in the comparison groups). In this population, DMPA seems to cause a mild decrease in BMD. There are not enough data to evaluate BMD recovery after DMPA discontinuation. Therefore, it is hard to extrapolate the information about BMD in an adolescent to future fracture risk.
One study examined serum estradiol levels and BMD in 22 adolescents ages 15 to 19 years who were new users of DMPA.16 Only 6 participants were still using DMPA at 1 year, and 4 used it throughout the 2 years of the study. The trend over 2 years was toward decreasing BMD. Serum estradiol levels were low, but were not correlated with BMD.
Another related study measured bone biochemical markers in 3 groups: 53 adolescents ages 12 to 18 starting DMPA; 165 adolescents starting oral contraceptive pills; and 152 adolescent women not using hormonal contraception.17 There was no relationship between bone biochemical markers and BMD at either the LS spine or the femoral neck.
TABLE 1
DMPA’s effect on BMD in adult women: What the studies reveal
| AUTHOR (TYPE OF STUDY) | # OF PARTICIPANTS/ POPULATION DESCRIPTION | OUTCOME MEASURE | RESULTS | COMMENTS |
|---|---|---|---|---|
| Gbolade, 199824 (cross-sectional) | N=185 Ages 17-52 (mean 33) Using DMPA for 1-16 years | DEXA of LS spine and femoral neck | Z-score lower at LS spine (P<.001) but not at the femoral neck (P=.25) | No significant association between duration of DMPA use and Z-score |
| Ryan, 200225 (cross-sectional) | N=32 Ages 19-53 Using DMPA >2 years Low serum estradiol level or menopausal symptoms | DEXA of LS spine and femoral neck | Z-scores were lower at both femoral neck (-0.84; 95% confidence interval [CI], -1.17 to -0.52) and LS spine (-0.32; 95% CI, -0.62 to -0.02) | 18 women had osteopenia at LS spine 3 women had osteoporosis at LS spine |
| Petitti, 200026 (cross-sectional) | n=350 (DMPA) n=695 (control) Ages 30-34 Using DMPA ≥2 years Control group: women who never used hormonal contraception | SXA of wrist | BMD was lower for DMPA current users vs nonusers 0.465 vs 0.471 g/cm2 in midshaft ulna (P<.001) 0.369 vs 0.382 g/cm2 in distal radius (P<.001) | Large WHO-sponsored, multinational study Past users of DMPA had bone densities not significantly different from nonusers Large variations in BMD among sites |
| Wanichsetakul, 200227 (cross-sectional) | n=34 (DMPA) n=62 (comparison) Ages 30-34 Using DMPA ≥2 years Comparison groups of women on no steroid contraception in prior 6 months | DEXA of LS spine, distal radius, and femoral neck | BMD at femoral neck and distal radius was not different between DMPA users and controls (P=.335 and P=.398) DMPA users had lower BMD at LS spine (P=.007) | Study conducted in Thailand |
| Beksinska, 200528 (cross-sectional) | n=127 (DMPA) n=161 (comparison) Ages 40-49 Using DMPA ≥1 year | DEXA of radius and ulna | No significant difference in BMD at distal radius (P=.26) or ulna (P=.21) | Higher BMD was associated with higher BMI Higher FSH levels were associated with lower BMD |
| Tang, 200029 (cohort) | N=59 Ages 37-49 Using DMPA for a mean of 10 years | DEXA of LS spine and femoral neck Annual measurements for 3 years | Small annual decreases in BMD at LS spine (-0.44%), femoral neck (-0.4%), and Ward’s triangle (-1.05%) | Duration of DMPA use not related to BMD Decreases in BMD less than projected for age Study conducted in China |
| Scholes, 200213 (cohort) | n=183 (DMPA) n=258 (comparison) Ages 18-39 Comparison group not exposed to DMPA | DEXA of LS spine and proximal femur Measurements every 6 months for 4 years | Total hip and LS spine BMD were lower for DMPA users (P=.002 at LS spine; P<.005 for proximal femur) | New users lost bone faster than longer-term users Women who discontinued DMPA showed increasing BMD levels, which reached levels of nonusers after 30 months 33% dropout rate among both groups at 3 years, 44% of DMPA users discontinued use within first 6 months of the study |
| Cundy, 199411 (cohort) | n=36 (DMPA) n=18 (comparison) Ages 25-51 (mean 41-45) 14 women had used DMPA for ≥3 years and discontinued 22 women were long-term DMPA users Individuals in comparison group were never users of DMPA | DEXA of LS spine and femoral neck Measured twice in each woman | Group I (discontinuers) BMD change at LS spine 3.4% per year (1.6% to 5.2%) and at femoral neck 0.8% per year (-1.8% to 3.4%) Group II (long-term users) BMD change at LS spine -0.2% per year (-2.0% to 1.6%) and at femoral neck -1.1% per year (-2.6% to 0.4%) Group III (nonusers) BMD change at LS spine 0.3% per year (-2.2% to 2.8%) and at femoral neck -1.5% per year (-3.2% to 0.2%) | BMD in LS spine in both groups of DMPA users was 9% lower than control group at baseline |
| Berenson, 200130 (cohort) | n=33 (DMPA) n=59 (comparison) Ages 18-33 New users of DMPA Comparison group not using any hormonal contraception | DEXA at LS spine 2 measurements for each participant 12 months apart | Adjusted percent change in BMD for DMPA users was -2.7% (-4.44% to -1.05%) and in nonusers was -0.37% (-1.98% to 1.25%), P=.01 | 39% dropout rate among both groups |
| Merki-Feld, 200031 (cohort) | N=36 Ages 30-45 Using DMPA ≥6 months | Quantitative CT of radius Measured twice over 12 months | Trabecular bone mass increased 1.6% (P=.8) Cortical bone mass decreased 0.6% (P<.04) | Duration of DMPA use was not associated with BMD change |
| Clark, 200414 (cohort) | n=178 (DMPA) n=145 (comparison) Ages 18-35 New users of DMPA Comparison group not using hormonal contraception | DEXA of LS spine and total hip Measured every 3 months for 2 years | At 24 months, change in BMD in DMPA users was -5.8% (SE=0.096) at hip and -5.7% (SE=0.034) at LS spine Significant difference between DMPA group and comparison group (P=.001) | Dropout rate 22% in both groups over 2 years Duration of use predicted decrease in BMD Among DMPA users, increasing BMI was protective against BMD loss at hip |
| Kaunitz, 200615 (cohort) | n=248 (DMPA) n=360 (comparison) Ages 25-35 New users of DMPA Comparison group not using hormonal contraception | DEXA LS spine, total hip, femoral neck, and trochanter Measured at baseline and every 48 weeks for up to 5 years | Mean decrease in BMD in DMPA users was 5.16% (±3.6) at hip and 5.38% (±3.57) at LS spine At 96 weeks after discontinuation, change was -0.20% at hip and -1.19% at LS spine | Decreases in BMD were linearly associated with duration of use up to 5 years 17% of DMPA group and 33% of comparison group completed entire 5 years of study |
| Clark, 200612 (cohort) | n=178 (DMPA) n=145 (comparison) Ages 18-35 New DMPA users Comparison group not using hormonal contraception | DEXA total hip and LS spine Measured every 3 months for up to 4 years | Mean change in BMD in DMPA users was -7.7% (±0.11) at hip and -6.4% (±0.36) at LS spine DMPA users of 24-36 months had BMD of -4.7% (hip) and -2.9% (spine) compared with baseline 18 months after discontinuation | Most loss was noted first 2 years after initiation of DMPA Most users of DMPA up to 2 years returned to baseline BMD by 3 years 36% dropout rate in both groups after second year of study Only 45% of DMPA group completed 4 years of study |
| BMD, bone mineral density; BMI, body mass index; CT, computed tomography; DEXA, dual-energy x-ray absorptiometry; DMPA, depot- medroxyprogesterone acetate; FSH, follicle-stimulating hormone; LS, lumbosacral; SE, standard error; SXA, single-energy x-ray absorptiometry; WHO, World Health organization. | ||||
TABLE 2
DMPA’s effect on BMD in adolescent women: What the studies reveal
| AUTHOR (TYPE OF STUDY) | # OF PARTICIPANTS/ POPULATION DESCRIPTION | OUTCOME MEASURE | RESULTS | COMMENTS |
|---|---|---|---|---|
| Scholes, 200432 (cross-sectional) | n=81 (DMPA) n=93 (comparison) Ages 14-18 Current users of DMPA, range of 1-13 injections (mean 3) | DEXA proximal femur and LS spine | Neither total hip (P=.1) nor spine (P=.19) BMD was significantly lower in DMPA users | 17 non-DMPA users were taking OCPs DMPA users were more likely to be African American and to have a previous pregnancy |
| Beksinska, 200733 (cohort) | n=115 (DMPA) n=144 (comparison) Ages 15-19 New users of DMPA Comparison group not using hormonal contraception | DEXA of distal radius and ulna | No significant difference in BMD between groups (P=.88) | 51 DMPA users completed the study vs 91 nonusers of hormonal contraception Majority of cohort was African American |
| Cromer, 200434 (cohort) | n=53 (DMPA) n=152 (comparison) Ages 12-18 New users of DMPA Comparison group not using hormonal contraception | DEXA of femoral neck and LS spine Measured at baseline, 6 months, and 12 months | LS spine BMD decreased in DMPA group 1.4% and increased in control group 3.8% (P<.001); femoral neck BMD decreased in DMPA group 2.2% and increased in control group 2.3% (P<.001) | 45% dropout rate by 12 months in the DMPA group |
| Lara-Torre, 200435 (cohort) | n=58 (DMPA) n=19 (comparison) Ages 12-21 New DMPA users Comparison group ages 15-19 not using any hormonal contraception | DEXA of LS spine Measured at baseline and every 6 months for 2 years | DMPA group had significantly more BMD changes than control group at each check: -3.02% at 6 months (P=.014); -3.38% at 12 months (P=.001); -4.81% at 18 months (P<.001); -6.81% at 24 months (P=.01) | DMPA group was more likely to be African American DMPA group had dropout rates of 54% at 12 months and 64% at 24 months |
| Scholes, 200536 (cohort) | n=80 (DMPA) n=90 (comparison) Ages 14-18 Baseline users of DMPA (duration of use from 1 to 13 injections) | DEXA of hip, spine, and whole body Measured at baseline and every 6 months for 24-36 months | Significant BMD decreases in DMPA users at each check vs comparison group in hip and spine (P=.001), but not in whole-body BMD (P=.78) Most discontinuers had regained BMD back to baseline by 12 months | 18.9% of non-DMPA users were taking OCPs 61 participants discontinued DMPA during the study DMPA group more likely to smoke and to have been pregnant |
| BMD, bone mineral density; DEXA, dual-energy x-ray absorptiometry; DMPA, depot-medroxyprogesterone acetate; LS, lumbosacral; OCPs, oral contraceptive pills. | ||||
Can estrogen therapy counteract DMPA’s effect?
If decreased BMD in women taking DMPA is due to low estradiol levels, it is logical that a trial of estradiol supplementation would mitigate the negative effect. Indeed, a bone-protective effect of supplemental estrogen therapy has been found in studies of young women with amenorrhea secondary to the female athlete triad. Similarly, in postmenopausal women with low serum estradiol levels, supplemental estrogen therapy helps maintain BMD.18
Two randomized trials have evaluated the use of supplemental estrogen on the adverse effects of DMPA on bone.19,20 The trial by Cromer et al19 randomized 123 adolescent women ages 12 to 18 to receive either estrogen supplementation or placebo. They found that the participants in the estrogen group had BMD gains vs BMD losses among those in the placebo group over the 2-year period of the study (2.8% vs -1.8% at the LS spine, and 4.7% vs -5.1% at the femoral neck; P<.001 for both). The limitations to this study include a high dropout rate (53 participants had left by 24 months) and incomplete data collection due to early stoppage of the study.
Cundy et al20 studied 38 adult women who had been on DMPA for at least 2 years and had below-average LS spine BMD. Nineteen women were randomized to receive estrogen supplementation and underwent bone density tests every 6 months; 19 women were also in the comparison placebo group. In the estrogen supplementation group, there was significant attenuation of lowering BMD that increased throughout the trial. However, only 26 subjects completed the 2-year study.
Limit DMPA use to 2 years? Experts disagree
The FDA, in 2004, placed a black box warning on DMPA: “Women who use Depo-Provera Contraceptive Injection may lose significant bone mineral density. Bone loss is greater with increasing duration of use and may not be completely reversible. It is unknown if use of Depo-Provera Contraceptive Injection during adolescence or early adulthood, a critical period of bone accretion, will reduce peak bone mass and increase the risk of osteoporotic fracture later in life. Depo-Provera Contraceptive Injection should be used as a long-term birth control method (eg, longer than 2 years) only if other birth-control methods are inadequate.”21 In light of these FDA guidelines, many practitioners have started limiting patients’ use of DMPA to 2 years.
The Society of Adolescent Medicine has produced clinical guidelines for treating adolescents who do well on DMPA for contraception (SOR: C, expert opinion).22 The guidelines recommend, among other things, that physicians:
- continue prescribing DMPA to adolescent girls needing contraception, while providing adequate explanation of benefits and potential risks.
- consider ordering a dual-energy x-ray absorptiometry (DEXA) scan to evaluate a patient’s risk.
- keep in mind that duration of use need not be restricted to 2 years.
- recommend 1300 mg calcium plus 400 IU vitamin D and daily exercise to all adolescents receiving DMPA.
- consider estrogen supplementation in those girls with osteopenia (or those at high risk of osteopenia who have not had a DEXA scan) who are otherwise doing well on DMPA and have no contraindication to estrogen.
The World Health Organization similarly published recommendations stating that no restriction should be placed on the use of DMPA due to bone effects (SOR: C, expert opinion).23
Formulate a reasonable approach
As with any other potentially harmful medication, weigh the risks and benefits of DMPA for the individual patient. It is unclear whether BMD lost during DMPA use completely recovers or even what the time frame for that recovery is. Whether the potential risk for future fracture is increased is unknown, but it certainly is cause for concern. Discuss potential risks with any woman who wants to use DMPA for contraception. Routine calcium and vitamin D supplementation for women using DMPA may be helpful and is unlikely to be harmful.
A search of PubMed, the Cochrane database, and all references from primary reviewed articles was performed in 2007 using the terms depot-medroxyprogesterone acetate, bone mineral density, osteoporosis, osteopenia, injectable contraception, progestin-only contraception, Depo-Provera, and DMPA. Studies qualified for analysis if they contained data about bone density in women who had used some type of progestin-only injectable contraception. All types of studies were included. Excluded were studies that did not use BMD as an outcome measure or that re-analyzed data published elsewhere.
Bone mineral density is traditionally used as a surrogate measure of fracture risk in postmenopausal women. However, most of the women included in the reviewed studies were young and at low risk of fracture. The relationship between bone density in premenopausal women and fracture risk later in life is unclear. There are no available studies relating injectable progestin-only contraception with future osteoporotic fractures.
There is not enough evidence to recommend for or against routine screening of BMD in long-term users of DMPA. Research should evaluate the efficacy of estrogen supplementation in women on prolonged DMPA. Long-term studies could provide more information regarding BMD recovery over several years.
Correspondence
Sarina Schrager, MD, MS, Department of Family Medicine, University of Wisconsin, 777 South Mills Street, Madison, WI 53715; sbschrag@wisc.edu
- Discuss the potential for decreased bone mineral density in using depot-medroxyprogesterone acetate (DMPA) with any woman who is thinking of it as a means of contraception (C).
- Recommend to women that they take 1300 mg of calcium and 400 IU of vitamin D when using DMPA (C).
- Consider prescribing estrogen replacement if DMPA is going to be used for more than 2 years (C).
Strength of recommendation (SOR)
- Good-quality patient-oriented evidence
- Inconsistent or limited-quality patient-oriented evidence
- Consensus, usual practice, opinion, disease-oriented evidence, case series
Among adolescent women who use contraception, the injectable progestin-only depot-medroxyprogesterone acetate (DMPA, Depo-Provera) is second in popularity only to oral contraceptive pills.1 A very real drawback with DMPA, however, is a resultant hypoestrogenic state that has been linked to lowered bone mineral density (BMD).
Although several studies have demonstrated a relationship between DMPA use and lower BMD among adults and adolescents (strength of recommendation [SOR]: B), many of them had small sample sizes and methodological flaws. Moreover, most studies have shown that BMD change is reversible after discontinuation of DMPA.
Experts recommend counseling young women about DMPA’s possible effects on bone. But they caution against limiting its use based on the insufficient research to date (SOR: C). Analysts estimate that the availability of DMPA has contributed significantly to decreased adolescent pregnancy rates in the United States over the last 10 years.2 This article reports on a systematic review of the literature concerning DMPA and BMD.
Reason for concern
A 1991 study by Cundy et al3 was the first to examine the relationship between DMPA and BMD and found that DMPA users had significantly lower BMD than nonusers. DMPA delivers high doses of progestin and inhibits ovulation in most women. Consequently, DMPA can decrease serum estradiol levels. Low serum estradiol levels have also been linked to lower BMD levels in women who are in menopause or who have eating disorders.
Adolescence is a time of bone building. The chief reason for interest in the association between DMPA and decreased BMD is the potential risk of future osteoporosis and osteoporotic fractures for women using DMPA during adolescence. A mature woman’s BMD at any given time is related to her peak bone mass and subsequent rate of decline. Ninety percent of peak bone mass (the highest level of BMD achieved during one’s lifetime) is determined by age 18 in women.4 Between the ages of 18 and 30, women gain the last 10% of their maximum bone density. After age 30, bone resorption outpaces bone formation and women start to lose bone slowly.5 This decline continues until menopause, when women experience a more rapid decline in BMD related to sudden withdrawal of estrogen.
Factors that affect peak BMD. Several factors influence the level of peak bone mass a woman will reach—genetics, race, hormonal milieu, and lifestyle factors.4,5 As for lifestyle, it’s been shown that both anorexia and the female athlete triad cause low estrogen levels, and the resultant loss of BMD may not be recovered.6,7
Pregnancy, too, is known to be a state of increased bone turnover and resorption,8,9 and pregnancy during adolescence may also negatively impact BMD. A small 2002 study compared teenagers who had been pregnant with age-matched controls who had not been pregnant, and found that hip bone density in the adolescent mothers was lower by approximately 10%.10
Use of bone-affecting medications by adolescents is worrisome because they are still building bone at a high rate.
What the literature tells us
Studies of adult women. Studies examining the relationship between DMPA use and BMD have yielded varying results ( TABLE 1 ). Most of them show that using DMPA over a course of 2 years decreases BMD by 5% to 10%. New users have the most significant decreases in BMD, suggesting the decline levels off after 2 years of use (SOR: B).11-13 However, most early studies were cross-sectional and small, and thus had limited power to determine causality. In addition, these trials were not randomized, and they may have suffered from bias because treatment groups were volunteers.
Three recent prospective studies12,14,15 found that bone density losses recover after discontinuation of DMPA. Kaunitz15 followed women for up to 2 years after DMPA discontinuation and found that BMD recovered almost completely (-0.2% at hip and -1.19% at lumbosacral [LS] spine at 2 years). However, only a small number of women were studied post-discontinuation for the full 2 years. Clark12 followed women for up to 18 months after discontinuation and found that those who had used DMPA still had significantly lower BMD (-4.7% at the hip and -2.9% at the spine).
These studies established that bone density decreases with the initiation of DMPA, but none of them addressed the key issue of whether BMD remains at lower levels long term (ie, decades) and thereby increases future fracture risk.
Studies of adolescents. Fewer studies have examined the relationship between DMPA use and BMD in adolescents ( TABLE 2 ). Most available studies have small sample sizes and methodological limitations (high dropout rates, different age criteria, and significant differences in the comparison groups). In this population, DMPA seems to cause a mild decrease in BMD. There are not enough data to evaluate BMD recovery after DMPA discontinuation. Therefore, it is hard to extrapolate the information about BMD in an adolescent to future fracture risk.
One study examined serum estradiol levels and BMD in 22 adolescents ages 15 to 19 years who were new users of DMPA.16 Only 6 participants were still using DMPA at 1 year, and 4 used it throughout the 2 years of the study. The trend over 2 years was toward decreasing BMD. Serum estradiol levels were low, but were not correlated with BMD.
Another related study measured bone biochemical markers in 3 groups: 53 adolescents ages 12 to 18 starting DMPA; 165 adolescents starting oral contraceptive pills; and 152 adolescent women not using hormonal contraception.17 There was no relationship between bone biochemical markers and BMD at either the LS spine or the femoral neck.
TABLE 1
DMPA’s effect on BMD in adult women: What the studies reveal
| AUTHOR (TYPE OF STUDY) | # OF PARTICIPANTS/ POPULATION DESCRIPTION | OUTCOME MEASURE | RESULTS | COMMENTS |
|---|---|---|---|---|
| Gbolade, 199824 (cross-sectional) | N=185 Ages 17-52 (mean 33) Using DMPA for 1-16 years | DEXA of LS spine and femoral neck | Z-score lower at LS spine (P<.001) but not at the femoral neck (P=.25) | No significant association between duration of DMPA use and Z-score |
| Ryan, 200225 (cross-sectional) | N=32 Ages 19-53 Using DMPA >2 years Low serum estradiol level or menopausal symptoms | DEXA of LS spine and femoral neck | Z-scores were lower at both femoral neck (-0.84; 95% confidence interval [CI], -1.17 to -0.52) and LS spine (-0.32; 95% CI, -0.62 to -0.02) | 18 women had osteopenia at LS spine 3 women had osteoporosis at LS spine |
| Petitti, 200026 (cross-sectional) | n=350 (DMPA) n=695 (control) Ages 30-34 Using DMPA ≥2 years Control group: women who never used hormonal contraception | SXA of wrist | BMD was lower for DMPA current users vs nonusers 0.465 vs 0.471 g/cm2 in midshaft ulna (P<.001) 0.369 vs 0.382 g/cm2 in distal radius (P<.001) | Large WHO-sponsored, multinational study Past users of DMPA had bone densities not significantly different from nonusers Large variations in BMD among sites |
| Wanichsetakul, 200227 (cross-sectional) | n=34 (DMPA) n=62 (comparison) Ages 30-34 Using DMPA ≥2 years Comparison groups of women on no steroid contraception in prior 6 months | DEXA of LS spine, distal radius, and femoral neck | BMD at femoral neck and distal radius was not different between DMPA users and controls (P=.335 and P=.398) DMPA users had lower BMD at LS spine (P=.007) | Study conducted in Thailand |
| Beksinska, 200528 (cross-sectional) | n=127 (DMPA) n=161 (comparison) Ages 40-49 Using DMPA ≥1 year | DEXA of radius and ulna | No significant difference in BMD at distal radius (P=.26) or ulna (P=.21) | Higher BMD was associated with higher BMI Higher FSH levels were associated with lower BMD |
| Tang, 200029 (cohort) | N=59 Ages 37-49 Using DMPA for a mean of 10 years | DEXA of LS spine and femoral neck Annual measurements for 3 years | Small annual decreases in BMD at LS spine (-0.44%), femoral neck (-0.4%), and Ward’s triangle (-1.05%) | Duration of DMPA use not related to BMD Decreases in BMD less than projected for age Study conducted in China |
| Scholes, 200213 (cohort) | n=183 (DMPA) n=258 (comparison) Ages 18-39 Comparison group not exposed to DMPA | DEXA of LS spine and proximal femur Measurements every 6 months for 4 years | Total hip and LS spine BMD were lower for DMPA users (P=.002 at LS spine; P<.005 for proximal femur) | New users lost bone faster than longer-term users Women who discontinued DMPA showed increasing BMD levels, which reached levels of nonusers after 30 months 33% dropout rate among both groups at 3 years, 44% of DMPA users discontinued use within first 6 months of the study |
| Cundy, 199411 (cohort) | n=36 (DMPA) n=18 (comparison) Ages 25-51 (mean 41-45) 14 women had used DMPA for ≥3 years and discontinued 22 women were long-term DMPA users Individuals in comparison group were never users of DMPA | DEXA of LS spine and femoral neck Measured twice in each woman | Group I (discontinuers) BMD change at LS spine 3.4% per year (1.6% to 5.2%) and at femoral neck 0.8% per year (-1.8% to 3.4%) Group II (long-term users) BMD change at LS spine -0.2% per year (-2.0% to 1.6%) and at femoral neck -1.1% per year (-2.6% to 0.4%) Group III (nonusers) BMD change at LS spine 0.3% per year (-2.2% to 2.8%) and at femoral neck -1.5% per year (-3.2% to 0.2%) | BMD in LS spine in both groups of DMPA users was 9% lower than control group at baseline |
| Berenson, 200130 (cohort) | n=33 (DMPA) n=59 (comparison) Ages 18-33 New users of DMPA Comparison group not using any hormonal contraception | DEXA at LS spine 2 measurements for each participant 12 months apart | Adjusted percent change in BMD for DMPA users was -2.7% (-4.44% to -1.05%) and in nonusers was -0.37% (-1.98% to 1.25%), P=.01 | 39% dropout rate among both groups |
| Merki-Feld, 200031 (cohort) | N=36 Ages 30-45 Using DMPA ≥6 months | Quantitative CT of radius Measured twice over 12 months | Trabecular bone mass increased 1.6% (P=.8) Cortical bone mass decreased 0.6% (P<.04) | Duration of DMPA use was not associated with BMD change |
| Clark, 200414 (cohort) | n=178 (DMPA) n=145 (comparison) Ages 18-35 New users of DMPA Comparison group not using hormonal contraception | DEXA of LS spine and total hip Measured every 3 months for 2 years | At 24 months, change in BMD in DMPA users was -5.8% (SE=0.096) at hip and -5.7% (SE=0.034) at LS spine Significant difference between DMPA group and comparison group (P=.001) | Dropout rate 22% in both groups over 2 years Duration of use predicted decrease in BMD Among DMPA users, increasing BMI was protective against BMD loss at hip |
| Kaunitz, 200615 (cohort) | n=248 (DMPA) n=360 (comparison) Ages 25-35 New users of DMPA Comparison group not using hormonal contraception | DEXA LS spine, total hip, femoral neck, and trochanter Measured at baseline and every 48 weeks for up to 5 years | Mean decrease in BMD in DMPA users was 5.16% (±3.6) at hip and 5.38% (±3.57) at LS spine At 96 weeks after discontinuation, change was -0.20% at hip and -1.19% at LS spine | Decreases in BMD were linearly associated with duration of use up to 5 years 17% of DMPA group and 33% of comparison group completed entire 5 years of study |
| Clark, 200612 (cohort) | n=178 (DMPA) n=145 (comparison) Ages 18-35 New DMPA users Comparison group not using hormonal contraception | DEXA total hip and LS spine Measured every 3 months for up to 4 years | Mean change in BMD in DMPA users was -7.7% (±0.11) at hip and -6.4% (±0.36) at LS spine DMPA users of 24-36 months had BMD of -4.7% (hip) and -2.9% (spine) compared with baseline 18 months after discontinuation | Most loss was noted first 2 years after initiation of DMPA Most users of DMPA up to 2 years returned to baseline BMD by 3 years 36% dropout rate in both groups after second year of study Only 45% of DMPA group completed 4 years of study |
| BMD, bone mineral density; BMI, body mass index; CT, computed tomography; DEXA, dual-energy x-ray absorptiometry; DMPA, depot- medroxyprogesterone acetate; FSH, follicle-stimulating hormone; LS, lumbosacral; SE, standard error; SXA, single-energy x-ray absorptiometry; WHO, World Health organization. | ||||
TABLE 2
DMPA’s effect on BMD in adolescent women: What the studies reveal
| AUTHOR (TYPE OF STUDY) | # OF PARTICIPANTS/ POPULATION DESCRIPTION | OUTCOME MEASURE | RESULTS | COMMENTS |
|---|---|---|---|---|
| Scholes, 200432 (cross-sectional) | n=81 (DMPA) n=93 (comparison) Ages 14-18 Current users of DMPA, range of 1-13 injections (mean 3) | DEXA proximal femur and LS spine | Neither total hip (P=.1) nor spine (P=.19) BMD was significantly lower in DMPA users | 17 non-DMPA users were taking OCPs DMPA users were more likely to be African American and to have a previous pregnancy |
| Beksinska, 200733 (cohort) | n=115 (DMPA) n=144 (comparison) Ages 15-19 New users of DMPA Comparison group not using hormonal contraception | DEXA of distal radius and ulna | No significant difference in BMD between groups (P=.88) | 51 DMPA users completed the study vs 91 nonusers of hormonal contraception Majority of cohort was African American |
| Cromer, 200434 (cohort) | n=53 (DMPA) n=152 (comparison) Ages 12-18 New users of DMPA Comparison group not using hormonal contraception | DEXA of femoral neck and LS spine Measured at baseline, 6 months, and 12 months | LS spine BMD decreased in DMPA group 1.4% and increased in control group 3.8% (P<.001); femoral neck BMD decreased in DMPA group 2.2% and increased in control group 2.3% (P<.001) | 45% dropout rate by 12 months in the DMPA group |
| Lara-Torre, 200435 (cohort) | n=58 (DMPA) n=19 (comparison) Ages 12-21 New DMPA users Comparison group ages 15-19 not using any hormonal contraception | DEXA of LS spine Measured at baseline and every 6 months for 2 years | DMPA group had significantly more BMD changes than control group at each check: -3.02% at 6 months (P=.014); -3.38% at 12 months (P=.001); -4.81% at 18 months (P<.001); -6.81% at 24 months (P=.01) | DMPA group was more likely to be African American DMPA group had dropout rates of 54% at 12 months and 64% at 24 months |
| Scholes, 200536 (cohort) | n=80 (DMPA) n=90 (comparison) Ages 14-18 Baseline users of DMPA (duration of use from 1 to 13 injections) | DEXA of hip, spine, and whole body Measured at baseline and every 6 months for 24-36 months | Significant BMD decreases in DMPA users at each check vs comparison group in hip and spine (P=.001), but not in whole-body BMD (P=.78) Most discontinuers had regained BMD back to baseline by 12 months | 18.9% of non-DMPA users were taking OCPs 61 participants discontinued DMPA during the study DMPA group more likely to smoke and to have been pregnant |
| BMD, bone mineral density; DEXA, dual-energy x-ray absorptiometry; DMPA, depot-medroxyprogesterone acetate; LS, lumbosacral; OCPs, oral contraceptive pills. | ||||
Can estrogen therapy counteract DMPA’s effect?
If decreased BMD in women taking DMPA is due to low estradiol levels, it is logical that a trial of estradiol supplementation would mitigate the negative effect. Indeed, a bone-protective effect of supplemental estrogen therapy has been found in studies of young women with amenorrhea secondary to the female athlete triad. Similarly, in postmenopausal women with low serum estradiol levels, supplemental estrogen therapy helps maintain BMD.18
Two randomized trials have evaluated the use of supplemental estrogen on the adverse effects of DMPA on bone.19,20 The trial by Cromer et al19 randomized 123 adolescent women ages 12 to 18 to receive either estrogen supplementation or placebo. They found that the participants in the estrogen group had BMD gains vs BMD losses among those in the placebo group over the 2-year period of the study (2.8% vs -1.8% at the LS spine, and 4.7% vs -5.1% at the femoral neck; P<.001 for both). The limitations to this study include a high dropout rate (53 participants had left by 24 months) and incomplete data collection due to early stoppage of the study.
Cundy et al20 studied 38 adult women who had been on DMPA for at least 2 years and had below-average LS spine BMD. Nineteen women were randomized to receive estrogen supplementation and underwent bone density tests every 6 months; 19 women were also in the comparison placebo group. In the estrogen supplementation group, there was significant attenuation of lowering BMD that increased throughout the trial. However, only 26 subjects completed the 2-year study.
Limit DMPA use to 2 years? Experts disagree
The FDA, in 2004, placed a black box warning on DMPA: “Women who use Depo-Provera Contraceptive Injection may lose significant bone mineral density. Bone loss is greater with increasing duration of use and may not be completely reversible. It is unknown if use of Depo-Provera Contraceptive Injection during adolescence or early adulthood, a critical period of bone accretion, will reduce peak bone mass and increase the risk of osteoporotic fracture later in life. Depo-Provera Contraceptive Injection should be used as a long-term birth control method (eg, longer than 2 years) only if other birth-control methods are inadequate.”21 In light of these FDA guidelines, many practitioners have started limiting patients’ use of DMPA to 2 years.
The Society of Adolescent Medicine has produced clinical guidelines for treating adolescents who do well on DMPA for contraception (SOR: C, expert opinion).22 The guidelines recommend, among other things, that physicians:
- continue prescribing DMPA to adolescent girls needing contraception, while providing adequate explanation of benefits and potential risks.
- consider ordering a dual-energy x-ray absorptiometry (DEXA) scan to evaluate a patient’s risk.
- keep in mind that duration of use need not be restricted to 2 years.
- recommend 1300 mg calcium plus 400 IU vitamin D and daily exercise to all adolescents receiving DMPA.
- consider estrogen supplementation in those girls with osteopenia (or those at high risk of osteopenia who have not had a DEXA scan) who are otherwise doing well on DMPA and have no contraindication to estrogen.
The World Health Organization similarly published recommendations stating that no restriction should be placed on the use of DMPA due to bone effects (SOR: C, expert opinion).23
Formulate a reasonable approach
As with any other potentially harmful medication, weigh the risks and benefits of DMPA for the individual patient. It is unclear whether BMD lost during DMPA use completely recovers or even what the time frame for that recovery is. Whether the potential risk for future fracture is increased is unknown, but it certainly is cause for concern. Discuss potential risks with any woman who wants to use DMPA for contraception. Routine calcium and vitamin D supplementation for women using DMPA may be helpful and is unlikely to be harmful.
A search of PubMed, the Cochrane database, and all references from primary reviewed articles was performed in 2007 using the terms depot-medroxyprogesterone acetate, bone mineral density, osteoporosis, osteopenia, injectable contraception, progestin-only contraception, Depo-Provera, and DMPA. Studies qualified for analysis if they contained data about bone density in women who had used some type of progestin-only injectable contraception. All types of studies were included. Excluded were studies that did not use BMD as an outcome measure or that re-analyzed data published elsewhere.
Bone mineral density is traditionally used as a surrogate measure of fracture risk in postmenopausal women. However, most of the women included in the reviewed studies were young and at low risk of fracture. The relationship between bone density in premenopausal women and fracture risk later in life is unclear. There are no available studies relating injectable progestin-only contraception with future osteoporotic fractures.
There is not enough evidence to recommend for or against routine screening of BMD in long-term users of DMPA. Research should evaluate the efficacy of estrogen supplementation in women on prolonged DMPA. Long-term studies could provide more information regarding BMD recovery over several years.
Correspondence
Sarina Schrager, MD, MS, Department of Family Medicine, University of Wisconsin, 777 South Mills Street, Madison, WI 53715; sbschrag@wisc.edu
1. Piccinino LJ, Mosher WK. Trends in contraceptive use in the United States: 1982-1995. Fam Plann Perspect. 1998;30:4-10.
2. Donovan P. Falling teen pregnancy, birthrates. What’s behind the declines? The Guttmacher Report on Public Policy. 1998;1(5).-
3. Cundy T, Evans M, Roberts H. Bone density in women receiving depot medroxyprogesterone acetate for contraception. BMJ. 1991;303:13-16.
4. Soyka LA, Fairfield WP, Klibanski A. Hormonal determinants and disorders of peak bone mass in children. J Clin Endocrinol Metab. 2000;85:3951-3963.
5. Tudor-locke C, McColl RS. Factors related to variation in premenopausal bone mineral status: a health promotion approach. Osteoporos Int. 2000;11:1-24.
6. Bachrach LK, Katzman DK, Litt IF, et al. Recovery from osteopenia in adolescent girls with anorexia nervosa. J Clin Endocrinol Metab. 1991;72:602-606.
7. Miller KK, Lee EE, Lawson Ea, et al. Determinants of skeletal loss and recovery in anorexia nervosa. J Clin Endocrinol Metab. 2006;91:2931-2937.
8. Silva HG, Tortora RP, Farias ML. Increased bone turnover during the third trimester of pregnancy and decreased bone mineral density after parturition in adolescents as compared to age-matched control patients. Gynecol Endocrinol. 2005;21:174-179.
9. Ulrich U, Miller PB, Eyre DR, et al. Bone remodeling and bone mineral density during pregnancy. Arch Gynecol Obstet. 2003;268:309-316.
10. Lloyd T, Beck TJ, Lin HM, et al. Modifiable determinants of bone status in young women. Bone. 2002;30:416-421.
11. Cundy T, Cornish J, Evans MC, et al. Recovery of bone density in women who stop using medroxyprogesterone acetate. BMJ. 1994;308:247-248.
12. Clark MK, Sowers M, Levy B, et al. Bone mineral density loss and recovery during 48 months in first-time users of depot medroxyprogesterone acetate. Fertil Steril. 2006;86:1466-1474.
13. Scholes D, LaCroix A Z, Ichikawa LE, et al. Injectable hormone contraception and bone density: results from a prospective study [erratum appears in Epidemiology.2002;13:749]. Epidemiology. 2002;13:581-587.
14. Clark MK, Sowers MR, Nichols S, et al. Bone mineral density changes over two years in first-time users of depot medroxyprogesterone acetate. Fertil Steril. 2004;82:1580-1586.
15. Kaunitz AM, Miller PD, Rice VM, et al. Bone mineral density in women aged 25-35 years receiving depot medroxyprogesterone acetate: recovery following discontinuation. Contraception. 2006;74:90-99.
16. Busen NH, Britt RB, Rianon N. Bone mineral density in a cohort of adolescent women using depot medroxyprogesterone acetate for one to two years. Adolesc Health. 2003;32:257-259.
17. Rome E, Ziegler J, Secic M, et al. Bone biochemical markers in adolescent girls using either depot medroxyprogesterone acetate or an oral contraceptive [see comment]. J Pediatr Adolesc Gynecol. 2004;17:373-377.
18. Cumming DC. Exercise associated amenorrhea, low bone density, and estrogen replacement therapy. Arch Intern Med. 1996;156:2193-2195.
19. Cromer B, Lazebnik R, Rome E, et al. Double-blinded randomized controlled trial of estrogen supplementation in adolescent girls who receive depot medroxyprogesterone acetate for contraception. Am J Obstet. Gynecol. 2005;192:42-47.
20. Cundy T, Ames R, Horne A, et al. A randomized controlled trial of estrogen replacement therapy in long-term users of depot medroxyprogesterone acetate. J Clin Endocrinol Metab. 2003;88:78-81.
21. U.S. Food and Drug Administration. Black box warning added concerning long-term use of Depo-Provera Contraceptive Injection. 2004. Available at: http://www.fda.gov/bbs/topics/ANSWERS/2004/ANS01325.html. Accessed April 7, 2009.
22. Cromer BA, Scholes D, Berenson A, et al. Depot medroxyprogesterone acetate and bone mineral density in adolescents: the black box warning: a position paper of the Society for Adolescent Medicine. Adolesc Health. 2006;39:296-301.
23. d’Arcanques D. WHO statement on hormonal contraception and bone health. Contraception. 2006;73:443-444.
24. Gbolade B, Ellis S, Murby B, et al. Bone density in long term users of depot medroxyprogesterone acetate. Brit J Obstet Gynaecol. 1998;105:790-794.
25. Ryan PJ, Singh SP, Guillebaud J. Depot medroxyprogesterone and bone mineral density. J Fam Plann Reproduct Health Care. 2002;28:12-15.
26. Petitti DB, Piaggio G, Mehta S, et al. 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. 2000;95:736-744.
27. Wanichsetakul P, Kamudhamas A, Watanaruangkovit P, et al. Bone mineral density at various anatomic bone sites in women receiving combined oral contraceptives and depot-medroxyprogesterone acetate for contraception. Contraception. 2002;65:407-410.
28. Beksinska ME, Smit JA, Kleinschmidt I, et al. Bone mineral density in women aged 40-49 years using depot-medroxyprogesterone acetate, norethisterone enanthate or combined oral contraceptives for contraception. Contraception. 2005;71:170-175.
29. Tang OS, Tang G, YIP PS, et al. Further evaluation on long-term depot-medroxyprogesterone acetate use and bone mineral density: a longitudinal cohort study. Contraception. 2000;62:161-164.
30. Berenson AB, Radecki CM, Grady JJ, et al. A prospective, controlled study of the effects of hormonal contraception on bone mineral density. Obstet Gynecol. 2001;98:576-582.
31. Merki-Feld GS, Neff M, Keller PJ. A prospective study on the effects of depot medroxyprogesterone acetate on trabecular and cortical bone after attainment of peak bone mass. BJOG. 2000;107:863-869.
32. Scholes D, LaCroix AZ, Ichikawa LE, et al. The association between depot medroxyprogesterone acetate contraception and bone mineral density in adolescent women. Contraception. 2004;69:99-104.
33. Beksinska ME, Kleinschmidt I, Smit JA, et al. Bone mineral density in adolescents using norethisterone enanthate, depot-medroxyprogesterone acetate or combined oral contraceptives for contraception. Contraception. 2007;75:438-443.
34. Cromer BA, Stager M, Bonny A, et al. Depot medroxyprogesterone acetate, oral contraceptives and bone mineral density in a cohort of adolescent girls [see comment]. Adolesc Health. 2004;35:434-441.
35. Lara-Torre E, Edwards CP, Perlman S, et al. Bone mineral density in adolescent females using depot medroxyprogesterone acetate. J Pediatr Adolesc Gynecol. 2004;17:17-21.
36. Scholes D, LaCroix AZ, Ichikawa LE, et al. Change in bone mineral density among adolescent women using and discontinuing depot medroxyprogesterone acetate contraception. Arch Pediatr Adolesc Med. 2005;159:139-144.
1. Piccinino LJ, Mosher WK. Trends in contraceptive use in the United States: 1982-1995. Fam Plann Perspect. 1998;30:4-10.
2. Donovan P. Falling teen pregnancy, birthrates. What’s behind the declines? The Guttmacher Report on Public Policy. 1998;1(5).-
3. Cundy T, Evans M, Roberts H. Bone density in women receiving depot medroxyprogesterone acetate for contraception. BMJ. 1991;303:13-16.
4. Soyka LA, Fairfield WP, Klibanski A. Hormonal determinants and disorders of peak bone mass in children. J Clin Endocrinol Metab. 2000;85:3951-3963.
5. Tudor-locke C, McColl RS. Factors related to variation in premenopausal bone mineral status: a health promotion approach. Osteoporos Int. 2000;11:1-24.
6. Bachrach LK, Katzman DK, Litt IF, et al. Recovery from osteopenia in adolescent girls with anorexia nervosa. J Clin Endocrinol Metab. 1991;72:602-606.
7. Miller KK, Lee EE, Lawson Ea, et al. Determinants of skeletal loss and recovery in anorexia nervosa. J Clin Endocrinol Metab. 2006;91:2931-2937.
8. Silva HG, Tortora RP, Farias ML. Increased bone turnover during the third trimester of pregnancy and decreased bone mineral density after parturition in adolescents as compared to age-matched control patients. Gynecol Endocrinol. 2005;21:174-179.
9. Ulrich U, Miller PB, Eyre DR, et al. Bone remodeling and bone mineral density during pregnancy. Arch Gynecol Obstet. 2003;268:309-316.
10. Lloyd T, Beck TJ, Lin HM, et al. Modifiable determinants of bone status in young women. Bone. 2002;30:416-421.
11. Cundy T, Cornish J, Evans MC, et al. Recovery of bone density in women who stop using medroxyprogesterone acetate. BMJ. 1994;308:247-248.
12. Clark MK, Sowers M, Levy B, et al. Bone mineral density loss and recovery during 48 months in first-time users of depot medroxyprogesterone acetate. Fertil Steril. 2006;86:1466-1474.
13. Scholes D, LaCroix A Z, Ichikawa LE, et al. Injectable hormone contraception and bone density: results from a prospective study [erratum appears in Epidemiology.2002;13:749]. Epidemiology. 2002;13:581-587.
14. Clark MK, Sowers MR, Nichols S, et al. Bone mineral density changes over two years in first-time users of depot medroxyprogesterone acetate. Fertil Steril. 2004;82:1580-1586.
15. Kaunitz AM, Miller PD, Rice VM, et al. Bone mineral density in women aged 25-35 years receiving depot medroxyprogesterone acetate: recovery following discontinuation. Contraception. 2006;74:90-99.
16. Busen NH, Britt RB, Rianon N. Bone mineral density in a cohort of adolescent women using depot medroxyprogesterone acetate for one to two years. Adolesc Health. 2003;32:257-259.
17. Rome E, Ziegler J, Secic M, et al. Bone biochemical markers in adolescent girls using either depot medroxyprogesterone acetate or an oral contraceptive [see comment]. J Pediatr Adolesc Gynecol. 2004;17:373-377.
18. Cumming DC. Exercise associated amenorrhea, low bone density, and estrogen replacement therapy. Arch Intern Med. 1996;156:2193-2195.
19. Cromer B, Lazebnik R, Rome E, et al. Double-blinded randomized controlled trial of estrogen supplementation in adolescent girls who receive depot medroxyprogesterone acetate for contraception. Am J Obstet. Gynecol. 2005;192:42-47.
20. Cundy T, Ames R, Horne A, et al. A randomized controlled trial of estrogen replacement therapy in long-term users of depot medroxyprogesterone acetate. J Clin Endocrinol Metab. 2003;88:78-81.
21. U.S. Food and Drug Administration. Black box warning added concerning long-term use of Depo-Provera Contraceptive Injection. 2004. Available at: http://www.fda.gov/bbs/topics/ANSWERS/2004/ANS01325.html. Accessed April 7, 2009.
22. Cromer BA, Scholes D, Berenson A, et al. Depot medroxyprogesterone acetate and bone mineral density in adolescents: the black box warning: a position paper of the Society for Adolescent Medicine. Adolesc Health. 2006;39:296-301.
23. d’Arcanques D. WHO statement on hormonal contraception and bone health. Contraception. 2006;73:443-444.
24. Gbolade B, Ellis S, Murby B, et al. Bone density in long term users of depot medroxyprogesterone acetate. Brit J Obstet Gynaecol. 1998;105:790-794.
25. Ryan PJ, Singh SP, Guillebaud J. Depot medroxyprogesterone and bone mineral density. J Fam Plann Reproduct Health Care. 2002;28:12-15.
26. Petitti DB, Piaggio G, Mehta S, et al. 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. 2000;95:736-744.
27. Wanichsetakul P, Kamudhamas A, Watanaruangkovit P, et al. Bone mineral density at various anatomic bone sites in women receiving combined oral contraceptives and depot-medroxyprogesterone acetate for contraception. Contraception. 2002;65:407-410.
28. Beksinska ME, Smit JA, Kleinschmidt I, et al. Bone mineral density in women aged 40-49 years using depot-medroxyprogesterone acetate, norethisterone enanthate or combined oral contraceptives for contraception. Contraception. 2005;71:170-175.
29. Tang OS, Tang G, YIP PS, et al. Further evaluation on long-term depot-medroxyprogesterone acetate use and bone mineral density: a longitudinal cohort study. Contraception. 2000;62:161-164.
30. Berenson AB, Radecki CM, Grady JJ, et al. A prospective, controlled study of the effects of hormonal contraception on bone mineral density. Obstet Gynecol. 2001;98:576-582.
31. Merki-Feld GS, Neff M, Keller PJ. A prospective study on the effects of depot medroxyprogesterone acetate on trabecular and cortical bone after attainment of peak bone mass. BJOG. 2000;107:863-869.
32. Scholes D, LaCroix AZ, Ichikawa LE, et al. The association between depot medroxyprogesterone acetate contraception and bone mineral density in adolescent women. Contraception. 2004;69:99-104.
33. Beksinska ME, Kleinschmidt I, Smit JA, et al. Bone mineral density in adolescents using norethisterone enanthate, depot-medroxyprogesterone acetate or combined oral contraceptives for contraception. Contraception. 2007;75:438-443.
34. Cromer BA, Stager M, Bonny A, et al. Depot medroxyprogesterone acetate, oral contraceptives and bone mineral density in a cohort of adolescent girls [see comment]. Adolesc Health. 2004;35:434-441.
35. Lara-Torre E, Edwards CP, Perlman S, et al. Bone mineral density in adolescent females using depot medroxyprogesterone acetate. J Pediatr Adolesc Gynecol. 2004;17:17-21.
36. Scholes D, LaCroix AZ, Ichikawa LE, et al. Change in bone mineral density among adolescent women using and discontinuing depot medroxyprogesterone acetate contraception. Arch Pediatr Adolesc Med. 2005;159:139-144.