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Contraception Corner

Depot Medroxyprogesterone Acetate, Skeletal Health, and Adolescent Girls: Implications of the Black-box Warning

Barbara Clark, RN, MSN, MPH; Andrew M. Kaunitz, MD

Depot medroxyprogesterone acetate (DMPA) would seem to be an almost ideal contraceptive method for adolescent girls, but now a ç"black-boxç" warning has raised fears about its effects on bone health. How can health care providers help their patients weigh the risks and benefits in this environment of uncertainty?

More teenagers are using contraception: About 83% used contraception at their first/most recent intercourse in 2002, compared with about 71% in 1995. Consequently, teenaged pregnancy rates have been dropping since the early 1990s. The National Survey of Family Growth authors have largely attributed this trend to the use of long-acting contraception—specifically DMPA. In fact, the percentage of teens that had used injectable contraception increased from 10% in 1995 to 21% in 2002.1

The convenience and high efficacy of DMPA is likely responsible for this drop in pregnancy rates among adolescents. During the first year of use, typical-use failure rates for DMPA are 3%, compared with 8% for oral contraceptives. However, the US Food and Drug Administration (FDA) issued a "black-boxç" warning in 2004 regarding the effects of DMPA on bone mineral density (BMD)—particularly in teenagers and young adults.

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DMPA USE

Women have used DMPA for over 30 years abroad and for a decade in the United States. In 2002, more than 2 million US women were using DMPA—most of them younger than age 35 years. For example, of contraceptive users, 14% of teenagers used DMPA in 2002 compared with only 2% of women aged 40 to 44 years.3 Although DMPA use is prevalent among all adolescents, Hispanic and black teens are more likely than white teens to use injectable contraception: In 2002, 18% of non- Hispanic white teens had ever used DMPA versus 24% of Hispanic and 27% of non-Hispanic black girls.1

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THE BLACK-BOX WARNING

Given intramuscularly every 3 months, DMPA suppresses ovarian production of estradiol, leading to declines in BMD in current users of injectable contraception.4 As a result, the FDA added a black-box warning to the labeling in November 2004.5 This warning states that users may experience a significant loss of BMD that may increase with longer duration of use and may not be completely reversible. The warning notes that it is unknown whether DMPA use during adolescence or early adulthood will reduce peak bone mass and raise the risk of future osteoporotic fractures. Finally, it advises that long-term use (ie, > 2 years) should only be considered if other birth control methods are inadequate.6 The manufacturer of DMPA also issued a letter to practitioners on this subject.

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EVIDENCE

(81 DMPA users and 93 nonusers) reported that mean BMD for the hip, spine, and whole body was lower in current DMPA users than nonusers.4 Although these differences were not significant, there was a trend toward lower spinal bone density with longer duration of use (P = .06).

However, it appears that BMD recovers completely after adolescents discontinue DMPA. A prospective study measured BMD in 80 DMPA nonusers and 90 teenaged users at baseline, and then every 6 months for 24 to 36 months thereafter in the nonusers, and in 61 women who had discontinued DMPA use.7 Bone mineral density increased significantly in discontinuers relative to never-users, with respective annualized mean percentage changes of 1.34% versus -0.19% at the hip (P = .004); 2.86% versus 1.32% at the spine (P = .004); and 3.56% versus 0.88% for the whole body (P < .001). Within 1 year after discontinuing injectable contraception, Scholes et al7 found that BMD was at least as great in former DMPA users as in those teens who had never used DMPA.

To determine whether DMPArelated bone loss could be prevented, Cromer et al9 studied whether the addition of low menopausal doses of supplemental estrogen to DMPA would stabilize BMD. She found that monthly injections of estradiol cypionate (the same dose as used in the monthly combination contraceptive injection) prevented any loss of BMD that occurred in those adolescents receiving DMPA plus placebo injections. In a 24-month study of 123 teenaged DMPA users randomly assigned to receive either estradiol cypionate 5 mg or a placebo, BMD at the lumbar spine increased by 2.8% in the estradiol group versus a 1.8% decrease in the placebo group.9

Lactation, also a hypoestrogenemic state, is associated with reversible loss of BMD of a magnitude similar to that associated with use of DMPA. As with DMPA use, BMD recovery appears to be complete after the baby is weaned. Using data from the National Health and Nutrition Examination Survey III,10 researchers measured hip BMD in young women.11 Women who had nursed an infant during adolescence had a higher adjusted hip BMD than those who had not breast-fed. In fact, it appeared that breast-feeding may protect the bone health of adolescents. A study of postmenopausal Swedish women also determined that there was no association between duration of lactation and fracture risk.12 There are similar findings regarding the relationship between DMPA use and BMD in adult women.13 In a prospective study of 457 women, BMD increased significantly after discontinuing DMPA, approaching levels for nonusers 30 months' postuse.14

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IMPLICATIONS

How can health care providers help their adolescent patients make an informed choice about DMPA use? First, they can show patients how their health behaviors, preferences, and lifestyle affect their contraceptive choices. If DMPA is a viable option in this context, the provider should discuss its advantages and disadvantages (see "Talking Points"). The main advantages of DMPA are its convenience and high contraceptive efficacy. The amenorrhea characteristic of long-term use is another positive attribute for many DMPA users, with at least one half of users developing amenorrhea within 12 months. Health care providers and women should keep in mind, however, that among reversible contraceptives, DMPA is unique in that return to fertility is delayed for a median of 9 to 10 months following the last injection.

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CONCLUSION

More than 400,000 teenagers rely on DMPA for contraception. Its efficacy rates confirm its success in preventing pregnancy. Although the FDA's black-box warning regarding BMD loss stresses caution, the best available evidence has noted recovery of bone density following DMPA discontinuation. There is no evidence that DMPA use leads to osteoporosis or fractures. Further long-term prospective studies are needed. Until these are completed, women and their health care providers should weigh the theoretic concerns indicated in the new FDA labeling with DMPA's convenience and well-established contraceptive efficacy.

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Barbara Clark, RN, MSN, MPH, is a freelance writer in Arlington, Va. Andrew M. Kaunitz, MD, is professor and assistant chairman, Department of Obstetrics and Gynecology, University of Florida Health Science Center, Jacksonville.

References

1. Abma JC, Martinez GM, Mosher WD, Dawson BS. Teenagers in the United States: sexual activity, contraceptive use, and childbearing, 2002. Vital Health Stat 23. 2004;(24):1-48.
2. Trussell J. Contraceptive failure in the United States. Contraception. 2004;70(2):89-96.
3. Mosher WD, Martinez GM, Chandra A, Abma JC, Willson SJ. Use of contraception and use of family planning services in the United States, 1982-2002. Adv Data. 2004;(350):1-36.
4. Scholes D, LaCroix AZ, Ichikawa LE, Barlow WE, Ott SM. The association between depot medroxyprogesterone acetate contraception and bone mineral density in adolescent women. Contraception. 2004;69(2):99-104.
5. FDA Talk Paper. Black box warning added concerning long-term use of Depo-Provera contraceptive injection [US Food and Drug Administration Web site].
   Available at: http://www.fda.gov/bbs/topics/ANSWERS/ 2004/ANS01325.html. Accessed January 24, 2006.
6. Prescribing information, Depo-Provera. Pfizer, Inc Web site.
   Available at: http://www.pfizer.com/pfizer/download/uspi_ depo_provera_contraceptive.pdf. Accessed January 24, 2006.
7. Scholes D, LaCroix AZ, Ichikawa LE, Barlow WE, Ott SM. Change in bone mineral density among adolescent women using and discontinuing depot medroxyprogesterone acetate contraception. Arch Pediatr Adolesc Med. 2005;159(2):139-144.
8. 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(1):78-81.
9. Cromer BA, 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(1):42-47.
10. National Center for Health Statistics. Plan and operation of the Third National Health and Nutrition Examination Survey, 1988-94. Series 1: programs and collection procedures. Vital Health Stat 1. 1994;(32):1-407.
11. Chantry CJ, Auinger P, Byrd RS. Lactation among adolescent mothers and subsequent bone mineral density. Arch Pediatr Adolesc Med. 2004;158(7):650-656.
12. Michaelsson K, Baron JA, Farahmand BY, Ljunghall S. Influence of parity and lactation on hip fracture risk. Am J Epidemiol. 2001;153(12):1166-1172.
13. Kaunitz A. Depo-Provera's black box: time to reconsider? Contraception. 2005;72(3):165-167.
14. Scholes D, LaCroix AZ, Ichikawa LE, Barlow WE, Ott SM. Injectable hormone contraception and bone density: results from a prospective study. Epidemiology. 2002;13(5):581-587.
15. Westhoff C. Depot-medroxyprogesterone acetate injection (Depo- Provera): a highly effective contraceptive option with proven long-term safety. Contraception. 2003;68(2):75-87.

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