DMPA’s effect on bone mineral density: A particular concern for adolescents

,

Applied Evidence

DMPA’s effect on bone mineral density: A particular concern for adolescents

J Fam Pract. 2009 May;58(5):E1-E8

By

Sarina B. Schrager, MD, MS

Contraceptive DMPA reduces bone mineral density. Supplement with calcium and vitamin D and urge exercise.

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References

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.

Practice recommendations

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.

FAST TRACK

In women, 90% of peak bone mass is determined by age 18.

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.

FAST TRACK

Reduction of bone mineral density with DMPA appears to level off after 2 years.

Three recent prospective studies^12,14,15 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).