Expert Commentary

Remove the black-box warning for depot medroxyprogesterone acetate!

OBG Manag. 2011 August;23(8):6-9

Guidance about DMPA in the black box isn’t evidence-based, and the warning deprives women of long-term use of this safe and effective contraceptive

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IN THIS ARTICLE

News from the medical literature

References

1. 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 Pediatric Adolesc Med. 2005;159(2):139-144.

2. Harel Z, Johnson CC, Gold MA, et al. Recovery of bone mineral density in adolescents following the use of depot medroxyprogesterone acetate contraceptive injections. Contraception. 2010;81(4):281-291.

3. 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):581-7.

4. Kaunitz AM, Miller PD, Rice VM, Ross D, McClung MR. Bone mineral density in women aged 25-35 years receiving depot medroxyprogesterone acetate: recovery following discontinuation. Contraception. 2006;74(2):90-99.

5. Schnatz PF, Barker KG, Marakovits KA, O’Sullivan DM. Effects of age at first pregnancy and breast-feeding on the development of postmenopausal osteoporosis. Menopause. 2010;17(6):1161-1166.

6. World Health Organization WHO Epidemiological Record No. 35: WHO statement on hormonal contraception and bone health. Geneva Switzerland: World Health Organization. 2005;80(35):302-304.

7. Grimes DA, Schulz KF. Surrogate end points in clinical research: hazardous to your health. Obstet Gynecol. 2005;105(5 pt 1):1114-1118.

8. Grimes DA, Schulz KF, Raymond EG. Surrogate end points in women’s health research: science protoscience, and pseudoscience. Fertil Steril. 2010;93(6):1731-1734.

9. Shulman LP, Bateman LH, Creinin MD, et al. Surrogate markers, emboldened and boxed warnings, and an expanding culture of misinformation: evidence-based clinical science should guide FDA decision making about product labeling. Contraception. 2006;73(5):440-442.

10. Cundy T, Cornish J, Roberts H, Reid IR. Menopausal bone loss in long-term users of depot medroxyprogesterone acetate contraception. Am J Obstet Gynecol. 2002;186(5):978-983.

11. Orr-Walker BJ, Evans MC, Ames RW, Clearwater JM, Cundy T, Reid IR. The effect of past use of the injectable contraceptive depot medroxyprogesterone acetate on bone mineral density in normal post-menopausal women. Clin Endocrinol (Oxf). 1998;49(5):615-618.

12. Viola AS, Castro S, Marchi NM, Bahamondes MV, Viola CFM, Bahamondes L. Long-term assessment of forearm bone mineral density in postmenopausal former users of depot medroxyprogesterone acetate. Contraception. In press.

13. Vestergaard P, Rejnmark L, Mosekilde L. The effects of depot medroxyprogesterone acetate and intrauterine device use on fracture risk in Danish women. Contraception. 2008;78(6):459-464.

14. Meier C, Brauchli YB, Jick SS, Kraenzlin ME, Meier CR. Use of depot medroxyprogesterone acetate and fracture risk. J Clin Endocrin Metab. 2010;95(11):4909-4916.

15. Kaunitz AM, Harel Z, Bone H, et al. Retrospective cohort study of DMPA and fractures in reproductive age women. Paper presented at: Association of Reproductive Health Professional Annual Meeting; September 24, 2010; Atlanta, GA.

16. Mosher WD, Jones J. Use of contraception in the United States: 1982-2008. National Center for Health Statistics. Vital Health Stat 23. 2010;23(29):1-44.

17. Paschall S, Kaunitz AM. Depo-Provera and skeletal health: A survey of Florida obstetrics and gynecologist physicians. Contraception. 2008;78(5):370-376.

18. American College of Obstetricians and Gynecologists Committee on Gynecologic Practice. ACOG Committee Opinion No. 415: Depot medroxyprogesterone acetate and bone effects. Obstet Gynecol. 2008;112(3):727-730.

19. Cromer BA, Scholes D, Berenson A, Cundy T, Clark MK, Kaunitz AM; Society for Adolescent Medicine. Depot medroxyprogesterone acetate and bone mineral density in adolescent—the black box warning: A position paper of the Society for Adolescent Medicine. J Adolesc Health. 2006;39(2):296-301.

20. Black A; Ad Hoc DMPA Committee of the Society of Obstetricians and Gynaecologists of Canada. Canadian contraception consensus: update on depot medroxyprogesterone acetate (DMPA). J Obstet Gynaecol Can. 2006;28(4):305-313.

21. Centers for Disease Control and Prevention. US medical eligibility criteria contraceptive use 2010. MMWR. 2010;59 (RR04);1:6.

22. Kaunitz AM, Grimes DA. Removing the black box warning for depot medroxyprogesterone acetate [published online ahead of print February 21 2011]. Contraception. doi:10.1016/j.contraception.2011.01.009.

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The Food and Drug Administration (FDA) should remove the black-box warning regarding skeletal health that the agency inserted into labeling for the injectable contraceptive depot medroxyprogesterone acetate (DMPA; Depo-Provera) in 2004. The black box 1) indicates that use of DMPA for longer than 2 years may reduce peak bone mass and place a woman at increased risk of osteoporotic fracture and 2) suggests that ObGyns order bone-density assessment in women who use DMPA long-term.

This warning is not based on scientific evidence. By depriving women of long-term use of a safe, effective contraceptive, the black-box warning damages women’s health and the public health.

The scientific argument for removing the black box

Although DMPA does cause reduced ovarian estradiol production, with a decline in bone mineral density (BMD), complete recovery of BMD occurs approximately 1 or 2 years after discontinuation in adolescent girls^1,2 and 3 years after discontinuation in adult women.^3,4 BMD trends observed with the use of DMPA parallel those associated with another normal but hypoestrogenic state: breastfeeding. Although BMD declines noted in nursing mothers are similar to those associated with DMPA, breastfeeding one or more infants has not been reported to increase the risk of subsequent osteoporotic fractures.⁵ The FDA does not warn women against breastfeeding for fear of a theoretical negative impact on skeletal health.

BMD can help predict a risk of osteoporotic fracture in menopausal women, but it is not a valid surrogate endpoint for fracture in women of reproductive age.⁶ Basing clinical recommendations on invalid surrogate endpoints can cause harm.^7-9 Clinical recommendations, including those from the FDA, should be based on sound studies that address important clinical outcomes.

No convincing evidence links the use of DMPA for contraception to fracture. Studies of menopausal women have not suggested that prior use of DMPA increased their risk of osteoporosis.^10-12 Two recently published case-control studies, one using a Danish National Patient Registry¹³ and one based on the United Kingdom Family Practice Research database,¹⁴ have demonstrated that DMPA is associated with an elevated risk of fracture in reproductive-age women. However, a cohort analysis using the same British Family Practice database clarifies that the elevated fracture risk observed in women using DMPA occurred before initiation of injectable contraception and was not the result of DMPA use.¹⁵

A clearly harmful effect on women’s health

The black-box warning for DMPA has caused clinicians and women to reduce use of this effective method of contraception. The 2008 National Survey of Family Growth shows that the overall percentage of US women, 15 to 44 years of age, who now use DMPA has declined—from 3.3% in 2002 to 2.0% in 2006 to 2008.¹⁶

In fact, a survey of ObGyns in Florida found that 1) almost one half of respondents place a time limit on duration of DMPA and 2) two thirds of those respondents base that restriction on the black-box warning.¹⁷ Restricting the use of DMPA can lead to more unintended pregnancies and induced abortions.

In the Florida survey, two thirds of respondents order BMD assessment in women who use DMPA, with 58% of those physicians who do so attributing their decision to, again, the black-box warning. Indeed, more than 5% of respondents reported that they selectively prescribe bisphosphonates to women of reproductive age who use DMPA—an expensive practice that is not evidence-based and is potentially dangerous.

FDA guidance is far out of step

The black-box warning for DMPA is not in accord with the guidance provided major medical and public health organizations. The World Health Organization,⁶ the American College of Obstetricians and Gynecologists,¹⁸ the Society for Adolescent Medicine,¹⁹ and the Society of Obstetrics and Gynecology of Canada,²⁰ have all stated that skeletal health concerns shouldn’t restrict the use of DMPA, including the duration of use.

In the US Medical Eligibility Criteria for contraceptive use, the Centers for Disease Control and Prevention declared that use of DMPA is Category 1 (no restriction on use) in women 18 to 45 years of age and Category 2 (advantages of the method generally outweigh theoretical or proven risks) in younger women.²¹ The FDA’s black-box warning is therefore inconsistent with the recommendation of its sister agency.