By Rebecca H. Allen, MD, MPH, Assistant Professor, Department of Obstetrics and Gynecology, Warren Alpert Medical School of Brown University, Women and Infants Hospital, Providence, RI. Dr. Allen reports no financial relationships relevant to this field of study.
Synopsis: Although users of depot medroxyprogesterone acetate (DMPA) experienced more bone fractures than users of other contraceptives, their risk of bone fractures was higher at baseline before initiating DMPA and did not change while on DMPA. This suggests that confounding, unknown factors led to the association between DMPA and fractures in previous studies.
Source: Lanza LL, et al. Use of depot medroxyprogesterone acetate contraception and incidence of bone fracture. Obstet Gynecol 2013;121:593-600.
The authors performed a retrospective cohort study using data from the General Practice Research Database in the United Kingdom, which contains de-identified records from more than 350 general practices. The data are collected longitudinally and have been validated for drug safety studies. The study population included all women under the age of 50 who had a least one prescription contraceptive record between January 1987 and December 2005. Women were followed until December 31, 2005, or until a first recorded fracture or termination from the practice. DMPA users were compared to non-users, who included women using oral contraceptives, the intrauterine device, cervical cap, or diaphragm.
Using data from the full cohort of 312,395 women, the authors found that prior to starting contraception, the crude incidence rate ratio for fractures for women who later became DMPA users was 1.28 (95% confidence interval [CI], 1.07-1.53) compared with women who had never used DMPA. The rate in DMPA users before starting contraception was 8.4 per 1000 person-years and in DMPA never-users it was 6.6 per 1000 person-years. After starting contraceptives, DMPA users still had a higher risk of fracture than never-users; however, it did not increase from baseline (relative risk [RR], 1.23; 95% CI, 1.16-1.30). Furthermore, longer use of DMPA did not increase fracture risk. Compared with nonusers, DMPA users had more codes for extremity and miscellaneous fractures but there was no excess risk for fractures typically associated with decreased bone mineral density (BMD) such as the hip, pelvis, and vertebrae.
DMPA is a highly effective, injectable contraceptive with a failure rate of 0.22 per 100 person-years when used correctly.1 DMPA does cause declines in BMD in adults, with mean loss of 5.4% (lumbar spine) and 5.2% (hip) after 5 years of use.2 In adolescents, there are mean decreases of 2.7% (spine), 4.1% (hip), and 3.9% (femoral neck) after 5 years.3 Given that decreased BMD in postmenopausal women is associated with fragility fractures, there was concern that decreased BMD in DMPA users could also lead to fractures. In 2004, the FDA placed a black box warning on DMPA, stating that it should not be used for longer than 2 years unless other birth control methods were inadequate and that evaluation of BMD was recommended for long-term use.4 In 2002, 5.3% of U.S. women on contraception used DMPA, declining to 3.2% as of 2008.3 Studies have shown, however, that the decreased BMD caused by DMPA is fully reversible on discontinuation.6 The American College of Obstetricians and Gynecologists (ACOG) does not place any limits on DMPA use and advises that BMD assessment in reproductive-aged women on DMPA is not useful. Despite reassurance from ACOG, the FDA warning caused physicians to limit patient use of DMPA.4
Although studies have documented BMD recovery after DMPA use, no study has examined the incidence of actual fractures in DMPA users in the general population. Research instead has focused on the intermediate outcome, BMD, which may not be an appropriate marker for fractures in premenopausal women. Therefore, the authors of this study explored the association between DMPA use and fracture incidence using a validated research database from the United Kingdom that contained medical and prescription records. Their study is unique in that they were able to assess fracture risk both before and after initiating DMPA. After controlling for many risk factors associated with fracture, such as smoking and alcohol abuse, DMPA use was still associated with increased fracture risk. Thus, the authors concluded that there must be some unmeasurable confounder that led to this association. Likely, women who choose DMPA are more at risk for trauma-related fractures due to behavioral or lifestyle factors. Or perhaps, over-reporting occurred with DMPA users because they presented every 3 months for their injection. It is reassuring that DMPA use was not associated with fractures of the axial skeleton, typically associated with decreased BMD. In addition, longer DMPA use was no more associated with fractures than short-term use.
In sum, the unintended pregnancy rate in the United States stands at 49%.7 DMPA is one of the methods of contraception that users do not have to remember on a daily, weekly, or monthly basis. In addition, young women and adolescents are able to use DMPA as reliably as adults.1 DMPA is very forgiving, as well, given that users can be up to 4 weeks late for an injection and still be protected. Keeping DMPA available as an option for women is important, and this study should reassure providers that use of DMPA does not need to be limited out of concern for fractures. In our clinic, per ACOG recommendations, we do not limit DMPA use, nor assess BMD in DMPA users.
1. Winner B, et al. Effectiveness of long-acting reversible contraception. N Engl J Med 2012;366:1998-2007.
2. Kaunitz AM, et al. Bone mineral density in women aged 25 to 35 years receiving depot medroxyprogesterone acetate: Recovery following discontinuation. Contraception 2006;74:90-99.
3. Harel Z, et al. Recovery of bone mineral density in adolescents following the use of depot medroxyprogesterone acetate contraceptive injections. Contraception 2010;81:281-291.
4. Paschall S, Kaunitz AM. Depo-provera and skeletal health: A survey of Florida obstetrics and gynecologist physicians. Contraception 2008;78:370-376.
5. Mosher WD, Jones J. Use of contraception in the United States: 1982-2008. Vital Health Stat 2010;23:1-44.
6. ACOG Committee Opinion No 415. Depot medroxyprogesterone acetate and bone effects. September 2008.
7. Finer LB, Henshaw SK. Disparities in rates of unintended pregnancy in the United States, 1994 and 2001. Perspect Sex Reprod Health 2006;38:90-96.