New research emerges on DMPA fracture risks

Results of a current study of women using the contraceptive injection depot medroxyprogesterone acetate (DMPA, Depo-Provera, Pfizer, New York City; Medroxyprogesterone Acetate Injectable Suspension USP, Teva Pharmaceuticals USA, North Wales, PA) indicate a modest increase in fracture risk compared with women using other contraceptive methods; however, the increased risk of fracture preceded the start of method use, analysis shows.1 The difference in fracture risk was primarily in fractures associated with trauma rather than those typical of osteoporosis, the research suggests.

Two earlier case-control reports have suggested that DMPA users might experience a higher risk of fractures during their reproductive years then women who use other contraceptives, notes Andrew Kaunitz, MD, professor and associate chair in the Obstetrics and Gynecology Department at the University of Florida College of Medicine — Jacksonville and a co-author of the current paper.2,3

The new analysis, which is based on the same United Kingdom Family Practice Research database as the British case-control study,2 points out the elevated fracture risk in DMPA users is real, but begins before women start DMPA injections, states Kaunitz. Therefore, the DMPA itself could not have been the cause of this elevated fracture risk, Kaunitz observes.

To estimate the extent to which DMPA might increase fracture risk, researchers in the current paper undertook a retrospective cohort study of fractures in DMPA users and users of non-DMPA contraceptives, using the General Practice Research Database, which contains deidentified data from more than 350 general practices in the United Kingdom. The study was funded by the drug’s manufacturer, Pfizer.

Women who used DMPA and were younger than age 50 at the qualifying first contraceptive prescription were included in the study. Users were classified by DMPA exposure (cumulative and time of last dose) based on prescription records. All incident fractures were included. Fracture incidence and risk factors before starting contraceptive use (DMPA or other) also were estimated.

Analysis identified 11,822 fractures in 312,395 women during 1,722,356 person-years of follow-up. Before contraceptive use started, DMPA users had higher fracture risk than nonusers [incidence rate ratio 1.28, 95% confidence interval (CI) 1.07-1.53]. After DMPA started, crude fracture incidence was 9.1 per 1,000 person-years for DMPA users and 7.3 for nonusers (crude incidence rate ratio 1.23, 95% CI 1.16-1.30).

Researchers found that fracture risk in DMPA users did not increase after starting DMPA (incidence rate ratio after or before 1.08, 95% CI 0.92-1.26). There was little confounding by age or other factors that could be measured. Fracture incidence was 9.4 per 1,000 person-years in low-exposure (one to seven injections) DMPA users, and 7.8 per 1,000 in high-exposure (at least eight injections) DMPA users. The DMPA users had higher fracture risk than nonusers at the start of contraceptive use, with no discernible induction period.

“Although DMPA users experienced more fractures than nonusers, this association may be the result of confounding by a pre-existing higher risk for fractures in women who chose DMPA for contraception,” researchers conclude.1

DMPA not culprit

Women who choose specific contraceptives often are different from women who choose other contraceptives, observes Kaunitz. For example, a Baltimore study found that prior to initiating DMPA, women who chose DMPA had a higher baseline prevalence of chlamydia infections than women who chose other contraceptives.4 In the Danish case control study, researchers found that women who chose DMPA were far more likely to abuse alcohol than women who used other contraceptives,3 says Kaunitz.

Data in two studies indicate that use of DMPA by reproductive-age women does not cause osteoporosis in menopausal women, says Kaunitz.5,6 In view of the current study, the language in the “black box” in the DMPA package labeling should be revised, he says. The language in the black box says, “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 for osteoporotic fracture in later life.” The warning cautions users that DMPA should be used as a long-term birth control method (longer than two years) only if other birth control methods are inadequate. A 2011 editorial called for its repeal.7 (See the Contraceptive Technology Update article, “DMPA: Time to repeal black box warning?” October 2011, p 112.)

“DMPA does not cause fractures in reproductive-age women,” says Kaunitz. “Concerns regarding skeletal health should not impact the decision to initiate or continue DMPA contraception.”

References

1. Lanza LL, McQuay LJ, Rothman KJ, et al. Use of depot medroxyprogesterone acetate contraception and incidence of bone fracture. Obstet Gynecol 2013; 121(3):593-600.

2. Meier C, Brauchli YB, Jick SS, et al. Use of depot medroxyprogesterone acetate and fracture risk. J Clin Endocrinol Metab 2010; 95(11):4,909-4,916.

3. 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.

4. Morrison CS, Bright P, Wong EL, et al. Hormonal contraceptive use, cervical ectopy, and the acquisition of cervical infections. Sex Transm Dis 2004; 31(9):561-567.

5. Orr-Walker BJ, Evans MC, Ames RW, et al. 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.

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

7. Kaunitz AM, Grimes DA. Remove the black-box warning for depot medroxyprogesterone acetate! OBG Management 2011; 28(3)6,8-9.