Original research articleSubcutaneous DMPA vs. intramuscular DMPA: a 2-year randomized study of contraceptive efficacy and bone mineral density
Introduction
Depot medroxyprogesterone acetate (Depo-Provera®; DMPA) is a highly effective, long-acting, reversible progestin-only contraceptive with an extensive history of safety worldwide [1], [2]. It has been available for contraception for several decades in a formulation for intramuscular injection (150 mg/mL once every 3 months; DMPA-IM) and provides convenient, private and immediate contraception, with failure rates during typical use that are substantially lower than those of oral contraceptives [1], [3].
A lower-dose formulation of DMPA for subcutaneous injection (104 mg/0.65 mL once every 3 months; DMPA-SC) has also been developed. DMPA-SC was approved by the US Food and Drug Administration (FDA) in December 2004 (depo-subQ provera 104™), and it has been shown to be well tolerated and highly effective in 1-year studies [4], [5]. Potential advantages of the subcutaneous formulation include increased convenience and ease of administration. Although DMPA-SC is not currently approved by the FDA for self-injection, self-administered DMPA-SC might increase compliance by eliminating the need for women to periodically return to their health care provider for injections [6]. The results of a questionnaire study have suggested that the option to self-administer DMPA-SC is likely to be popular with many women [7].
While DMPA is highly effective and is the contraceptive of choice for millions of women worldwide, its use has been associated with a decline in bone mineral density (BMD) [8]. Estrogen plays an important role in the regulation of bone mass in premenopausal women by down-regulating osteoclast activity, thereby controlling bone resorption [9], [10]. As medroxyprogesterone acetate (MPA) acts to inhibit gonadotropin secretion, and therefore to suppress ovarian estradiol production [11], [12], the effect of DMPA on BMD is a direct consequence of its contraceptive action.
BMD, along with age, is an important predictor of skeletal strength in postmenopausal women [13], [14] and decreases in BMD correlate with an increased risk of a “fragility” fracture in the older, postmenopausal population [13], [15]. This association has led to concerns that BMD reductions induced by DMPA may lead to an increased long-term fracture risk; however, fragility fractures are very uncommon in premenopausal women and fracture risk is not significantly correlated with changes in BMD in women younger than 45 years [16]. Furthermore, as demonstrated in a recent systematic review of studies [17], we and others have shown that bone loss associated with DMPA use is substantially or completely reversed after DMPA use is discontinued [18], [19], [20], [21], [22], [23], [24]. There is currently no evidence of a significant increase in the risk of fractures as a result of DMPA use [8]. Despite these data, concerns persist that DMPA-induced bone loss might increase the long-term risk of fracture, particularly in young women who have not reached peak bone mass and perimenopausal women who may be starting to lose bone mass.
The subcutaneous formulation of DMPA has a slower rate of absorption than the intramuscular formulation [4]. DMPA-SC has the same high level of contraceptive efficacy as DMPA-IM and a tolerability profile that is similar to or better than that of DMPA-IM [5]. The two large, open 1-year studies reported by Jain et al. [5] assessed the contraceptive efficacy and safety of DMPA-SC; however, these studies did not assess BMD. Decreases in BMD would be expected based on the known action of MPA to reversibly suppress estradiol production. The current study was initiated as a substudy of one of the trials reported by Jain et al. [5] but was conducted in a separate group of women. The present study compared BMD changes relative to baseline together with efficacy, safety and user satisfaction in women receiving either DMPA-SC or DMPA-IM for up to 3 years; the primary objectives were to evaluate BMD changes and contraceptive efficacy after 2 years.
Section snippets
Participants
Women aged between 18 and 35 years who were sexually active and who desired long-term contraception (including women who used oral, intrauterine, or barrier methods before initiation of the study and who wished to switch to DMPA contraception) were recruited from clinics (hospital associated and independent) providing contraceptive services. Additional inclusion criteria included regular menstruation (with an average cycle length of 25–35 days) during the 3 months before enrollment, a negative
Baseline demographics and participant disposition
A total of 535 women were enrolled in the study (Fig. 1). Ten participants (four receiving DMPA-SC and six receiving DMPA-IM) had a lumbar spine or total hip T-score of less than −1 at enrollment, in violation of the entry criterion. While this criterion was employed to avoid any risk of BMD loss in women with low BMD, it was anticipated that the rate of change of BMD in participants with low BMD would be similar to that in the rest of the study population and that inclusion of these women
Discussion
This large multinational, multicenter, Phase 3 study showed DMPA-SC administered every 3 months to be as well tolerated and effective a contraceptive as DMPA-IM over periods of up to 3 years. In this population of women with normal bone density at baseline, changes from baseline in total hip and lumbar spine BMD were similar in the DMPA-SC and DMPA-IM groups,. There were no pregnancies in the DMPA-SC group and only one occurred in the DMPA-IM group. Both DMPA-SC and DMPA-IM were ranked highly
Acknowledgments
This study was sponsored by Pfizer. Editorial support was provided by Julie Ponting at Anthemis Consulting and was funded by Pfizer. Dr. Kaunitz, Dr. Darney, and Dr. Speroff were not compensated, and the authors retained full editorial control over the content of the paper. Dr. Kaunitz is a consultant to and the University of Florida Research Foundation receives research support from Bayer, Johnson & Johnson, Organon, and Warner-Chilcott. Dr. Darney is a consultant to Organon and Bayer and
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