Depot Medroxyprogesterone Acetate Contraceptive Injections and Skeletal Health

“The best available evidence supports the notion that DMPA use decreases BMD but that the decrease is small, reversible and has not been associated with osteoporotic fractures.”

Background

Depo-Provera® (Pfizer, NY, USA), or DMPA, is a progestin-only contraceptive that provides highly effective, private, long-acting and reversible contraception. Unfortunately, DMPA's many benefits are often overshadowed by the controversy that arose in 2004 regarding its effects on skeletal health. The US FDA issued a Black Box Warning to providers based on data demonstrating that BMD decreased during DMPA use and BMD recovery might not be 100%. The FDA stated that:

“DMPA should be used as a long-term birth control method (e.g., longer than 2 years) only if other birth control methods are inadequate” [101].

To make matters worse, the manufacturers of DMPA issued a follow-up statement suggesting that providers should perform BMD testing in patients after 2 years of DMPA use. The UK Committee on Safety of Medicines (CSM) followed suit with similar warnings regarding the use of DMPA [102].

What have the consequences been?

According to a survey of US obstetrician–gynecologists, these warnings led some to restrict the duration of DMPA use and to order BMD testing in DMPA users of reproductive age [1]. A total of 16% of UK primary care providers surveyed reported that they would deter all women from using DMPA, another third would deter young women from using DMPA and one in five said they would limit the use of DMPA to 2 years [2].

What is the evidence?

Skeletal health is not a trivial concern since osteoporosis is costly, both medically and financially for individuals and society [3]. In suppressing ovulation, DMPA also causes a hypoestrogenemic state, which in turn promotes bone resorption over bone formation. Therefore, this leads us to the questions that we will address in this editorial: what happens to BMD during and after DMPA use; what is the clinical significance of this effect; how do research findings translate to the bedside; and why is DMPA still important?

What happens to BMD during Depo-Provera® use?

Compared with nonusers, BMD at the hip and spine of DMPA users decreases by 0.5–3.5% after 1 year and 5.7–7.5% after 2 years of use [4–6]. The greatest loss occurs during the first 1–2 years of use and then BMD levels appear to stabilize [7,8]. However, it is important to note that the BMD loss experienced by both adult and adolescent DMPA users is never below one standard deviation of normal, even after 5 years of use [9]. Subcutaneous and intramuscular formulations of DMPA have similar effects on bone density [10].

What happens after Depo-Provera is discontinued?

A systematic review of the literature demonstrated BMD recovery with DMPA discontinuation [8]. This is true for both ends of the age spectrum (i.e., adolescents and perimenopausal women); BMD returned to baseline within approximately 30 months in premenopausal women [8,11]. The largest study was a 7-year open-label, prospective, race- and age-matched-cohort study of women aged 25–35 years using DMPA versus nonhormonal contraception [6]. Differences in recovery, after adjustment for baseline, were of borderline significance for the hip (-2.08 mean percentage change from baseline in former DMPA users; p = 0.047) and were significant for lumbar spine BMD (-2.04%; p = 0.017). None of the participants lost 10% or more of their BMD, and recovery appeared to be ongoing at 96 weeks [6].

In adolescent DMPA users, BMD recovery occurred within 12 months following DMPA discontinuation and was associated with significant increases in BMD relative to nonusers at all anatomical sites. The time of recovery was independent of the length of DMPA use or first use at a younger age [11,12].

“Not only is DMPA a highly effective method of birth control for healthy women, it is one of the few options available to women who cannot safely use contraceptive doses of estrogen…”

Women using DMPA close to (within 2 years) or around the time of menopause versus nonusers demonstrated no difference in menopausal BMD levels. Interestingly, one prospective study showed the change in BMD that occurs with menopause to be larger in nonusers than in DMPA users, suggesting that DMPA users had already experienced the estrogen-related bone changes [8].

How do research findings translate to the bedside?

Research may demonstrate a statistically significant decrease in BMD with DMPA use, but is this a clinically significant finding? Do BMD changes increase the risk of fractures? BMD has been found to predict fracture risk in post-menopausal women; however, this association has not been found in premenopausal women. In addition, not a single randomized controlled trial has examined the risk of fractures related to DMPA use [13] and observational data are conflicting [6,8,14–16].

Why is Depo-Provera still important?

The potential impact of DMPA on skeletal health must be balanced against the significant personal and public health impact of unintended pregnancy. In addition, lactation, a hypoestrogenemic state, causes similar decreases in BMD to DMPA [9]. Lactation has not been found to predict osteoporosis or fractures later in life. For adolescents, a population in whom contraceptive adherence is low, DMPA has a higher continuation rate than oral contraceptives [17].

Not only is DMPA a highly effective method of birth control for healthy women, it is one of the few options available to women who cannot safely use contraceptive doses of estrogen, including those aged over 35 years who smoke, women with a history of blood clots and those with migraines preceded by aura [18,103]. Noncontraceptive benefits, such as decreased menstrual bleeding and amenorrhea in 46–75% of women with ongoing use [19,20], make it a useful medication for decreasing blood loss in anemic women and managing menstrual hygiene in individuals with special needs (e.g., those with physical or cognitive impairment) [21].

What now?

The best available evidence supports the notion that DMPA use decreases BMD but that the decrease is small, reversible and has not been associated with osteoporotic fractures. Withholding DMPA or restricting its duration of use is likely to increase the risk of unintended pregnancies and induced abortions. Accordingly, skeletal health concerns should not restrict initiation or continuation of DMPA beyond 2 years in adolescents, premenopausal or perimenopausal women. Given that the effect of DMPA on BMD is similar to that of lactation, the use of DMPA is not an indication for BMD testing before, during or after use [4,22]. Our conclusions are supported by a number of professional medical organizations. The American College of Obstetricians and Gynecologists (ACOG) [4], the Society for Adolescent Medicine (SAM) [22], the WHO [23], the Society of Obstetricians and Gynecologists of Canada (SOGC) [24,25] and the UK NICE [104] state that the advantages of DMPA use as a contraceptive generally outweigh the theoretical concerns regarding skeletal harm.

“Withholding DMPA or restricting its duration of use is likely to increase the risk of unintended pregnancies and induced abortions. Accordingly, skeletal health concerns should not restrict initiation or continuation of DMPA beyond 2 years in adolescents, premenopausal or perimenopausal women.”

Providers should counsel DMPA users on the risks and benefits, and should advise users to ensure an adequate intake of calcium and vitamin D and to engage in regular exercise in order to promote bone health, just as they would any other woman, regardless of her contraceptive choice. However, calcium and vitamin D supplementation should not be recommended solely based on a woman's use of DMPA. While some data support the preventative effects of supplemental estrogen on bone loss in DMPA users, we agree with the ACOG and SAM recommendations not to recommend routine estrogen supplementation. Owing to a lack of data, we also do not recommend the use of antiresorptive agents (e.g., bisphosphonates, calcitonin and selective estrogen receptor modulators) to prevent bone loss in DMPA users.

What remains unanswered?

Data are conflicting regarding whether BMD recovery is 100% following discontinuation of DMPA in adults. Overall, the amount of data in adolescents is relatively small and it is unknown whether DMPA use prior to achieving peak bone mass alters this recovery. Long-term follow-up and randomized controlled trials on fracture risk related to DMPA are lacking.