This document reflects emerging clinical and scientific advances as of the date issued and is subject to change. The information should not be construed as dictating an exclusive course of treatment or procedure to be followed.
ABSTRACT: Although depot medroxyprogesterone acetate (DMPA) is associated with bone mineral density (BMD) loss during use, current evidence suggests that partial or full recovery of BMD occurs at the spine and at least partial recovery occurs at the hip after discontinuation of DMPA. Given the efficacy of DMPA, particularly for populations such as adolescents for whom contraceptive adherence can be challenging or for those who feel they could not comply with a daily contraceptive method or a method that must be used with each act of intercourse, the possible adverse effects of DMPA must be balanced against the significant personal and public health impact of unintended pregnancy. Concerns regarding the effect of DMPA on BMD should neither prevent practitioners from prescribing DMPA nor limit its use to 2 consecutive years. Practitioners should not perform BMD monitoring solely in response to DMPA use because any observed short-term loss in BMD associated with DMPA use may be recovered and is unlikely to place a woman at risk of fracture during use or in later years.
Depot medroxyprogesterone acetate (DMPA) is a highly effective, long-acting contraceptive injection used by more than two million women annually in the United States, including approximately 400,000 adolescents (1). Convenient dose administration and privacy are appealing to adolescents, and the expanded use of DMPA has been credited for at least part of the decrease in adolescent pregnancy rates over the past decade (2, 3). Depot medroxyprogesterone acetate prevents pregnancy by inhibiting the secretion of pituitary gonadotropins resulting in anovulation, amenorrhea, and a decreased production of serum estrogen. Hypoestrogenism is associated with a decrease in bone mineral density (BMD). In older women, low BMD consistent with osteopenia or osteoporosis is associated with an increased risk of fracture. No studies have been conducted to examine the association between BMD and fractures in low-risk young women, including those using DMPA or those experiencing the physiologic hypoestrogenism of lactation. Although DMPA is associated with BMD loss during use, current evidence suggests that partial or full recovery of BMD occurs at the spine and at least partial recovery occurs at the hip after discontinuation of DMPA. Given the efficacy of DMPA, particularly for populations such as adolescents for whom contraceptive adherence can be challenging or for those who feel they could not comply with a daily contraceptive method or a method that must be used with each act of intercourse, the possible adverse effects of DMPA must be balanced against the significant personal and public health impact of unintended pregnancy.
Bone Mineral Density
A number of studies demonstrate the effect of DMPA on BMD. Cross-sectional and longitudinal studies using dual-energy X-ray absorptiometry (DXA) technology among current users of DMPA (ages 18–54 years) demonstrate that DMPA use results in lower BMD compared with nonusers regardless of the anatomic site measured (4–10). Longi-tudinal studies report BMD losses at the hip and spine of 0.5–3.5% after 1 year of DMPA use (5, 11) and a 5.7–7.5% loss in BMD after 2 years of use (8, 10).
Although few studies have examined long-term use of DMPA, it appears that the greatest BMD loss is experienced during the first few years of use (7, 10, 11). In one 3-year longitudinal study, mean change in BMD at each 6-month interval decreased as the number of cumulative months of DMPA use increased (7). Those using DMPA for 12 months or less lost BMD at a faster rate than those using DMPA for 13 months or more (7). Another recent longitudinal study with a 4-year follow-up period demonstrated that almost 75% of the BMD lost at the hip and 90% lost at the spine occurred during the first 24 months of use (9). Women who continued DMPA use beyond 24 months still lost additional bone, but the magnitude of loss was smaller with each subsequent year of use (9).
A recent prospective study of BMD monitored DMPA users and nonhormonal contraceptive users 20–25 years of age for up to 5 years of use and for up to 2 years after discontinuation. Despite BMD loss during use, total hip BMD among DMPA users had returned almost to baseline levels at 2 years after discontinuation (from -5.16% after 240 weeks of use to -0.2% at 96 weeks after discontinuation), and BMD values in the lumbar spine showed partial recovery (from -5.38% after 240 weeks of use to -1.19% at 96 weeks after discontinuation) (12). As in prior studies, the rate of BMD loss was greater in the first year of treatment than in subsequent years.
Bone loss during the reproductive years is not unique to DMPA use. Studies of adult women show a decrease in BMD of 2–8% during pregnancy and 3–5% during breastfeeding (13, 14). These losses are temporary; 6–12 months after birth or cessation of breast-feeding BMD values increase to near preconception values in most women (11). Similarly, studies suggest that at least some of the bone loss experienced as a result of DMPA use is recovered after discontinuation. However, studies differ in their assessment of the speed and completeness of this recovery (7, 9, 10, 12, 15–17). Furthermore, the degree of recovery appears to differ by site. A 3-year longitudinal study of 18–39-year-old DMPA users noted that women experienced steady gains in BMD after discontinuation, regardless of duration of DMPA use (7). Lumbar spine BMD of DMPA users was similar to that of nonusers by 30 months after discontinuation (7). Increases in BMD at the hip among those discontinuing use of DMPA also were noted, but the gain in BMD at this location was lower than that of nonusers 30 months after discontinuation. Similarly, a 4-year study of first-time users of DMPA 18–35 years of age demonstrated that the length of time required for BMD values to return to baseline levels depended on the site measured and the duration of DMPA use. Complete recovery occurred at the spine within 27–30 months among those using DMPA up to 24 months. Recovery at the hip was slower; among those women who used DMPA for 24 months or less, a return to baseline values was not observed by 30 months after discontinuation (9).
Bone mineral density normally increases during the teenaged years. Therefore, a decrease or stabilization in BMD during this period may be cause for concern. In a study of DMPA users aged 12–21 years, BMD decreased an average of 3.1% (18). In contrast, adolescents who were not using hormonal contraception gained BMD at an average rate of 9.5% over 2 years (18). Among new DMPA users aged 14–18 years, a decrease of 5% at the spine occurred after 24 months compared with an increase of 2.3% in nonusers (16). The decrease in BMD observed in these studies may be mitigated by the short-term or intermittent nature of DMPA use in many adolescents because the discontinuation rate is 50% in the first year (19). Furthermore, increases in BMD of 1–4% at the hip and spine 12 months after discontinuation of DMPA have been shown in adolescents aged 14–18 years (16).
At least two cross-sectional studies provide reassuring data that BMD in former adult DMPA users is similar to that of never users (20, 21). A World Health Organization study observed this lack of difference in BMD in an international population of former DMPA users and nonusers (20). Another study of postmenopausal women in New Zealand indicated similar BMD in former adult DMPA users compared with that of never users (21).
Although many studies have examined the intermediate outcome of decreased BMD related to DMPA, few investigations have examined the outcome of critical importance to women's health—that of fracture risk. Two studies have examined DMPA use and fracture, both in high-risk populations. A prospective, short-term study of female military recruits found that, in white women only, history of DMPA use was one of several factors associated with an increased risk of stress fractures of the calcaneus (22). This study was limited to women at high risk of fractures and is not applicable to the general population. Another recent study of developmentally delayed women suggests an increased risk of fractures in those with a history of DMPA use. This study is limited by its cross-sectional design and its use of retrospective data (23).
There are no reported studies in which the risk of osteoporosis or fractures has been examined in a low-risk population of prior DMPA users. A recent Cochrane review reveals that not a single randomized controlled trial of DMPA and fracture risk has been performed (24).
The "Black Box" Warning
Concerns over the effect of DMPA use on BMD caused the U.S. Food and Drug Administration to issue a "black box" warning in November 2004. This warning stated that prolonged use of DMPA may result in significant loss of BMD, that the loss is greater the longer the drug is used, and that the loss may not be completely reversible after discontinuation. The warning cautions that use of DMPA beyond 2 years should be considered only if other contraceptive methods are inadequate. In a letter to physicians, a manufacturer of DMPA suggested DXA monitoring after 2 years of use.
The U.S. Food and Drug Administration warning is based on intermediate effects on BMD, which may or may not be relevant to increased fracture risk. Because the evidence suggests that the rate of BMD loss may slow with longer term DMPA use, the rationale for restriction to 2 years of use or DXA monitoring is unclear. Practitioners should not perform BMD monitoring solely in response to DMPA use because any observed short-term losses in BMD may be recovered and are unlikely to place women at risk of fracture during DMPA use or in later years.
Risks of Bone Loss Versus the Benefits of Contraception
Most women and adolescents use DMPA to avoid pregnancy. The failure rate in typical users is 2–3% for DMPA (25). As a result, DMPA is widely used by women for whom successful use of a daily or partner-dependent contraceptive method is difficult. Increased use of DMPA in the past 15 years has been paralleled by a decrease in the adolescent pregnancy rate (2, 3). Although there are many factors contributing to the decrease in adolescent pregnancies, DMPA has likely played a role. It is important to weigh the theoretical risk of future fracture from decreased BMD in DMPA users against the very real risk of pregnancy if contraceptive choices are limited (26). For example, an adolescent who is at high risk for pregnancy may be best served by the use of DMPA as a contraceptive option; both pregnancy and DMPA are associated with loss of BMD. The risk–benefit ratio might differ for a noncontraceptive indication such as dysmenorrhea (23).
Women initiating DMPA should be thoroughly counseled about the benefits and the potential risks of DMPA. Daily exercise and age-appropriate calcium and vitamin D intake should be encouraged. No studies have shown that these measures will offset loss of BMD during DMPA use, but these recommendations can benefit general health, and most adolescents do not ingest sufficient dietary calcium. Although studies of adolescents and adult women demonstrate that low-dose estrogen supplementation limits BMD loss in DMPA users (27, 28), estrogen supplementation during DMPA use is not currently recommended. Most importantly, clinicians should provide counseling regarding the side effects of DMPA, including irregular bleeding, in order to attempt to reduce the high rates of discontinuation of this method.
Depot medroxyprogesterone acetate is a safe and effective means of long-term contraception, which has likely contributed to a decrease in adolescent pregnancy rates over the past decade. Concerns regarding the effect of DMPA on BMD should neither prevent practitioners from prescribing DMPA nor limit its use to 2 consecutive years. Appropriate counseling with a discussion of current medical evidence should occur before the initiation of this medication and during prolonged use. Practitioners should not perform BMD monitoring solely in response to DMPA use because any observed short-term loss in BMD associated with DMPA use may be recovered and is unlikely to place a woman at risk of fracture during use or in later years. Effective long-term contraceptive methods that have no effect on BMD and have high continuation rates, such as contraceptive implants and intrauterine devices, should also be considered as first-line methods for adolescents.
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- Cundy T, Cornish J, Roberts H, Elder H, Reid IR. Spinal bone density in women using depot medroxyprogesterone contraception. Obstet Gynecol 1998;92:569–73.
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