Bone Density Recovery with DMPA

Abstract & Commentary

By Jeffrey T. Jensen, MD, MPH, Editor, Leon Speroff Professor of Obstetrics and Gynecology, Vice Chair for Research, Oregon Health and Science University, Portland, is Editor for OB/GYN Clinical Alert.

Source: Harel Z, et al. Recovery of bone mineral density in adolescents following the use of depot medroxyprogesterone acetate contraceptive Contraception 2010;81:281-291.

Synopsis: Although adolescents receiving depot medroxyprogesterone acetate experience a decline in bone mineral density, the effects appear mostly reversible within 60 months following discontinuation. Changes at the hip recover more slowly, and persist longer in those women that experience the greatest amount of bone loss.

Depot medroxyprogesterone acetate (DMPA) is a highly effective progestin-only contraceptive that is widely used by adolescents. DMPA is also associated with suppression of ovarian production of estradiol, and with a decrease in bone density in some users. To determine the long-term effects of DMPA on bone mineral density (BMD) changes in female adolescents during and following use of this contraceptive method, the authors conducted a multicenter, prospective, non-randomized observational study of healthy female adolescents ages 12-18 years who initiated DMPA intramuscular injections for contraception. An enrolled cohort of 98 girls provided BMD data for up to 240 weeks while receiving DMPA and for up to 300 weeks after DMPA cessation. BMD at the lumbar spine (LS), total hip (TH), and femoral neck (FN) was assessed by dual-energy X-ray absorptiometry (DEXA). At the time of their final DMPA injection, participants demonstrated significant declines in mean BMD from baseline of 2.7% (LS), 4.1% (TH), and 3.9% (FN). Within 60 weeks of discontinuation of DMPA, mean LS BMD had returned to baseline levels, and by 240 weeks after DMPA discontinuation, the mean LS BMD was 4.7% above baseline. Although the mean TH and FN BMD values recovered to baseline values more slowly, by 240 weeks after the last DMPA injection these parameters had either recovered to baseline or increased. The authors concluded that BMD loss in female adolescents receiving DMPA for contraception is substantially or fully reversible in most girls following discontinuation of DMPA, with faster recovery at the LS than at the hip.

Commentary

This large multicenter prospective study provides additional reassuring evidence that contraceptive use of DMPA by adolescents is not associated with long-term adverse effects on bone mineral density in the majority of users. Although adolescents do lose bone during DMPA use, most of them rapidly regain bone after discontinuation. The effects are similar to those expected following pregnancy and lactation. While these results are reassuring that most adolescents can safely use this important contraceptive option, the clinician should be aware of the underlying issues to better explain the black box warning to potential users, community health groups, and other health care providers.

DMPA potently suppresses gonadotropins, leading not only to inhibition of ovulation, but also follicle growth. For women who have used DMPA for several years, serum estradiol levels range between 10 and 92 pg/mL, with mean levels of about 40 pg/mL.1 Despite these low levels of estradiol, hot flashes are a rare event, the vaginal epithelium typically remains moist and well rugated, and breast size does not decrease. However concerns about low levels of estrogen leading to suboptimal gains in bone density, particularly during adolescent growth, warrant careful investigation. Most studies in both adult and adolescent women have documented a loss of bone density with long-term use.2 Since the teenage years represent a particularly important interval for development of peak bone mass, any long-term adverse effect could have significant health effects in adulthood. Unfortunately, BMD is only a surrogate measure, and no studies have been conducted using fracture (the primary outcome of clinical interest) as an endpoint.

The study by Harel et al was originally proposed as a 7-year prospective non-randomized multicenter study comparing initiators of DMPA with other adolescents that were either sexually abstinent or using non-hormonal contraceptive methods. However, the baseline demographic characteristics and risk-related differences of the groups were (not surprisingly) substantially different, so this comparison was abandoned. DMPA use was discontinued after a maximum of 240 weeks of use to allow sufficient follow-up time to answer the question about reversibility of bone loss.3

Of the 389 adolescent girls enrolled in the study, 191 received at least one injection of DMPA, and 98 contributed DEXA data after the end of treatment. There was no significant difference between the baseline characteristics of participants that provided follow-up data and those that did not. Overall, the mean baseline BMD Z-scores of participants were higher than the age-specific reference population. Most (57%) of the subjects received between 5 and 16 injections, with about 19% receiving 17 or more and 24% receiving 4 or less shots. Tobacco and alcohol use were significantly correlated with longer-term use. Although none of the baseline characteristics of the study group was significantly associated with bone loss of 5% or more, this level of decline in BMD was positively linked with the number of DMPA shots (median, 13). Subjects losing > 8% of bone had lower baseline BMI than those losing < 5%.

For the entire analysis population, the median number of DMPA injections was 9, and the mean BMD declines from baseline were 2.7% at the LS, 4.1% at the TH, and 3.9% at the FN. It is reassuring to note that 84% of subjects had a LS BMD that surpassed baseline at 240 weeks, with a mean increase in BMD of 4.7% at that site. Recovery in the spine was observed in subjects that lost < 5% or ≥ 5% of BMD. Results at the hip are less reassuring; while recovery and positive gains were observed among subjects that experienced losses < 5% of BMD, those that experienced a loss ≥ 5% continued to register a > 4% decrease from baseline even after 240 months of follow-up. Subjects reporting adequate dietary calcium intake tended to have higher BMD levels than those that did not, but there was no significant effect of dietary calcium on BMD recovery.

While these results suggest that BMD is mostly reversible in adolescent women receiving DMPA, I think it is naïve for clinicians to dismiss the issue as unimportant. To provide the best possible patient care, we need to apply an evidence- and population-based approach to health care on an individual level. The human genome project places us at the cusp of personalized medicine. In the coming years we may have office tests at our disposal that will help us determine which of our patients using a combined hormonal method are at risk for a failure due to increased metabolism, or a blood clot due to poor metabolism. We may also be able to predict the woman at risk for significant adverse events due to bone loss with DMPA. Until that day comes, we will need to rely on our clinical judgment.

For most adolescents, the benefits of DMPA use will clearly outweigh the risks, as pregnancy is a serious and likely outcome in sexually active teens using no method or non-hormonal methods of contraception. While DMPA is highly effective when used correctly and consistently, the failure with typical use is at least 3% and probably higher when method discontinuation is considered. A study by Goldberg et al found that almost 80% of women who started DMPA as their contraceptive method post-abortion discontinued the method within a year, and more than 20% experienced a repeat unintended pregnancy.4 Therefore, most teens will not be expected to continue with DMPA for multiple years of use and effects on bone become a moot point. In fact, we can expect more reliable protection from pregnancy if we can encourage more of our adolescent patients to accept long-acting methods that do not require frequent visits to the clinic, like the etonogestrel implant, LNG IUS, or copper IUD.

But what about the adolescent long-term DMPA user? I think that this study provides additional reassurance at least for the spine, but we should continue to follow the recommendations from the 2006 position paper of the Society for Adolescent Medicine5:

  1. Continue prescribing DMPA to adolescent girls needing contraception with adequate explanation of benefits and potential risks.
  2. Inform patients of the possible risk for bone loss.
  3. Understand individual risk profile for osteopenia on DMPA.
  4. Consider the inclusion of bone density monitoring if DMPA is the desired method and some particularly concerning conditions apply to a given patient.
  5. Duration of use need not be restricted to 2 years.
  6. Recommend a daily intake of 1300 mg calcium plus 400 IU vitamin D and daily weight-bearing exercise to all adolescents receiving DMPA.
  7. Consider estrogen supplementation in those girls with osteopenia (or those who have not had DEXA but are at high risk for osteopenia) who are otherwise doing well on DMPA and have no contraindication to estrogen.

To these I would add that there is no indication for routine DEXA screening.

References

  1. Mishell DR Jr. Pharmacokinetics of depot medroxyprogesterone acetate contraception. J Reprod Med 1996;41(5 Suppl):381-390.
  2. Lopez LM, et al. Steroidal contraceptives: Effect on bone fractures in women. Cochrane Database Syst Rev2009;(2):CD006033.
  3. Johnson CC, et al. Longitudinal study of depot medroxyprogesterone acetate (Depo-Provera) effects on bone health in adolescents. Contraception 2008;77:239-248.
  4. Goldberg AB, et al. Post-abortion depot medroxyprogesterone acetate continuation rates. Contraception 2002;66:215-220.
  5. Cromer BA, et al. Depot medroxyprogesterone acetate and bone mineral density in adolescents — the Black Box Warning. J Adolesc Health 2006;39:296-301.