DR. EDELMAN is assistant professor, department of obstetrics and gynecology, Oregon Health and Science University, Portland,
Ore. She has
nothing to disclose in regard to affiliations with, or financial interests in, any organization that may have an interest
in any part of this
article, which is adapted from Contemporary OB/GYN, an Advanstar publication.
DR. JENSEN is professor, department of obstetrics and gynecology, Oregon Health and Science University, Portland, Ore. Dr.
Jensen reports
that he receives grant/research support from and is a retained consultant for Wyeth-Ayerst and Berlex (and is also on the
latter’s speaker’s
bureau); he also receives grant/research support from Organon, Symbollon, Pfizer (which makes DepoProvera), and Warner-Chilcott.
If you feel uneasy prescribing depot medroxyprogesterone acetate (DMPA [Depo-Provera Contraceptive Injection]) to adolescent
patients in light of the Food and Drug Administration's (FDA) recent black box warning, and find yourself grappling uncomfortably
with this option when advising and treating teenagers who need contraception, you're not alone.
For many adolescents, DMPA (150 mg, intramuscularly, every 12 weeks) continues to be the contraceptive of choice. The method
is highly effective, reversible, and long acting. Moreover, adherence (often a major challenge in this age group) requires
only minimal effort. DMPA reduces menstrual symptoms like excessive bleeding and dysmenorrhea and improves anemia.1,2 The drug's other advantages include a progestin-only formulation that can be safely used by women with contraindications
to estrogen and a unique injectable delivery system that offers your patient privacy.
Unfortunately, the FDA's recent black box warning about the adverse effects of DMPA on bone density in adolescents has left
many clinicians at a loss for how to advise and treat their teenage patients. Some have stopped providing DMPA to adolescents,
while others continue to prescribe it, but feel uneasy doing so. With the United States leading other developed countries
in the teenage pregnancy rate, clinicians need to carefully weigh concerns about the effects of DMPA on bone density against
the consequences of withholding this important contraceptive option.3 The alternative, an unplanned pregnancy, could severely harm—even ruin—an adolescent's future. To help interpret this information,
let's examine the evidence behind the FDA's decision.
How does DMPA work, and why does it affect bone density?
DMPA works by inhibiting the pituitary gland from secreting gonadotropin, especially luteinizing hormone (LH). It provides
contraception by blocking the LH surge and thereby prevents ovulation.4 Additional mechanisms of contraception include a progestin-induced thickening of the cervical mucus (preventing sperm from
penetrating) and thinning of the endometrial lining (creating an inhospitable environment for ovum and sperm).
Estrogen suppresses bone remodeling and resorption, and lower levels or a lack of estrogen (as occurs in menopause) can negatively
impact bone density.4 Although DMPA suppresses follicle-stimulating hormone (FSH), this effect is typically not complete, and most users' ovaries
continue to produce some estradiol.4 Because many of these young women experience symptoms of hypoestrogenism, however, we must consider the effect on bone density.
An additional concern for teenagers is that peak bone mass in females occurs in late adolescence.5 Theoretically, lower levels of estrogen during DMPA use in the active phase of bone development might affect the skeleton
more than with use later in life. The reassuring news is that the recovery of bone density after DMPA use in teenagers appears
to be no different than that of breastfeeding.6,7 In addition, bone mineral density (BMD) is only a surrogate for fracture risk, and no information exists on how this temporary
decrease in BMD during DMPA use might translate to future fracture risk.
What does the literature show?
Table 1 Studies of DMPA and bone mineral density
|
Table 1 summarizes the major research on DMPA and bone density.8-19 Most studies have focused on bone density in adults using DMPA and do show that prolonged use of DMPA decreases BMD over
time. Compared to never or non-users of DMPA, however, the reduction in BMD among longer-term users is small (within one standard
deviation) and clinically insignificant for most users.20 Importantly, the decrease in BMD also appears to be reversible when premenopausal women stop taking the drug.21 Studies of adolescents show this same association between BMD loss and DMPA (Table 1). Like adults, the decrease in BMD among
DMPA users compared to non-users is small and is less than one standard deviation after two years of use.20 To date, there are no studies that show how this small temporary decrease in BMD increases the risk of osteoporosis or fracture
risk.
Table 2 Studies of BMD recovery after cessation of DMPA
|
Two small studies have shown that BMD recovers when both adolescents and adults stop injecting DMPA (Table 2).6,21-24 In premenopausal adults, BMD values in past-users of DMPA (two to three years) are similar to BMD values in those who have
never used the drug.8,25 Other placebo-controlled studies have shown that estrogen supplementation (add-back estrogen) increases BMD in DMPA (Table
2). To date, no studies exist on the effect of calcium supplementation on the maintenance or recovery of BMD in current or
past DMPA users.
Recommendations
The World Health Organization (WHO) published a statement in July 2005 in response to the FDA's black box warning regarding
DMPA use in adolescents. The WHO's recommendations provide a reasonable, evidence-based, practical approach. The WHO statement
is at http://www.who.int/reproductivehealth/family_planning/bone_health.html.20 The WHO recommendations "with regard to metabolism" (stated there and used with permission) are as follows:20
- There should be no restriction on the use of DMPA, including no restriction on the duration of use, among women aged 18 to
45 who are otherwise eligible to use the method.
- Among adolescents (menarche to <18 years) and women over 45 years, the advantages of using DMPA generally outweigh the theoretical
safety concerns regarding fracture risk. Because data are insufficient to determine if this is the case with long-term use
among these age groups, the overall risks and benefits for continuing use of the method should be reconsidered over time with
the individual user.
- There should be no restriction on the use of other progestogen-only contraceptive methods among women who are otherwise eligible
to use these methods, including no restriction on duration of use.
- There should be no restriction on the use of combined hormonal methods among women who are otherwise eligible to use these
methods, including no restriction on duration of use.
Key points
|
Although add-back estrogen has been successful in maintaining bone density in research studies, we do not recommend incorporating
add-back estrogen into clinical practice at this time. In addition, measuring BMD in adolescents using DMPA is not recommended.
A number of recommendations are prudent, particularly so in teens with poor dietary habits. Encourage DMPA users to foster
good bone health by increasing calcium and vitamin D intake, engaging in weight-bearing activities, and quitting or avoiding
smoking. These healthy lifestyle practices can increase peak bone mass by as much as 5% to 10%.26It is reasonable to consider an alternative birth control method to DMPA for adolescents at highest risk of low BMD, including
heavy smokers, patients with anorexia nervosa, and those who chronically use steroids. But do not withhold DMPA if this drug
turns out to be the best birth control method for your patient. Rather, educate the young woman about the risks, encourage
her to practice healthy lifestyle habits (exercise, take enough calcium, and stop smoking), and readdress DMPA use annually.
Final word
Although increasing data are accumulating about the negative impact of DMPA on BMD in adolescents, the magnitude of the effect
is small and temporary, and the decline in BMD has not been linked to fracture risk. The best available evidence suggests
that BMD recovers after DMPA is stopped, in a manner similar to what occurs naturally following lactation. According to the
WHO, there should be no restrictions on DMPA use in adolescents who are otherwise eligible to use the method. If DMPA is the
best contraceptive option for your teen patient, then by all means prescribe it. And be sure to encourage adopting better
lifestyle behaviors, like getting sufficient calcium and weight-bearing exercise and avoiding smoking, which can have a significant
impact on peak bone mass.
REFERENCES
1. Gardner JM, Mishell DR Jr: Analysis of bleeding patterns and resumption of fertility following discontinuation of a long
acting injectable contraceptive. Fertil Steril 1970;21:286
2. Cromer BA, Smith RD, Blair JM, et al: A prospective study of adolescents who choose among levonorgestrel implants (Norplant),
medroxyprogesterone acetate (Depo-Provera), or the combined oral contraceptive pill as contraception. Pediatrics 1994;94:687
3. Darroch JE, Frost JJ, Singh S, et al: Teenage sexual and reproductive behavior in developed countries: Can more progress
be made? Occasional Report, No. 3, New York, NY: Allen Guttmacher Institute; 2001.
4. Speroff L, Glass RH, Kase NG, eds.: Clinical Gynecologic Endocrinology and Infertility. 6th ed. Baltimore, Md: Lippincott
Williams & Wilkins; 1999.
5. Matkovic V, Jelic T, Wardlaw G, et al: Timing of peak bone mass in Caucasian females and its implication for the prevention
of osteoporosis. Inference from a cross-sectional model. J Clin Invest 1994;93:799
6. Scholes D, LaCroix AZ, Ichikawa LE, et al: Change in bone mineral density among adolescent women using and discontinuing
depot medroxyprogesterone acetate contraception. Arch Pediatr Adolesc Med 2005;159:139
7. Chantry CJ, Auinger P, Byrd RS: Lactation among adolescent mothers and subsequent bone mineral density. Arch Pediatr Adolesc Med 2004;158:650
8. Cundy T, Evans M, Roberts H, et al: Bone density in women receiving depot medroxyprogesterone acetate for contraception.
BMJ 1991;303:13
9. Cromer BA, Blair JM, Mahan JD, et al: A prospective comparison of bone density in adolescent girls receiving depot medroxyprogesterone
acetate (Depo-Provera), levonorgestrel (Norplant), or oral contraceptives. J Pediatr 1996;129:671
10. Taneepanichskul S, Intaraprasert S, Theppisai U, et al: Bone mineral density in long-term depot medroxyprogesterone acetate
acceptors. Contraception 1997;56:1
11. Gbolade B, Ellis S, Murby B, et al: Bone density in long term users of depot medroxyprogesterone acetate. Br J Obstet Gynaecol 1998;105:790
12. Tang OS, Tang G, Yip P, et al: Long-term depot-medroxyprogesterone acetate and bone mineral density. Contraception 1999;59:25
13. Scholes D, LaCroix AZ, Ott SM, et al: Bone mineral density in women using depot medroxyprogesterone acetate for contraception.
Obstet Gynecol 1999;93:233
14. Petitti D, Piaggio G, Mehta S, et al: Steroid hormone contraception and bone mineral density: A cross-sectional study
in an international population. The WHO Study of Hormonal Contraception and Bone Health. Obstet Gynecol 2000;95:736
15. Berenson AB, Breitkopf CR, Grady JJ, et al: Effects of hormonal contraception on bone mineral density after 24 months
of use. Obstet Gynecol 2004;103:899
16. Clark MK, Sowers MR, Nichols S, et al: Bone mineral density changes over two years in first-time users of depot medroxyprogesterone
acetate. Fertil Steril 2004;82:1580
17. Cromer BA, Stager M, Bonny A, et al: Depot medroxy-progesterone acetate, oral contraceptives and bone mineral density
in a cohort of adolescent girls. J Adolesc Health 2004;35:434
18. Lara-Torre E, Edwards CP, Perlman S, et al: Bone mineral density in adolescent females using depot medroxyprogesterone
acetate. J Pediatr Adolesc Gynecol 2004;17:17
19. Scholes D, LaCroix AA, Ichikawa LE, et al: The association between depot medroxyprogesterone acetate contraception and
bone mineral density in adolescent women. Contraception 2004;69:99
20. World Health Organization. WHO statement on hormonal contraception and bone health. July 2005. Available at: http://www.who.int/reproductivehealth/family_planning/bone_health.html. Accessed August 18, 2005.
21. Cundy T, Cornish J, Evans MC, et al: Recovery of bone density in women who stop using medroxyprogesterone acetate. BMJ 1994;308:247
22. 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;186:978
23. Cundy T, Ames R, Horne A, et al: A randomized controlled trial of estrogen replacement therapy in long-term users of depot
medroxyprogesterone acetate. J Clin Endocrinol Metab 2003;88:78
24. Cromer BA, Lazebnik R, Rome E, et al: Double-blinded randomized controlled trial of estrogen supplementation in adolescent
girls who receive depot medroxyprogesterone acetate for contraception. Am J Obstet Gynecol 2005;192:42
25. Banks E, Berrington A, Casabonne D: Overview of the relationship between use of progestin-only contraceptives and bone
mineral density. Br J Obstet Gynaecol 2001; 108:1214
26. Bachrach L, Cundy T, Ott S: Depot medroxyprogesterone acetate in teens: A risk for bone health? Pediatrics 2000;106:1137
