Be prepared to counsel on use of DMPA and bone health issues
New labeling warns prolonged drug use may result in bone density loss
It’s time to update your counseling on the injectable contraceptive depot medroxyprogesterone acetate (DMPA, Depo-Provera, Pfizer; New York City). The Food and Drug Administration (FDA) has added a "black box" warning to the drug’s labeling to highlight that prolonged use may result in the loss of bone mineral density (BMD).
The new label states that bone loss in women who use Depo-Provera is greater with increased duration of use and may not be completely reversible. The injectable contraceptive should be used as a long-term birth control method (longer than two years) only if other birth control methods are inadequate, the label advises. Women who continue to use Depo-Provera past the two-year mark should have their BMD evaluated, according to the new labeling.
Since Depo-Provera was approved for U.S. use in 1992, its prescribing information has included a warning that use of the product may be considered among the risk factors for development of osteoporosis. Two studies, one enrolling women ages 25-35 and the other aimed at adolescents, were begun in the mid-1990s to clarify the drug’s impact on BMD. Results from the studies, which have not yet been published, provide the background for the drug’s revised labeling.
According to Pfizer, the new research indicates that a decrease in BMD appears to be at least partially reversible in adults and adolescents when the use of Depo-Provera is discontinued. A study to assess the reversibility of loss of BMD in adolescents is ongoing.1
Pfizer and the FDA decided to add the warning following review of the two studies, states Christine Parker, FDA spokeswoman. According to Parker, both studies were seven-year, prospective, nonrandomized surveillance studies designed to evaluate bone mineral density changes.
Pfizer has issued a revised patient information sheet for the drug and distributed a "Dear Health Care Practitioner" letter to alert potential and existing prescribers of the new labeling. (See the resources below to get web access to these and other pertinent documents, as well as Pfizer telephone contact numbers for clinicians and patients.)
Will warning affect use?
According to an FDA talk paper issued on the new labeling, black box warnings are used "to highlight special problems, particularly those that are serious, and to give health care professionals a clear understanding of a potential medical complication associated with a drug."2 Family planning clinicians are familiar with such warnings; combined oral contraceptives carry a black box warning to alert that cigarette smoking increases the risk of serious cardiovascular side effects from Pill use.
Seeing such a warning on the contraceptive injectable label may seem scary for some clinicians and patients, says Andrew Kaunitz, MD, professor and assistant chair in the Obstetrics and Gynecology Department at the University of Florida Health Science Center/Jacksonville. Understanding that reaction is a new reality with the use of Depo-Provera for contraception, he adds.
However, concerns about BMD should not prevent use of DMPA in any appropriate user, states Kaunitz, who will present results from the adult DMPA study at the annual clinical meeting of the Washington, DC-based American College of Obstetricians and Gynecologists May 7-11.
Review earlier research
Clinicians have eyed DMPA’s potential impact on bone health since the 1990s, when initial research determined that women using DMPA had bone density values intermediate between those of normal premenopausal and postmenopausal women.3 A subsequent study of some of the original DMPA users who discontinued the method found that bone density tended to increase after the method was stopped.4
A more recent investigation indicates that women using the injectable for two years recorded an approximate 6% decline in bone mineral density, compared with a loss of 2.6% among women on oral contraceptives.5
Further research indicates that DMPA may be used on a long-term basis without fear of linear bone loss leading to early osteoporosis. Scientists who conducted a small study in China followed women for three years.6 They found the annual rate of bone loss at three sites was significantly less than projected values, and the duration of DMPA use was not significantly related with the rate of bone loss. Results from two cross-sectional studies indicate that DMPA’s effect on BMD is small and reversible.7,8
Adding back estrogen may be effective in mediating the effects of DMPA; results from a 2003 published study show that when DMPA users were given a daily dose of 0.625 mg conjugated estrogens, no loss of BMD was seen.9
What about use of DMPA in adolescents? The contraceptive injection has become a popular choice for teens, who have come to rely on its convenience. Many family planners ascribe the drop in teen pregnancy in the United States in the 1990s to use of such contraceptives as DMPA and the contraceptive six-rod implant Norplant.10
According to Pfizer, it is unknown if use of Depo-Provera during adolescence or early adulthood will reduce peak bone mass and increase the risk of osteoporotic fracture in later life. Half of a woman’s bone mass is gained during puberty and the first several years after menarche; peak bone mass is achieved in the early to mid-20s.11
The new concern raised by the FDA addresses bone loss in adolescent women, comments David Archer, MD, professor of obstetrics and gynecology and director of the Clinical Research Center at the Eastern Virginia Medical Center in Norfolk. This bone loss is believed to be due to the low estradiol levels in these women during the use of DMPA, he notes.
"Clinicians should be aware of this issue and use discretion in terms of the duration of DMPA use in young [under age 16] women," states Archer.
How about calcium supplementation? While there is no research to point to whether adequate calcium use can mitigate the bone loss with DMPA injections, all women and teens should be encouraged to take calcium supplementation, as well as have adequate magnesium and vitamin D intake in their diets, says Sharon Schnare, RN, FNP, CNM, MSN, clinician at South Kitsap Family Care Clinic, Port Orchard, WA.
Clinicians will want to review the new Depo-Provera labeling with patients who are considering DMPA use. Include a discussion of other contraceptive options with women who have any of the following risk factors for osteoporosis:
- metabolic bone disease;
- chronic alcohol and/or tobacco use;
- anorexia nervosa;
- strong family history of osteoporosis;
- chronic use of drugs that can reduce bone mass, such as anticonvulsants or corticosteroids.
How about women who have been successful with DMPA use and wish to continue past two years with the method? Consider adding back estrogen, whether in postmenopausal doses of 0.625 mg conjugated estrogen in pill or transdermal form, or 1 mg estradiol in pill form, suggests Kaunitz. The estrogen dose in such postmenopausal therapies will be effective, even though they are much lower than that encountered with combined oral contraceptives, he adds.
How about using a time-out period after two years of DMPA use to mitigate any possible impact on bone?
"We have not had the opportunity to review any data on dosing regimens that incorporate periodic time off from using DMPA; therefore, we cannot comment on the potential benefit of such a dosing regimen in order to reduce the decrease in bone mineral density that is likely to be associated with the long-term use of DMPA," says Parker.
It is too early to say what recommendations will emerge regarding complete cessation or time off from DMPA, states Susan Wysocki, RNC, NP, president and CEO of the Washington, DC-based National Association of Nurse Practitioners in Women’s Health.
"There will probably be some recommendations that come out about switching to other methods on a periodic basis," she observes. "There is no hard-and-fast rule."
1. Pfizer. Pfizer statement regarding additional prescribing information for Depo-Provera. Press release. Nov. 17, 2004. Accessed at: www.pfizer.com/are/news_releases/2004pr/mn_2004_1118.html.
2. Food and Drug Administration. Black box warning added concerning long-term use of Depo-Provera contraceptive injection. Nov. 17, 2004. Accessed at: www.fda.gov/bbs/topics/ANSWERS/2004/ANS01325.html.
3. Cundy T, Evans M, Roberts H, et al. Bone density in women receiving depot medroxyprogesterone acetate for contraception. BMJ 1991; 303:13-16.
4. Cundy T, Cornish J, Evans MC, et al. Recovery of bone density in women who stop using medroxyprogesterone acetate. BMJ 1994; 308:247-248.
5. 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(5 Pt 1):899-906.
6. Tang OS, Tang G, Yip P, et al. Further evaluation on long-term depot-medroxyprogesterone acetate use and bone mineral density: A longitudinal cohort study. Contraception 62:161-164.
7. Orr-Walker BJ, Evans MC, Ames RW, et al. The effect of past use of the injectable contraceptive depot medroxyprogesterone acetate on bone mineral density in normal post-menopausal women. Clin Endocrinol (Oxf) 1998; 49:615-618.
8. Petitti DB, Piaggio G, Mehta S, et al. Steroid hormone contraception and bone mineral density: A cross-sectional study in an international population. Obstet Gynecol 2000; 95:736-744.
9. Cundy T, Ames R, Horne A, et al. A randomized controlled trial of estrogen replacement therapy in long-term users of depot medroxyprogesterone acetate. Clin Endocrinol Metab 2003; 88:78-81.
10. Brindis C. Building for the future: adolescent pregnancy prevention. J Am Med Womens Assoc 1999; 54:129-132.
11. DMPA and bone density loss: An update. Contraception Report 1999; 10(5). Accessed at www.contraceptiononline.org/contrareport/article01.cfm?art=86.
- To review the updated material on Depo-Provera, visit the Pfizer corporate web page, www.pfizer.com, Click on "News," then under "News Release Archive," click on "2004." Click on the date "November 18, 2004." A copy of the press release is available for on-line reading as well as links to the "Dear Healthcare Professional" and "Dear Healthcare Organization Leader" letters, full prescribing information, and patient product information.
- Clinicians with questions about Depo-Provera should contact Pfizer’s medical information line. Dial (800) 438-1985 and select option 6. Medical information is available Monday through Friday, 8:30 a.m. to 6 p.m., Eastern Time. Patients should call the Depo-Provera Contraceptive Injection patient support line at (866) 554-3376.
- The Washington, DC-based U.S. Agency for International Development (USAID) has issued a helpful technical bulletin on the DMPA labeling change. To review the bulletin, visit the agency’s Maximizing Access and Quality (MAQ) Initiative web site, www.maqweb.org, and click on the link "Technical Update: USAID/W Technical Assessment of Recent Evidence on Depo-Provera and Bone Density."