Depot medroxyprogesterone acetate (DMPA) is a popular contraceptive method because it is effective, convenient, and reversible. DMPA (Depo-Provera) works by suppressing ovulation and ovarian production of estrogen. This reduction of estrogen levels has been shown to reduce bone mass when used over the long term. In adult women, this bone mass loss can be recovered when women stop using DMPA and their estrogen levels are restored. However, concerns have been raised that DMPA in adolescent patients may have an adverse effect on bone growth because these patients have not attained maximal bone mass. This potential decrease in maximal bone mass may have a significant impact on bone fracture risk as these patients age. Cromer and colleagues evaluated the use of monthly injections of estradiol cypionate in adolescents who receive DMPA and its potential benefit on bone mineral density.

The trial was a double-blind, placebo-controlled, randomized study of adolescent females from 12 to 18 years of age who were seeking contraception. Exclusion criteria included the use of DMPA, pregnancy or abortion during the past six months, the use of oral contraception over the past three months, or a treatment or medical condition that may affect bone mineral density. Before the randomization, participants were stratified by recruitment site, race, and number of years since menarche (i.e., three years or less or more than three years). All of the participants received DMPA 150 mg intramuscularly every 12 weeks with an intramuscular injection of 5 mg estradiol cypionate or placebo on a monthly basis. Participant information gathered included tobacco use, calcium intake, physical activity, and menstrual bleeding pattern. Height and weight were measured before the start of the study. Bone mineral density was evaluated using a dual energy x-ray absorptiometry scan at baseline and at 12 and 24 months using standardized techniques. The main outcome measure was bone mineral density at the end of 24 months.

The trial design was such that at the end of 12 months, if the differences in bone mineral density between the active treatment and placebo groups were significant, the trial would be stopped. Because the levels did reach significance at 12 months, the trial was stopped and those in the placebo group were offered estradiol treatment. At 12 months, those in the DMPA plus estradiol group had an increase in bone mineral density at the lumbar spine of 1.0 percent, whereas those on DMPA plus placebo had a decrease of 2.2 percent, a significant difference. There was no significant difference in femoral neck mineral density at 12 months between the two groups. The number of participants who completed the 24-month study was 19 in the DMPA-plus-estradiol group and 17 in the DMPA-plus-placebo group. At 24 months, when adjusting for body weight and baseline bone density, the group that received DPMA plus estradiol had an increase in bone mineral density at the lumbar spine of 2.8 percent, whereas those receiving DMPA plus placebo had a decrease in bone mineral density of 1.8 percent. The change at the femoral neck was an increase of 4.7 percent in the DMPA-plus-estradiol group, whereas the DMPA-plus-placebo group had a decrease of 5.1 percent. Both changes were statistically significant.

The authors conclude that estrogen supplementation may be protective of bone mineral density in adolescents who use DMPA injections for contraception. They add that further research needs to be performed to address the recovery of bone mineral density after discontinuing DMPA in adolescents; they also suggest evaluating the impact diet and exercise may have on this recovery.

editor’s note: Long-term use of depot medroxyprogesterone acetate (DMPA) has been shown to have a negative impact on bone mineral density, and there is some concern that this loss may not be completely reversible after discontinuing the drug. This concern has led the U.S. Food and Drug Administration to recommend that a black box warning be added to the drug information.¹ The warning states that DMPA contraceptive injection should be used long term (longer than two years) only in women in whom other birth control methods are inadequate.¹ The above study by Cromer and associates demonstrated that the addition of estrogen to DMPA may reduce the negative impact on bone mineral density.—k.e.m.

1U.S. Food and Drug Administration. Black box warning added concerning long-term use of Depo-Provera contraceptive injection. Accessed online November 17, 2004, at: http://www.fda.gov/bbs/topics/ANSWERS/2004/ANS01325.html.