What is the black box warning for Depo-Provera?

October 7, 2025 •

4 min read

In 2004, the U.S. Food and Drug Administration (FDA) issued a black box warning for Depo-Provera (medroxyprogesterone acetate) regarding a serious side effect. The warning addresses the risk of significant loss of bone mineral density with prolonged use of the injectable contraceptive. This was a significant development, as a black box warning is the most serious type of warning issued by the FDA for a medication.

Quick Summary

The Depo-Provera black box warning concerns significant bone mineral density loss with prolonged use, recommending use beyond two years only if other methods are inadequate. The bone loss is related to decreased estrogen levels and may not be completely reversible, particularly for long-term users and adolescents.

Key Points

Black Box Warning: The FDA's most serious safety alert for Depo-Provera concerns significant bone mineral density (BMD) loss.
Duration-Dependent Risk: The longer Depo-Provera is used, the greater the risk of BMD loss, which is particularly relevant for adolescents developing peak bone mass.
Not for Routine Long-Term Use: The warning advises against using Depo-Provera for over two years unless other birth control methods are unsuitable.
Partial Reversibility: While some bone density may return after stopping, full recovery is not guaranteed, especially with prolonged use.
Differing Clinical Opinions: Organizations like ACOG and WHO often conclude that the contraceptive benefits of Depo-Provera outweigh the theoretical fracture risk, differing from the FDA's initial stance.
Comprehensive Counseling is Key: Healthcare providers must discuss the bone density warning, other potential side effects, and alternative contraceptives with patients.

Understanding a Black Box Warning

A "black box" warning, also known as a boxed warning, is the highest-level safety alert the FDA can issue for a drug. It is intended to highlight medications with potentially serious side effects so that healthcare providers and patients are well-informed of the risks. For Depo-Provera, the warning specifically draws attention to the risk of bone mineral density (BMD) loss.

The FDA's Black Box Warning for Depo-Provera

The FDA's black box warning for Depo-Provera details several key points regarding bone health:

Significant Bone Mineral Density Loss: Use of Depo-Provera can lead to a notable reduction in BMD.
Duration-Dependent Risk: The extent of bone loss is linked to how long the medication is used.
Potential for Incomplete Reversibility: The loss of bone density might not be fully recovered even after stopping the injections.
Long-Term Use Caution: The warning advises against using Depo-Provera for more than two years unless other contraceptive options are not suitable.
Adolescent Concerns: There are specific concerns for adolescents and young women, who are in a crucial phase of bone development. The long-term impact on peak bone mass and future fracture risk in this group is not fully understood.

The Mechanism Behind Bone Density Loss

Depo-Provera contains medroxyprogesterone acetate (MPA), which prevents pregnancy by suppressing ovulation. This mechanism also leads to reduced estrogen levels in the body. Since estrogen is important for maintaining bone density by balancing bone breakdown and formation, lower levels can result in a loss of bone mass.

Bone Mineral Density Recovery After Discontinuation

Many users want to know if bone density loss from Depo-Provera is permanent. Studies indicate that BMD often starts to recover after stopping Depo-Provera, though the extent and speed of recovery can vary.

Individual Factors: Recovery differs depending on how long Depo-Provera was used, individual health, and the specific bone areas measured.
Incomplete Recovery for Some: Full recovery may not occur for long-term users and adolescents, and some studies suggest recovery can take years and may not reach baseline levels.
Site-Specific Recovery: Recovery may be faster in areas like the lumbar spine compared to the hip.

The Clinical Debate and Professional Guidance

There is ongoing discussion among medical professionals about the significance of the BMD loss associated with Depo-Provera and the FDA's two-year usage restriction. Organizations like the American College of Obstetricians and Gynecologists (ACOG) and the World Health Organization (WHO) have offered guidance that differs from the FDA's initial recommendation.

ACOG and WHO Views: Both ACOG and WHO suggest that the benefits of Depo-Provera often outweigh the theoretical risk of fracture. They point out that bone density changes appear reversible and there isn't strong data linking Depo-Provera use to increased fracture risk later in life in the general population.
Balancing Considerations: Clinicians are advised to discuss the FDA warning with patients, consider individual osteoporosis risk factors, and weigh these against the benefits of contraception. For many women, especially when other methods are not suitable, the effectiveness of Depo-Provera as a contraceptive may be the priority.

Other Important Depo-Provera Side Effects

In addition to the bone density warning, other potential side effects of Depo-Provera include:

Menstrual Changes: Irregular bleeding, spotting, or no periods (amenorrhea) are common, with amenorrhea becoming more frequent over time.
Weight Gain: Users often experience weight gain.
Delayed Fertility: Returning to fertility after stopping Depo-Provera can take several months.
Mood Changes: Some women report depression or nervousness.
Cancer Risk: There's a possible slightly increased risk of breast cancer in current and recent users, which is still under research.
Meningioma Risk: Recent studies suggest a potential link between long-term Depo-Provera use and an increased risk of meningiomas, which are usually noncancerous brain tumors.

Comparison of Contraceptives and Bone Health


Contraceptive Method	Active Ingredients	Impact on Bone Mineral Density	Duration of Effect	Notes
Depo-Provera Injection	Medroxyprogesterone acetate	Significantly reduces BMD, especially in early use; recovery is partial and slow after discontinuation.	3 months per injection	Requires black box warning discussion; prolonged use over two years discouraged unless necessary.
Oral Contraceptives (Combined)	Estrogen and Progestin	Typically no significant effect on BMD in the general population; may offer some protection in perimenopausal women.	Daily pill	Estrogen component helps maintain bone health.
Hormonal IUDs (e.g., Mirena)	Levonorgestrel	No significant negative impact on BMD reported.	Up to 8 years	Localized hormone release with minimal systemic effects on bone.
Contraceptive Implants (e.g., Nexplanon)	Etonogestrel	No significant negative impact on BMD reported.	Up to 5 years	Subdermal implant with localized hormone action.
Barrier Methods (e.g., Condoms)	None	No effect on bone health.	During use	Non-hormonal, no impact on bone density.

Conclusion

The FDA's black box warning for Depo-Provera highlights the risk of bone mineral density loss and is a crucial safety consideration. While this side effect is established, its long-term clinical impact, including fracture risk, is still a subject of ongoing study and discussion. Healthcare providers should counsel patients thoroughly, considering individual risks, benefits, and alternative contraceptive options, particularly for extended use or in younger individuals. Informed decision-making, based on a personalized assessment, is vital.

Frequently Asked Questions

The black box warning for Depo-Provera indicates that prolonged use can lead to a significant loss of bone mineral density, with the risk increasing with the duration of use. This bone loss may not be fully reversible after stopping the medication.

Depo-Provera reduces estrogen production in the body by suppressing ovulation. Estrogen is essential for maintaining bone density, so lower levels can result in a net loss of bone mass.

Bone density often begins to recover after discontinuing Depo-Provera, but the recovery may not be complete, particularly with long-term use or use during adolescence. Full recovery can take several years and varies among individuals.

The FDA recommends against using Depo-Provera for more than two years unless other contraceptive methods are not considered adequate for the patient.

No. While the FDA has issued the black box warning, organizations such as ACOG and WHO often consider the contraceptive benefits to outweigh the theoretical fracture risk and do not necessarily restrict use based solely on bone density changes.

Beyond bone density loss, other potential serious side effects include an increased risk of blood clots, a slightly increased risk of breast cancer in current and recent users, and a possible association with meningiomas (noncancerous brain tumors) with prolonged use.

Adolescents and young women are of particular concern because they are still developing peak bone mass. The potential long-term impact of Depo-Provera use during this critical period on their lifetime risk of osteoporotic fractures is not yet fully known.