14 CLINICAL STUDIES
In five clinical studies using Depo-Provera CI, the 12-month failure rate for the group of women treated with Depo-Provera CI was zero (no pregnancies reported) to 0.7 by Life-Table method. The effectiveness of Depo-Provera CI is dependent on the patient returning every 3 months (13 weeks) for reinjection.
14.2 Bone Mineral Density Changes in Women Treated with Depo-Provera CI
In a controlled, clinical study, adult women using Depo-Provera CI (150mg) for up to 5 years showed spine and hip bone mineral density (BMD) mean decreases of 5–6%, compared to no significant change in BMD in the control group. The decline in BMD was more pronounced during the first two years of use, with smaller declines in subsequent years. Mean changes in lumbar spine BMD of -2.86%, -4.11%, -4.89%, -4.93% and -5.38% after 1, 2, 3, 4, and 5 years, respectively, were observed. Mean decreases in BMD of the total hip and femoral neck were similar.
After stopping use of Depo-Provera CI, there was partial recovery of BMD toward baseline values during the 2-year post-therapy period. Longer duration of treatment was associated with less complete recovery during this 2-year period following the last injection. Table 4 shows the change in BMD in women after 5 years of treatment with Depo-Provera CI and in women in a control group, as well as the extent of recovery of BMD for the subset of the women for whom 2-year post treatment data were available.
|Time in Study||Spine||Total Hip||Femoral Neck|
14.3 Bone Mineral Density Changes in Adolescent Females (12 to 18 Years of Age) Treated with Depo-Provera CI
The impact of Depo-Provera CI (150 mg) use for up to 240 weeks (4.6 years) was evaluated in an open-label non-randomized clinical study in 389 adolescent females (12 to 18 years of age). Use of Depo-Provera CI was associated with a significant decline from baseline in BMD.
Partway through the trial, drug administration was stopped (at 120 weeks). The mean number of injections per Depo-Provera CI user was 9.3. Table 5 summarizes the study findings. The decline in BMD at total hip and femoral neck was greater with longer duration of use. The mean decrease in BMD at 240 weeks was more pronounced at total hip (-6.4%) and femoral neck (-5.4%) compared to lumbar spine (-2.1%).
Adolescents in the untreated cohort had an increase in BMD during the period of growth following menarche. However, the two cohorts were not matched at baseline for age, gynecologic age, race, BMD and other factors that influence the rate of acquisition of BMD.
|Duration of Treatment||Depo-Provera CI|
(150 mg IM)
|Unmatched, Untreated Cohort|
|N||Mean % Change||N||Mean % Change|
|Total Hip BMD|
|Week 60 (1.2 years)||113||-2.75||166||1.22|
|Week 120 (2.3 years)||73||-5.40||109||2.19|
|Week 240 (4.6 years)||28||-6.40||84||1.71|
|Femoral Neck BMD|
|Lumbar Spine BMD|
BMD Recovery Post-Treatment in Adolescents
Longer duration of treatment and smoking were associated with less recovery of BMD following the last injection of Depo-Provera CI. Table 6 shows the extent of recovery of BMD up to 60 months post-treatment for adolescents who received Depo-Provera CI for two years or less compared to more than two years. Post-treatment follow-up showed that, in women treated for more than two years, only lumbar spine BMD recovered to baseline levels after treatment was discontinued. Adolescents treated with Depo-Provera CI for more than two years did not recover to their baseline BMD level at femoral neck and total hip even up to 60 months post-treatment. Adolescents in the untreated cohort gained BMD throughout the trial period (data not shown) [see Warnings and Precautions (5.1)].
|Duration of Treatment||2 years or less||More than 2 years|
|N||Mean % Change from baseline||N||Mean % Change from baseline|
|Total Hip BMD|
|End of Treatment||49||-1.5%||49||-6.2%|
|12 M post-treatment||33||-1.4%||24||-4.6%|
|24 M post-treatment||18||0.3%||17||-3.6%|
|36 M post-treatment||12||2.1%||11||-4.6%|
|48 M post-treatment||10||1.3%||9||-2.5%|
|60 M post-treatment||3||0.2%||2||-1.0%|
|Femoral Neck BMD|
|End of Treatment||49||-1.6%||49||-5.8%|
|12 M post-treatment||33||-1.4%||24||-4.3%|
|24 M post-treatment||18||0.5%||17||-3.8%|
|36 M post-treatment||12||1.2%||11||-3.8%|
|48 M post-treatment||10||2.0%||9||-1.7%|
|60 M post-treatment||3||1.0%||2||-1.9%|
|Lumbar Spine BMD|
|End of Treatment||49||-0.9%||49||-3.5%|
|12 M post-treatment||33||0.4%||23||-1.1%|
|24 M post-treatment||18||2.6%||17||1.9%|
|36 M post-treatment||12||2.4%||11||0.6%|
|48 M post-treatment||10||6.5%||9||3.5%|
|60 M post-treatment||3||6.2%||2||5.7%|
14.4 Bone Fracture Incidence in Women Treated with Depo-Provera CI
A retrospective cohort study to assess the association between Depo-Provera CI injection and the incidence of bone fractures was conducted in 312,395 female contraceptive users in the UK. The incidence rates of fracture were compared between Depo-Provera CI users and contraceptive users who had no recorded use of Depo-Provera CI. The Incident Rate Ratio (IRR) for any fracture during the follow-up period (mean=5.5 years) was 1.41 (95% CI 1.35, 1.47). It is not known if this is due to Depo-Provera CI use or to other related lifestyle factors that have a bearing on fracture rate.
In the study, when cumulative exposure to Depo-Provera CI was calculated, the fracture rate in users who received fewer than 8 injections was higher than that in women who received 8 or more injections. However, it is not clear that cumulative exposure, which may include periods of intermittent use separated by periods of non-use, is a useful measure of risk, as compared to exposure measures based on continuous use.
There were very few osteoporotic fractures (fracture sites known to be related to low BMD) in the study overall, and the incidence of osteoporotic fractures was not found to be higher in Depo-Provera CI users compared to non-users. Importantly, this study could not determine whether use of Depo-Provera CI has an effect on fracture rate later in life.