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Meta-Analysis
. 2014 Jun 24;2014(6):CD006033.
doi: 10.1002/14651858.CD006033.pub5.

Steroidal contraceptives: effect on bone fractures in women

Laureen M Lopez  1 , David A Grimes, Kenneth F Schulz, Kathryn M Curtis, Mario Chen
Affiliations
Meta-Analysis

Steroidal contraceptives: effect on bone fractures in women

Laureen M Lopez et al. Cochrane Database Syst Rev. .

Abstract

Background: Steroidal contraceptive use has been associated with changes in bone mineral density in women. Whether such changes increase the risk of fractures later in life is not clear. Osteoporosis is a major public health concern. Age-related decline in bone mass increases the risk of fracture, especially of the spine, hip, and wrist. Concern about bone health influences the recommendation and use of these effective contraceptives globally.

Objectives: Our aim was to evaluate the effect of using hormonal contraceptives before menopause on the risk of fracture in women.

Search methods: Through April 2014, we searched for studies of fracture or bone health and hormonal contraceptives in MEDLINE, POPLINE, CENTRAL, EMBASE, and LILACS, as well as ClinicalTrials.gov and ICTRP. We examined reference lists of relevant articles for other trials. For the initial review, we wrote to investigators to find additional trials.

Selection criteria: Randomized controlled trials (RCTs) were considered if they examined fractures, bone mineral density (BMD), or bone turnover markers in women with hormonal contraceptive use prior to menopause. Eligible interventions included comparisons of a hormonal contraceptive with a placebo or with another hormonal contraceptive that differed in terms of drug, dosage, or regimen. They also included providing a supplement to one group.

Data collection and analysis: We assessed all titles and abstracts identified through the literature searches. Mean differences were computed using the inverse variance approach. For dichotomous outcomes, the Mantel-Haenszel odds ratio (OR) was calculated. Both included the 95% confidence interval (CI) and used a fixed-effect model. Due to differing interventions, no trials could be combined for meta-analysis. We applied principles from GRADE to assess the evidence quality and address confidence in the effect estimates. In addition, a sensitivity analysis included trials that provided sufficient data for this review and evidence of at least moderate quality.

Main results: We found 19 RCTs that met our eligibility criteria. Eleven trials compared different combined oral contraceptives (COCs) or regimens of COCs; five examined an injectable versus another injectable, implant, or IUD; two studied implants, and one compared the transdermal patch versus the vaginal ring. No trial had fracture as an outcome. BMD was measured in 17 studies and 12 trials assessed biochemical markers of bone turnover. Depot medroxyprogesterone acetate (DMPA) was associated with decreased bone mineral density (BMD). The placebo-controlled trials showed BMD increases for DMPA plus estrogen supplement and decreases for DMPA plus placebo supplement. COCs did not appear to negatively affect BMD, and some formulations had more positive effects than others. However, no COC trial was placebo-controlled. Where studies showed differences between groups in bone turnover markers, the results were generally consistent with those for BMD. For implants, the single-rod etonogestrel group showed a greater BMD decrease versus the two-rod levonorgestrel group but results were not consistent across all implant comparisons.The sensitivity analysis included 11 trials providing evidence of moderate or high quality. Four trials involving DMPA showed some positive effects of an estrogen supplement on BMD, a negative effect of DMPA-subcutaneous on lumbar spine BMD, and a negative effect of DMPA on a bone formation marker. Of the three COC trials, one had a BMD decrease for the group with gestodene plus EE 15 μg. Another indicated less bone resorption in the group with gestodene plus EE 30 μg versus EE 20 μg.

Authors' conclusions: Whether steroidal contraceptives influence fracture risk cannot be determined from existing information. The evidence quality was considered moderate overall, largely due to the trials of DMPA, implants, and the patch versus ring. The COC evidence varied in quality but was low overall. Many trials had small numbers of participants and some had large losses. Health care providers and women should consider the costs and benefits of these effective contraceptives. For example, injectable contraceptives and implants provide effective, long-term birth control yet do not involve a daily regimen. Progestin-only contraceptives are considered appropriate for women who should avoid estrogen due to medical conditions.

PubMed Disclaimer

Conflict of interest statement

DA Grimes has consulted with the pharmaceutical companies Bayer Healthcare Pharmaceuticals and Merck & Co, Inc.

Figures

1.1
1.1. Analysis
Comparison 1 Levonorgestrel‐releasing implants: Norplant versus Chinese implant, Outcome 1 Bone mineral density (L2 to L4) at 12 months.
1.2
1.2. Analysis
Comparison 1 Levonorgestrel‐releasing implants: Norplant versus Chinese implant, Outcome 2 Bone mineral density (femoral neck) at 12 months.
1.3
1.3. Analysis
Comparison 1 Levonorgestrel‐releasing implants: Norplant versus Chinese implant, Outcome 3 Bone mineral density (trochanter) at 12 months.
1.4
1.4. Analysis
Comparison 1 Levonorgestrel‐releasing implants: Norplant versus Chinese implant, Outcome 4 Bone mineral density (Ward's triangle) at 12 months.
1.5
1.5. Analysis
Comparison 1 Levonorgestrel‐releasing implants: Norplant versus Chinese implant, Outcome 5 Serum osteocalcin at 12 months.
1.6
1.6. Analysis
Comparison 1 Levonorgestrel‐releasing implants: Norplant versus Chinese implant, Outcome 6 Serum alkaline phosphatase at 12 months.
1.7
1.7. Analysis
Comparison 1 Levonorgestrel‐releasing implants: Norplant versus Chinese implant, Outcome 7 Urine hydroxyproline/creatinine at 12 months.
1.8
1.8. Analysis
Comparison 1 Levonorgestrel‐releasing implants: Norplant versus Chinese implant, Outcome 8 Urine calcium/creatinine at 12 months.
2.1
2.1. Analysis
Comparison 2 Etonogestrel‐releasing implant versus levonorgestrel‐releasing implant, Outcome 1 Bone mineral density (midshaft ulna) at 18 months.
2.2
2.2. Analysis
Comparison 2 Etonogestrel‐releasing implant versus levonorgestrel‐releasing implant, Outcome 2 Percent change in bone mineral density (midshaft ulna) by 18 months.
2.3
2.3. Analysis
Comparison 2 Etonogestrel‐releasing implant versus levonorgestrel‐releasing implant, Outcome 3 Bone mineral density (distal radius) at 18 months.
2.4
2.4. Analysis
Comparison 2 Etonogestrel‐releasing implant versus levonorgestrel‐releasing implant, Outcome 4 Percent change in bone mineral density (distal radius) by 18 months.
2.5
2.5. Analysis
Comparison 2 Etonogestrel‐releasing implant versus levonorgestrel‐releasing implant, Outcome 5 Bone mineral density (distal radius) at 36 months.
3.1
3.1. Analysis
Comparison 3 DMPA 150 mg versus levonorgestrel‐releasing implant, Outcome 1 Serum alkaline phosphatase at 6 months.
3.2
3.2. Analysis
Comparison 3 DMPA 150 mg versus levonorgestrel‐releasing implant, Outcome 2 Serum osteocalcin at 6 months.
3.3
3.3. Analysis
Comparison 3 DMPA 150 mg versus levonorgestrel‐releasing implant, Outcome 3 Serum calcium at 6 months.
3.4
3.4. Analysis
Comparison 3 DMPA 150 mg versus levonorgestrel‐releasing implant, Outcome 4 Urinary hydroxyproline/creatinine at 6 months.
4.1
4.1. Analysis
Comparison 4 DMPA 150 mg + estradiol cypionate 5 mg versus DMPA 150 mg + placebo, Outcome 1 Percent change in bone mineral density (spine) by 12 months.
4.2
4.2. Analysis
Comparison 4 DMPA 150 mg + estradiol cypionate 5 mg versus DMPA 150 mg + placebo, Outcome 2 Percent change in bone mineral apparent density (spine) by 12 months.
4.3
4.3. Analysis
Comparison 4 DMPA 150 mg + estradiol cypionate 5 mg versus DMPA 150 mg + placebo, Outcome 3 Percent change in bone mineral density (femoral neck) by 12 months.
4.4
4.4. Analysis
Comparison 4 DMPA 150 mg + estradiol cypionate 5 mg versus DMPA 150 mg + placebo, Outcome 4 Percent change in bone mineral apparent density (femoral neck) by 12 months.
4.5
4.5. Analysis
Comparison 4 DMPA 150 mg + estradiol cypionate 5 mg versus DMPA 150 mg + placebo, Outcome 5 Percent change in bone mineral density (spine) by 24 months.
4.6
4.6. Analysis
Comparison 4 DMPA 150 mg + estradiol cypionate 5 mg versus DMPA 150 mg + placebo, Outcome 6 Percent change in bone mineral apparent density (spine) by 24 months.
4.7
4.7. Analysis
Comparison 4 DMPA 150 mg + estradiol cypionate 5 mg versus DMPA 150 mg + placebo, Outcome 7 Percent change in bone mineral density (femoral neck) by 24 months.
4.8
4.8. Analysis
Comparison 4 DMPA 150 mg + estradiol cypionate 5 mg versus DMPA 150 mg + placebo, Outcome 8 Percent change in bone mineral apparent density (femoral neck) by 24 months.
5.1
5.1. Analysis
Comparison 5 DMPA 150 mg + conjugated estrogens 625 µg versus DMPA 150 mg + placebo, Outcome 1 Change in bone mineral density (lumbar spine) by 12 months.
5.2
5.2. Analysis
Comparison 5 DMPA 150 mg + conjugated estrogens 625 µg versus DMPA 150 mg + placebo, Outcome 2 Change in bone mineral density (lumbar spine) by 24 months.
5.3
5.3. Analysis
Comparison 5 DMPA 150 mg + conjugated estrogens 625 µg versus DMPA 150 mg + placebo, Outcome 3 Change in bone mineral density (Ward's triangle) by 12 months.
5.4
5.4. Analysis
Comparison 5 DMPA 150 mg + conjugated estrogens 625 µg versus DMPA 150 mg + placebo, Outcome 4 Change in bone mineral density (Ward's triangle) by 24 months.
5.5
5.5. Analysis
Comparison 5 DMPA 150 mg + conjugated estrogens 625 µg versus DMPA 150 mg + placebo, Outcome 5 Change in bone mineral density (trochanter) by 12 months.
5.6
5.6. Analysis
Comparison 5 DMPA 150 mg + conjugated estrogens 625 µg versus DMPA 150 mg + placebo, Outcome 6 Change in bone mineral density (trochanter) by 24 months.
5.7
5.7. Analysis
Comparison 5 DMPA 150 mg + conjugated estrogens 625 µg versus DMPA 150 mg + placebo, Outcome 7 Change in bone mineral density (femoral neck) by 12 months.
5.8
5.8. Analysis
Comparison 5 DMPA 150 mg + conjugated estrogens 625 µg versus DMPA 150 mg + placebo, Outcome 8 Change in bone mineral density (femoral neck) by 24 months.
5.9
5.9. Analysis
Comparison 5 DMPA 150 mg + conjugated estrogens 625 µg versus DMPA 150 mg + placebo, Outcome 9 Change in bone mineral density (total body) by12 months.
5.10
5.10. Analysis
Comparison 5 DMPA 150 mg + conjugated estrogens 625 µg versus DMPA 150 mg + placebo, Outcome 10 Change in bone mineral density (total body) by 24 months.
6.1
6.1. Analysis
Comparison 6 DMPA‐SC 104 mg versus DMPA‐IM 150 mg, Outcome 1 Decrease in total hip BMD >= 5% from baseline (year 1).
6.2
6.2. Analysis
Comparison 6 DMPA‐SC 104 mg versus DMPA‐IM 150 mg, Outcome 2 Decrease in total hip BMD >= 5% from baseline (year 2).
6.3
6.3. Analysis
Comparison 6 DMPA‐SC 104 mg versus DMPA‐IM 150 mg, Outcome 3 Decrease in total hip BMD >= 5% from baseline (year 3).
6.4
6.4. Analysis
Comparison 6 DMPA‐SC 104 mg versus DMPA‐IM 150 mg, Outcome 4 Decrease in lumbar spine BMD >= 5% from baseline (year 1).
6.5
6.5. Analysis
Comparison 6 DMPA‐SC 104 mg versus DMPA‐IM 150 mg, Outcome 5 Decrease in lumbar spine BMD >= 5% from baseline (year 2).
6.6
6.6. Analysis
Comparison 6 DMPA‐SC 104 mg versus DMPA‐IM 150 mg, Outcome 6 Decrease in lumbar spine BMD >= 5% from baseline (year 3).
7.1
7.1. Analysis
Comparison 7 Norethindrone 1 mg + EE 35 µg versus desogestrel 150 µg + EE 30 µg, Outcome 1 Percent change in bone mineral density (lumbar spine) by 12 months.
7.2
7.2. Analysis
Comparison 7 Norethindrone 1 mg + EE 35 µg versus desogestrel 150 µg + EE 30 µg, Outcome 2 Percent change in bone mineral density (lumbar spine) by 24 months.
8.1
8.1. Analysis
Comparison 8 Desogestrel 150 µg + EE 30 µg versus cyproterone acetate 2 mg + EE 35 µg, Outcome 1 Change in BMD of lumbar spine by 12 months.
8.2
8.2. Analysis
Comparison 8 Desogestrel 150 µg + EE 30 µg versus cyproterone acetate 2 mg + EE 35 µg, Outcome 2 Change in BMD of lumbar spine by 24 months.
8.3
8.3. Analysis
Comparison 8 Desogestrel 150 µg + EE 30 µg versus cyproterone acetate 2 mg + EE 35 µg, Outcome 3 Change in BMD of femoral neck by 12 months.
8.4
8.4. Analysis
Comparison 8 Desogestrel 150 µg + EE 30 µg versus cyproterone acetate 2 mg + EE 35 µg, Outcome 4 Change in BMD of femoral neck by 24 months.
9.1
9.1. Analysis
Comparison 9 Levonorgestrel 100 µg + EE 20 µg versus levonorgestrel 150 µg + EE 30 µg, Outcome 1 Bone mineral density (lumbar spine) at 12 months.
9.2
9.2. Analysis
Comparison 9 Levonorgestrel 100 µg + EE 20 µg versus levonorgestrel 150 µg + EE 30 µg, Outcome 2 Bone mineral density (lumbar spine) at 24 months.
9.3
9.3. Analysis
Comparison 9 Levonorgestrel 100 µg + EE 20 µg versus levonorgestrel 150 µg + EE 30 µg, Outcome 3 Bone mineral density (lumbar spine) at 36 months.
9.4
9.4. Analysis
Comparison 9 Levonorgestrel 100 µg + EE 20 µg versus levonorgestrel 150 µg + EE 30 µg, Outcome 4 Percent change in bone mineral density (lumbar spine) by 36 months.
9.5
9.5. Analysis
Comparison 9 Levonorgestrel 100 µg + EE 20 µg versus levonorgestrel 150 µg + EE 30 µg, Outcome 5 Percent change in serum alkaline phosphatase (36 months).
9.6
9.6. Analysis
Comparison 9 Levonorgestrel 100 µg + EE 20 µg versus levonorgestrel 150 µg + EE 30 µg, Outcome 6 Percent change in cross‐linked N‐telopeptides (36 months).
10.1
10.1. Analysis
Comparison 10 Levonorgestrel 100 µg + EE 20 µg versus desogestrel 150 µg + EE 20 µg, Outcome 1 Percent change in areal bone mineral density (lumbar spine) by 12 months.
10.2
10.2. Analysis
Comparison 10 Levonorgestrel 100 µg + EE 20 µg versus desogestrel 150 µg + EE 20 µg, Outcome 2 Percent change in areal bone mineral density (femoral neck) by 12 months.
10.3
10.3. Analysis
Comparison 10 Levonorgestrel 100 µg + EE 20 µg versus desogestrel 150 µg + EE 20 µg, Outcome 3 Percent change in serum bone‐specific alkaline phosphatase by 12 months.
10.4
10.4. Analysis
Comparison 10 Levonorgestrel 100 µg + EE 20 µg versus desogestrel 150 µg + EE 20 µg, Outcome 4 Percent change in serum osteocalcin by 12 months.
10.5
10.5. Analysis
Comparison 10 Levonorgestrel 100 µg + EE 20 µg versus desogestrel 150 µg + EE 20 µg, Outcome 5 Percent change in serum cross‐linked telopeptides by 12 months.
11.1
11.1. Analysis
Comparison 11 Nomegestrol 2.5 mg + estradiol 1.5 mg versus levonorgestrel 150 µg + EE 30 µg, Outcome 1 Change in z‐score of lumbar spine after cycle 26.
11.2
11.2. Analysis
Comparison 11 Nomegestrol 2.5 mg + estradiol 1.5 mg versus levonorgestrel 150 µg + EE 30 µg, Outcome 2 Change in z‐score of femoral neck after cycle 26.
12.1
12.1. Analysis
Comparison 12 Gestodene 75 µg + EE 20 µg versus gestodene 75 µg + EE 30 µg, Outcome 1 Urinary pyridinoline at 12 months.
12.2
12.2. Analysis
Comparison 12 Gestodene 75 µg + EE 20 µg versus gestodene 75 µg + EE 30 µg, Outcome 2 Urinary deoxypyridinoline at 12 months.
12.3
12.3. Analysis
Comparison 12 Gestodene 75 µg + EE 20 µg versus gestodene 75 µg + EE 30 µg, Outcome 3 Serum osteocalcin at 12 months.
13.1
13.1. Analysis
Comparison 13 Drospirenone 3 mg + EE 30 µg versus gestodene 75 µg + EE 30 µg, Outcome 1 Bone mineral density (lumbar spine) at 12 months.
14.1
14.1. Analysis
Comparison 14 Drospirenone 3 mg + EE 30 µg versus drospirenone 3 mg + EE 20 µg, Outcome 1 Bone mineral density (lumbar spine) at 12 months.
15.1
15.1. Analysis
Comparison 15 Transdermal patch (norelgestromin 150 µg plus EE 20 µg) versus vaginal ring (etonogestrel 120 µg plus EE 15 µg), Outcome 1 Lumbar spine BMD at 12 months.
15.2
15.2. Analysis
Comparison 15 Transdermal patch (norelgestromin 150 µg plus EE 20 µg) versus vaginal ring (etonogestrel 120 µg plus EE 15 µg), Outcome 2 Urinary pyridinoline at 12 months.
15.3
15.3. Analysis
Comparison 15 Transdermal patch (norelgestromin 150 µg plus EE 20 µg) versus vaginal ring (etonogestrel 120 µg plus EE 15 µg), Outcome 3 Urinary deoxypyridinoline at 12 months.
15.4
15.4. Analysis
Comparison 15 Transdermal patch (norelgestromin 150 µg plus EE 20 µg) versus vaginal ring (etonogestrel 120 µg plus EE 15 µg), Outcome 4 Serum osteocalcin at 12 months.
16.1
16.1. Analysis
Comparison 16 Norethisterone enanthate 50 mg + estradiol valerate 5 mg versus Nova T IUD, Outcome 1 Percent change in bone mineral density (lumbar spine) by 12 months.
16.2
16.2. Analysis
Comparison 16 Norethisterone enanthate 50 mg + estradiol valerate 5 mg versus Nova T IUD, Outcome 2 Percent change in bone mineral density (lumbar spine) by 24 months.
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References

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