Steroidal contraceptives and bone fractures in women: evidence from observational studies
Abstract
Background
Age‐related decline in bone mass increases the risk of skeletal fractures, especially those of the hip, spine, and wrist. Steroidal contraceptives have been associated with changes in bone mineral density in women. Whether such changes affect the risk of fractures later in life is unclear. Hormonal contraceptives are among the most effective and most widely‐used contraceptives. Concern about fractures may limit the use of these effective contraceptives. Observational studies can collect data on premenopausal contraceptive use as well as fracture incidence later in life.
Objectives
We systematically reviewed the evidence from observational studies of hormonal contraceptive use for contraception and the risk of fracture in women.
Search methods
Through June 2015, we searched for observational studies. The databases included PubMed, POPLINE, Cochrane Central Register of Controlled Trials (CENTRAL), LILACS, EMBASE, CINAHL, and Web of Science. We also searched for recent clinical trials through ClinicalTrials.gov and the ICTRP. For other studies, we examined reference lists of relevant articles and wrote to investigators for additional reports.
Selection criteria
We included cohort and case‐control studies of hormonal contraceptive use. Interventions included comparisons of a hormonal contraceptive with a non‐hormonal contraceptive, no contraceptive, or another hormonal contraceptive. The primary outcome was the risk of fracture.
Data collection and analysis
Two authors independently extracted the data. One author entered the data into RevMan, and a second author verified accuracy. We examined the quality of evidence using the Newcastle‐Ottawa Quality Assessment Scale (NOS), developed for case‐control and cohort studies. Sensitivity analysis included studies of moderate or high quality based on our assessment with the NOS.
Given the need to control for confounding factors in observational studies, we used adjusted estimates from the models as reported by the authors. Where we did not have adjusted analyses, we calculated the odds ratio (OR) with 95% confidence interval (CI). Due to varied study designs, we did not conduct meta‐analysis.
Main results
We included 14 studies (7 case‐control and 7 cohort studies). These examined oral contraceptives (OCs), depot medroxyprogesterone acetate (DMPA), and the hormonal intrauterine device (IUD). This section focuses on the sensitivity analysis with six studies that provided moderate or high quality evidence.
All six studies examined oral contraceptive use. We noted few associations with fracture risk. One cohort study reported OC ever‐users had increased risk for all fractures (RR 1.20, 95% CI 1.08 to 1.34). However, a case‐control study with later data from a subset reported no association except for those with 10 years or more since use (OR 1.55, 95% CI 1.03 to 2.33). Another case‐control study reported increased risk only for those who had 10 or more prescriptions (OR 1.09, 95% CI 1.03 to 1.16). A cohort study of postmenopausal women found no increased fracture risk for OC use after excluding women with prior fracture. Two other studies found little evidence of association between OC use and fracture risk. A cohort study noted increased risk for subgroups, such as those with longer use or specific intervals since use. A case‐control study reported increased risk for any fracture only among young women with less than average use.
Two case‐control studies also examined progestin‐only contraceptives. One reported increased fracture risk for DMPA ever‐use (OR 1.44, 95% CI 1.01 to 2.06), more than four years of use (OR 2.16, 95% CI 1.32 to 3.53), and women over 50 years old. The other reported increased risk for any past use, including one or two prescriptions (OR 1.17, 95% CI 1.07 to 1.29) and for current use of 3 to 9 prescriptions (OR 1.36, 95% CI 1.15 to 1.60) or 10 or more (OR 1.54, 95% CI 1.33 to 1.78). For the levonorgestrel‐releasing IUD, one study reported reduced fracture risk for ever‐use (OR 0.75, 95% CI 0.64 to 0.87) and for longer use.
Authors' conclusions
Observational studies do not indicate an overall association between oral contraceptive use and fracture risk. Some reported increased risk for specific user subgroups. DMPA users may have an increased fracture risk. One study indicated hormonal IUD use may be associated with decreased risk. Observational studies need adjusted analysis because the comparison groups usually differ. Investigators should be clear about the variables examined in multivariate analysis.
PICOs
Plain language summary
Hormonal birth control and fracture risk in observational studies
When bone mass declines with age, the risk of fractures increases. Birth control methods that have hormones may lead to changes in women’s bone density. Worry about fractures may limit the use of these effective methods. Observational studies can collect data on birth control use as well as fractures later in life. Through June 2015, we searched for such studies in several databases.
We included studies that looked at hormonal birth control use and fracture risk. We examined the quality of research methods using a tool for observational studies. With these types of studies, investigators need to control for differences in the study groups. We used the results from adjusted analyses as reported. Where we did not have adjusted analysis, we used the odds ratio to look at differences between groups.
We found 14 studies. Six of them had good quality results and looked at use of birth control pills. We did not find an overall difference in fracture risk for users and nonusers of birth control pills. One study found pill users were more likely to have fractures overall. Another had later data for a subset of those women. Pill use was not related to fracture risk except for 10 or more years since use. Still another study showed more risk when the woman had 10 or more prescriptions. When a study of postmenopausal women removed the women with prior fracture, pill users did not have higher fracture risk. Two more studies saw more fractures in pill users but only for certain subgroups.
Two studies looked at birth control methods that contain only the hormone progestin. They found that users of the injected ‘depo’ (depot medroxyprogesterone acetate) had more fractures as did women with longer current use. One showed more fractures for women with any past 'depo' use. Another study showed that women who had used the hormonal intrauterine device (IUD) were less likely to have a fracture.
These studies did not show that birth control pills are generally related to more fractures. Some studies reported greater risk for subgroups. Users of ‘depo’ may have more fracture risk. Observational studies need to examine differences between study groups. Investigators should be clear about the factors studied in the analysis.
Authors' conclusions
Summary of findings
| Oral contraceptive (OC) use compared with nonuse for contraceptiona | ||||
| Patient or population: women Settings: hospital or clinical site Intervention: oral contraceptive (OC) use Comparison: no use of OC | ||||
| Outcomes | Relative effect (95% CI)b | Participants | Quality of evidence | Participant ages |
| All fractures | RR 1.20 (1.08 to 1.34) | 1365 | ⊕⊕⊕⊝ | Mean age 29 years; ranged from < 25 to > 65 OC use ever vs never |
| First fracture | OR 1.55 (1.03 to 2.33) | 819 | ⊕⊕⊕⊕ | Age 20 to 87 years Last OC use > 10 years vs never |
| First fracture: radius or ulna; all sites | RR 1.5 (1.1 to 2.1); RR 1.2 (1.1 to 1.4) | 17,032 | ⊕⊕⊕⊕ | Recruited age 25 to 39 years; followed to 45 years OC use > 97 months vs no use |
| First fracture: radius or ulna; all sites | RR 2.5 (1.5 to 4.0); RR 1.3 (1.1 to 1.5) | 17,032 | ⊕⊕⊕⊕ | Recruited age 25 to 39 years; followed to 45 years Interval since use: 73 to 96 months vs no use (radius or ulna); < 12 months vs no use (all fractures) |
| First fracture | HR 1.07 (1.01 to 1.15); HR 1.09 (1.01 to 1.18) | 80,947 | ⊕⊕⊕⊝ | Recruited age 50 to 74 years OC use: any vs none; < 5 years vs none |
| First fracture | OR 1.09 (1.03 to 1.16) | 87,627 | ⊕⊕⊕⊝ | Age 20 to 44 years Current OC use > 10 prescriptions vs no use |
| Fracture, any | OR 1.50 (1.03 to 2.18); OR 1.30 (1.05 to 1.61) | 258,189 | ⊕⊕⊕⊝ | Mean age 51.7 years OC daily dose 0.3 to 0.99 tablet vs never user: < 15 years old; 15.1 to 17 years old |
| Fracture, any | OR 1.42 (1.09 to 1.84); OR 1.13 (1.05 to 1.22) | 258,189 | ⊕⊕⊕⊝ | Mean age 51.7 years OC ethinyl estradiol dose changed between 20 µg and > 30 µg vs no OC use: 15.1 to 17 years old; > 19 years old |
| GRADE Working Group grades of evidence | ||||
| aFrom sensitivity analysis (moderate or high quality evidence); significant differences in fracture risk | ||||
| Progestin‐only contraceptive use compared with nonuse for contraceptiona | ||||
| Patient or population: women Settings: hospital or clinical setting Intervention: use of progestin‐only contraceptive Comparison: nonuse of progestin‐only contraceptive | ||||
| Outcomes | Relative effect (95% CI)b | Participants | Quality of evidence | Participant ages |
| Fracture | OR 1.44 (1.01 to 2.06); OR 2.25 (1.14 to 4.42); 1.94 (1.09 to 3.45); OR 2.16 (1.32 to 3.53) | 258,189 | ⊕⊕⊕⊝ | Mean age 51.7 years DMPA use vs nonuse: ever use; use among women > 50 years old; daily dose > 1; use > 4 years |
| Fracture | OR 0.75 (0.64 to 0.87); OR 0.77 (0.59 to 0.99) | 258,189 | ⊕⊕⊕⊝ | Mean age 51.7 years Hormonal IUD use vs nonuse: ever use; use 1.6 to 4 years |
| First fracture | OR 1.36 (1.15 to 1.60); OR 1.54 (1.33 to 1.78) | 87,627 | ⊕⊕⊕⊝ | Age 20 to 44 years DMPA current use vs nonuse: use 3 to 9 years; use > 10 years |
| First fracture | OR 1.17 (1.07 to 1.29); OR 1.23 (1.11 to 1.36); OR 1.30 (1.09 to 1.55) | 87,627 | ⊕⊕⊕⊝ | Age 20 to 44 years DMPA past use (prescriptions) vs nonuse: 1 to 2; 3 to 9 ; > 10 |
| GRADE Working Group grades of evidence | ||||
| aFrom sensitivity analysis (moderate or high quality evidence); significant differences in fracture risk | ||||
Background
Description of the condition
Age‐related decline in bone mass increases the risk of skeletal fractures, especially those of the hip, spine, and wrist (Howe 2011; Rachner 2011). Prevalence estimates for osteoporosis include the following: 30% for postmenopausal women and 70% for women aged 80 years or more in the USA; 29% of women in India; for Japanese women aged 50 to 79 years, 35% at the spine and 9.5% at the hip; and in Latin America, 12% to 18% for women at least 50 years old (Sanchez‐Riera 2010). The costs of osteoporosis‐related fractures can be substantial for the individual due to disability and to society for health and social care (Howe 2011). Steroidal contraceptives, particularly injectable contraceptives and combined oral contraceptives (COCs), have been associated with changes in bone mineral density in women. Whether such changes affect the risk of fractures later in life is unclear. Concern about bone health and fracture risk influences the recommendation and use of these effective contraceptives globally.
Description of the intervention
In the US, more than 60% of women in their childbearing years use contraceptives, and 40% of those women use hormonal contraceptives (Isley 2011). Steroidal contraceptives include combined contraceptives, containing both progestin and estrogen, as well as progestin‐only contraceptives. Combined hormonal contraceptives include a wide variety of pills, the vaginal ring, the transdermal patch, and combined injectables. Delivery methods for progestin‐only contraceptives include pills, injectables, implants, and a levonorgestrel‐releasing intrauterine device.
Depot medroxyprogesterone acetate (DMPA) is an effective contraceptive and the most widely‐used injectable (Goldberg 2011). First‐year failure rates for DMPA in the USA have been estimated at 0.2% for perfect use and 6% for typical use (Trussell 2011). Data from developing countries showed median failure rates of 2.4% for injectables versus 10.3% for condoms and 6.5% for pills (Cleland 2004). DMPA has attracted the most attention regarding bone health. This injectable may reduce bone mineral density (BMD), a potential concern for younger women who have not achieved peak bone mass and for perimenopausal women who may begin to lose bone mass. In 2004, the US Food and Drug Administration added a warning to DMPA labeling about the potential loss of BMD (FDA 2004), which might limit long‐term use. A systematic review of progestin‐only methods found an association between DMPA use and loss of bone mineral density (Curtis 2006). The clinical significance of this association was not clear. Evidence suggested that women gained BMD after discontinuation of DMPA. Another review concluded that adolescent users of DMPA do have decreases in BMD, but the loss can be recovered within one or two years after discontinuation (Isley 2011). Major health organizations have recommended not restricting DMPA use among women 18 to 45 years old (WHO 2006; Guilbert 2009; ACOG 2014). In Medical Eligibility Criteria (MEC) for contraceptive use, DMPA is category 1 (no restriction) for women aged 18 to 45 years. For women less than 18 and greater than 45 years of age, DMPA is category 2 (CDC 2010; WHO 2015a; WHO 2015b), which indicates the advantages of using the method generally outweigh the theoretical or proven risks.
Oral contraceptives (OCs) are the most commonly used reversible method in more developed regions (UN 2013). Intrauterine devices (IUDs) are widely used in developing areas, but most are non‐hormonal. Hormonal IUDs are not widely used. Failure rates for oral contraceptives in the USA (combined and progestin‐only) are estimated at 0.3% for perfect use and 9% for typical use in the first year (Trussell 2011). In a review of randomized controlled trials (RCTs) on steroidal contraceptives and bone health, combination contraceptives did not appear to have a negative effect, but no trials were placebo‐controlled and none had fracture as an outcome (Lopez 2014). An earlier review focused on combined hormonal contraceptives and bone health and included studies of varying designs (Martins 2006). Bone mineral density appeared to be affected by combined oral contraceptive (COC) use in adolescent and young women but not in premenopausal or postmenopausal women. A recent review noted that COCs have little effect on BMD (Isley 2011), and concluded that healthy women could use COCs without concerns regarding skeletal health.
How the intervention might work
The development of osteoporosis depends on tissue, cellular, and molecular interactions (Rachner 2011). Bone turnover involves a continuing process of formation and resorption (loss). Sex hormones help regulate bone metabolism (Herrmann 2010). Skeletal fragility, and the risk of fracture, results from low bone mass and deterioration of bone tissue (Sanchez‐Riera 2010). Low estrogen levels, whether related to progestin‐only contraceptives or menopause, can lead to increased bone turnover and bone loss (Isley 2011; Herrmann 2010). However, bone loss during contraceptive use may be temporary, similar to that which occurs during pregnancy or breastfeeding (ACOG 2014). Risk of future fractures after contraceptive use depends on whether the bone mass is restored or not.
Why it is important to do this review
Hormonal contraceptives are among the most effective and most widely‐used contraceptives. Concern about fractures may limit the use of these effective contraceptives. Women might switch to less effective methods or use nothing, and those alternatives could lead to increased rates of unintended pregnancy. Therefore, the question about an association between steroidal contraceptives and fractures is important to examine systematically with the available evidence.
Skeletal fragility fractures are rare in premenopausal women. Consequently, randomized controlled trials of contraceptive use may not be the best design for assessing fracture risk. Observational studies include case‐control studies as well as cohort studies. Such designs allow for collecting data on premenopausal contraceptive use as well as fracture incidence later in life. Reviewing observational studies does present additional challenges, including heterogeneity in study design and populations as well as increased risk of bias. However, a meta‐analysis compared estimates of intervention harm from studies of varying designs (Golder 2011). The investigators found the risk estimate of adverse effects to be similar from meta‐analyses of RCTs and from meta‐analyses of observational studies.
Objectives
We systematically reviewed the evidence from observational studies of hormonal contraceptive use for contraception and the risk of fracture in women.
Methods
Criteria for considering studies for this review
Types of studies
We considered cohort studies of contraceptive users as well as case‐control studies. Post hoc analysis from such studies was also considered. Randomized controlled trials were excluded, as they were reviewed elsewhere (Lopez 2014) and no RCT had fracture as an outcome. The Discussion contains pertinent results from the review of RCTs to provide context for the results here.
Types of participants
Participants were women who used steroidal contraceptives during their reproductive years or women in a comparison group who did not use hormonal contraceptives during their reproductive years. We excluded studies that focused on women with specific conditions or situations that can affect bone health, such as epilepsy because some medications have a negative influence and athletes given that exercise can have a positive influence (Howe 2011).
Types of interventions
Interventions included comparisons of a hormonal contraceptive with a non‐hormonal contraceptive, no contraceptive, or another hormonal contraceptive. The contraceptive must have been intended for contraception and not as treatment for another health condition, such as hormone replacement therapy for postmenopausal women. Interventions could also include a supplement for one group, such as another hormone or a vitamin or mineral preparation.
Types of outcome measures
The primary outcome was the risk of fracture, particularly fracture of the spine, hip, or wrist. We did not examine data on bone mineral density, which is considered a surrogate marker for fracture. Data from RCTs on hormonal contraceptives and bone mineral density have been reviewed elsewhere (Lopez 2014).
Search methods for identification of studies
Electronic searches
Through June 2015, we searched for studies of steroidal contraceptives and fractures. Databases included PubMed, POPLINE, Cochrane Central Register of Controlled Trials (CENTRAL), LILACS, and Web of Science. In addition, we searched for recent clinical trials through ClinicalTrials.gov and the International Clinical Trials Registry Platform (ICTRP). Details of the search strategy are given in Appendix 1. The previous search strategies, which also included EMBASE and CINAHL, can be found in Appendix 2.
Searching other resources
For other relevant studies, we examined reference lists of included studies as well as review articles. For the initial review, we wrote to investigators for information about other published or unpublished studies not identified in our search.
Data collection and analysis
Selection of studies
We assessed for inclusion all titles and abstracts identified during the literature search. In 2015, one author reviewed the search results for potentially eligible studies; another author checked for appropriate categorization. For the initial review, two authors independently examined the search results for eligible studies. We resolved any discrepancies by discussion. For studies that appeared to meet the criteria for this review, we obtained and examined the full‐text articles.
Data extraction and management
Two authors extracted the data. One author entered the data into Review Manager (RevMan 2014), and a second author verified accuracy. We resolved any discrepancies through discussion.
Assessment of risk of bias in included studies
We assessed the methodological quality of included studies by reviewing study design, implementation, and losses to follow‐up. We also examined the methods used for assessing the outcomes. To assess the observational data, we used the principles outlined in section 13.5 of Higgins 2011 and in the Newcastle‐Ottawa Scale for assessing the quality of non‐randomized studies (Wells 2011). The investigators reported that the content validity and inter‐rater reliability of this scale have been established and that they are currently examining criterion validity and intra‐rater reliability. The scale does not yet have an overall scoring or threshold for a 'good' or 'poor' study.
We adapted the Newcastle‐Ottawa Quality Assessment Scale (NOS) items for the interventions and outcomes in this review as per the developers' suggestions (Wells 2011). The scale has two versions; one is applicable to case‐control studies (Appendix 3) and one is pertinent to cohort studies (Appendix 4), although the criteria are similar for several items. Each version has eight items within three domains: selection (representativeness), comparability (due to design or analysis), and outcomes (assessment and follow‐up). For the risk of bias tables, we used headings appropriate to the Newcastle‐Ottawa Scale. Assessment of analysis included any adjustment for potential confounding factors related to fracture risk. The study groups could differ in ways related to the outcome, such as body mass index, exercise patterns, or use of steroids other than contraceptives. A study can receive one star (✸) for meeting each criterion. The exception is comparability (design or analysis), for which a study can receive a maximum of two stars. In this review, for one star under comparability, the study controlled for age. For two stars under comparability, the study also controlled for other important variables such as exercise, body mass index, use of hormone replacement therapy or use of other relevant drugs. We present study limitations in each area of the scale and considered them when interpreting results.
Measures of treatment effect
Given the need to control for confounding factors in observational studies, we used adjusted measures as the primary effect measures when available. We used the adjusted estimates from the models reported by the authors. Odds ratio (OR) is an appropriate effect measure for both cohort and case‐control studies and is commonly provided when adjusted analyses are obtained using logistic regression models. However, we considered other effect measures if an appropriate adjusted OR was not available from the report. The effect measure may have been an odds ratio, risk ratio, or hazard ratio.
Investigators used a variety of adjustment strategies. We specified whether confounding was considered in the design (e.g., matching, stratification). We provided the confounding factors considered in the design and analysis when presenting results. When investigators used multivariate models to adjust for potential confounding, we did not analyze the treatment effect as that would usually require individual participant data. Rather we presented the results from adjusted models as reported by the investigators. If no adjusted measures were given as part of the primary analysis, we used unadjusted measures. If data were available for unadjusted dichotomous outcomes, we calculated the OR with 95% confidence interval (CI).
Given the diversity of design features with observational studies, we did not conduct meta‐analysis for pooled estimates. We assessed sources of heterogeneity without pooling the data.
Unit of analysis issues
We did not encounter crossover studies or clustered designs for studies that met our inclusion criteria. However, if clustering was part of the design, we had planned to assess whether estimates were properly adjusted to account for clustering effects.
Dealing with missing data
If reports were missing data needed for analysis, we wrote to the authors. However, we limited our data requests to studies less than 10 years old. Investigators are unlikely to have access to data for older studies.
Assessment of heterogeneity
Due to varied study designs, we were unable to conduct meta‐analysis. Therefore, we did not need to assess statistical heterogeneity. However, we address heterogeneity due to differences in study design, analysis strategy (in particular the issue of confounding adjustments), and populations (Discussion).
Data synthesis
We intended to combine data from studies if they had similar designs, interventions, and outcome measures. Where we could analyze data, we used a fixed‐effect model for the dichotomous outcomes (Measures of treatment effect). Fixed‐effect and random‐effects models will give the same result if no heterogeneity exists and when a comparison does not involve a meta‐analysis, that is, has only one study (Higgins 2011). There is little consensus regarding the use of either model.
We organized the Results by the type of intervention (exposure) examined in the study. The major categories were oral contraceptives and progestin‐only injectables. Within those categories, we present results by outcome, that is, the type of fracture.
To assess the quality of the body of evidence, we tried to extrapolate our findings from the Newcastle‐Ottawa Scale (NOS) (Wells 2011) to the GRADE ratings that address confidence in the effect estimate (Balshem 2011). However, the GRADE approach has mainly focused on RCTs, given that much is based on the Risk of Bias tables (Higgins 2011). As noted earlier, the NOS does not have an overall scoring, but we wanted to synthesize results across studies. We assessed evidence from individual studies rather than from a meta‐analysis. Our approach is explained below (Sensitivity analysis).
Sensitivity analysis
We summarized the results from studies that provided at least moderate quality evidence. For inclusion as moderate quality evidence, studies had to meet at least six criteria of the Newcastle‐Ottawa Quality Assessment Scale (NOS) (Assessment of risk of bias in included studies).
-
Case‐control studies: selection of cases and controls (four items), comparability of cases and controls (at least one star), and exposure ascertainment (one item, i.e., method used).
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Cohort studies: selection of exposed and non‐exposed cohorts (four items), comparability of cohorts (at least one star), and outcome assessment.
We downgraded the evidence a level for each criterion that was not met. A study might not have met the criteria due to design issues or insufficient information in the report. We upgraded the evidence by one level if the study had two stars for comparability.
Results
Description of studies
Results of the search
In 2015, the database searches produced 192 references. After we removed 62 duplicates electronically or by hand, we had 130 unduplicated references (Figure 1). The search for the initial review in 2012 yielded 429 unduplicated references for a grand total of 559. For this update, we identified one published article from a previously included study that had only had a conference presentation. We discarded the remaining citations based on title or abstract. Searches of clinical trials databases yielded only three unduplicated listings, none of which appeared relevant to this review.
Study flow diagram.
Included studies
We included 14 studies plus 10 reports with additional analyses or design information (Characteristics of included studies). Studies could have examined more than one type of steroidal contraceptive; the 14 studies examined oral contraceptives (N = 12), DMPA (N = 4) and the hormonal IUD (N = 1). The type of fracture studied varied, e.g., first fracture, hip fracture, or forearm fracture. Details are provided in Effects of interventions. Designs included seven case‐control studies and seven cohort studies (of which two only analyzed baseline data). Six were conducted in the UK, two in Sweden and two in the USA, and one in each of Finland, Denmark, Italy, and Australia.
Excluded studies
We excluded 11 studies. Reasons included not having fracture as an outcome, not being a comparative study, or being a cross‐sectional study (Characteristics of excluded studies).
Risk of bias in included studies
We used the Newcastle‐Ottawa Scale (NOS) for assessing the quality of included studies (Appendix 3; Appendix 4). Assessments of case‐control studies are shown in Table 1. Assessments for cohort studies are shown in Table 2; we also included baseline assessments within cohort studies. We grouped the results from our Risk of bias tables into the main domains of the NOS.
| Studya | Selection | Comparability of cases and controls | Exposure | Evidence qualityb | |||||
| Case definition | Cases representative | Control selection | Control definition | Ascertainment method | Same ascertainment both groups | Nonresponse rate | |||
| ✸ | ✸ | ‐ | ‐ | ✸ | ‐ | ✸ | ✸ | Very low | |
| ✸ | ✸ | ✸ | ✸ | ✸ | ‐ | ✸ | ✸ | Low | |
| ✸ | ✸ | ✸ | ‐ | ✸✸ | ✸ | ✸ | ✸ | Moderate | |
| ✸ | ✸ | ✸ | ✸ | ✸✸ | ✸ | ✸ | ✸ | High | |
| ✸ | ✸ | ✸ | ‐ | ✸✸ | ‐ | ✸ | ✸ | Low | |
| ✸ | ✸ | ✸ | ‐ | ✸✸ | ‐ | ✸ | ‐ | Low | |
| ✸ | ✸ | ✸ | ‐ | ✸✸ | ✸ | ✸ | ✸ | Moderate | |
aNewcastle‐Ottawa Quality Assessment Scale (Appendix 3): 1 star (✸) for meeting each criterion, except comparability (design or analysis) can have 2 stars. For comparability in this review: 1 star if controlled for age; 2 stars if also controlled for other important variables, e.g., exercise, body mass index, use of hormone replacement therapy or other relevant drugs
bModerate quality evidence: met criteria for selection (4 items), comparability (1 star; upgraded for 2 stars), and ascertainment method; downgrading due to design limitation or lack of information in report
cVestergaard 2006 includes 3 reports: OC use (2006), OC use among young women (2008a); use of DMPA or hormonal IUD (2008b)
| Studya | Selection | Comparability of cohorts | Outcome | Evidence qualityb | |||||
| Exposed cohort representative | Nonexposed cohort selection | Exposure ascertainment | Outcome not present at start | Assessment | Follow‐up length | Follow‐up | |||
| ✸ | ✸ | ✸ | ‐ | ✸✸ | ✸ | ‐ | ✸ | Moderate | |
| ✸ | ✸ | ✸ | ✸ | ✸ | ✸ | ✸ | ‐ | Moderate | |
| ‐ | ✸ | ‐ | ✸ | ‐ | ‐ | ✸ | ‐ | Very low | |
| ✸ | ✸ | ✸ | ‐ | ✸ | ✸ | ✸ | ‐ | Low | |
| ✸ | ✸ | ‐ | ‐ | ‐ | ‐ | ‐ | ‐ | Very Low | |
| ✸ | ✸ | ✸ | ✸ | ✸✸ | ✸ | ✸ | ✸ | High | |
| ✸ | ✸ | ‐ | ‐ | ‐ | ‐ | ‐ | ‐ | Very low | |
aNewcastle‐Ottawa Quality Assessment Scale (Appendix 4): 1 star (✸) for meeting each criterion, except comparability (design or analysis) can have 2 stars. For comparability in this review: 1 star if controlled for age; 2 stars if also controlled for other important variables, e.g., exercise, body mass index, use of hormone replacement therapy or other relevant drugs
bModerate quality evidence: met criteria for selection (4 items), comparability (1 star; upgraded for 2 stars), and outcome assessment. downgrading due to design limitation or lack of information in report.
Selection
This domain included four criteria, which differed between case‐control and cohort studies. All seven case‐control studies met the NOS criteria for case definition (having independent validation) and for representativeness of cases. Six studies met the criterion for control selection. For control definition, only two studies met the criterion, i.e., were clear about the controls not having a history of fracture.
The seven cohort studies met the criteria for representativeness of the exposed cohort and for selection of the non‐exposed cohort. Four met the criterion for exposure ascertainment; the others used written survey responses or did not report sufficient information. For the outcome not being present at study start, only three studies had such evidence and therefore met the criterion.
Exposure (case‐control)
Three criteria comprised this domain. Five of the case‐control studies met the criterion for ascertainment of exposure, which was based on the information source such as secure records or structured interview. Two did not meet the criterion due to insufficient information. All seven studies met the criterion for using the same ascertainment method for both cases and controls. Only three studies had comparable non‐response rates by group and overall non‐response rates less than 20%.
Comparability of study groups
This section addresses comparability based on design or analysis. All seven case‐control studies adjusted for age or matched on age. In addition, four adjusted for other important potential confounders. Another listed the important variables examined that reportedly had no association with the outcome (O'Neill 1996). The remaining two studies did not meet the criterion due to inadequate information on variables examined (La Vecchia 1999) or to conducting only univariate analysis (Mallmin 1994).
Of the cohort studies, two adjusted for age and other important potential confounders. Three did not have comparable cohorts or did not adjust for potential confounders (Tuppurainen 1994; Kaunitz 2006; Wei 2011). In addition, Cooper 1993 adjusted for age and parity but did not address other important variables. Lanza 2013 adjusted for age and stated that other (unspecified) variables were examined that did not make a meaningful difference after age.
An additional factor for this review was the type of OC used. Most studies had records of the specific pill type but analyzed the data as any OC. Vestergaard 2006 was the exception in examining the estrogen dose as well as the type of progestin for the 2008 paper on COCs.
Outcome (cohort)
This domain included three criteria. For outcome assessment, four cohort studies had an independent assessment or record linkage for the outcome. Of the other three studies, two were baseline assessments within cohort studies and one gathered fracture data as an adverse event.
The length of follow‐up appeared adequate in four of the seven studies. Those with shorter follow‐up included Barad 2005 with a 2.5 year mean as well as the two baseline assessments within cohort studies (Table 2). Losses were high however, so we assessed follow‐up as adequate (at least 80%) for only two studies.
Effects of interventions
See: Summary of findings for the main comparison ; Summary of findings 2
Most studies used adjusted analyses, so we were not able to analyze the data (Measures of treatment effect). We provide the results as reported by the investigators (Additional tables). For the few studies without adjusted analyses, we analyzed the data as noted below. Information on the specific confounders that the investigator considered are given in the Characteristics of included studies (Risk of bias, Comparability of groups).
Oral contraceptives
First fracture
Five studies examined first fractures for oral contraceptive users. Cooper 1993 was a prospective cohort study of OC users and nonusers. Data were from the Royal College of General Practitioners Oral Contraception Study in the UK. The same research group used a subset of these women with later data (Memon 2011). The relative risk (RR) was adjusted for some potential confounders. Ever users of OCs were more likely to have a fracture than never users (reported RR 1.20, 95% CI 1.08 to 1.34) (Table 3). Risk for forearm fracture did not differ between the groups. Standardized fracture rates were provided for years of OC use (Table 3). The rate for no use was 2.54; rates for users ranged from 3.10 (1 to 4 years) to 2.86 for 10 or more years.
| Number | Ratea | Standardized rateb | Relative risk (95% CI)b | ||
| All fractures | |||||
| OC use
| Never | 512 | 2.60 | 2.54 | 1.00 |
| Ever | 853 | 2.99 | 3.04 | 1.20 (1.08 to 1.34) | |
|
| |||||
| Duration of OC use (years)
| 0 | 512 | 2.60 | 2.54 | ‐ |
| 1 to 4 | 497 | 2.82 | 3.10 | ‐ | |
| 5 to 9 | 259 | 3.19 | 3.01 | ‐ | |
| > 10 | 97 | 3.53 | 2.86 | ‐ | |
| Forearm fractures | |||||
| OC use
| Never | 132 | 0.67 | 0.64 | 1.00 |
| Ever | 187 | 0.66 | 0.68 | 1.06 (0.95 to 1.32) | |
aPer 1000 person‐years of observation
bStandardized for age, parity at time of event, and smoking and social class at recruitment; not reported for 'Duration of OC use'
The case‐control study of Memon 2011 examined first‐time fracture versus no fracture. The investigators used data from a subset of women in the Royal College of General Practitioners Oral Contraception Study (UK). These women would have been older and followed longer than they had been for Cooper 1993. Cases and controls were age‐matched, and ORs were adjusted for some potential confounders. No association was apparent between risk of fracture and OC use ever nor for years of OC use (Table 4). For interval since OC use, the only increased risk noted was for those with 10 years or more since use (reported adjusted OR 1.55, 95% CI 1.03 to 2.33). The investigators also conducted analyses by age group and by fracture site, but showed no significant difference in risk between OC users and nonusers (data not shown here).
|
| Cases | Controls | OR (95% CI)a | |
| All fractures | ||||
| OC use | Never | 227 | 472 | 1.00 |
| Ever | 420 | 823 | 1.05 (0.86 to 1.29) | |
| Fractures while under observation of general practitioner | ||||
| OC use | Never | 89 | 207 | 1.00 |
| Ever | 184 | 339 | 1.25 (0.90 to 1.72) | |
| Duration of OC use (years) | Never | 89 | 207 | 1.00 |
| < 5 | 116 | 212 | 1.25 (0.89 to 1.77) | |
| 5 to 9 | 53 | 97 | 1.25 (0.80 to 1.94) | |
| 10 to 14 | 13 | 26 | 1.16 (0.56 to 2.42) | |
| > 15 | 2 | 4 | 1.23 (0.22 to 7.02) | |
| Time since OC use and | Never | 89 | 207 | 1.00 |
| < 5 | 49 | 100 | 1.06 (0.65 to 1.72) | |
| 5 to 9 | 35 | 75 | 1.01 (0.62 to 1.65) | |
| > 10 | 100 | 164 | 1.55 (1.03 to 2.33) | |
aAdjusted for smoking, social class, parity
Vessey 1998, a cohort study, used data from the Oxford‐Family Planning Association study in the UK. Women were OC users or nonusers. Few associations were apparent (Table 5). The relative risks (RRs) were adjusted for age. Increased fracture risk was noted for those who used OCs for longer periods, but the only notable increase was for those with use of 97 months or longer. For fractures of the radius and all fractures, the reported RRs were 1.5 (95% CI 1.1 to 2.1) and 1.2 (95% CI 1.1 to 1.4), respectively. When the interval since OC use was examined, increased risks for two groups were noted. For recent users (interval of 12 months or less), the reported RR for all fractures was 1.3 (95% CI 1.1 to 1.5). For an interval of 73 to 96 months, the RR for radius fracture was 2.5 (95% CI 1.5 to 4.0).
|
| Relative risk (95% CI)a by fracture site | ||||
| Radius or ulna | Ankle | Tarsals or | All fractures | ||
| Duration of OC use (months)b | Nonuser | 1.0 | 1.0 | 1.0 | 1.0 |
| < 12 | 1.1 (0.3 to 2.8) | 0.7 (0.1 to 2.1) | 0.4 (0.0 to 1.5) | 0.8 (0.5 to 1.2) | |
| 13 to 24 | 1.8 (0.8 to 3.8) | 1.6 (0.7 to 3.2) | 0.9 (0.3 to 2.2) | 0.9 (0.6 to 1.3) | |
| 25 to 48 | 1.3 (0.7 to 2.2) | 0.9 (0.4 to 1.6) | 1.2 (0.7 to 2.0) | 1.2 (1.0 to 1.5) | |
| 49 to 72 | 1.1 (0.6 to 2.0) | 0.7 (0.3 to 1.3) | 1.2 (0.7 to 2.0) | 1.2 (0.9 to 1.4) | |
| 73 to 96 | 1.1 (0.6 to 2.1) | 1.3 (0.7 to 2.3) | 1.2 (0.6 to 2.0) | 1.2 (1.0 to 1.5) | |
| >= 97 | 1.5 (1.1 to 2.1) | 1.0 (0.7 to 1.5) | 0.8 (0.5 to 1.2) | 1.2 (1.1 to 1.4) | |
| Interval since OC use (months)b | Nonuser | 1.0 | 1.0 | 1.0 | 1.0 |
| Current user < 12 | 1.2 (0.7 to 1.8) | 1.2 (0.8 to 1.8) | 1.1 (0.7 to 1.6) | 1.3 (1.1 to 1.5) | |
| 13 to 24 | 1.2 (0.4 to 2.8) | 1.0 (0.4 to 2.3) | 1.1 (0.4 to 2.3) | 1.2 (0.9 to 1.6) | |
| 25 to 48 | 1.0 (0.4 to 1.9) | 1.0 (0.5 to 1.9) | 1.2 (0.6 to 2.2) | 1.0 (0.8 to 1.3) | |
| 49 to 72 | 1.7 (0.9 to 3.0) | 0.7 (0.3 to 1.5) | 0.8 (0.3 to 1.6) | 1.1 (0.8 to 1.4) | |
| 73 to 96 | 2.5 (1.5 to 4.0) | 0.9 (0.4 to 1.8) | 0.8 (0.4 to 1.8) | 1.2 (0.9 to 1.5) | |
| 97 to 120 | 1.6 (0.8 to 2.8) | 1.1 (0.5 to 2.1) | 0.8 (0.3 to 1.8) | 1.3 (1.0 to 1.6) | |
| > 121 | 1.1 (0.7 to 1.8) | 0.9 (0.5 to 1.4) | 0.7 (0.3 to 1.2) | 1.0 (0.8 to 1.2) | |
aAdjusted for age
bSample sizes per cell not provided; recruited 17,032 women. OC ever‐use: 187,000 woman‐years; nonuse by age 45: 123,000 woman‐years
The cohort study of Barad 2005 used data from the observational study of the Women's Health Initiative in the USA. The women were postmenopausal. Hazard ratios were adjusted for a number of important potential confounders. The investigators examined any OC use, years of OC use, and years of OC use after excluding women with a prior fracture. Two associations were noted between OC use and fracture (Table 6). Small increased risks were found for any OC use (HR 1.07; 95% CI 1.01 to 1.15) and for OC use up to five years (HR 1.09; 95% CI 1.01 to 1.18). The latter was not evident after excluding women with prior fracture.
| Oral contraceptive usea | Hazard ratio (95% CI) | |
| Any OC useb | None | 1.00 |
| Any | 1.07 (1.01 to 1.15) | |
| Years of OC usec | None | 1.00 |
| < 5 years | 1.09 (1.01 to 1.18) | |
| 5 to 10 years | 1.07 (0.96 to 1.20) | |
| > 10 years | 1.02 (0.91 to 1.15) | |
| Excluding women with prior fractured | No OC use | 1.00 |
| < 5 years OC use | 1.08 (0.99 to 1.18) | |
| > 5 years OC use | 1.05 (0.96 to 1.16) | |
aSample sizes overall: OC users 33,025; OC nonusers 47,922
bAdjusted for baseline age (1‐year intervals), hormone therapy use and duration, follow‐up time, calcium intake (mg); use of corticosteroids, vitamin D, thiazide, thyroid hormone; age, race or ethnicity, smoking, alcohol use, exercise, body mass index, parity, irregular menses before menopause, hysterectomy, age at menopause, menopausal symptoms, prior fracture before age 55, length of OC use, age of last OC use, and age of first OC use.
cModel adjusted as above, with duration of OC use in 5‐year intervals (excluding adjustment for duration of OC use as covariate)
dBase model used excluding participants with prior fracture
The case‐control study of Meier 2010 examined use of combined oral contraceptives (COCs). The investigators used the UK‐based General Practice Research Database as did Lanza 2013. Cases were 20 to 44 years old and had a first‐time fracture diagnosis between 1995 and 2008. Controls were randomly selected from the base population and matched on several variables including age. The only subgroup with a significantly higher fracture risk than nonusers was current users with 10 or more prescriptions (reported OR 1.09, 95% CI 1.03 to 1.16) (Table 7).
|
| Prescriptions (N) | Cases (N) | Controls (N) | OR (95% CI)a | Adjusted OR (95% CI)b |
| Nonuse | ‐ | 6591 | 26,578 | reference | reference |
| Current use
| 1 to 2 | 215 | 871 | 0.99 (0.85 to 1.16) | 1.01 (0.87 to 1.18) |
| 3 to 9 | 1136 | 4696 | 0.98 (0.91 to 1.05) | 1.01 (0.94 to 1.09) | |
| > 10 | 2327 | 9073 | 1.04 (0.98 to 1.10) | 1.09 (1.03 to 1.16) | |
| Past use
| 1 to 2 | 1972 | 7820 | 1.02 (0.96 to 1.08) | 1.00 (0.95 to 1.07) |
| 3 to 9 | 3178 | 12,787 | 1.01 (0.96 to 1.06) | 0.99 (0.94 to 1.04) | |
| > 10 | 2108 | 8305 | 1.03 (0.97 to 1.10) | 1.03 (0.97 to 1.10) |
aCases and controls matched on age, general practice, calendar time, and history in database.
bAdjusted for body mass index, smoking, asthma, epilepsy; use of progestin‐only preparations, medroxyprogesterone acetate low dose, β‐blockers, proton pump inhibitors, systemic corticosteroids, benzodiazepines, serotonin reuptake inhibitors, anticonvulsants, and contraceptive not under investigation.
Any fracture
For the case‐control study of Vestergaard 2006, cases were women with any fracture sustained in the year 2000. Fracture data were from the National Hospital Discharge Register of Denmark. Controls were from the general population database. Exposure was calculated as the average daily dose, i.e., the sum of redeemed prescriptions divided by time interval from first prescription to date of fracture or censoring; further details are in Characteristics of included studies. The 2006 paper compared OC use versus nonuse for all women. The crude ORs had indicated some association between OC use and fracture, but the reported adjusted ORs showed no association (Table 8). The investigators also examined the type of fracture; no association with OC use was apparent (data not shown here). A 2008 paper examined combined OC (COC) use rather than all OC use, and focused on very young women. Few significant differences were noted (Table 9):
| Age group (years) | Daily OC dosea | Cases (N) | Controls (N) | ORb (95% CI) |
| < 25 | ‐ | 16,219 | 48,659 | ‐‐‐ |
|
| < 0.3 | 331 | 795 | 0.97 (0.91 to 1.03) |
|
| 0.3 to 0.99 | 1445 | 3872 | 0.96 (0.92 to 1.01) |
|
| > 1 | 1156 | 3546 | 0.92 (0.86 to 0.98) |
| 25 to 49 | ‐ | 10,545 | 31,631 | ‐ |
|
| < 0.3 | 1895 | 5491 | 0.91 (0.82 to 1.00) |
|
| 0.3 to 0.99 | 2444 | 7445 | 0.90 (0.77 to 1.05) |
|
| > 1 | 783 | 2546 | 0.87 (0.64 to 1.18) |
| > 50 | ‐ | 37,784 | 113,351 | ‐ |
|
| < 0.3 | 799 | 2820 | 0.92 (0.77 to 1.10) |
|
| 0.3 to 0.99 | 253 | 977 | 0.69 (0.45 to 1.05) |
|
| > 1 | 6 | 266 | 0.62 (0.27 to 1.41) |
aExposure as average daily dose, i.e., redeemed prescriptions/time interval from first prescription to fracture or censoring (Characteristics of included studies); < 1 indicates < regular use; > 1 suggests lost prescription and obtained new one.
bAdjusted for Charlson index (19 comorbid conditions), ever use of corticosteroids, alcoholism, working or not, number of bed days in 1999, contacts with physician in 1999, income, living with someone or living alone, prior fracture, education level, pregnancy; use of anti‐epileptic drugs, thyroid active drugs (levothyroxine or antithyroid drugs), or hormone replacement therapy.
| Age group (years) | Daily COC dosea | Cases (N) | Controls (N) | Adjusted OR (95% CI)b |
| < 15
| Never users | 12,192 | 36,652 | reference |
| < 0.3 | 19 | 71 | 0.58 (0.22 to 1.55) | |
| 0.3 to 0.99 | 63 | 146 | 1.50 (1.03 to 2.18) | |
| > 1 | 121 | 310 | 1.02 (0.77 to 1.35) | |
| 15.1 to 17
| Never users | 495 | 1731 | reference |
| < 0.3 | 36 | 86 | 1.04 (0.68 to 1.60) | |
| 0.3 to 0.99 | 196 | 434 | 1.30 (1.05 to 1.61) | |
| > 1 | 254 | 704 | 1.05 (0.87 to 1.27) | |
| 17.1 to 19
| Never users | 271 | 856 | reference |
| < 0.3 | 72 | 145 | 1.32 (0.94 to 1.85) | |
| 0.3 to 0.99 | 294 | 793 | 0.99 (0.80 to 1.22) | |
| > 1 | 265 | 908 | 0.83 (0.67 to 1.03) | |
| > 19
| Never users | 42,433 | 126,644 | reference |
| < 0.3 | 2888 | 8804 | 1.03 (0.98 to 1.08) | |
| 0.3 to 0.99 | 3589 | 10,921 | 1.04 (0.99 to 1.08) | |
| > 1 | 1360 | 4436 | 1.06 (0.99 to 1.13) | |
| Age group (years) | Ethinyl estradiol (EE) dose | Cases (N) | Controls (N) | Adjusted OR (95% CI)a |
| < 15
| 20 µg | 100 | 264 | 1.23 (0.92 to 1.64) |
| > 30 µg | 82 | 225 | 0.97 (0.69 to 1.37) | |
| Changed between 20 µg and 30 µg | 32 | 59 | 1.34 (0.75 to 2.37) | |
| Other OCs | 13 | 45 | 0.20 (0.04 to 1.12) | |
| 15.1 to 17
| 20 µg | 205 | 550 | 1.07 (0.88 to 1.31) |
| > 30 µg | 181 | 478 | 1.08 (0.87 to 1.33) | |
| Changed between 20 µg and 30 µg | 113 | 236 | 1.42 (1.09 to 1.84) | |
| Other OCs | 11 | 35 | 0.95 (0.40 to 2.30) | |
| 17.1 to 19
| 20 µg | 209 | 645 | 0.96 (0.76 to 1.21) |
| > 30 µg | 286 | 787 | 0.98 (0.79 to 1.21) | |
| Changed between 20 µg and 30 µg | 157 | 451 | 0.95 (0.74 to 1.23) | |
| Other OCs | 13 | 55 | 0.78 (0.35 to 1.72) | |
| > 19
| 20 µg | 785 | 2643 | 0.97 (0.89 to 1.06) |
| > 30 µg | 4718 | 14,498 | 1.03 (0.99 to 1.07) | |
| Changed between 20 µg and 30 µg | 1173 | 3195 | 1.13 (1.05 to 1.22) | |
| Other OCs | 1349 | 4396 | 1.03 (0.97 to 1.11) | |
| Analysis of young womenc | ||||
| Age group (years) | Daily COC dosea | Cases (N) | Controls (N) | ORb (95% CI) |
| < 19 years | 0.3 to 0.99 | 393 | 943 | 1.17 (1.01 to 1.37) |
| 19 to 25 | < 0.3 | 297 | 731 | 1.22 (1.02 to 1.47) |
| 0.3 to 0.99 | 1281 | 3573 | 1.14 (1.00 to 1.30) | |
| > 35 | > 1 | 367 | 1424 | 0.88 (0.78 to 0.99) |
aExposure as average daily dose, i.e., redeemed prescriptions/time interval from first prescription to fracture or censoring (Characteristics of included studies); < 1 indicates < regular use; > 1 suggests lost prescription and obtained new one
bAdjusted for Charlson index (19 comorbid conditions), ever‐use of corticosteroids, alcoholism, working or not, bed days in 1999, contacts with physician in 1999, income, living with someone or living alone, prior fracture, education level, pregnancy; use of anti‐epileptic drugs, estrogen therapy, or estrogen–progestin therapy.
cResults presented for reported significant differences.
-
For very young women: Reported adjusted ORs indicated increased risk in two age groups when the average dose was 0.3 to 0.99 per day. For those up to 15 years of age, the reported OR was 1.50 (95% CI 1.03 to 2.18). For those 15.1 to 17 years old, the reported OR was 1.30 (95% CI 1.05 to 1.61).
-
By dose of ethinyl estradiol: Risk was increased within the 15.1 to 17 year‐olds and those older than 19 years if they had changed between 20 µg and > 30 µg of ethinyl estradiol (EE). The reported adjusted ORs were 1.42 (95% CI 1.09 to 1.84) and 1.13 (95% CI 1.05 to 1.22), respectively.
-
By type of progestin for very young women: No association with fracture was apparent (data not shown here).
-
Young women: The report focused on 'very young women' but also analyzed 'young women.' Results indicated a difference in risk. Increased risk was noted for women less than 19 years old with an average dose of 0.3 to 0.99 (reported OR 1.17, 95% CI 1.01 to 1.37) and for women aged 19 to 25 years with an average dose less than 0.3 (reported OR 1.22, 95% CI 1.02 to 1.47) or dose of 0.3 to 0.99 (reported OR 1.14, 95% CI 1.00 to 1.30). Lower risk was noted for women older than 35 with an average dose of one or greater (reported OR 0.88, 95% CI 0.78 to 0.99). The investigators also analyzed forearm fractures within these age groups but showed no association with OC use.
From baseline data of cohort studies, two reports examined history of OC use and fracture history (Tuppurainen 1994; Wei 2011). Neither adjusted fracture risk for potential confounding factors. Tuppurainen 1994 analyzed fractures since age 15 (Analysis 1.1) and fractures sustained from 1980 to 1989 (Analysis 1.2). Analysis included OC use versus no use, as well as subgroups of use less than one year, one to five years, and more than six years versus no use. No relationship was shown between OC use and fractures. Wei 2011 analyzed history of any fracture. The investigators used baseline data from a cohort study in Tasmania. Unadjusted fracture rates did not differ significantly between OC users and nonusers (Analysis 1.3).
Specific fracture sites
Two case‐control studies examined hip fractures (La Vecchia 1999; Michaelsson 1999). The data for La Vecchia 1999 came from a case‐control study of hip fracture (versus no fracture) in Italy. Women were 25 to 74 years old. No association was noted between OC use ever and hip fracture nor for OC use for two years or more (Table 10). The brief report, in a letter to a journal editor, did not state the variables for which the ORs were adjusted. Michaelsson 1999 studied hip fractures among postmenopausal women in Sweden. Controls were obtained from the national population registry. The report provided age‐adjusted ORs as well as ORs adjusted for age and other potential confounders (Table 11). Decreased risk for fracture was noted for ever‐use of OCs (reported OR 0.75, 95% CI 0.59 to 0.96) and for ever‐use of high‐dose OCs (reported OR 0.56, 95% CI 0.42 to 0.75). Decreased risk was also noted for those who used OCs at age 40 or later (reported OR 0.69, 95% CI 0.51 to 0.94) and for those who used high‐dose OCs at age 40 or later (reported OR 0.61, 95% CI 0.42 to 0.89).
| ORa (95% CI) | ||
| OC useb | Ever | 0.98 (0.47 to 2.03) |
| > 2 years | 1.04 (0.42 to 2.55) | |
aOdds ratio for 'ever' identified as multivariate OR; variables not provided. For use > 2 years, did not specify whether OR adjusted or not.
bSample sizes: cases 279; controls 1861. OC use ever: cases 10; controls 167
|
| Number | Age‐adjusted OR | Multivariate ORa | ||
| Cases | Controls | ||||
| OC use | Never | 994 | 2373 | 1.00 | 1.00 |
| Ever (any type) | 130 | 562 | 0.75 (0.60 to 0.95) | 0.75 (0.59 to 0.96) | |
| High dose ever | 77 | 456 | 0.54 (0.40 to 0.72) | 0.56 (0.42 to 0.75) | |
| Duration of OC use (per 2 years) | 116 | 526 | 1.06 (0.92 to 1.22) | 1.03 (0.89 to 1.19) | |
| Time since last OC use (per 2 years) | 117 | 529 | 1.01 (0.95 to 1.08) | 1.02 (0.96 to 1.09) | |
| Time since last OC use and menopause (per 2 years) | 117 | 529 | 0.95 (0.84 to 1.08) | 0.97 (0.85 to 1.11) | |
| Age at use of any OC | Never used | 994 | 2373 | 1.00 | 1.00 |
| < 30 years | 34 | 193 | 1.11 (0.68 to 1.82) | 1.26 (0.76 to 2.09) | |
| 30 to 39 years | 60 | 294 | 0.80 (0.57 to 1.12) | 0.82 (0.57 to 1.16) | |
| > 40 years | 64 | 271 | 0.72 (0.54 to 0.98) | 0.69 (0.51 to 0.94) | |
| Age at use of high‐dose OCb | Never used | 994 | 2373 | 1.00 | 1.00 |
| < 30 years | 27 | 183 | 0.97 (0.56 to 1.68) | 1.12 (0.64 to 1.97) | |
| 30 to 39 years | 46 | 264 | 0.74 (0.50 to 1.08) | 0.76 (0.51 to 1.13) | |
| > 40 years | 40 | 215 | 0.62 (0.43 to 0.90) | 0.61 (0.42 to 0.89) | |
1Adjusted for age (5‐year intervals), hormone replacement therapy, parity, body mass index (by quintiles).
2Containing > 50 µg ethinyl estradiol
Forearm fractures were examined in two case‐control studies (Mallmin 1994; O'Neill 1996). The Swedish study of Mallmin 1994 included women 40 to 80 years of age with fracture of distal forearm between April 1989 and March 1990. Controls were from the population registry. The investigators did not adjust fracture risk for potential confounding factors. They found no association between OC use and forearm fracture (Analysis 1.4). O'Neill 1996 was conducted in England. Cases were 45 years of age or older and had sustained a fracture of distal forearm between October 1991 and March 1993. Fracture cases were less likely to have used OCs than population controls (reported OR 0.3, 95% CI 0.1 to 0.9) (Table 12).
| Control group | ||
| Population | Had fall | |
| OC useb | 0.3 (0.1 to 0.9) | 0.7 (0.2 to 2.4) |
aAge adjusted
bSample sizes: cases 62; fall control 50; population control 116
Progestin‐only contraceptives
Depot medroxyprogesterone acetate
In the cohort study of Kaunitz 2006, women were 25 to 35 years old at recruitment. New users of DMPA were compared with users of non‐hormonal contraceptive methods. The primary endpoint was change in bone mineral density. Fracture was recorded as an adverse event, and shown for the treatment phase and the post‐treatment follow‐up. Fracture risk was not adjusted for potential confounding factors; the study groups did not differ significantly for fracture risk (Analysis 2.1).
The case‐control study of Vestergaard 2006 also analyzed DMPA use versus nonuse in a 2008 paper. As noted earlier, cases were women with any fracture sustained in the year 2000. Exposure was calculated as the average daily dose, i.e., the sum of redeemed prescriptions divided by time interval from first prescription to date of fracture or censoring; further details are in Characteristics of included studies. ORs were adjusted (Table 13). DMPA use was associated with an increased risk of fracture compared with nonuse. The reported OR for ever‐using DMPA was 1.44 (95% CI 1.01 to 2.06). Increased risk was more apparent among women over 50 years of age (reported adjusted OR 2.25, 95% CI 1.14 to 4.42), those with regular use (reported OR 1.94, 95% CI 1.09 to 3.45), and those who used DMPA for more than four years (reported OR 2.16, 95% CI 1.32 to 3.53).
|
| Subgroup | Cases (N) | Controls (N) | ORa (95% CI) |
| DMPAb use ever | ‐ | 58 | 105 | 1.44 (1.01 to 2.06) |
| Age of woman (years)
| < 25 | 15 | 29 | 1.20 (0.59 to 2.45) |
| 25 to 50 | 25 | 51 | 1.09 (0.64 to 1.85) | |
| > 50 | 18 | 25 | 2.25 (1.14 to 4.42) | |
| Average daily DMPA dosec
| < 0.25 | 21 | 32 | 1.73 (0.96 to 3.09) |
| 0.26 to 0.99 | 13 | 38 | 0.88 (0.45 to 1.74) | |
| > 1 | 24 | 35 | 1.94 (1.09 to 3.45) | |
| Duration of DMPA use (years)
| < 2.5 | 16 | 45 | 0.82 (0.43 to 1.56) |
| 2.6 to 4 | 9 | 20 | 1.51 (0.66 to 3.46) | |
| > 4 | 33 | 40 | 2.16 (1.32 to 3.53) | |
aAdjusted for prior fracture, Charlson index (comorbidities), income, working status, living with someone or not, pregnancy, IUD use, hysterectomy, alcoholism; use of OC, corticosteroid, hormonal replacement therapy, anti‐epileptic drugs, and strong (morphine and opioid agonists) and weak analgesics (acetaminophen, nonsteroidal anti‐inflammatory drugs, and acetylsalicylic acid).
bDMPA = depot medroxyprogesterone acetate
cExposure as average daily dose, i.e., redeemed prescriptions/time from first prescription to fracture or censoring (Characteristics of included studies); < 1 indicates < regular use; > 1 suggests lost prescription and obtained new one.
As noted above, the case‐control study of Meier 2010 used the UK‐based General Practice Research Database, as did Lanza 2013. Cases were 20 to 44 years old and had a first‐time fracture diagnosis between 1995 and 2008. Controls were randomly selected from the base population and matched on several variables including age. Current and past users of DMPA were generally more likely to have had a fracture than nonusers (Table 14). The odds increased slightly with the number of prescriptions. For current users with three to nine prescriptions, the reported adjusted OR was 1.36 (95% CI 1.15 to 1.60). For those with 10 or more prescriptions, the adjusted OR was reported as 1.54 (95% CI 1.33 to 1.78). Past DMPA use was also associated with increased risk regardless of the number of prescriptions (Table 14). The reported adjusted ORs were as follows: for one to two prescriptions, 1.17 (95% CI 1.07 to 1.29); for three to nine prescriptions, 1.23 (95% CI 1.11 to 1.36), and for 10 or more prescriptions, 1.30 (95% CI 1.09 to 1.55).
|
| Prescriptions (N) | Cases (N) | Controls (N) | OR (95% CI)a | Adjusted OR (95% CI)b |
| Nonuse | ‐ | 15,614 | 64,415 | reference | reference |
| Current use
| 1 to 2 | 93 | 305 | 1.27 (1.01 to 1.61) | 1.18 (0.93 to 1.49) |
| 3 to 9 | 209 | 573 | 1.52 (1.30 to 1.79) | 1.36 (1.15 to 1.60) | |
| > 10 | 280 | 710 | 1.67 (1.45 to 1.92) | 1.54 (1.33 to 1.78) | |
| Past use
| 1 to 2 | 620 | 1985 | 1.31 (1.19 to 1.44) | 1.17 (1.07 to 1.29) |
| 3 to 9 | 529 | 1609 | 1.38 (1.25 to 1.53) | 1.23 (1.11 to 1.36) | |
| > 10 | 182 | 533 | 1.45 (1.22 to 1.72) | 1.30 (1.09 to 1.55) |
aCases and controls matched on age, general practice, calendar time, and history in database
bAdjusted for body mass index, smoking, asthma, epilepsy; use of progestin‐only preparations, MPA low dose, β‐blockers, proton pump inhibitors, systemic corticosteroids, benzodiazepines, serotonin reuptake inhibitors, anticonvulsants, and contraceptive not under investigation.
Lanza 2013 was a cohort study of DMPA users versus users of other hormonal contraceptives (mostly OCs). The investigators analyzed data from the UK‐based General Practice Research Database, as Meier 2010 did. Incident fractures were those assessed after the first DMPA injection or first OC prescription. DMPA users had an increased fracture risk compared with users of other hormonal contraceptives. The rate ratio for incident fractures was (RR 1.41, 95% CI 1.35 to 1.47) (Analysis 3.1). Compared with nonusers of DMPA, the increased risk was greater for those with one to seven DMPA injections (RR 1.47, 95% CI 1.40 to 1.54) than for those who had eight or more injections (RR 1.22, 95% CI 1.13 to 1.32) (Analysis 3.2).When fracture site was analyzed, the two groups did not differ significantly for axial fractures (Analysis 3.3). Compared with nonusers of DMPA, users had greater risk for fracture of the appendicular skeleton, i.e., arm, leg, wrist, ankle, hand, foot, clavicle, rib or sternum, and shoulder (RR 1.38, 95% CI 1.31 to 1.46). The risk for all other fractures (finger, toe, skull, face, multiple trauma, and unspecified) was also greater for DMPA users versus nonusers (RR 1.49, 95% CI 1.39 to 1.59) (Analysis 3.3).
Levonorgestrel‐releasing intrauterine device
In the 2008 paper on DMPA use, Vestergaard 2006 also examined use of the hormonal IUD versus nonuse. Cases were women with any fracture sustained in the year 2000. All ORs were adjusted (Table 15). Hormonal IUD use was associated with reduced odds of fracture (reported OR 0.75, 95% CI 0.64 to 0.87). Fracture was also less likely for those who used the hormonal IUD for 1.6 to 4 years (reported OR 0.77, 95% CI 0.59 to 0.99).
|
| Subgroup | Cases (N) | Controls (N) | OR (95% CI)a |
| Hormonal IUDb use ever | ‐ | 219 | 791 | 0.75 (0.64 to 0.87) |
| Age of woman (years)
| < 25 | 3 | 5 | 0.82 (0.19 to 3.67) |
| 25 to 50 | 187 | 639 | 0.87 (0.73 to 1.04) | |
| > 50 | 29 | 147 | 0.72 (0.48 to 1.09) | |
| IUDs per year
| < 0.25 | 59 | 234 | 0.74 (0.55 to 1.00) |
| 0.26 to 0.6 | 84 | 280 | 0.84 (0.65 to 1.08) | |
| > 0.6 | 76 | 277 | 0.81 (0.62 to 1.05) | |
| Duration of hormonal IUD use (years)
| < 1.5 | 68 | 244 | 0.78 (0.59 to 1.03) |
| 1.6 to 4 | 83 | 289 | 0.77 (0.59 to 0.99) | |
| > 4 | 68 | 258 | 0.77 (0.58 to 1.01) | |
aAdjusted for prior fracture, Charlson index (comorbidities), income, working status, living with someone or not, pregnancy, DMPA use, hysterectomy, alcoholism; use of OC, corticosteroid, hormonal replacement therapy, anti‐epileptic drugs, and strong (morphine and opioid agonists) and weak analgesics (acetaminophen, nonsteroidal anti‐inflammatory drugs, and acetylsalicylic acid)
bIUD = intrauterine device
Discussion
Summary of main results
Of 14 studies, six provided at least moderate quality evidence, according to our assessment with the Newcastle‐Ottawa Scale (Table 1; Table 2). The other eight studies provided lower quality evidence, in some cases due to reporting less information or to having a different focus. This section focuses on the sensitivity analysis from the six studies providing moderate or high quality evidence. Four of the six studies used data from the UK, one study was from the USA and one was from Denmark. Results of the lower quality studies are summarized separately below.
All six studies in our sensitivity analysis examined oral contraceptive use (summary of findings Table for the main comparison); two also examined use of progestin‐only contraceptives (summary of findings Table 2). Few associations were noted between oral contraceptive use and fracture risk. In Cooper 1993, OC ever‐users had some increased risk for all fractures. However, Memon 2011 used a subset of women from Cooper 1993 several years later, and found no association of OC use with fracture except for those with 10 years or more since use. Barad 2005 studied postmenopausal women and did not find increased risk for OC use after excluding women with prior fracture. Meier 2010 reported increased risk only for those who had 10 or more prescriptions. Vessey 1998 and Vestergaard 2006 found little evidence of association between OC use and fracture risk. Some increased risk was noted for subgroups, such as those with longer use or specific intervals since use (Vessey 1998) and young women with less than average use (Vestergaard 2006).
Two studies in the sensitivity analysis examined use of progestin‐only contraceptives (Vestergaard 2006; Meier 2010). Both studies reported increased fracture risk for longer current use of DMPA. In addition, one noted increased risk with ever using DMPA and the other noted increased risk for any past use. Vestergaard 2006 also examined use of the hormonal IUD and found reduced fracture risk for ever using the hormonal IUD and for longer use of that IUD.
Eight studies were not in the sensitivity analysis. Two studies of OC use indicated some association. O'Neill 1996 noted that forearm fracture cases were less likely to be OC users than population controls. Michaelsson 1999 found decreased hip fracture risk among postmenopausal women for ever‐use of OCs overall or high‐dose OCs. In contrast, La Vecchia 1999 showed no association of hip fracture with OC use. Mallmin 1994 indicated no association of OC use with forearm fracture, and Tuppurainen 1994 and Wei 2011 did not show any association between OC use and fracture risk. Two studies excluded from the sensitivity analysis examined DMPA use. Lanza 2013 noted increased risk for DMPA users versus users of other hormonal methods. The groups did not differ significantly for axial fractures (vertebrae, hip, and pelvis), but did differ in risk for fractures of the appendicular skeleton and for all other fractures. In Kaunitz 2006, fracture was provided as an adverse event. The incidence of fracture was not significantly different for DMPA users versus users of non‐hormonal methods.
Overall completeness and applicability of evidence
Data sources for the sensitivity analysis included country‐wide hospital discharges in Denmark and general practice in the UK. The others were a study of postmenopausal women in the USA and two long‐term studies of family planning methods in the UK. None of the studies in this review came from a less‐developed country.
Most studies did not report on the types of oral contraceptives used. However, Vestergaard 2006 examined risk by estrogen dose and progestin type. The investigators found no association with high‐dose estrogen use but some increased risk for OC users who changed between 20 µg and > 30 µg estrogen. Progestin type was apparently not associated with any increased risk. Of the DMPA studies, one had a small sample for DMPA users. The two large studies of DMPA used the same database, although one used population controls.
The timeframe for the studies affects exposure to the contraceptive method and years of follow‐up for outcome assessment. Since fragility fractures are rare in young people, fracture is not usually an outcome in studies of premenopausal bone health (Gourlay 2004). The two DMPA studies used national databases. Meier 2010 selected premenopausal women, while Vestergaard 2006 examined all fractures in a specific year regardless of the woman's age; DMPA users were few. Hormonal IUD use came from the same source. Of the OC studies, Vessey 1998 recruited premenopausal women and followed them until age 45 or for 20 years. Memon 2011 gathered fracture data 40 years after study enrollment. Barad 2005 enrolled women after menopause, so contraceptive use was assessed retroactively.
Quality of the evidence
We used the Newcastle‐Ottawa Scale (NOS) items to assess the quality of evidence (Wells 2011). Less than half of the evidence was considered to be moderate or high quality (from three case‐control and three cohort studies). In some cases, downgrading the evidence was due to study design; in others, it was due to lack of information in the report.
Most studies did not mention an a priori power analysis. The exceptions were two excluded from the sensitivity analysis. Mallmin 1994 was focused on HRT and fracture; O'Neill 1996 was exploratory and did not specify outcomes of interest.
Most of the cohort studies had large losses or differential losses between the exposed and non‐exposed cohorts. Large losses are not usual for contraceptive studies and some of these were long‐term studies. For the case‐control studies, the response rate was generally adequate or was not an issue due to gathering information from existing databases. One study in the sensitivity analysis had a limited length of follow‐up (Barad 2005).
Potential biases in the review process
Adjusted analysis addresses potential differences between study groups in observational studies. This can reduce confounding of fracture rates. Five of the six studies in the sensitivity analysis controlled for age and examined other important variables such as exercise, body mass index, hormone replacement therapy, and use of other relevant drugs. However, studies that used existing databases did not have access to some important variables, such as body mass index and exercise. Because studies conducted adjusted analyses, we could not analyze most of the data in this review. We would have needed individual participant data to do so. Consequently, we showed the results as given by the investigators, except for studies that provided unadjusted fracture incidence.
Maximum exposure time in Vestergaard 2006 was five years. Memon 2011 examined fractures after the study ended; OC use was obtained during the study. Nonusers of OCs during the study may have started using OCs later, which would not have been captured in the database.
Our criteria for the sensitivity analysis were determined post hoc, which could have biased the results. We used the findings from the Newcastle‐Ottawa Scale to determine the quality of the evidence. Of the eight studies excluded from the sensitivity analysis, five were published in the 1990s. The older studies did not meet some criteria due to information missing from the report. Newer studies tend to have better reporting due to standards for observational studies and clinical trials (Strobe 2007; Schulz 2010).
Agreements and disagreements with other studies or reviews
A review of RCTs examined the effect of hormonal contraceptives on the risk of fracture in women (Lopez 2014). Outcomes included fracture, bone mineral density (BMD) and biochemical markers of bone turnover. No trial had fracture as an outcome. Depot medroxyprogesterone acetate (DMPA) was associated with decreased bone mineral density. The placebo‐controlled trials showed BMD increases for DMPA plus an estrogen supplement and decreases for DMPA plus placebo (Cundy 2003; Cromer 2005). Combination contraceptives did not appear to negatively affect bone health, but those studies were not placebo‐controlled.
Other reviews were mentioned earlier (Description of the condition). Two systematic reviews included studies of various designs and considered bone mineral density as well as fractures. After reviewing the evidence for combined hormonal contraceptives, Martins 2006 noted that bone mineral density was affected by COC use in adolescent and young women but not in premenopausal or postmenopausal women. In our current review of fracture risk, we had more recent reports but no additional studies of younger women. Information from the more recent studies of older women was consistent with the conclusions of Martins 2006. For progestin‐only methods, Curtis 2006 noted an association between DMPA use and loss of bone mineral density but noted the clinical significance was not clear. More recently, Isley 2011 concluded that adolescent users of DMPA do have decreases in BMD, but stated the loss can be recovered one or two years after discontinuation. We did not have data specifically on adolescents, who are unlikely to have fragility fractures. We noted increased fracture risk for DMPA ever‐users, but the difference may not be due to fragility fractures.
Comparison 1 Oral contraceptives versus no oral contraceptives, Outcome 1 Fracture since age 15.
Comparison 1 Oral contraceptives versus no oral contraceptives, Outcome 2 Fracture during 1980 to 1989.
Comparison 1 Oral contraceptives versus no oral contraceptives, Outcome 3 Self‐reported fracture.
Comparison 1 Oral contraceptives versus no oral contraceptives, Outcome 4 Forearm fracture.
Comparison 2 DMPA versus non‐hormonal contraceptives, Outcome 1 Adverse event: fracture.
Comparison 3 DMPA: use versus nonuse, Outcome 1 Fractures (per woman‐years).
Comparison 3 DMPA: use versus nonuse, Outcome 2 Fractures (per woman‐year) by exposure.
Comparison 3 DMPA: use versus nonuse, Outcome 3 Fractures (per woman‐years) by site.
| Oral contraceptive (OC) use compared with nonuse for contraceptiona | ||||
| Patient or population: women Settings: hospital or clinical site Intervention: oral contraceptive (OC) use Comparison: no use of OC | ||||
| Outcomes | Relative effect (95% CI)b | Participants | Quality of evidence | Participant ages |
| All fractures | RR 1.20 (1.08 to 1.34) | 1365 | ⊕⊕⊕⊝ | Mean age 29 years; ranged from < 25 to > 65 OC use ever vs never |
| First fracture | OR 1.55 (1.03 to 2.33) | 819 | ⊕⊕⊕⊕ | Age 20 to 87 years Last OC use > 10 years vs never |
| First fracture: radius or ulna; all sites | RR 1.5 (1.1 to 2.1); RR 1.2 (1.1 to 1.4) | 17,032 | ⊕⊕⊕⊕ | Recruited age 25 to 39 years; followed to 45 years OC use > 97 months vs no use |
| First fracture: radius or ulna; all sites | RR 2.5 (1.5 to 4.0); RR 1.3 (1.1 to 1.5) | 17,032 | ⊕⊕⊕⊕ | Recruited age 25 to 39 years; followed to 45 years Interval since use: 73 to 96 months vs no use (radius or ulna); < 12 months vs no use (all fractures) |
| First fracture | HR 1.07 (1.01 to 1.15); HR 1.09 (1.01 to 1.18) | 80,947 | ⊕⊕⊕⊝ | Recruited age 50 to 74 years OC use: any vs none; < 5 years vs none |
| First fracture | OR 1.09 (1.03 to 1.16) | 87,627 | ⊕⊕⊕⊝ | Age 20 to 44 years Current OC use > 10 prescriptions vs no use |
| Fracture, any | OR 1.50 (1.03 to 2.18); OR 1.30 (1.05 to 1.61) | 258,189 | ⊕⊕⊕⊝ | Mean age 51.7 years OC daily dose 0.3 to 0.99 tablet vs never user: < 15 years old; 15.1 to 17 years old |
| Fracture, any | OR 1.42 (1.09 to 1.84); OR 1.13 (1.05 to 1.22) | 258,189 | ⊕⊕⊕⊝ | Mean age 51.7 years OC ethinyl estradiol dose changed between 20 µg and > 30 µg vs no OC use: 15.1 to 17 years old; > 19 years old |
| GRADE Working Group grades of evidence | ||||
| aFrom sensitivity analysis (moderate or high quality evidence); significant differences in fracture risk | ||||
| Progestin‐only contraceptive use compared with nonuse for contraceptiona | ||||
| Patient or population: women Settings: hospital or clinical setting Intervention: use of progestin‐only contraceptive Comparison: nonuse of progestin‐only contraceptive | ||||
| Outcomes | Relative effect (95% CI)b | Participants | Quality of evidence | Participant ages |
| Fracture | OR 1.44 (1.01 to 2.06); OR 2.25 (1.14 to 4.42); 1.94 (1.09 to 3.45); OR 2.16 (1.32 to 3.53) | 258,189 | ⊕⊕⊕⊝ | Mean age 51.7 years DMPA use vs nonuse: ever use; use among women > 50 years old; daily dose > 1; use > 4 years |
| Fracture | OR 0.75 (0.64 to 0.87); OR 0.77 (0.59 to 0.99) | 258,189 | ⊕⊕⊕⊝ | Mean age 51.7 years Hormonal IUD use vs nonuse: ever use; use 1.6 to 4 years |
| First fracture | OR 1.36 (1.15 to 1.60); OR 1.54 (1.33 to 1.78) | 87,627 | ⊕⊕⊕⊝ | Age 20 to 44 years DMPA current use vs nonuse: use 3 to 9 years; use > 10 years |
| First fracture | OR 1.17 (1.07 to 1.29); OR 1.23 (1.11 to 1.36); OR 1.30 (1.09 to 1.55) | 87,627 | ⊕⊕⊕⊝ | Age 20 to 44 years DMPA past use (prescriptions) vs nonuse: 1 to 2; 3 to 9 ; > 10 |
| GRADE Working Group grades of evidence | ||||
| aFrom sensitivity analysis (moderate or high quality evidence); significant differences in fracture risk | ||||
| Studya | Selection | Comparability of cases and controls | Exposure | Evidence qualityb | |||||
| Case definition | Cases representative | Control selection | Control definition | Ascertainment method | Same ascertainment both groups | Nonresponse rate | |||
| ✸ | ✸ | ‐ | ‐ | ✸ | ‐ | ✸ | ✸ | Very low | |
| ✸ | ✸ | ✸ | ✸ | ✸ | ‐ | ✸ | ✸ | Low | |
| ✸ | ✸ | ✸ | ‐ | ✸✸ | ✸ | ✸ | ✸ | Moderate | |
| ✸ | ✸ | ✸ | ✸ | ✸✸ | ✸ | ✸ | ✸ | High | |
| ✸ | ✸ | ✸ | ‐ | ✸✸ | ‐ | ✸ | ✸ | Low | |
| ✸ | ✸ | ✸ | ‐ | ✸✸ | ‐ | ✸ | ‐ | Low | |
| ✸ | ✸ | ✸ | ‐ | ✸✸ | ✸ | ✸ | ✸ | Moderate | |
| aNewcastle‐Ottawa Quality Assessment Scale (Appendix 3): 1 star (✸) for meeting each criterion, except comparability (design or analysis) can have 2 stars. For comparability in this review: 1 star if controlled for age; 2 stars if also controlled for other important variables, e.g., exercise, body mass index, use of hormone replacement therapy or other relevant drugs | |||||||||
| Studya | Selection | Comparability of cohorts | Outcome | Evidence qualityb | |||||
| Exposed cohort representative | Nonexposed cohort selection | Exposure ascertainment | Outcome not present at start | Assessment | Follow‐up length | Follow‐up | |||
| ✸ | ✸ | ✸ | ‐ | ✸✸ | ✸ | ‐ | ✸ | Moderate | |
| ✸ | ✸ | ✸ | ✸ | ✸ | ✸ | ✸ | ‐ | Moderate | |
| ‐ | ✸ | ‐ | ✸ | ‐ | ‐ | ✸ | ‐ | Very low | |
| ✸ | ✸ | ✸ | ‐ | ✸ | ✸ | ✸ | ‐ | Low | |
| ✸ | ✸ | ‐ | ‐ | ‐ | ‐ | ‐ | ‐ | Very Low | |
| ✸ | ✸ | ✸ | ✸ | ✸✸ | ✸ | ✸ | ✸ | High | |
| ✸ | ✸ | ‐ | ‐ | ‐ | ‐ | ‐ | ‐ | Very low | |
| aNewcastle‐Ottawa Quality Assessment Scale (Appendix 4): 1 star (✸) for meeting each criterion, except comparability (design or analysis) can have 2 stars. For comparability in this review: 1 star if controlled for age; 2 stars if also controlled for other important variables, e.g., exercise, body mass index, use of hormone replacement therapy or other relevant drugs | |||||||||
| Number | Ratea | Standardized rateb | Relative risk (95% CI)b | ||
| All fractures | |||||
| OC use
| Never | 512 | 2.60 | 2.54 | 1.00 |
| Ever | 853 | 2.99 | 3.04 | 1.20 (1.08 to 1.34) | |
|
| |||||
| Duration of OC use (years)
| 0 | 512 | 2.60 | 2.54 | ‐ |
| 1 to 4 | 497 | 2.82 | 3.10 | ‐ | |
| 5 to 9 | 259 | 3.19 | 3.01 | ‐ | |
| > 10 | 97 | 3.53 | 2.86 | ‐ | |
| Forearm fractures | |||||
| OC use
| Never | 132 | 0.67 | 0.64 | 1.00 |
| Ever | 187 | 0.66 | 0.68 | 1.06 (0.95 to 1.32) | |
| aPer 1000 person‐years of observation | |||||
|
| Cases | Controls | OR (95% CI)a | |
| All fractures | ||||
| OC use | Never | 227 | 472 | 1.00 |
| Ever | 420 | 823 | 1.05 (0.86 to 1.29) | |
| Fractures while under observation of general practitioner | ||||
| OC use | Never | 89 | 207 | 1.00 |
| Ever | 184 | 339 | 1.25 (0.90 to 1.72) | |
| Duration of OC use (years) | Never | 89 | 207 | 1.00 |
| < 5 | 116 | 212 | 1.25 (0.89 to 1.77) | |
| 5 to 9 | 53 | 97 | 1.25 (0.80 to 1.94) | |
| 10 to 14 | 13 | 26 | 1.16 (0.56 to 2.42) | |
| > 15 | 2 | 4 | 1.23 (0.22 to 7.02) | |
| Time since OC use and | Never | 89 | 207 | 1.00 |
| < 5 | 49 | 100 | 1.06 (0.65 to 1.72) | |
| 5 to 9 | 35 | 75 | 1.01 (0.62 to 1.65) | |
| > 10 | 100 | 164 | 1.55 (1.03 to 2.33) | |
| aAdjusted for smoking, social class, parity | ||||
|
| Relative risk (95% CI)a by fracture site | ||||
| Radius or ulna | Ankle | Tarsals or | All fractures | ||
| Duration of OC use (months)b | Nonuser | 1.0 | 1.0 | 1.0 | 1.0 |
| < 12 | 1.1 (0.3 to 2.8) | 0.7 (0.1 to 2.1) | 0.4 (0.0 to 1.5) | 0.8 (0.5 to 1.2) | |
| 13 to 24 | 1.8 (0.8 to 3.8) | 1.6 (0.7 to 3.2) | 0.9 (0.3 to 2.2) | 0.9 (0.6 to 1.3) | |
| 25 to 48 | 1.3 (0.7 to 2.2) | 0.9 (0.4 to 1.6) | 1.2 (0.7 to 2.0) | 1.2 (1.0 to 1.5) | |
| 49 to 72 | 1.1 (0.6 to 2.0) | 0.7 (0.3 to 1.3) | 1.2 (0.7 to 2.0) | 1.2 (0.9 to 1.4) | |
| 73 to 96 | 1.1 (0.6 to 2.1) | 1.3 (0.7 to 2.3) | 1.2 (0.6 to 2.0) | 1.2 (1.0 to 1.5) | |
| >= 97 | 1.5 (1.1 to 2.1) | 1.0 (0.7 to 1.5) | 0.8 (0.5 to 1.2) | 1.2 (1.1 to 1.4) | |
| Interval since OC use (months)b | Nonuser | 1.0 | 1.0 | 1.0 | 1.0 |
| Current user < 12 | 1.2 (0.7 to 1.8) | 1.2 (0.8 to 1.8) | 1.1 (0.7 to 1.6) | 1.3 (1.1 to 1.5) | |
| 13 to 24 | 1.2 (0.4 to 2.8) | 1.0 (0.4 to 2.3) | 1.1 (0.4 to 2.3) | 1.2 (0.9 to 1.6) | |
| 25 to 48 | 1.0 (0.4 to 1.9) | 1.0 (0.5 to 1.9) | 1.2 (0.6 to 2.2) | 1.0 (0.8 to 1.3) | |
| 49 to 72 | 1.7 (0.9 to 3.0) | 0.7 (0.3 to 1.5) | 0.8 (0.3 to 1.6) | 1.1 (0.8 to 1.4) | |
| 73 to 96 | 2.5 (1.5 to 4.0) | 0.9 (0.4 to 1.8) | 0.8 (0.4 to 1.8) | 1.2 (0.9 to 1.5) | |
| 97 to 120 | 1.6 (0.8 to 2.8) | 1.1 (0.5 to 2.1) | 0.8 (0.3 to 1.8) | 1.3 (1.0 to 1.6) | |
| > 121 | 1.1 (0.7 to 1.8) | 0.9 (0.5 to 1.4) | 0.7 (0.3 to 1.2) | 1.0 (0.8 to 1.2) | |
| aAdjusted for age | |||||
| Oral contraceptive usea | Hazard ratio (95% CI) | |
| Any OC useb | None | 1.00 |
| Any | 1.07 (1.01 to 1.15) | |
| Years of OC usec | None | 1.00 |
| < 5 years | 1.09 (1.01 to 1.18) | |
| 5 to 10 years | 1.07 (0.96 to 1.20) | |
| > 10 years | 1.02 (0.91 to 1.15) | |
| Excluding women with prior fractured | No OC use | 1.00 |
| < 5 years OC use | 1.08 (0.99 to 1.18) | |
| > 5 years OC use | 1.05 (0.96 to 1.16) | |
| aSample sizes overall: OC users 33,025; OC nonusers 47,922 | ||
|
| Prescriptions (N) | Cases (N) | Controls (N) | OR (95% CI)a | Adjusted OR (95% CI)b |
| Nonuse | ‐ | 6591 | 26,578 | reference | reference |
| Current use
| 1 to 2 | 215 | 871 | 0.99 (0.85 to 1.16) | 1.01 (0.87 to 1.18) |
| 3 to 9 | 1136 | 4696 | 0.98 (0.91 to 1.05) | 1.01 (0.94 to 1.09) | |
| > 10 | 2327 | 9073 | 1.04 (0.98 to 1.10) | 1.09 (1.03 to 1.16) | |
| Past use
| 1 to 2 | 1972 | 7820 | 1.02 (0.96 to 1.08) | 1.00 (0.95 to 1.07) |
| 3 to 9 | 3178 | 12,787 | 1.01 (0.96 to 1.06) | 0.99 (0.94 to 1.04) | |
| > 10 | 2108 | 8305 | 1.03 (0.97 to 1.10) | 1.03 (0.97 to 1.10) | |
| aCases and controls matched on age, general practice, calendar time, and history in database. | |||||
| Age group (years) | Daily OC dosea | Cases (N) | Controls (N) | ORb (95% CI) |
| < 25 | ‐ | 16,219 | 48,659 | ‐‐‐ |
|
| < 0.3 | 331 | 795 | 0.97 (0.91 to 1.03) |
|
| 0.3 to 0.99 | 1445 | 3872 | 0.96 (0.92 to 1.01) |
|
| > 1 | 1156 | 3546 | 0.92 (0.86 to 0.98) |
| 25 to 49 | ‐ | 10,545 | 31,631 | ‐ |
|
| < 0.3 | 1895 | 5491 | 0.91 (0.82 to 1.00) |
|
| 0.3 to 0.99 | 2444 | 7445 | 0.90 (0.77 to 1.05) |
|
| > 1 | 783 | 2546 | 0.87 (0.64 to 1.18) |
| > 50 | ‐ | 37,784 | 113,351 | ‐ |
|
| < 0.3 | 799 | 2820 | 0.92 (0.77 to 1.10) |
|
| 0.3 to 0.99 | 253 | 977 | 0.69 (0.45 to 1.05) |
|
| > 1 | 6 | 266 | 0.62 (0.27 to 1.41) |
| aExposure as average daily dose, i.e., redeemed prescriptions/time interval from first prescription to fracture or censoring (Characteristics of included studies); < 1 indicates < regular use; > 1 suggests lost prescription and obtained new one. | ||||
| Age group (years) | Daily COC dosea | Cases (N) | Controls (N) | Adjusted OR (95% CI)b |
| < 15
| Never users | 12,192 | 36,652 | reference |
| < 0.3 | 19 | 71 | 0.58 (0.22 to 1.55) | |
| 0.3 to 0.99 | 63 | 146 | 1.50 (1.03 to 2.18) | |
| > 1 | 121 | 310 | 1.02 (0.77 to 1.35) | |
| 15.1 to 17
| Never users | 495 | 1731 | reference |
| < 0.3 | 36 | 86 | 1.04 (0.68 to 1.60) | |
| 0.3 to 0.99 | 196 | 434 | 1.30 (1.05 to 1.61) | |
| > 1 | 254 | 704 | 1.05 (0.87 to 1.27) | |
| 17.1 to 19
| Never users | 271 | 856 | reference |
| < 0.3 | 72 | 145 | 1.32 (0.94 to 1.85) | |
| 0.3 to 0.99 | 294 | 793 | 0.99 (0.80 to 1.22) | |
| > 1 | 265 | 908 | 0.83 (0.67 to 1.03) | |
| > 19
| Never users | 42,433 | 126,644 | reference |
| < 0.3 | 2888 | 8804 | 1.03 (0.98 to 1.08) | |
| 0.3 to 0.99 | 3589 | 10,921 | 1.04 (0.99 to 1.08) | |
| > 1 | 1360 | 4436 | 1.06 (0.99 to 1.13) | |
| Age group (years) | Ethinyl estradiol (EE) dose | Cases (N) | Controls (N) | Adjusted OR (95% CI)a |
| < 15
| 20 µg | 100 | 264 | 1.23 (0.92 to 1.64) |
| > 30 µg | 82 | 225 | 0.97 (0.69 to 1.37) | |
| Changed between 20 µg and 30 µg | 32 | 59 | 1.34 (0.75 to 2.37) | |
| Other OCs | 13 | 45 | 0.20 (0.04 to 1.12) | |
| 15.1 to 17
| 20 µg | 205 | 550 | 1.07 (0.88 to 1.31) |
| > 30 µg | 181 | 478 | 1.08 (0.87 to 1.33) | |
| Changed between 20 µg and 30 µg | 113 | 236 | 1.42 (1.09 to 1.84) | |
| Other OCs | 11 | 35 | 0.95 (0.40 to 2.30) | |
| 17.1 to 19
| 20 µg | 209 | 645 | 0.96 (0.76 to 1.21) |
| > 30 µg | 286 | 787 | 0.98 (0.79 to 1.21) | |
| Changed between 20 µg and 30 µg | 157 | 451 | 0.95 (0.74 to 1.23) | |
| Other OCs | 13 | 55 | 0.78 (0.35 to 1.72) | |
| > 19
| 20 µg | 785 | 2643 | 0.97 (0.89 to 1.06) |
| > 30 µg | 4718 | 14,498 | 1.03 (0.99 to 1.07) | |
| Changed between 20 µg and 30 µg | 1173 | 3195 | 1.13 (1.05 to 1.22) | |
| Other OCs | 1349 | 4396 | 1.03 (0.97 to 1.11) | |
| Analysis of young womenc | ||||
| Age group (years) | Daily COC dosea | Cases (N) | Controls (N) | ORb (95% CI) |
| < 19 years | 0.3 to 0.99 | 393 | 943 | 1.17 (1.01 to 1.37) |
| 19 to 25 | < 0.3 | 297 | 731 | 1.22 (1.02 to 1.47) |
| 0.3 to 0.99 | 1281 | 3573 | 1.14 (1.00 to 1.30) | |
| > 35 | > 1 | 367 | 1424 | 0.88 (0.78 to 0.99) |
| aExposure as average daily dose, i.e., redeemed prescriptions/time interval from first prescription to fracture or censoring (Characteristics of included studies); < 1 indicates < regular use; > 1 suggests lost prescription and obtained new one | ||||
| ORa (95% CI) | ||
| OC useb | Ever | 0.98 (0.47 to 2.03) |
| > 2 years | 1.04 (0.42 to 2.55) | |
| aOdds ratio for 'ever' identified as multivariate OR; variables not provided. For use > 2 years, did not specify whether OR adjusted or not. | ||
|
| Number | Age‐adjusted OR | Multivariate ORa | ||
| Cases | Controls | ||||
| OC use | Never | 994 | 2373 | 1.00 | 1.00 |
| Ever (any type) | 130 | 562 | 0.75 (0.60 to 0.95) | 0.75 (0.59 to 0.96) | |
| High dose ever | 77 | 456 | 0.54 (0.40 to 0.72) | 0.56 (0.42 to 0.75) | |
| Duration of OC use (per 2 years) | 116 | 526 | 1.06 (0.92 to 1.22) | 1.03 (0.89 to 1.19) | |
| Time since last OC use (per 2 years) | 117 | 529 | 1.01 (0.95 to 1.08) | 1.02 (0.96 to 1.09) | |
| Time since last OC use and menopause (per 2 years) | 117 | 529 | 0.95 (0.84 to 1.08) | 0.97 (0.85 to 1.11) | |
| Age at use of any OC | Never used | 994 | 2373 | 1.00 | 1.00 |
| < 30 years | 34 | 193 | 1.11 (0.68 to 1.82) | 1.26 (0.76 to 2.09) | |
| 30 to 39 years | 60 | 294 | 0.80 (0.57 to 1.12) | 0.82 (0.57 to 1.16) | |
| > 40 years | 64 | 271 | 0.72 (0.54 to 0.98) | 0.69 (0.51 to 0.94) | |
| Age at use of high‐dose OCb | Never used | 994 | 2373 | 1.00 | 1.00 |
| < 30 years | 27 | 183 | 0.97 (0.56 to 1.68) | 1.12 (0.64 to 1.97) | |
| 30 to 39 years | 46 | 264 | 0.74 (0.50 to 1.08) | 0.76 (0.51 to 1.13) | |
| > 40 years | 40 | 215 | 0.62 (0.43 to 0.90) | 0.61 (0.42 to 0.89) | |
| 1Adjusted for age (5‐year intervals), hormone replacement therapy, parity, body mass index (by quintiles). | |||||
| Control group | ||
| Population | Had fall | |
| OC useb | 0.3 (0.1 to 0.9) | 0.7 (0.2 to 2.4) |
| aAge adjusted | ||
|
| Subgroup | Cases (N) | Controls (N) | ORa (95% CI) |
| DMPAb use ever | ‐ | 58 | 105 | 1.44 (1.01 to 2.06) |
| Age of woman (years)
| < 25 | 15 | 29 | 1.20 (0.59 to 2.45) |
| 25 to 50 | 25 | 51 | 1.09 (0.64 to 1.85) | |
| > 50 | 18 | 25 | 2.25 (1.14 to 4.42) | |
| Average daily DMPA dosec
| < 0.25 | 21 | 32 | 1.73 (0.96 to 3.09) |
| 0.26 to 0.99 | 13 | 38 | 0.88 (0.45 to 1.74) | |
| > 1 | 24 | 35 | 1.94 (1.09 to 3.45) | |
| Duration of DMPA use (years)
| < 2.5 | 16 | 45 | 0.82 (0.43 to 1.56) |
| 2.6 to 4 | 9 | 20 | 1.51 (0.66 to 3.46) | |
| > 4 | 33 | 40 | 2.16 (1.32 to 3.53) | |
| aAdjusted for prior fracture, Charlson index (comorbidities), income, working status, living with someone or not, pregnancy, IUD use, hysterectomy, alcoholism; use of OC, corticosteroid, hormonal replacement therapy, anti‐epileptic drugs, and strong (morphine and opioid agonists) and weak analgesics (acetaminophen, nonsteroidal anti‐inflammatory drugs, and acetylsalicylic acid). | ||||
|
| Prescriptions (N) | Cases (N) | Controls (N) | OR (95% CI)a | Adjusted OR (95% CI)b |
| Nonuse | ‐ | 15,614 | 64,415 | reference | reference |
| Current use
| 1 to 2 | 93 | 305 | 1.27 (1.01 to 1.61) | 1.18 (0.93 to 1.49) |
| 3 to 9 | 209 | 573 | 1.52 (1.30 to 1.79) | 1.36 (1.15 to 1.60) | |
| > 10 | 280 | 710 | 1.67 (1.45 to 1.92) | 1.54 (1.33 to 1.78) | |
| Past use
| 1 to 2 | 620 | 1985 | 1.31 (1.19 to 1.44) | 1.17 (1.07 to 1.29) |
| 3 to 9 | 529 | 1609 | 1.38 (1.25 to 1.53) | 1.23 (1.11 to 1.36) | |
| > 10 | 182 | 533 | 1.45 (1.22 to 1.72) | 1.30 (1.09 to 1.55) | |
| aCases and controls matched on age, general practice, calendar time, and history in database | |||||
|
| Subgroup | Cases (N) | Controls (N) | OR (95% CI)a |
| Hormonal IUDb use ever | ‐ | 219 | 791 | 0.75 (0.64 to 0.87) |
| Age of woman (years)
| < 25 | 3 | 5 | 0.82 (0.19 to 3.67) |
| 25 to 50 | 187 | 639 | 0.87 (0.73 to 1.04) | |
| > 50 | 29 | 147 | 0.72 (0.48 to 1.09) | |
| IUDs per year
| < 0.25 | 59 | 234 | 0.74 (0.55 to 1.00) |
| 0.26 to 0.6 | 84 | 280 | 0.84 (0.65 to 1.08) | |
| > 0.6 | 76 | 277 | 0.81 (0.62 to 1.05) | |
| Duration of hormonal IUD use (years)
| < 1.5 | 68 | 244 | 0.78 (0.59 to 1.03) |
| 1.6 to 4 | 83 | 289 | 0.77 (0.59 to 0.99) | |
| > 4 | 68 | 258 | 0.77 (0.58 to 1.01) | |
| aAdjusted for prior fracture, Charlson index (comorbidities), income, working status, living with someone or not, pregnancy, DMPA use, hysterectomy, alcoholism; use of OC, corticosteroid, hormonal replacement therapy, anti‐epileptic drugs, and strong (morphine and opioid agonists) and weak analgesics (acetaminophen, nonsteroidal anti‐inflammatory drugs, and acetylsalicylic acid) | ||||
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Fracture since age 15 Show forest plot | 1 | Odds Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 1.1 OC user versus nonuser | 1 | 3222 | Odds Ratio (M‐H, Fixed, 95% CI) | 1.00 [0.83, 1.20] |
| 1.2 OC use < 1 year versus nonuser | 1 | 4561 | Odds Ratio (M‐H, Fixed, 95% CI) | 1.00 [0.87, 1.15] |
| 1.3 OC use 1 to 5 years versus nonuser | 1 | 2977 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.98 [0.80, 1.21] |
| 1.4 OC use > 6 years versus nonuser | 1 | 2533 | Odds Ratio (M‐H, Fixed, 95% CI) | 1.01 [0.73, 1.38] |
| 2 Fracture during 1980 to 1989 Show forest plot | 1 | Odds Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 2.1 OC user versus nonuser | 1 | 3222 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.89 [0.70, 1.12] |
| 2.2 OC use < 1 year versus nonuser | 1 | 4561 | Odds Ratio (M‐H, Fixed, 95% CI) | 1.00 [0.84, 1.19] |
| 2.3 OC use 1 to 5 years versus nonuser | 1 | 2977 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.86 [0.66, 1.12] |
| 2.4 OC use > 6 years versus nonuser | 1 | 2533 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.94 [0.63, 1.40] |
| 3 Self‐reported fracture Show forest plot | 1 | 492 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.69 [0.45, 1.07] |
| 4 Forearm fracture Show forest plot | 1 | Odds Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 4.1 OC use 0 to 4 years versus no OC use | 1 | 602 | Odds Ratio (M‐H, Fixed, 95% CI) | 1.18 [0.71, 1.97] |
| 4.2 OC use 4 to 10 years versus no OC use | 1 | 602 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.94 [0.46, 1.89] |
| 4.3 OC use > 10 years versus no OC use | 1 | 602 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.54 [0.25, 1.19] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Adverse event: fracture Show forest plot | 1 | Odds Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 1.1 Treatment phase | 1 | 538 | Odds Ratio (M‐H, Fixed, 95% CI) | 1.02 [0.35, 2.98] |
| 1.2 Post‐treatment phase | 1 | 229 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.76 [0.07, 8.46] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Fractures (per woman‐years) Show forest plot | 1 | 1.722356E6 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.41 [1.35, 1.47] |
| 2 Fractures (per woman‐year) by exposure Show forest plot | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 2.1 Low: 1 to 7 DMPA injections | 1 | 1.639319E6 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.47 [1.40, 1.54] |
| 2.2 High: 8 or more DMPA injections | 1 | 1.478078E6 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.22 [1.13, 1.32] |
| 3 Fractures (per woman‐years) by site Show forest plot | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 3.1 Axial | 1 | 1.722356E6 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.95 [0.74, 1.23] |
| 3.2 Appendicular skeleton | 1 | 1.722356E6 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.38 [1.31, 1.46] |
| 3.3 All other fractures | 1 | 1.722356E6 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.49 [1.39, 1.59] |
