Steroidal contraceptives and bone fractures in women: evidence from observational studies. 2015

Laureen M Lopez, and Mario Chen, and Sarah Mullins Long, and Kathryn M Curtis, and Frans M Helmerhorst
Clinical and Epidemiological Sciences, FHI 360, 359 Blackwell St, Suite 200, Durham, North Carolina, USA, 27701.

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. OBJECTIVE We systematically reviewed the evidence from observational studies of hormonal contraceptive use for contraception and the risk of fracture in women. 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. METHODS 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. METHODS 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. 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. 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.

UI MeSH Term Description Entries
D007436 Intrauterine Devices, Medicated Intrauterine devices that release contraceptive agents. Hormone-Releasing IUDs,IUD, Hormone Releasing,Intrauterine Devices, Hormone-Releasing,Intrauterine Devices, Progesterone-Releasing,Medicated Intrauterine Devices,Device, Hormone-Releasing Intrauterine,Device, Medicated Intrauterine,Device, Progesterone-Releasing Intrauterine,Devices, Hormone-Releasing Intrauterine,Devices, Medicated Intrauterine,Devices, Progesterone-Releasing Intrauterine,Hormone Releasing IUD,Hormone-Releasing IUD,Hormone-Releasing Intrauterine Device,Hormone-Releasing Intrauterine Devices,IUD, Hormone-Releasing,IUDs, Hormone-Releasing,Intrauterine Device, Hormone-Releasing,Intrauterine Device, Medicated,Intrauterine Device, Progesterone-Releasing,Intrauterine Devices, Hormone Releasing,Intrauterine Devices, Progesterone Releasing,Medicated Intrauterine Device,Progesterone-Releasing Intrauterine Device,Progesterone-Releasing Intrauterine Devices
D011372 Progestins Compounds that interact with PROGESTERONE RECEPTORS in target tissues to bring about the effects similar to those of PROGESTERONE. Primary actions of progestins, including natural and synthetic steroids, are on the UTERUS and the MAMMARY GLAND in preparation for and in maintenance of PREGNANCY. Gestagenic Agent,Progestagen,Progestagenic Agent,Progestational Agent,Progestational Compound,Progestational Hormone,Progestogen,Progestogens,Gestagen,Gestagen Effect,Gestagen Effects,Gestagenic Agents,Gestagenic Effect,Gestagenic Effects,Gestagens,Progestagenic Agents,Progestagens,Progestational Agents,Progestational Compounds,Progestational Hormones,Progestin,Progestin Effect,Progestin Effects,Progestogen Effect,Progestogen Effects,Agent, Gestagenic,Agent, Progestagenic,Agent, Progestational,Compound, Progestational,Effect, Gestagen,Effect, Gestagenic,Effect, Progestin,Effect, Progestogen,Effects, Gestagen,Effects, Gestagenic,Effects, Progestin,Effects, Progestogen,Hormone, Progestational
D003278 Contraceptives, Oral, Hormonal Oral contraceptives which owe their effectiveness to hormonal preparations. Hormonal Oral Contraceptive,Hormonal Oral Contraceptive Agent,Contraceptive Agents, Estrogen,Contraceptive Agents, Oral, Hormonal,Hormonal Oral Contraceptive Agents,Oral Contraceptive Agents, Hormonal,Oral Contraceptives, Hormonal,Contraceptive, Hormonal Oral,Contraceptives, Hormonal Oral,Estrogen Contraceptive Agents,Hormonal Oral Contraceptives,Oral Contraceptive, Hormonal
D005260 Female Females
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000367 Age Factors Age as a constituent element or influence contributing to the production of a result. It may be applicable to the cause or the effect of a circumstance. It is used with human or animal concepts but should be differentiated from AGING, a physiological process, and TIME FACTORS which refers only to the passage of time. Age Reporting,Age Factor,Factor, Age,Factors, Age
D013997 Time Factors Elements of limited time intervals, contributing to particular results or situations. Time Series,Factor, Time,Time Factor
D015331 Cohort Studies Studies in which subsets of a defined population are identified. These groups may or may not be exposed to factors hypothesized to influence the probability of the occurrence of a particular disease or other outcome. Cohorts are defined populations which, as a whole, are followed in an attempt to determine distinguishing subgroup characteristics. Birth Cohort Studies,Birth Cohort Study,Closed Cohort Studies,Cohort Analysis,Concurrent Studies,Historical Cohort Studies,Incidence Studies,Analysis, Cohort,Cohort Studies, Closed,Cohort Studies, Historical,Studies, Closed Cohort,Studies, Concurrent,Studies, Historical Cohort,Analyses, Cohort,Closed Cohort Study,Cohort Analyses,Cohort Studies, Birth,Cohort Study,Cohort Study, Birth,Cohort Study, Closed,Cohort Study, Historical,Concurrent Study,Historical Cohort Study,Incidence Study,Studies, Birth Cohort,Studies, Cohort,Studies, Incidence,Study, Birth Cohort,Study, Closed Cohort,Study, Cohort,Study, Concurrent,Study, Historical Cohort,Study, Incidence
D016022 Case-Control Studies Comparisons that start with the identification of persons with the disease or outcome of interest and a control (comparison, referent) group without the disease or outcome of interest. The relationship of an attribute is examined by comparing both groups with regard to the frequency or levels of outcome over time. Case-Base Studies,Case-Comparison Studies,Case-Referent Studies,Matched Case-Control Studies,Nested Case-Control Studies,Case Control Studies,Case-Compeer Studies,Case-Referrent Studies,Case Base Studies,Case Comparison Studies,Case Control Study,Case Referent Studies,Case Referrent Studies,Case-Comparison Study,Case-Control Studies, Matched,Case-Control Studies, Nested,Case-Control Study,Case-Control Study, Matched,Case-Control Study, Nested,Case-Referent Study,Case-Referrent Study,Matched Case Control Studies,Matched Case-Control Study,Nested Case Control Studies,Nested Case-Control Study,Studies, Case Control,Studies, Case-Base,Studies, Case-Comparison,Studies, Case-Compeer,Studies, Case-Control,Studies, Case-Referent,Studies, Case-Referrent,Studies, Matched Case-Control,Studies, Nested Case-Control,Study, Case Control,Study, Case-Comparison,Study, Case-Control,Study, Case-Referent,Study, Case-Referrent,Study, Matched Case-Control,Study, Nested Case-Control
D017258 Medroxyprogesterone Acetate A synthetic progestin that is derived from 17-hydroxyprogesterone. It is a long-acting contraceptive that is effective both orally or by intramuscular injection and has also been used to treat breast and endometrial neoplasms. Depo-Medroxyprogesterone Acetate,Medroxyprogesterone 17-Acetate,Pregn-4-ene-3,20-dione, 17-(acetyloxy)-6-methyl-, (6alpha)-,(6 alpha)-17-(Acetoxy)-6-methylpregn-4-ene-3,20-dione,6-alpha-Methyl-17alpha-hydroxyprogesterone Acetate,Curretab,Cycrin,Depo-Provera,Farlutal,Gestapuran,Medroxyprogesterone 17-Acetate, (6 alpha,17 alpha)-Isomer,Medroxyprogesterone 17-Acetate, (6 beta)-Isomer,Perlutex,Provera,Veramix,6 alpha Methyl 17alpha hydroxyprogesterone Acetate,Depo Medroxyprogesterone Acetate,Depo Provera,DepoProvera,Medroxyprogesterone 17 Acetate

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