Vestergaard, P., Rejnmark, L., & Mosekilde, L. (2008). Fracture risk in very young women using combined oral contraceptives. Contraception, 78(5), 358-364. https://doi.org/10.1016/j.contraception.2008.06.010
Vestergaard P, Rejnmark L, Mosekilde L. Fracture risk in very young women using combined oral contraceptives. Contraception. 2008;78(5):358-364. doi:10.1016/j.contraception.2008.06.010
Vestergaard, Peter, et al. "Fracture risk in very young women using combined oral contraceptives." Contraception, vol. 78, no. 5, 2008, pp. 358-364.
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Little is known on fracture risk in young women using oral contraceptives.
Study Design
Case-control study (64,548 cases, 193,641 controls).
Results
Overall, no major association with risk of fracture was present. Only in a few age groups a limited increase (OR 1.1-1.5) was seen in those using low average doses (less than one tablet per day - i.e., intermittent use). Neither 20 nor >or=30 mcg per day of ethinylestradiol was associated with risk of fractures, while changing from 20 to >or=30 mcg per day or vice versa was associated with a limited increase in fracture risk (OR 1.1-1.4) in some age groups.
Conclusions
In general, use of oral contraceptives in young women did not seem to be associated with an increased risk of fractures. The isolated increase seen in some strata with low average doses may be linked to factors associated with discontinuation of oral contraceptives rather than pharmacological effects.
Depot medroxyprogesterone acetate (DMPA) use may be associated with an increased risk of fractures; however, nothing is known about the risk associated with intrauterine contraceptive device (IUD) use. Case-control study. All women with a fracture (n=64,548) in the year 2000 in Denmark served as cases. For each case, three age-matched controls were randomly drawn from the general population (n=193,641). Exposure was present or previous DMPA or IUD use (only IUD coated with hormones, not those coated solely with copper). Adjustments were made for confounders. DMPA use seemed to be associated with an increased risk of fractures [odds ratio (OR)=1.44, 95% confidence interval (CI): 1.01-2.06], while IUD use appeared to be associated with a decreased risk of fractures (OR=0.75, 95% CI: 0.64-0.87). DMPA use may cause an increased risk of fracture. However, the fact that use of DMPA is rare in Danish women and the lack of baseline data including smoking status and BMI does not allow causal inferences to be made. Likewise, the seemingly decreased risk of fractures with IUD use is probably not a pharmacological effect but rather the effect of residual confounding related to nonincluded confounders regarding lifestyle.
Prior studies have suggested that oral contraceptives (OCs) may be associated with an increased fracture risk. However, the previous studies have only performed a limited adjustment for other potential risk factors. Subjects and methodsAll women with a fracture (n=64,548) in the year 2000 in Denmark served as cases. For each case, three age-matched controls were randomly drawn from the general population (n=193,641). Exposure was use of OCs between January 1, 1996, and December 31, 2000. Adjustments were made for use of other drugs, pregnancy, prior fracture, other diseases and social variables. In the unadjusted analysis, use of OCs in low dose was associated with a small increase in overall fracture risk. However, upon adjustment, no increase in fracture risk could be demonstrated in any age or dose group. Oral contraceptives are not associated with an increase or a decrease in fracture risk. Any change in fracture risk may be due to confounders.
It has been suggested that use of the oral contraceptive pill by women confers protection against osteoporosis later in life. However, cross-sectional studies of bone density among pill users have yielded discrepant results. We therefore investigated the relationship between pill use and subsequent occurrence of fracture in a cohort of 46,000 women enrolled in the Royal College of General Practitioners Oral Contraception Study during 482,083 person-years of follow-up. Fracture risk was lower among multiparous women, non-smokers, and those of lower socio-economic class. The risk of subsequent fractures among the women who had ever used the oral contraceptive pill was significantly greater than that among women who had never used it (relative risk 1.20, 95% confidence intervals 1.08-1.34) after adjustment for these variables. When the analysis was confined to forearm fractures, no significant effect of pill use on fracture risk was detected. Although the study only includes limited observation of older women to date, these data do not support the hypothesis that pill use protects women against the occurrence of osteoporotic fractures in later life.
Epidemiological studies indicate a protective effect of postmenopausal oestrogen therapy on the risk of osteoporotic fractures. Whether premenopausal oestrogen exposure in the form of oral contraceptives also reduces the risk of osteoporotic fractures remains uncertain. We did a population-based case control study of hip fracture among Swedish postmenopausal women, 50-81 years of age, through mailed questionnaires and telephone interviews. Of those women who were eligible, 1327 (82.5%) cases and 3312 (81.6%) randomly selected controls responded. Findings: 130 (11.6%) cases and 562 (19.1%) controls reported ever-use of oral contraceptives. Ever-use of oral contraceptives was associated with a 25% reduction in hip fracture risk (odds ratio 0.75 [95% CI 0.59-0.96]). Women who had ever used a high-dose pill (equivalent to > or = 50 microg ethinylestradiol per tablet) had a 44% lower risk for hip fracture than never-users (0.56 [0.42-0.75]). No overall trend was observed with duration of oral-contraceptive use, or time since last use. However, when making comparisons with women who have never used oral contraceptives, the odds ratios for hip-fracture were 0.69 (0.51-0.94) for use after age 40, 0.82 (0.57-1.16) for use at ages 30-39, and 1.26 (0.76-2.09) for use before age 30. Interpretation: Our results imply that in postmenopausal women, oral-contraceptive use late in reproductive life may reduce the risk of hip fracture, although we recognise the limitations of the case-control method.
Brajic TS et al., 2018·J Musculoskelet Neuronal Interact
To assess combined hormonal contraceptives (CHC) use and adolescent women's peak areal bone mineral density (BMD) accrual. We enrolled 527 randomly selected women across Canada (2004-6) divided by age into adolescents (16-19) and young adults (20-24) and by CHC use to ever (E-CHC)/never (N-CHC) users. At baseline and year 2 we measured height, weight, and BMD at lumbar spine (L1-4), femoral neck, and total hip sites. Interviewer-administered questionnaires addressed menarche age, cigarette and alcohol use, calcium/vitamin D intakes, physical activity and estrogen dose (≤30/>30 micrograms). Linear regression models examined associations of CHC use with 2-year BMD change adjusted for bone-related variables. Of 307 women with complete data, 229 (75%) used CHC. N-CHC adolescents gained significantly more unadjusted total hip BMD +0.012 g/cm(2)/2-y (95% C.I.: 0.001, 0.023) with similar trends at all sites. N-CHC adolescents tended to have greater adjusted femoral neck BMD gain: mean difference +0.009 g/cm(2) (95% CI: -0.002; 0.021). In young women N-CHC, however, adjusted femoral neck BMD decreased significantly more -0.021 g/cm(2) (95%CI: -0.006; -0.036) with similar trends at other sites. BMD changes were unrelated to estrogen dose and age at starting CHC. Adolescent CHC users in a random population demonstrated less hip region peak BMD accrual than non-users. This requires randomized control trial confirmation.
Lopez LM et al., 2015·Cochrane Database Syst Rev·Free full text on PubMed Central
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. We systematically reviewed the evidence from observational studies of hormonal contraceptive use for contraception and the risk of fracture in women. 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 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' 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.
Pete Vestergaard, P Vestergaard, L Rejnmark, L Mosekilde
PMID 18929731 18929731 DOI 10.1016/j.contraception.2008.06.010 10.1016/j.contraception.2008.06.010 Vestergaard et al. 2008, Vestergaard 2008
Cite this article
Vestergaard, P., Rejnmark, L., & Mosekilde, L. (2008). Fracture risk in very young women using combined oral contraceptives. Contraception, 78(5), 358-364. https://doi.org/10.1016/j.contraception.2008.06.010
Vestergaard P, Rejnmark L, Mosekilde L. Fracture risk in very young women using combined oral contraceptives. Contraception. 2008;78(5):358-364. doi:10.1016/j.contraception.2008.06.010
Vestergaard, Peter, et al. "Fracture risk in very young women using combined oral contraceptives." Contraception, vol. 78, no. 5, 2008, pp. 358-364.
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