The impact of depot medroxyprogesterone acetate on fracture risk: a case-control study from the UK

Global, regional, and national burden of breast cancer among females, 1990-2023, with forecasts to 2050: a systematic analysis for the Global Burden of Disease Study 2023

GBD 2023 Breast Cancer Collaborators, 2026 · The Lancet Oncology · Free to read

The effects of depot medroxyprogesterone acetate and intrauterine device use on fracture risk in Danish women

Vestergaard P et al., 2008 · Contraception

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.

Progestogen-only contraception and bone mineral density: a systematic review

Curtis KM et al., 2006 · Contraception · Free to read

Questions have been raised about the effects of progestogen-only contraceptive use on bone health, particularly among young women who have not yet reached peak bone mass and perimenopausal women who may be starting to lose bone mass. We conducted a systematic review that evaluated the association between progestogen-only contraceptive use and fracture risk or bone mineral density (BMD). We identified 39 articles from MEDLINE and EMBASE, published through July 2005. One study reported that depot medroxyprogesterone acetate (DMPA) users were more likely to experience stress fractures than nonusers; this association was not statistically significant after controlling for baseline bone density. In cross-sectional studies, the mean BMD in DMPA users was usually below that of nonusers, but within 1 SD. In longitudinal studies, BMD generally decreased more over time among DMPA users than among nonusers, but women gained BMD upon discontinuation of DMPA. Limited evidence suggested that use of progestogen-only contraceptives other than DMPA did not affect BMD.

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

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.

Oral contraceptive use and risk of fractures

Vestergaard P et al., 2006 · Contraception

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.