title: Steroidal contraceptives: effect on bone fractures in women.
abstract: BACKGROUND
  Steroidal contraceptive use has been associated with changes in bone mineral density in women. Whether such changes increase the risk of fractures later in life is not clear. Osteoporosis is a major public health concern. Age-related decline in bone mass increases the risk of fracture, especially of the spine, hip, and wrist. Concern about bone health influences the recommendation and use of these effective contraceptives globally.
  
  
  OBJECTIVE
  Our aim was to evaluate the effect of using hormonal contraceptives before menopause on the risk of fracture in women.
  
  
  METHODS
  Through April 2014, we searched for studies of fracture or bone health and hormonal contraceptives in MEDLINE, POPLINE, CENTRAL, EMBASE, and LILACS, as well as ClinicalTrials.gov and ICTRP. We examined reference lists of relevant articles for other trials. For the initial review, we wrote to investigators to find additional trials.
  
  
  METHODS
  Randomized controlled trials (RCTs) were considered if they examined fractures, bone mineral density (BMD), or bone turnover markers in women with hormonal contraceptive use prior to menopause. Eligible interventions included comparisons of a hormonal contraceptive with a placebo or with another hormonal contraceptive that differed in terms of drug, dosage, or regimen. They also included providing a supplement to one group.
  
  
  METHODS
  We assessed all titles and abstracts identified through the literature searches. Mean differences were computed using the inverse variance approach. For dichotomous outcomes, the Mantel-Haenszel odds ratio (OR) was calculated. Both included the 95% confidence interval (CI) and used a fixed-effect model. Due to differing interventions, no trials could be combined for meta-analysis. We applied principles from GRADE to assess the evidence quality and address confidence in the effect estimates. In addition, a sensitivity analysis included trials that provided sufficient data for this review and evidence of at least moderate quality.
  
  
  RESULTS
  We found 19 RCTs that met our eligibility criteria. Eleven trials compared different combined oral contraceptives (COCs) or regimens of COCs; five examined an injectable versus another injectable, implant, or IUD; two studied implants, and one compared the transdermal patch versus the vaginal ring. No trial had fracture as an outcome. BMD was measured in 17 studies and 12 trials assessed biochemical markers of bone turnover. Depot medroxyprogesterone acetate (DMPA) was associated with decreased bone mineral density (BMD). The placebo-controlled trials showed BMD increases for DMPA plus estrogen supplement and decreases for DMPA plus placebo supplement. COCs did not appear to negatively affect BMD, and some formulations had more positive effects than others. However, no COC trial was placebo-controlled. Where studies showed differences between groups in bone turnover markers, the results were generally consistent with those for BMD. For implants, the single-rod etonogestrel group showed a greater BMD decrease versus the two-rod levonorgestrel group but results were not consistent across all implant comparisons.The sensitivity analysis included 11 trials providing evidence of moderate or high quality. Four trials involving DMPA showed some positive effects of an estrogen supplement on BMD, a negative effect of DMPA-subcutaneous on lumbar spine BMD, and a negative effect of DMPA on a bone formation marker. Of the three COC trials, one had a BMD decrease for the group with gestodene plus EE 15 μg. Another indicated less bone resorption in the group with gestodene plus EE 30 μg versus EE 20 μg.
  
  
  CONCLUSIONS
  Whether steroidal contraceptives influence fracture risk cannot be determined from existing information. The evidence quality was considered moderate overall, largely due to the trials of DMPA, implants, and the patch versus ring. The COC evidence varied in quality but was low overall. Many trials had small numbers of participants and some had large losses. Health care providers and women should consider the costs and benefits of these effective contraceptives. For example, injectable contraceptives and implants provide effective, long-term birth control yet do not involve a daily regimen. Progestin-only contraceptives are considered appropriate for women who should avoid estrogen due to medical conditions.
authors: Clinical Sciences, FHI 360, 359 Blackwell St, Suite 200, Durham, North Carolina, USA, 27701.
authors: Laureen M
authors: LM
authors: Lopez
authors: David A
authors: DA
authors: Grimes
authors: Kenneth F
authors: KF
authors: Schulz
authors: Kathryn M
authors: KM
authors: Curtis
authors: Mario
authors: M
authors: Chen
mesh_terms: D015519:Bone Density / Q000187:drug effects*; D016723:Bone Remodeling / Q000187:drug effects; D003278:Contraceptives, Oral, Hormonal / Q000009:adverse effects / Q000494:pharmacology*; D004967:Estrogens / Q000494:pharmacology; D005260:Female; D050723:Fractures, Bone / Q000139:chemically induced*; D006801:Humans; D017258:Medroxyprogesterone Acetate / Q000009:adverse effects / Q000494:pharmacology; D017697:Premenopause; D011372:Progestins / Q000494:pharmacology; D016032:Randomized Controlled Trials as Topic
chemical_list: D003278:Contraceptives, Oral, Hormonal; D004967:Estrogens; D011372:Progestins; D017258:Medroxyprogesterone Acetate