A 3-year double-blind, randomized, controlled study on the influence of two oral contraceptives containing either 20 microg or 30 microg ethinylestradiol in combination with levonorgestrel on bone mineral density

Contraception. 2004 Mar;69(3):179-87. doi: 10.1016/j.contraception.2003.10.002.


In this first prospective, double-blind, randomized, parallel-group study we evaluated the influence of two combined oral contraceptives on bone mineral density (BMD) and metabolic bone parameters. One dose-reduced preparation contained 20 microg ethinylestradiol (EE) in combination with 100 microg levonorgestrel (LNG) (20/100) was compared with the reference preparation which contained 30 microg EE in combination with 150 microg LNG (30/150). Data from 48 volunteers aged 20-35 years were obtained over an observation period of 36 treatment cycles. The direction of the change (increase or decrease) in all investigated bone-related variables was similar in both treatment groups. As compared to baseline, bone mineral density decreased by 0.4% in the 20/100 group and by 0.8% in the 30/150 group after 36 treatment cycles. These changes were not significantly different between the two treatment groups (p = 0.902). For bone-specific alkaline phosphatase, we measured a mean increase of 55.4% (20/100 group) and of 113.2% (30/150 group) after 36 treatment cycles. The two treatments did not differ statistically significantly (p = 0.522). With respect to cross-linked N-telopeptides (NTx), we detected a decrease of the mean NTx urine concentrations of 21.1% (20/100) and of 13.4% (30/150). These changes also did not significantly differ between the two treatments (p = 0.613). Both study treatments were safe and well-tolerated by all volunteers participating in the study. In conclusion, BMD did not change during the 3-year observation period. Thus, both trial preparations containing either 20 or 30 microg EE in combination with LNG were capable of maintaining BMD in young fertile women. There is no reason to assume that the EE dose reduction had any negative impact on BMD. Because there were no differences in BMD between the treatment groups, it can be assumed that even lower dosages than 20 microg EE might be sufficient for bone protection. Biochemical markers provided evidence for a reduced bone resorption.

Publication types

  • Clinical Trial
  • Comparative Study
  • Randomized Controlled Trial

MeSH terms

  • Adult
  • Bone Density / drug effects*
  • Collagen / drug effects
  • Collagen / urine
  • Collagen Type I
  • Contraceptives, Oral, Combined / administration & dosage
  • Contraceptives, Oral, Combined / adverse effects
  • Contraceptives, Oral, Combined / pharmacology*
  • Contraceptives, Oral, Synthetic / administration & dosage
  • Contraceptives, Oral, Synthetic / adverse effects
  • Contraceptives, Oral, Synthetic / pharmacology
  • Cysteine Endopeptidases / blood
  • Cysteine Endopeptidases / drug effects
  • Dose-Response Relationship, Drug
  • Double-Blind Method
  • Erythema Nodosum / chemically induced
  • Female
  • Headache / chemically induced
  • Humans
  • Levonorgestrel / administration & dosage
  • Levonorgestrel / adverse effects
  • Levonorgestrel / pharmacology*
  • Lynestrenol / administration & dosage
  • Lynestrenol / adverse effects
  • Lynestrenol / pharmacology*
  • Peptides / drug effects
  • Peptides / urine
  • Prospective Studies
  • Respiratory Tract Infections / chemically induced
  • Treatment Outcome
  • Vomiting / chemically induced


  • Collagen Type I
  • Contraceptives, Oral, Combined
  • Contraceptives, Oral, Synthetic
  • Peptides
  • collagen type I trimeric cross-linked peptide
  • Levonorgestrel
  • Collagen
  • Cysteine Endopeptidases
  • Tc 120 proteinase
  • Lynestrenol