Original article| Volume 99, ISSUE 6, P329-334, June 2019

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Bone turnover markers in women participating in a dose-finding trial of a contraceptive vaginal ring releasing Nestorone and estradiol



      To evaluate changes in the bone turnover markers CTx and P1NP during 6 months' use of novel continuous contraceptive vaginal rings delivering Nestorone (NES) 200 mcg/day and three doses of estradiol (E2) (10, 20, and 40 mcg/day).

      Study design

      This randomized trial enrolled 189 women who used two consecutive vaginal rings over 180 days. Frequent blood sampling permitted analysis of NES, E2, CTx and P1NP concentrations. The bone-turnover marker analyses included only women with complete sampling and excluded women with characteristics that might interfere with accurate measurement of bone markers such as afternoon sampling, poor ring compliance or recent pregnancy. We evaluated the change from baseline to 6 months in CTx and P1NP, stratified by ring dose and by average circulating E2 concentrations.


      One hundred fifty-one women completed the study, and 82 women had complete data available for the bone marker analyses; the three dosage groups were balanced with regard to baseline characteristics. E2 concentrations remained low throughout treatment, regardless of which dose ring the participant used. Individual CTx changes from baseline averaged 27±56% (p<.01). Similarly, individual P1NP changes averaged 11±33% (p=.04). These increases were within the premenopausal reference ranges, and unrelated to treatment dose or to circulating E2 concentrations.


      The low E2 dose of these rings was associated with low E2 concentrations and modest increases in serum bone turnover makers. Because we have only 6-month bone turnover markers and no direct evidence of bone loss or bone density change, these results must be interpreted with caution.


      Nestorone, a 19-norprogesterone derivative, leads to complete ovarian suppression, which should yield excellent contraceptive effectiveness. To prevent potential adverse effects on bone, the NES contraceptive ring should be combined with higher doses of E2 than were assessed in this study.


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