Abstract
Objective
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.
Results
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.
Conclusions
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.
Implications
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.
Keywords
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References
- Bone gain in young adult women.JAMA. 1992; 268: 2403-2408
- Bone mineral density in diagnosis of osteoporosis: Reference population, definition of peak bone mass, and measured site determine prevalence.J Clin Densitom. 2000; 3: 177-186
- Effects of contraceptive use on bone biochemical markers in young women.J Clin Endocrinol Metab. 2001; 86: 179-185
- Determinants of bone density in normal women: risk factors for future osteoporosis?.BMJ. 1989; 298: 924-928
- Effects of transdermal versus oral hormone replacement therapy on bone density in spine and proximal femur in postmenopausal women.Lancet. 1990; 336: 265-269
- Effect of oral contraceptives and hormone replacement therapy on bone mineral density in premenopausal and perimenopausal women: a systematic review.Br J Sports Med. 2006; 40: 11-24
- The association between oral contraceptive use, bone mineral density and fractures in women aged 50-80 years.Contraception. 2011; 84: 357-362
- Steroidal contraceptives: Effect on bone fractures in women.The Cochrane library, 2014
- Differential effects on bone density of progestogen-only methods for contraception in premenopausal women.Contraception. 1995; 52: 35-39
- Effects of the long-term use of depot medroxyprogesterone acetate as hormonal contraceptive on bone mineral density and biochemical markers of bone remodeling.Contraception. 2006; 74: 297-302
- Effects of depot medroxyprogesterone acetate on bone density and bone metabolism before and after peak bone mass: a case-control study.J Clin Endocrinol Metab. 2008; 93: 1317-1323
- Effects of hormonal contraception on bone mineral density after 24 months of use.Obstet Gynecol. 2004; 103: 899-906
- Bone mineral density changes over two years in first-time users of depot medroxyprogesterone acetate.Fertil Steril. 2004; 82: 1580-1586
- Change in bone mineral density among adolescent women using and discontinuing depot medroxyprogesterone acetate contraception.Arch Pediatr Adolesc Med. 2005; 159: 139-144
- The impact of depot medroxyprogesterone acetate on fracture risk: a case-control study from the UK.Osteoporos Int. 2017; 28: 291-297
- The effect of past use of the injectable contraceptive depot medroxyprogesterone acetate on bone mineral density in normal post-menopausal women.Clin Endocrinol (Oxf). 1998; 49: 615-618
- Steroid hormone contraception and bone mineral density: a cross-sectional study in an international population. The WHO Study of Hormonal Contraception and Bone Health.Obstet Gynecol. 2000; 95: 736-744
- Long-term assessment of forearm bone mineral density in postmenopausal former users of depot medroxyprogesterone acetate.Contraception. 2011; 84: 122-127
- Biochemical markers of bone turnover part II: clinical applications in the management of osteoporosis.Clin Biochem Rev. 2006; 27: 123-138
- The use of biochemical markers of bone turnover in osteoporosis. Committee of Scientific Advisors of the International Osteoporosis Foundation.Osteoporos Int. 2000; 11: S2-17
- Biochemical markers of bone turnover and prediction of hip bone loss in older women: the study of osteoporotic fractures.J Bone Miner Res. 1999; 14: 1404-1410
- The predictive value of biochemical markers of bone turnover for bone mineral density in postmenopausal Japanese women.J Bone Miner Res. 2000; 15: 1537-1544
- Serial assessment of serum bone metabolism markers identifies women with the highest rate of bone loss and osteoporosis risk.J Clin Endocrinol Metab. 2008; 93: 2622-2632
- Markers of bone turnover for the prediction of fracture risk and monitoring of osteoporosis treatment: a need for international reference standards.Osteoporos Int. 2011; 22: 391-420
- Decreased bone turnover in oral contraceptive users.Bone. 1995; 16: 499-503
- A cross-sectional study of bone turnover markers in healthy premenopausal women.Bone. 2007; 40: 1222-1230
- Nestorone®: a progestin with a unique pharmacological profile.Steroids. 2000; 65: 629-636
- Pharmacological profile of progestins.Maturitas. 2004; 47: 277-283
- New progestogens for contraceptive use.Hum Reprod Update. 2005; 12: 169-178
- Risk of venous thromboembolism events in postmenopausal women using oral versus non-oral hormone therapy: a systematic review and meta-analysis.Thromb Res. 2018; 168: 83-95
- Continuous dosing of a novel contraceptive vaginal ring releasing Nestorone® and estradiol: pharmacokinetics from a dose-finding study.Contraception. 2018; 97: 422-427
- Minimal levels of serum estradiol prevent postmenopausal bone loss.Calcif Tissue Int. 1992; 51: 340-343
- Liquid chromatography–tandem mass spectrometry assay for simultaneous measurement of estradiol and estrone in human plasma.Clin Chem. 2004; 50: 373-384
- Lupron add-Back study group. Leuprolide acetate depot and hormonal add-back in endometriosis: a 12-month study.Obstet Gynecol. 1998; 91: 16-24
- Prevention of estrogen deficiency–related bone loss with human parathyroid hormone–(1-34): a randomized controlled trial.JAMA. 1998; 280: 1067-1073
- The use of biochemical markers of bone turnover in osteoporosis.Osteoporosis Int. 2000; 11: S2-17
- Biochemical markers of bone turnover after surgical menopause and hormone replacement therapy.Bone. 1999; 25: 349-353
- Comparison of the acute alterations in serum bone turnover markers and bone mineral density among women with surgical menopause.Eur J Obstet Gynecol Reprod Biol. 2011; 159: 194-197
- Changes in bone resorption across the menopause transition: effects of reproductive hormones, body size, and ethnicity.J Clin Endocrinol Metab. 2013; 98: 2854-2863
- Effect of treatment with GnRH agonists on new markers of bone metabolism.Gynecol Obstet Invest. 1999; 47: 194-196
- Examining the efficacy, safety, and patient acceptability of the combined contraceptive vaginal ring (NuvaRing®).Int J Womens Health. 2010; 2: 401
- The combined contraceptive vaginal ring and bone mineral density in healthy pre-menopausal women.Hum Reprod. 2005; 20: 2764-2768
- Effects of the contraceptive patch and the vaginal ring on bone metabolism and bone mineral density: a prospective, controlled, randomized study.Contraception. 2010; 81: 209-214
- Ovarian function during use of vaginal rings delivering three different doses of Nestorone.Contraception. 2001; 63: 257-261
Article info
Publication history
Published online: March 11, 2019
Accepted:
February 18,
2019
Received in revised form:
February 1,
2019
Received:
August 9,
2018
Footnotes
☆Financial Support: Support for this research was from NICHD Contraception Clinical Trial: Network HHSN275200403378I (OHSU); HHSN 275201300019I (EVMS); HHSN 275201300020I (UPenn); HHSN27521100043U (UPitt); HHSN275201300002I (NYU); HHSN275201300004I (JHU); HHSN275201300010I (Columbia). The authors also acknowledge grant support from the National Institutes of Health for the OHSU Oregon Clinical & Translational Research Institute (NIH NCRR 1 UL1 RR024120), the Bioanalytical Shared Resource/ Pharmacokinetics Core at OHSU, the Biomarkers Core Laboratory of Columbia University's Irving Institute for Clinical and Translational Research (NIH UL1 TR000040), and the work conducted at the Population Council. The content of this publication is the sole responsibility of the authors and does not necessarily represent the official views of the NIH.
☆☆Disclosures:
☆☆MT reports no conflicts of interest
☆☆CW is a consultant to Merck, Bayer, Cooper Surgical, Agile Therapeutics and Allergan. Research support from Estetra SPRL, Leon Farma and Medicines360, all managed through Columbia University.
★AC reports no conflicts of interest.
★SC reports no conflicts of interest.
★RSW is an employee of the Population Council, a not-for-profit organization, IND holder for Nestorone formulations, and developer of the vaginal ring described in this paper.
★DB is an employee of the NIH and is a principal investigator on a Cooperative Research and Development Agreement with HRA Pharma.
Identification
Copyright
© 2019 Published by Elsevier Inc.
