Osteoporosis International

, Volume 30, Issue 12, pp 2391–2400 | Cite as

Bone health in estrogen-free contraception

  • P. Hadji
  • E. Colli
  • P.-A. RegidorEmail author


Estrogens and progestogens influence the bone. The major physiological effect of estrogen is the inhibition of bone resorption whereas progestogens exert activity through binding to specific progesterone receptors. New estrogen-free contraceptive and its possible implication on bone turnover are discussed in this review. Insufficient bone acquisition during development and/or accelerated bone loss after attainment of peak bone mass (PBM) are 2 processes that may predispose to fragility fractures in later life. The relative importance of bone acquisition during growth versus bone loss during adulthood for fracture risk has been explored by examining the variability of areal bone mineral density (BMD) (aBMD) values in relation to age. Bone mass acquired at the end of the growth period appears to be more important than bone loss occurring during adult life. The major physiological effect of estrogen is the inhibition of bone resorption. When estrogen transcription possesses binds to the receptors, various genes are activated, and a variety modified. Interleukin 6 (IL-6) stimulates bone resorption, and estrogen blocks osteoblast synthesis of IL-6. Estrogen may also antagonize the IL-6 receptors. Additionally, estrogen inhibits bone resorption by inducing small but cumulative changes in multiple estrogen-dependent regulatory factors including TNF-α and the OPG/RANKL/RANK system. Review on existing data including information about new estrogen-free contraceptives. All progestins exert activity through binding to specific progesterone receptors; hereby, three different groups of progestins exist: pregnanes, gonanes, and estranges. Progestins also comprise specific glucocorticoid, androgen, or mineralocorticoid receptor interactions. Anabolic action of a progestogen may be affected via androgenic, anti-androgenic, or synadrogenic activity. The C 19 nortestosterone class of progestogens is known to bind with more affinity to androgen receptors than the C21 progestins. This article reviews the effect of estrogens and progestogens on bone and presents new data of the currently approved drospirenone-only pill. The use of progestin-only contraceptives leading to an estradiol level between 30 and 50 pg/ml does not seem to lead to an accelerate bone loss.


Bone mineral density Estrogen Fracture Osteoporosis Progestin 


Compliance with ethical standards

Conflict of interest

Peyman Hadji had received traveling support and speaker’s fees from Amgen, Dr. Kade/Besin, Elly Lilly, Exeltis, Gedeon Richter, MEDA, MSD, Mylan, Theramex, and UCB: Enrico Colli and Pedro-Antonio Regidor are employees of Exeltis Healthcare.


  1. 1.
    Kanis JA, Brazier JE, Stevenson M, Calvert NW, Lloyd JM (2002) Treatment of established osteoporosis: a systematic review and cost-utility analysis. Health Technol Assess 6(29):1–146. CrossRefPubMedGoogle Scholar
  2. 2.
    Kanis JA, McCloskey EV, Harvey NC, Johansson H, Leslie WD (2015) Intervention thresholds and the diagnosis of osteoporosis. J Bone Miner Res 30(10):1747–1753. CrossRefPubMedGoogle Scholar
  3. 3.
    Hernlund E, Svedbom A, Ivergård M, Compston J, Cooper C, Stenmark J, McCloskey EV, Jönsson B, Kanis JA (2013) Osteoporosis in the European Union: medical management, epidemiology and economic burden. A report prepared in collaboration with the International Osteoporosis Foundation (IOF) and the European Federation of Pharmaceutical Industry Associations (EFPIA). Arch Osteoporos 8:136. CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Bonjour JP, Chevalley T (2014) Pubertal timing, bone acquisition, and risk of fracture throughout life. Endocr Rev 35(5):820–847. CrossRefPubMedGoogle Scholar
  5. 5.
    Chevalley T, Bonjour JP, van Rietbergen B, Rizzoli R, Ferrari S (2012) Fractures in healthy females followed from childhood to early adulthood are associated with later menarcheal age and with impaired bone microstructure at peak bone mass. J Clin Endocrinol Metab 97(11):4174–4181. CrossRefPubMedGoogle Scholar
  6. 6.
    Cadogan J, Blumsohn A, Barker ME, Eastell R (1998) A longitudinal study of bone gain in pubertal girls: anthropometric and biochemical correlates. J Bone Miner Res 13(10):1602–1612. CrossRefPubMedGoogle Scholar
  7. 7.
    Seeman E (2002) Pathogenesis of bone fragility in women and men. Lancet 359:1841–1850. CrossRefPubMedGoogle Scholar
  8. 8.
    Riggs BL (2000) The mechanisms of estrogen regulation of bone resorption. J Clin Investig 106(10):1203–1204. CrossRefPubMedGoogle Scholar
  9. 9.
    Lloyd T, Rollings N, Andon MB, Demers LM, Eggli DF, Kieselhorst K, Kulin H, Landis JR, Martel JK, Orr G et al (1992) Determinants of bone density in young women. I. Relationships among pubertal development, total body bone mass, and total body bone density in premenarchal females. J Clin Endocrinol Metab 75(2):383–387. CrossRefPubMedGoogle Scholar
  10. 10.
    Berger C, Goltzman D, Langsetmo L, Joseph L, Jackson S, Kreiger N, Tenenhouse A, Davison KS, Josse RG, Prior JC, Hanley DA, CaMos Research Group (2010) Peak bone mass from longitudinal data: implications for the prevalence, pathophysiology, and diagnosis of osteoporosis. J Bone Miner Res 25(9):1948–1957. CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Barbieri RL (1992) Hormone treatment of endometriosis: the estrogen threshold hypothesis. Am J Obstet Gynecol 166(2):740–745. CrossRefPubMedGoogle Scholar
  12. 12.
    Mawi M (2010) Serum estradiol levels and bone mineral density in postmenopausal women. Univ Med 29:90–95Google Scholar
  13. 13.
    Bagur A, Oliveri B, Mautalen C, Belotti M, Mastaglia S, Yankelevich D, Sayegh F, Royer M (2004) Low levels of endogenous estradiol protect bone mineral density in young postmenopausal women. Climacteric 7(2):181–188. CrossRefPubMedGoogle Scholar
  14. 14.
    Cummings SR, Browner WS, Bauer D, Stone K, Ensrud K, Jamal S, Ettinger B (1998) Endogenous hormones and the risk of hip and vertebral fractures among older women. Study of Osteoporotic Fractures Research Group. N Engl J Med 339(11):733–738. CrossRefPubMedGoogle Scholar
  15. 15.
    Lopez LM, Grimes DA, Schultz KF, Curtis KM, Chen M. (2014) Steroidal contraceptives: effect on bone fractures in women. Cochrane Database of System Rev (6):CD006033.
  16. 16.
    Dombrowski S, Jacob L, Hadji P, Kostev K (2017) Oral contraceptive risk- a retrospective study of 12,970 women in the UK. Osteoporos Int 28(8):2349–2355. CrossRefPubMedGoogle Scholar
  17. 17.
    Cromer BA (2003) Bone mineral density in adolescent and young adult women on injectable or oral contraception. Curr Opin Obstet Gynecol 15(5):353–357. CrossRefPubMedGoogle Scholar
  18. 18.
    Cibula D, Skrenkova J, Hill M, Stepan JJ (2012) Low-dose estrogen combined oral contraceptives may negatively influence physiological bone mineral density acquisition during adolescence. Eur J Endocrinol 166(6):1003–1011. CrossRefPubMedGoogle Scholar
  19. 19.
    Hartard M, Kleinmond C, Wiseman M (2007) Detrimental effect of oral contraceptives on parameters of bone mass and geometry in a cohort of 248 young women. Bone. 40(2):444–450. CrossRefPubMedGoogle Scholar
  20. 20.
    Almstedt SH, Snow CM (2005) Oral contraceptive use in young women is associated with lower bone mineral density than that of controls. Osteoporos Int 16(12):1538–1544. CrossRefGoogle Scholar
  21. 21.
    Herrmann M, Seibel MJ (2010) The effects of hormonal contraceptives on bone turnover markers and bone health. Clin Endocrinol 72(5):571–583. CrossRefGoogle Scholar
  22. 22.
    Broulík PD, Broulíková K, Nečas E (2006) Progestogens androgenic action on the bone of male castrated mice. Prague Medical Report 107(4):401–408PubMedGoogle Scholar
  23. 23.
    Onobrakpeya OA, Fall PM, Willard A, Chakravarthi P, Hansen A, Raisz LG (2001) Effect of norethindrone acetate on hormone levels and markers of bone turnover in estrogen-treated postmenopausal women. Endocr Res 27(4):473–480CrossRefGoogle Scholar
  24. 24.
    Liu JH, Muse KN (2005) The effects of progestins on bone density and bone metabolism in postmenopausal women: a randomized controlled trial. Am J Obstet Gynecol 192(4):1316–1323; discussion 1323–4. CrossRefPubMedGoogle Scholar
  25. 25.
    DeCherney A (1993) Physiologic and pharmacologic effects of estrogen and progestins on bone. J Reprod Med 38(12 Sup):1007–1014 ReviewPubMedGoogle Scholar
  26. 26.
    Hartard M, Kleinmond C, Luppa P (2006) Comparison of the skeletal effects of the progestogens desogestrel and levonorgestrel in oral contraceptive preparations in young women: controlled, open, partly randomized investigation over 13 cycles. Contraception. 74(5):365–375. CrossRefGoogle Scholar
  27. 27.
    Black A, Guilbert Q, Costescu D, Dunn S, Fisher W, Kives S, Mirosh M, Norman W, Pymar H, Reid R, Roy G, Varto H, Waddington A, Wagner MS, Whelan AM, Mansouri S (2016) Canadian contraception Consensus (Part 3 of 4): Chapter 7 – Intrauterine contraception. J Obstet Gynaecol Can 38(2):182–222. CrossRefPubMedGoogle Scholar
  28. 28.
    Mansour D (2012) The benefits and risks of using a levonorgestrel-releasing intrauterine system for contraception. Contraception. CrossRefGoogle Scholar
  29. 29.
    Sarfati J, Marie-Christine De Vernejoul MC (2009) Impact of combined and progestogen-only contraceptives on bone mineral density. Joint Bone Spine 76(2):134–138. CrossRefPubMedGoogle Scholar
  30. 30.
    Modesto W, Dal Ava N, Monteiro I, Bahamondes L (2015) Body composition and bone mineral density in users of the etonogestrel-releasing contraceptive implant. Arch Gynecol Obstet 292(6):1387–1391. CrossRefPubMedGoogle Scholar
  31. 31.
    Petitti DB, Piagio G, Metha S, Cravioto MC, Meirik O (2000) Steroid hormone contraception and bone mineral density: a cross-sectional study in an international population. Obstet Gynecol 96(5 - part 19):736–744. CrossRefGoogle Scholar
  32. 32.
    Beerthuizen R, van Beek A, Massai R, Mäkäräinen L, In’t Hout J, Bennink HC (2000) Bone mineral density during long-term use of the progestogen contraceptive implant Implanon compared to a non-hormonal method of contraception. Hum Reprod 15(1):118–122. CrossRefPubMedGoogle Scholar
  33. 33.
    Cundy T, Evans M, Roberts H (1991) Bone density in women receiving depot medroxyprogesterone acetate for contraception. BMJ. 303(6793):13–16. CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Cundy T, Ames R, Horne A, Clearwater J, Roberts H, Gamble G et al (2003) A randomized controlled trial of estrogen replacement therapy in long-term users of depot medroxyprogesterone acetate. J Clin Endocrinol Metab 88(1):78–81. CrossRefPubMedGoogle Scholar
  35. 35.
    Walsh JS, Eastell R, Peel NF (2008) 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 93(4):1317–1323. CrossRefPubMedGoogle Scholar
  36. 36.
    Ott SM, Scholes D, Lacroix AZ, Ichikawa LE, Yoshida CK, Barlow WE (2001) Effects of contraceptive use on bone biochemical markers in young women. J Clin Endocrinol Metab 86(1):179–185. CrossRefPubMedGoogle Scholar
  37. 37.
    Kyvernitakis I, Kostev K, Nassour T, Thomasius F, Hadji P (2017) The impact of depot medroxyprogesterone acetate on fracture risk: a case-control study from the UK. Osteoporos Int 28(1):291–297. CrossRefPubMedGoogle Scholar
  38. 38.
    Vestergaard P, Rejnmark L, Mosekilde L (2006) Oral contraceptive use and risk of fracture. Contraception 73(6):571–576. CrossRefPubMedGoogle Scholar
  39. 39.
    Meier C, Brauchli YB, Jick SS, Kraenzlin ME, Meier CR (2010) Use of depot medroxyprogesterone acetate and fracture risk. J Clin Endocrinol Metab 95(11):4909–4916. CrossRefPubMedGoogle Scholar
  40. 40.
    Cromer BA, Blair JM, Mahan JD et al (1996) A prospective comparison of bone density in adolescent girls receiving depot medroxyprogesterone acetate (Depo-Provera), levonorgestrel (Norplant), or oral contraceptives. J Pediatr 129(5):671–676. CrossRefPubMedGoogle Scholar
  41. 41.
    Miller L, Patton DL, Meier A, Thwin SS, Hooton TM, David A, Eschenbach DA (2000) Depomedroxyprogesterone-induced hypoestrogenism and changes in vaginal flora and epithelium. Obstet Gynecol 96(3):431–439PubMedGoogle Scholar
  42. 42.
    ORTHO-McNEIL (1998) Ortho Micronor® tablets (noretindrone) Pharmaceutical, INC.
  43. 43.
    Caird LE, Reid-Thomas V, Hannan WJ et al (1994) Oral progestogen-only contraception may protect against loss of bone mass in breastfeeding women. Clin Endocrinol 41(6):739–745. CrossRefGoogle Scholar
  44. 44.
    Thijssen JH (2007) Long-term effects of progestins on bone quality and fractures. Gynecol Endocrinol 23(Sup1):45–52. CrossRefPubMedGoogle Scholar
  45. 45.
    Strowitzki T, Marr J, Gerlinger C, Faustmann T, Seitz C (2010) Dienogest is as effective as leuprolide acetate in treating the painful symptoms of endometriosis: a 24-week, randomized, multicentre, open-label trial. Hum Reprod 25:633–641. CrossRefPubMedGoogle Scholar
  46. 46.
    Klipping C, Duijkers I, Remmers A, Faustmann T, Zurth C, Klein S, Schuett B (2012) Ovulation-inhibiting effects of dienogest in a randomized, dose-controlled pharmacodynamic trial of healthy women. J Clin Pharmacol 52(11):1704–1713. CrossRefPubMedGoogle Scholar
  47. 47.
    Momoeda M, Harada T, Terakawa N, Aso T, Fukunaga M, Hagino H, Taketani Y (2009) Long-term use of dienogest for the treatment of endometriosis. J Obstet Gynaecol Res 35(6):1069–1076. CrossRefPubMedGoogle Scholar
  48. 48.
    Rice CF, Killick SR, Dieben T, Bennink HC (1999) A comparison of the inhibition of ovulation achieved by desogestrel 75 mg and levonorgestrel 30 mg daily. Hum Reprod 14(4):982–985. CrossRefPubMedGoogle Scholar
  49. 49.
    Fuhrmann U, Krattenmacher R, Slater EP, Fritzemeier KH (1996) The novel progestin drospirenone and its natural counterpart progesterone: biochemical profile and antiandrogenic potential. Contraception. 54(4):243–251. CrossRefPubMedGoogle Scholar
  50. 50.
    Duijkers IJM, Herger-Mahn D, Drouin D, Skouby S (2015) A randomised study comparing the effect on ovarian activity of a progestogen-only pill (POP) containing desogestrel and a new POP containing drospirenone in a 24/4 regimen. Eur J Contracept Reprod Health Care 20(6):419–427. CrossRefPubMedGoogle Scholar
  51. 51.
    Rice C, Killick S, Hickling D, Bennink HC (1996) Ovarian activity and vaginal bleeding patterns with a desogestrel-only preparation at three different doses. Hum Reprod 11(4):737–740. CrossRefPubMedGoogle Scholar
  52. 52.
    Doran PM, Riggs BL, Atkinson EJ, Khosla S (2001) Effects of raloxifene, a selective estrogen receptor modulator, on bone turnover markers and serum sex steroid and lipid levels in elderly men. J Bone Miner Res 16(11):2118–2125. CrossRefPubMedGoogle Scholar
  53. 53.

Copyright information

© International Osteoporosis Foundation and National Osteoporosis Foundation 2019

Authors and Affiliations

  1. 1.Frankfurter Center of Bone HealthFrankfurt/MainGermany
  2. 2.Philipps University of MarburgMarburgGermany
  3. 3.Exeltis HealthCare MadridMadridSpain
  4. 4.Exeltis EuropeIsmaningGermany

Personalised recommendations