Efecto de Tibolona en el Hueso

La tibolona previene la pérdida ósea en las mujeres postmenopáusicas tan efectivamente como la terapia con estrógenos o estrógenosprogestágenos24,42,96,100.

El impacto benéfico en el hueso se puede atribuir a los metabolitos estrogénicos actuando a través del receptor de estrógenos debido a que éste es bloqueado por un antiestrógeno pero no por un antiandrógeno o un antiprogestina101. En un estudio grande en EE. UU. con dosis entre 0.3 mg a 2.5 mg por día, solamente las dosis de 1.25 y 2.5 mg produjeron progresivo aumento de la densidad ósea en el cuello femoral42. Indudablemente, el impacto en el hueso fue esencialmente el mismo para las dos dosis más altas de 1.25 y 2.5 mg. Aunque la dosis de 1.25 mg es aceptable para la prevénción de masa ósea, la dosis de 2.5 mg es más efectiva para el alivio de los fogajes17. La tibolona previene la pérdida ósea asociada con el tratamiento con agonista de GnRH (y los efectos secundarios de los fogajes)78,102.

El estudio LIFT (Long-term Intervention on Fractures with Tibolone) fue un estudio randomizado controlado con placebo multicéntrico en 22 países con 1.25 mg de tibolona dada diariamente por 3 años95. Las 4.538 mujeres participantes en el estudio fueron entre 60 y 85 años de edad, todas en alto riesgo de fractura debido a osteoporosis, y todas tratadas con suplementos de calcio y vitamina D. El estudio se suspendió en febrero de 2006 después de un tratamiento promedio de 34 meses debido al aumento de riesgo de ACV. Los riesgos de todos los eventos fueron medidos después de 5 años de seguimiento. El tratamiento con tibolona redujo el número de fracturas vertebrales en cerca del 45%, y no vertebrales del 25%. La reducción de las fracturas fue de cerca de 4 veces mayor en mujeres quienes ya habían tenido una fractura vertebral al entrar al estudio comparadas con mujeres quienes no habían tenido una fractura de base. Es notable que el número de caídas en el grupo de tratamiento fue de 2% menos.

Basados en estudios previos de densidad ósea, los resultados del LIFT en la reducción de las fracturas no fue inesperado. La magnitud de los eventos es comparable con la de los estrógenos, bisfosfonatos y raloxifeno (con la excepción importante de la falta de efecto del raloxifeno en las fracturas de cadera). La reducción de cáncer de mama fue comparable con la reportada con tamoxifeno y raloxifeno, pero este no fue el objetivo primario del estudio. Aunque la diferencia no fue estadísticamente significante, hubo 4 casos de cáncer endometrial en el grupo de tibolona y ninguno en el grupo placebo.

El reportado aumento de 2 veces en ACV en el LIFT fue mayor en mujeres más viejas (por encima de los 70), similar a la observada con los estrógenos. Es mejor evitar el uso de tibolona en mujeres mayores quienes estén a riesgo ACV (específicamente aquellas con hipertensión, fumadoras, diabéticas o con fibrilación atrial).

La tibolona es una opción apropiada para terapia hormonal, indicada en muchas mujeres postmenopáusicas. La dosis estándar de tibolona por muchos años fue de 2.5 mg diarios, pero los estudios clínicos apoyan el uso de 1.25 mg diarios, sin mayor pérdida de eficacia. Debido a su metabolismo único y variado, la tibolona tiene diferentes acciones en diferentes tejidos, lo cual provee un perfil global riesgo beneficio benéfico. Clínicamente la tibolona trata síntomas menopáusicos, incluyendo los fogajes y la resequedad vaginal tan efectivamente como la terapia estrogénica y más importante, mejora la respuesta sexual. La seguridad endometrial y la prevención de la perdida ósea son comparables a las alcanzadas con los regímenes continuos combinados de estrógenos-progestinas y con una menor tasa de sangrado de deprivación.

La suma de varios efectos biológicos de la tibolona y sus metabolitos en el sistema cardiovascular podría aumentar o disminuir el riesgo de enfermedad arterial coronaria. No ha habido inicio de un aumento de riesgo de tromboembolismo venoso, pero este es un efecto secundario potencial que requiere estudio epidemiológico en una población grande. La tibolona no estimula la proliferación de células mamarias y afecta la actividad enzimática en la mama para disminuir las concentraciones en el tejido mamario de estrógenos activos. La tibolona no aumenta la densidad mamaria en la mamografía y no aumenta la frecuencia de mastalgia.

Los reportados aumentos de riesgo de cáncer de mama y cáncer endometrial en estudios observacionales muy posiblemente representada por “una prescripción preferencial” de tibolona en Europa. Las mujeres prescritas con tibolona en Europa a menudo tienen enfermedad mamaria crónica, una historia personal de cáncer de mama, hemorragia uterina disfuncional previa, hipertensión y operaciones uterinas previas. Más importante, más mujeres prescritas con tibolona tienen una historia previa de tratamiento con estrógenos sin oposición. Así, los clínicos fueron más propensos a prescribir tibolona a mujeres que ellos creían estaban a mayor riesgo para estos dos cánceres, y esto podría alcanzar tasas más altas en los grupos tratados comparados con los grupos controles.

Referencias

1. Kloosterboer HJ. Tibolone: a steroid with a tissue-specific mode of action. J Steroid Biochem 2001;76:231-238.
2. de Gooyer ME, Deckers GH, Schoonen WGEJ, Verheul HAM, Kloosterboer HJ. Receptor profiling and endocrine interactions of tibolone. Steroids 2003;68:21-30.
3. Timmer CJ, Huisman JAM. Effect of a standardized meal on the bioavailability of a single oral dose of tibolone 2.5 mg in healthy postmenopausal women. Pharmacotherapy 2002;22:310-315.
4. Vos RME, Krebbers SFM, Verhoeven CHJ, Delbressine LPC. The in vivo human metabolism of tibolone. Drug Metab Disposition 2002;30:106-112.
5. Timmer CJ, Houwing NS. Dose proportionality of three different doses of tibolone. Pharmacotherapy 2002;22:6-13.
6. Markiewicz L, Gurpide E. In vitro evaluation of estrogenic, estrogen antagonistic and progestagenic effects of a steroidal drug (Org OD-14) and its metabolites on human endometrium. J Steroid Biochem 1990;35:535- 541.
7. Tang B, Markiewicz L, Kloosterboer HJ, Gurpide E. Human endometrial 3 betahydroxysteroid dehydrogenase/isomerase can locally reduce intrinsic estrogenic/progestagenic activity ratios of a steroidal drug (Org OD 14). J Steroid Biochem Mol Biol 1993;45:345- 351.
8. Punnonen R, Liukko P, Cortes-Prieto J, et al. Multicentre study of effects of Org OD14 on endometrium, vaginal cytology and cervical mucus in postmenopausal and oophorectomized women. Maturitas 1984;5:281-286.
9. Genazzani AR, Benedek Jaszmann L, Hart DM, Andolsek L, Kicovic PM, Tax L. Org OD14 and the endometrium. Maturitas 1991; 13:243-251.
10. Trevoux R, Dieulangard P, Blum A. Efficacy and safety of Org OD 14 in the treatment of climacteric complaints. Maturitas 1983;5:89-96.
11. Volpe A, Facchinetti F, Grasso A, Petraglia F, Campanini D, Genazzani AR. Benefits and risks of different hormonal replacement therapies in postmenopausal women. Maturitas 1986;8:327-334.
12. Siseles NO, Halperin H, Benencia HJ, et al. A comparative study of two hormone replacement therapy regimens on safety and efficacy variables. Maturitas 1995;21:201-210.
13. Nathorst-Böös J, Hammar M. Effect on sexual life — a comparison between tibolone and a continuous estradiol-norethisterone acetate regimen. Maturitas 1997;26:15-20.
14. Hammar M, Christau S, Nathorst-Böös J, Rud T, Garre K. A double-blind, randomized trial comparing the effects of tibolone and continuous combined hormone replacement therapy in postmenopausal women with menopausal symptoms. Br J Obstet Gynaecol 1998;105:904-911.
15. Al-Azzawi F, Wahab M, Habiba M, Akkad A, Mason T. Continuous combined hormone replacement therapy compared with tibolone. Obstet Gynecol 1999;93:258-264.
16. Kökçü A, Centinkaya MB, Yanik F, Alper T, Malatydlioglu E. The comparison of effects of tibolone and conjugated estrogenmedroxyprogesterone acetate therapy on sexual performance in postmenopausal women. Maturitas 2000;36:75-80.
17. Landgren MB, Coelingh Benink HJT, Helmond FA, Engelen S. Dose-response analysis of effects of tibolone on climacteric symptoms. Br J Obstet Gynaecol 2002;109:1109- 1114.
18. Taskin O, Yalcinoglu AI, Kucuk S, Uryan I, Buhur A, Burak F. Effectiveness of tibolone on hypoestrogenic symptoms induced by goserelin treatment in patients with endometriosis. Fertil Steril 1997;67:40-45.
19. Crona N, Silfverstolpe G, Samsioe G. A double-blind cross-over study on the effects of Org OD 14 compared to estradiol valerate and placebo on lipid and carbohydrate metabolism in oophorectomized women. Acta Endocrinol 1983;102:451-455.
20. Rymer J, Chapman MG, Fogelman I, Wilson POG. A study of the effect of tibolone on the vagina in postmenopausal women. Maturitas 1994;18:127-133.
21. Botsis D, Kassanos D, Kalogirous D, Antonious G, Vitoratos N, Karakitsos P. Vaginal ultrasound of the endometrium in postmenopausal women with symptoms of urogenital atrophy on low-dose estrogen or tibolone treatment: a comparison. Maturitas 1997;26:57-62.
22. Laan E, van Lunsen RHW, Everaerd W. The effects of tibolone on vaginal blood flow, sexual desire and arousability in postmenopausal women. Climacteric 2001;4:28-41.
23. Mendoza N, Suárez AM, Álamo F, Bartual E, Vergara F, Herruzo A. Lipid effects, effectiveness and acceptability of tibolone versus transdermic 17ß-estradiol for hormonal replacement therapy in women with surgical menopause. Maturitas 2000;37:37-43.
24. Castelo-Branco C, Vicente JJ, Figueras F, et al. Comparative effects of estrogens plus androgens and tibolone on bone, lipid pattern and sexuality in postmenopausal women. Maturitas 2000;34:161-168.
25. Huber J, Palacios S, Berglund L, et al. Effects of tibolone and continuous combined hormone replacement therapy on bleeding rates, quality of life and tolerability in postmenopausal women. Br J Obstet Gynaecol 2002;109:886-893.
26. Egarter C, Topcuoglu AM, Vogl S, Sator M. Hormone replacement therapy with tibolone: effects on sexual functioning in postmenopausal women. Acta Obstet Gynecol Scand 2002;81:649-653.
27. Palacios S, Menendez C, Jurado R, Castano JC, Vargas JC. Changes in sex behaviour after menopause: effects of tibolone. Maturitas 1995;22:155-161.
28. Nijland EA, Weijmar Schultz WC, Nathorst- Böös J, et al. Tibolone and transdermal E2/ NETA for the treatment of sexual dysfunction in naturally menopausal women: results of a randomized active-controlled trial. J Sex Med 2008;5:646-656.
29. Dören M, Rubig A, Coelingh Benink HJT, Holzgreve W. Differential effects on the androgen status of postmenopausal women treated with tibolone and continuous combined estradiol and norethindrone acetate replacement therapy. Fertil Steril 2001; 75:554-559.
30. Fluck E, File SE, Rymer J. Cognitive effects of 10 years of hormone-replacement therapy with tibolone. J Clin Psychopharmacol 2002; 22:62-67.
31. Bukulmez O, Al A, Gurdal H, Yarali H, Ulug B, Gurgan T. Short-term effects of three continuous hormone replacement therapy regimens on platelet tritiated imipramine binding and mood scores: a prospective randomized trial. Fertil Steril 2001;75:737- 743.
32. Clarkson TB, Anthony M, Wagner JD. A comparison of tibolone and conjugated equine estrogens effects on coronary artery atherosclerosis and bone density of postmenopausal monkeys. J Clin Endocrinol Metab 2001;86:5396-5404.
33. Clarkson TB, Anthony MS, Mikkola TS, St Clair RW. Comparison of tibolone and conjugated equine estrogens effects on carotid artery atherosclerosis of postmenopausal monkeys. Stroke 2002;33:2700-2703.
34. Fielding CJ, Fielding PE. Molecular physiology of reverse cholesterol transport. J Lipid Res 1995;36:211-228.
35. Pajunen P, Syvänne M, Castro G, Nieminen MS, Taskinen MR. Cholesterol efflux capacity in vitro predicts the severity and extent of coronary artery disease in patients with and without Type 2 diabetes. Scand Cardiovasc J 2001;35:96-100.
36. Mikkola TS, Anthony M, Clarkson TB, St. Clair RW. Serum cholesterol efflux in postmenopausal monkeys treated with tibolone or conjugated estrogens. Metabolism 2002; 51:523-530.
37. Rymer J, Crook D, Sidhu M, Chapman M, Stevenson JC. Effects of tibolone on serum concentrations of lipoprotein(a) in postmenopausal women. Acta Endocrinol 1993; 128:259-262.
38. Milner MH, Sinnot MM, Cooke TM, Kelly A, McGill T, Harrison RF. A 2-year study of lipid and lipoprotein changes in postmenopausal women with tibolone and estrogen-progestin. Obstet Gynecol 1996; 87:593-599.
39. Cagnacci A, Mallus E, Tuveri F, Cirillo R, Setteneri AM, Melis GB. Effects of tibolone on glucose and lipid metabolism in postmen pausal women. J Clin Endocrinol Metab 1997;82:251- 253.
40. Lloyd G, McGing E, Cooper A, et al. A randomised placebo controlled trial of the effects of tibolone on blood pressure and lipids in hypertensive women. J Hum Hypertension 2000;14:99-104.
41. Ginsburg J, Prelevic GM. Antiatherosclerotic effects of tibolone. Menopause 2001;8:79-80.
42. Gallagher JC, Baylink DJ, Freeman R, McClung M. Prevention of bone loss with tibolone in postmenopausal women: results of two randomized double-blind, placebo-controlled, dose-finding studies. J Clin Endocrinol Metab 2001;86:4717-4726.
43. Barnes JF, Farish E, Rankin M, Hart DM. A comparison of the effects of two continuous HRT regimens on cardiovascular risk factors. Atherosclerosis 2002;160:185-193.
44. Haenggi W, Bersinger NA, Mueller MD, Bikhaeuser MH. Decrease of serum endothelin levels with postmenopausal hormone replacement therapy or tibolone. Gynecol Endocrinol 1999;13:202-205.
45. Farish E, Barnes JF, Rolton HA, Spowart K, Fletcher CD, Hart DM. Effects of tibolone on lipoprotein(a) and HDL subfractions. Maturitas 1994;20:215-219.
46. Lloyd GWL, Patel NR, McGing EA, Cooper AF, Kamalvand K, Jackson G. Acute effects of hormone replacement with tibolone on myocardial ischaemia in women with angina. Int J Clin Pract 1998;52:155-157.
47. von Eckardstein A, Schmiddem K, Hövels A, et al. Lowering of HDL cholesterol in postmenopausal women by tibolone is not associated with changes in cholesterol efflux capacity or paraoxonase activity. Atherosclerosis 2001;159:433-439.
48. Castelo-Branco C, Casals E, Figueras F, et al. Two-year prospective and comparative study on the effects of tibolone on lipid pattern, behavior of apolipoproteins A1 and B. Menopause 1999;6:92-97.
49. Bjarnason NH, Bjarnason K, Haarbo J, Coelingh Bennink HJT, Christiansen C. Tibolone: influence on markers of cardiovascular disease. J Clin Endocrinol Metab 1997;82:1752-1756.
50. Kloosterboer HJ, Benedek Jaszmann L, Kicovic PM. Long-term effects of OrgOD14 on lipid metabolism in post-menopausal women. Maturitas 1990;12:37-42.
51. Pan H-A, Wang S-T, Chen C-H, Pai M-C, Wu M-H, Huang K-E. Flow resistance in carotid and middle cerebral arteries in postmenopausal women: a comparative study of tibolone and continuous combined hormone replacement therapy. Climacteric 2002;5:259-265.
52. Cetinkaya MB, Alper T, Kökcü A, Yanik FF, Malatyalioglu E. Tibolone versus four estrogen replacement therapy protocols and plasma lipid levels in postmenopausal women. Int J Gynaecol Obstet 2002;79:17-23.
53. von Eckardstein A, Nofer JR, Assmann G. High density lipoproteins and atherosclerosis. Role of cholesterol efflux and reverse cholesterol transport. Arterioscl Thromb Vasc Biol 2001;21:13-27.
54. von Eckardstein A, Crook D, Elbers J, et al. Tibolone lowers high density lipoprotein cholesterol by increasing hepatic lipase activity but does not impair cholesterol efflux. Clin Endocrinol 2003;58:49-58.
55. Morris EP, Denton ERE, Robinson JG, MacDonald LM, Rymer JM. High resolution ultrasound assessment of the carotid artery: its relevance in postmenopausal women and the effects of tibolone on carotid artery ultrastructure. Climacteric 1999;2:13-20.
56. de Kleijn MJ, Wilmink HW, Bots ML, et al. Hormone replacement therapy and endothelial function. Results of a randomized controlled trial in healthy postmenopausal women. Atherosclerosis 2001;159:357-365.
57. Ceballos C, Ribes C, Amado JA, de Mier I, de Rozas LS, Berrazueta JR. Venous endotelial function in postmenopausal women after six months of tibolone therapy. Maturitas 2001;39:63-70.
58. Manzella D, Fornaro F, Carbonella M, Picardi C, Paolisso G, Colacurci N. Effect of tibolone administration on heart rate variability and free fatty acid levels in postmenopausal women. Fertil Steril 2002;78:1005-1009.
59. Simoncini T, Genazzani AR. Tibolone inhibits leukocyte adhesion molecule expression in human endothelial cells. Mol Cell Endocrinol 2000;162:87-94.
60. Bots ML, Evans GW, Riley W, et al. The effect of tibolone and continuous combined conjugated equine oestrogens plus medroxyprogesterone acetate on progression of carotid intima-media thickness. Eur Heart J 2006; 27:746-755.
61. De Beer F, Smelt AHM, Van Vark LC, Hoogerbrugge N, Havekes LM, Gevers Leuven JA. The effect of tibolone on the lipoprotein profile of postmenopausal women with type III hyperlipoproteinemia. J Int Med 2002;251:148-155.
62. Prelevic GM, Beljic T, Balint-Peric L, Ginsburg J. Metabolic effects of tibolone in postmenopausal women with non-insulin dependent diabetes mellitus. Maturitas 1998; 28:271-276.
63. Wiegratz I, Starflinger F, Tetzloff W, et al. Effect of tibolone compared with sequential hormone replacement therapy on carbohydrate metabolism in postmenopausal women. Maturitas 2002;41:133-141.
64. Ginsburg J, Prelevic G, Butler D, Okolo S. Clinical experience with tibolone (Livial) over 8 years. Maturitas 1995;21:71-76.
65. Meuwissen J, Wiegerinck M, Haverkorn M. Regression on endometrial thickness in combination with reduced withdrawal bleeding as a progestational effect of tibolone in postmenopausal women on oestrogen replacement therapy. Maturitas 1995;21:121-125.
66. Egarter C, Sator M, Berghammer P, Huber J. Efficacy, tolerability, and rare side effects of tibolone treatment in postmenopausal women. Int J Gynaecol Obstet 1999;64:281-286.
67. Völker W, Coelingh Bennink HJT, Helmond FA. Effects of tibolone on the endometrium. Climacteric 2001;4:203-208.
68. Ginsburg J, Prelevic GM. Cause of vaginal bleeding in postmenopausal women taking tibolone. Maturitas 1996;24:1-7-110.
69. Archer DF, Henddrix S, Gallagher JC, et al. Endometrial effects of tibolone. J Clin Endocrinol Metab 2007;92:911-918.
70. Wu M-H, Pan H-A, Wang S-T, Hsu C-C, Chang F-M, Huang K-E. Quality of life and sexuality changes in postmenopausal women receiving tibolone therapy. Climacteric 2001; 4:314-319.
71. Nijland EA, Nathorst-Böös J, Palacios S, et al. Improved bleeding profile and tolerability of tibolone versus transdermal E2/NETA treatment in postmenopausal women with female sexual dysfunction. Climacteric 2009;12:114-121.
72. Rymer J, Fogelman I, Champman MG. The incidence of vaginal bleeding with tibolone treatment. Br J Obstet Gynaecol 1994;101:53-56.
73. Berning B, van Kuijk C, Coelingh Benink HJT, Fauser BCJM. Absent correlation between vaginal bleeding and oestradiol levels or endometrial morphology during tibolone use in early postmenopausal women. Maturitas 2000;35:81-88.
74. Hanggi W, Lippuner K, Riesen W, Jaeger P, Birkauser MH. Long-term influence of different postmenopausal hormone replacement regimens on serum lipids and lipoprotein(a): a randomised trial. Br J Obstet Gynaecol 1997; 104:708-717.
75. Fedele L, Bianchi S, Raffaelli R, Zanconato G. A randomized study of the effects of tibolone and transdermal estrogen replacement therapy in postmenopausal women with uterine myomas. Eur J Obstet Gynecol Reprod Biol 2000;88:91-94.
76. Gregoriou O, Konidaris S, Botsis D, Papadias C, Makrakis E, Creatsas G. Long term effects of tibolone on postmenopausal women with uterine myomas. Maturitas 2001;40:95-99.
77. Simsek T, Karakus C, Trak B. Impact of different hormone replacement therapy regimens on the size of myoma uteri in postmenopausal period. Tibolone versus transdermal hormonal replacement system. Maturitas 2002;42:243-246.
78. Palomba S, Affinito P, Tommaselli GA, Nappi C. A clinical trial of the effects of tibolone administered with gonadotropin-releasing hormone analogues for the treatment of uterine leiomyomata. Fertil Steril 1998;70:111-118.
79. Santner SJ, Feil PD, Santen RJ. In situ estrogen production via estrone sulfatase pathway in breast tumors: relative importance versus aromatase pathway. J Clin Endocrinol Metab 1984;59:29-33.
80. Chetrite GS, Cortes-Prieto J, Philippe JC, Wright F, Pasqualini JR. Comparison of estrogen concentrations, estrone sulfatase and aromatase activities in normal, and in cancerous, human breast tissues. J Steroid Biochem Molec Biol 2000;72:23-27.
81. Chetrite G, Kloosterboer HJ, Pasqualini JR. Effect of tibolone (Org OD14) and its metabolites on estrone sulphatase activity in MCF-7 and T-47D mammary cancer cells. Anticancer Res 1997;17:135-140.
82. Chetrite GS, Kloosterboer HJ, Philippe JC, Pasqualini JR. Effects of Org OD14 (Livial) and its metabolites on 17-beta-hydroxysteroid dehydrogenase activity in hormone-dependent MDF-7 and T-47D breast cancer cells. Anticancer Res 1999;19:261-267.
83. van de Ven J, Donker GH, Spsrong M, Blankenstein MA, Thijssen JHH. Effect of tibolone (Org OD14) and its metabolites on aromatase and estrone sulfatase activity in human breast adipose stromal cells and in MCF-7 and T47D breast cancer cells. J Steroid Biochem Molec Biol 2002;81:237-247.
84. Purohit A, Malini B, Hooymans C, Newman SP. Inhibition of oestrone sulphatase activity by tibolone and its metabolites. Horm Metab Res 2002;1:1-6.
85. Chetrite GS, Kloosterboer HJ, Philippe JC, Pasqualini JR. Effect of Org OD14 (Livial) and its metabolites on human estrogen sulphotransferase activity in the hormonedependent MDF-7 and T-47D, and hormoneindependent MDA-MB-231, breast cancer cell lines. Anticancer Res 1999;19:269-275.
86. Kloosterboer HJ. Endocrine prevention of breast: any role for tibolone? Eur J Cancer 2002;Suppl 6:S24-S25.
87. Gompel A, Siromachkova M, Lombet A, Kloosterboer HJ, Rostene W. Tibolone actions on normal and breast cancer cells. Eur J Cancer 2000;36:76-77.
88. de Gooyer ME, Overklift Vaupel Kleyn GT, Smits KC, Ederveen AGH, Verheul HAM, Kloosterboer HJ. Tibolone: a compound with tissue specific inhibitory effects on sulfatase. Mol Cell Endocrinol 2001;183:55-62.
89. Valdivia I, Ortega D. Mammographic density in postmenopausal women treated with tibolone, estriol or conventional hormone replacement therapy. Clin Drug Invest 2000;20:101-107.
90. Colacurci N, Fornaro F, De Franciscis P, Palermo M, del Vecchio W. Effects of different types of hormone replacement therapy on mammographic density. Maturitas 2001; 40:159-164.
91. Sendag F, Terek MC, Õzsener S, et al. Mammographic density changes during different postmenopausal hormone replacement therapies. Fertil Steril 2001;76:445-450.
92. Lundström E, Christow A, Kersemaekers W, et al. Effects of tibolone and continuous combined hormone replacement therapy on mammographic breast density. Am J Obstet Gynecol 2002;186:717-722.
93. Egarter C, Eppel W, Vogel S, Wolf G. A pilot study of hormone replacement therapy with tibolone in women with mastopathic breasts. Maturitas 2001;40:165-171.
94. Kenemans P, Bundred NJ, Foidart J-M, et al. Safety and efficacy of tibolone in breastcancer patients with vasomotor symptoms: a double-blind, randomised, non-inferiority trial. Lancet Oncol 2009;10:135-146.
95. Cummings SR, Ettinger B, Delmas PD, et al. The effects of tibolone in older postmenopausal women. New Engl J Med 2008;359:697-708.
96. Berning B, Kuijk CV, Kuper JW, Bennink HJ, Kicovic PM, Fauser BC. Effects of two doses of tibolone on trabecular and cortical bone loss in early postmenopausal women: a twoyear randomized placebo-controlled study. Bone 1996;19:395-399.
97. Lippuner K, Haenggi W, Birkhaeuser MH, Casez J-P, Jaeger P. Prevention of postmenopausal bone loss using tibolone or conventional peroral or transdermal hormone replacement therapy with 17b-estradiol and dihydrogesterone. J Bone Miner Res 1997;12:806-812.
98. Studd J, Arnala I, Kicovic PM, Zamblera D, Kröger H, Holland N. A randomized study of tibolone on bone mineral density in osteoporotic postmenopausal women with previous fractures. Obstet Gynecol 1998; 92:574-579.
99. Milner M, Harrison RF, Gilligan E, Kelly A. Bone density changes during two years’ treatment with tibolone or conjugated estrogens and norgestrel, compared with untreated controls in postmenopausal women. Menopause 2000; 7:327-333.
100. Rymer J. Effects of 8 years of treatment with tibolone 2.5 mg daily on postmenopausal bone loss. Osteoporos Int 2001;12:478-483.
101. Ederveen AGH, Kloosterboer HJ. Tibolone exerts an estrogenic effect on bone leading to
prevention of bone loss and reduction in bone resorption in ovariectomized rats. Osteoporos Int 1999;8:95.
102. Palomba S, Morelli M, Di Carlo C, Noia R, Pellicano M, Zullo F. Bone metabolism in postmenopausal women who were treated with a gonadotropin-releasing hormone agonist and tibolone. Fertil Steril 2002;78:63-68.
103. Wierik EJ, Hendricks PT, Boerstoel-Streefland M. Clinical background of women prescribed tibolone or combined estrogen + progestogen therapies: a UK MediPlus study. Climacteric 2004;7:197-209.
104. Velthuis-te Wierik EJ, Hendricks PT, Martinez C. Preferential prescribing of tibolone and combined estrogen plus progestogen therapy in postmenopausal women. Menopause 2007;14:518-527.