Updated clinical recommendations for the use of tibolone in Asian women

Figures & data

Table 1  Consensus statements on the use of tibolone and levels of supporting evidence

Updated statements and/or new evidence published since 2005	Level of evidence*
Tibolone is as effective as currently used EPT/ET regimens in the management of climacteric symptoms^Citation34	1b
Tibolone treats vaginal atrophy and alleviates local vaginal symptoms^Citation34	1b
Tibolone has a positive effect on sexual well-being and is more effective than oral EPT/ET in some respects, namely arousal, desire, and satisfaction^Citation8,Citation34	1b
Tibolone positively affects mood and quality of life^Citation8,Citation34	1b
Tibolone prevents bone loss and is as effective as standard doses of EPT/ET and more effective than raloxifene^Citation36	1b
Tibolone reduces the risk of vertebral and non-vertebral fracture in older osteoporotic women. The absolute reduction was greater among women who had already had a vertebral fracture than among those who had not^Citation16	1b
Tibolone does not stimulate the endometrium or induce endometrial hyperplasia or carcinoma in postmenopausal women in randomized controlled clinical trials and has a low incidence of bleeding^Citation34,Citation35,Citation61	1b
In observational studies, an increased relative risk of endometrial cancer has been shown^Citation56,Citation57	3b
Tibolone causes less breast tenderness and less mastalgia than EPT^Citation34	1b
Tibolone does not increase mammographic density	2b
Tibolone, taken by women with a personal history of breast cancer, is associated with an increased risk of recurrence^Citation18	1b
The evidence of tibolone use and increased risk of breast cancer from observational studies remains inconclusive^Citation41	3b
Tibolone 1.25 mg does not increase breast cancer risk in older osteoporotic women with no history of breast cancer^Citation16	1b
There are still no hard endpoint data on the effect of tibolone on cardiovascular health^Citation38	1b
Tibolone has different effects on lipids compared with EPT/ET^Citation38	1b
Tibolone increases CIMT in a manner similar to EPT^Citation38	1b
In one randomized, controlled trial, use of tibolone 1.25 mg in older women was associated with an increased risk of stroke^Citation16. Hence, tibolone should be used with caution in elderly women (i.e. over 60 years) and should not be used in those who have strong risk factors for stroke	1b
Tibolone did not increase the risk of stroke, VTE or myocardial infarction in observational studies^Citation37,Citation40	2b

*Definitions of levels of evidence: 1b, individual randomized trials; 2b, individual cohort study; 3b, individual case–control study⁵⁵

EPT, estrogen–progestogen therapy; ET, estrogen therapy; CIMT, carotid intima-media thickness; VTE, venous thromboembolism

Figure 1  Algorithm for the use of tibolone in Asian menopausal women. *, Tibolone treatment is preferable to hormone replacement therapy (HRT) for postmenopausal women who report mastalgia, breast tenderness, increasing mammographic density and sexual problems. ^†, Contraindications for tibolone should be considered the same as for estrogen–progestogen therapy/estrogen therapy (EPT/ET). In addition, tibolone should only be used in women with no history of breast cancer. Tibolone should be used with caution in elderly women (i.e. over 60 years) and should not be used in those who have strong risk factors for stroke. OSTA, Osteoporosis self-assessment tool for Asians; FRAX, World Health Organization's fracture risk assessment tool; BP, blood pressure; BMD, bone mineral density; DXA, dual-energy X-ray absorptiometry; AEs, adverse events

Appendix 1 Summary of data from large international clinical studies of tibolone published since 2005

	Long-Term Intervention on Fractures with Tibolone (LIFT)^Citation16	Tibolone Histology of the Endometrium and Breast Endpoints Study (THEBES)^Citation35	Livial® Intervention following Breast cancer: Efficacy, Recurrence and Tolerability Endpoints (LIBERATE)^Citation18
Design	Randomized, placebo-controlled study of older postmenopausal women (60–85 years) with hip and/or spine BMD T score of ≤− 2.5, or ≤− 2.0 with vertebral fracture	Double-blind study of postmenopausal women randomized (1 : 1 : 2) to receive different doses of tibolone or CEE + MPA	Randomized, double-blind, placebo-controlled study to assess safety and efficacy of tibolone in women with vasomotor symptoms and history of breast cancer
n	4538	3240	3098
Mean age (years)	68.3	54.4	52.7
Dose	Tibolone 1.25 mg/day vs. placebo	Tibolone 1.25 mg/day vs. tibolone 2.5 mg/day vs. CEE/MPA 0.625/2.5 mg/day	Tibolone 2.5 mg/day vs. placebo
Primary endpoint	Reduction in incidence of new vertebral fractures after 3 years	Endometrial safety (hyperplasia, cancer) of tibolone (1.25 and 2.5 mg/day) after 1 and 2 years	To demonstrate the non-inferiority of tibolone compared with placebo regarding breast cancer recurrence
Major findings	Fractures	Endometrium	Breast cancer recurrence
	Tibolone reduced the risk of both vertebral (45% compared with placebo) and non-vertebral (26% compared with placebo) fractures Tibolone showed a 6.6% increase in lumbar spine BMD compared to 1.4% with placebo at Year 4 (p < 0.001) Total hip BMD increased by 2.8% with tibolone by Year 4, but no change was seen with placebo (p < 0.001)	No incidence of endometrial hyperplasia or cancer with tibolone 1.25 or 2.5 mg; two cases of endometrial hyperplasia observed in CEE/MPA group; no endometrial carcinoma in any group. Small mean increase in double-wall endometrial thickness by TVUS in both tibolone and CEE/MPA over 2 years but no difference between groups Both treatments considered safe with regard to endometrium at study end	Overall, increased risk of recurrence with tibolone compared with placebo: 15.2% recurrence with tibolone vs. 10.7% with placebo (p = 0.001). Difference in incidence was not immediate, but emerged after 1 year. Most pronounced difference was observed for distal recurrence: 11.0% with tibolone vs. 7.8% with placebo (p = 0.007) Hot flushes Significantly greater decrease from baseline with tibolone than placebo at all time points (p < 0.0001)
	Stroke	Vaginal bleeding/spotting	BMD
	Increased risk of stroke within 1 year compared with placebo, with a relative hazard of 2.19 by 4 years (95% CI 1.4–4.23); p = 0.02]	Over 2 years, vaginal bleeding occurred in 13.3%, 20.2% and 42.6% of those in tibolone 1.25 mg, 2.5 mg and CEE/MPA groups, respectively	Significantly greater increases with tibolone than placebo from baseline in lumbar (3.3%) and hip BMD (2.9%) (p < 0.0001)
	Cancer	Breast pain
	Decreased risk of invasive breast cancer with tibolone compared with placebo (relative hazard 0.32; 95% CI 0.13–0.80; p = 0.02)	4.3% in tibolone groups (combined) vs. 12.7% with CEE/MPA (p < 0.001)
	Decreased risk of colon cancer with tibolone compared with placebo (relative hazard 0.31; 95% CI 0.10–0.96; p = 0.04)
Notes	Study stopped prematurely after a mean follow-up period of 2.9 years as endpoints had been reached and stroke increased		Discontinued just before 3 years' exposure as unlikely to meet pre-specified inferiority criteria

	Trial to compare the effects of tibolone (Livial®) and continuous combined low-dose E2/NETA (Activelle®) (TOTAL)^Citation34	Osteoporosis Prevention and Arterial effects of tiboLone (OPAL)^Citation38	Livial® International Study in sexual Arousal disorders (LISA)^Citation8,Citation61	Study of Tibolone's Effects on osteoPenia (STEP)^Citation36,Citation62
Design	Multinational, randomized, double-blind study of tibolone vs. low-dose continuous combined E2/NETA	Multicenter, randomized controlled trial of tibolone vs. CEE/MPA or placebo	Randomized, controlled trial comparing tibolone with continuous combined transdermal E2/NETA	Multicenter randomized, double-blind, parallel-group, comparative trial to compare response to tibolone and raloxifene in osteopenic women
n	572	886	403	308
Mean age (years)	55	58 (mean years since menopause: 10)	56	66
Dose	Tibolone 2.5 mg; E2/NETA 1 mg/0.5 mg	Tibolone 2.5 mg vs. CEE/MPA 0.625/2.5 mg vs. placebo	Tibolone 2.5 mg; E2/NETA 50 μg/140 μg	Tibolone 1.25 mg; raloxifene 60 mg
Primary endpoint	Compare vaginal bleeding pattern between treatments	Change in mean CIMT	Changes in composite subscore for desire, arousal and satisfaction domains of the FSFI; vaginal bleeding and breast symptoms	Effects of treatment on BMD in osteopenic women
Major findings	Bleeding	CIMT	Sexual dysfunction	BMD
	Significantly less bleeding with tibolone compared with E2/NETA during first 3 months (18.3% vs. 33.1%; p < 0.001); effect on bleeding pattern sustained throughout study Vasomotor Significant and similar reduction in prevalence of vasomotor symptoms with both treatments Vaginal tissue atrophy Similar increases for both treatments in Karyopyknotic index and Maturation index through week 48 (p < 0.001 vs. baseline) Sexuality and quality of life Greater score on McCoy's Sexuality Questionnaire with tibolone (p < 0.05 between groups); sexual interest significantly improved with tibolone vs. E2/NETA (p = 0.003 by week 48); treatments comparable in terms of effect on health-related quality of life Breast tenderness Significantly less frequently reported in tibolone group (3.2% vs. 9.8% with E2/NETA; p < 0.001)	Both tibolone and CEE/MPA showed similar mean common CIMT progression that was greater than with placebo CVD risk factors Mean total cholesterol was reduced by 9.3%, 8.1% and 2.5% with tibolone, CEE/MPA and placebo, respectively Mean HDL cholesterol decreased by 21.7% from baseline with tibolone, but increased by 9.2% and 1.2% with CEE/MPA and placebo, respectively NOTE Subsequent comment published that OPAL shows that neither tibolone nor CEE/MPA has beneficial effects on atherosclerosis, but does not convincingly show harm^Citation39	FSFI subscores for arousal, desire, satisfaction showed a significant increase from baseline (p < 0.001) for both tibolone (32%) and E2/NETA (26%; per protocol analysis: p = 0.036 between groups) Total FSFI score showed a significant increase from baseline (p < 0.001) for tibolone (31%) and E2/NETA (26%; per protocol analysis: p = 0.025 between groups) FSDS showed significant reduction from baseline with both treatments (p < 0.001) Vaginal bleeding Incidence of spotting/bleeding was 16% vs. 56% (weeks 1–12) and 12% vs. 51% (weeks 13–24) for tibolone and E2/NETA, respectively (p < 0.001) Vaginal hemorrhage reported as an adverse event by 11% on E2/NETA and none on tibolone (p < 0.001) Breast symptoms Overall incidence of breast signs and symptoms was 4% with tibolone vs. 11% with E2/NETA (p = 0.015 between groups)	Significant (p < 0.001) increases in lumbar spine BMD at week 52 for tibolone (2.2%) vs. raloxifene (1.2%; p < 0.01 between groups) and at week 104 ( 3.8% and 2.1% respectively; p < 0.001 between groups) Tibolone significantly increased hip BMD at week 52 (p < 0.05) and at week 104 increase was 1.26% (p < 0.0001) with tibolone vs. 0.44% with raloxifene (p < 0.05 between groups)

BMD, bone mineral density; CEE, continuous combined conjugated equine estrogen; MPA, medroxyprogesterone acetate; TVUS, transvaginal ultrasonography; 95% CI, 95% confidence interval; E2/NETA, estradiol plus norethisterone acetate; CIMT, common carotid intima media thickness; FSFI, Female Sexual Functioning Index; CVD, cardiovascular disease; HDL, high density lipoprotein; FSDS, Female Sexual Distress Scale

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