Tibolone

Tibolone is a synthetic steroid with oestrogenic, progestational and androgenic properties. It was first marketed in April 1991 for post-menopausal vasomotor symptoms. Tibolone is also licensed for the prevention of osteoporosis and it appears the effect of tibolone on preventing bone loss is similar to other types of menopausal hormonal therapy (MHT) (1). The surrogate measure of bone density show increases of the same magnitude as with alendronate (2).

In the LIFT randomised study in older postmenopausal women with low bone mineral density,4538 women age 60-85 years with osteoporosis on the basis of BMD or minimal trauma vertebral fracture, were randomised to 1.25mg tibolone or placebo. After a median of 34 months, there was a significant reduction in the absolute risk of both vertebral and non-vertebral fractures. The reduction in fracture risk was also seen in women with a pre-existing vertebral fracture. (2)

A major advantage is that it is a bleed-free form of hormone replacement therapy.

Tibolone and cardiovascular disease:

• there is evidence that tibolone increased the risk of stroke in patients with osteoporosis (2)
  • the risk of stroke rises exponentially with age: therefore tibolone should generally not be used in elderly women although conversely a Cochrane systematic review which included 4 RCT’s, showed no increase in stroke rate with tibolone use (3)
    • "..Tibolone has been used by women between the ages of 50 and 60 years for menopausal symptoms and the prevention of osteoporosis when the risk of stroke was low, but it should be avoided in women who have strong risk factors for stroke, such as hypertension, smoking, diabetes, and atrial fibrillation.." (2)
• there has been no evidence of an increased risk of thromboembolism with tibolone (2); in contrast to the increased risk that has been seen with hormone therapy and selective estrogen-receptor modulators (SERMs) (2)
• there is no evidence of increased risk of coronary events associated with tibolone use (2)

Tibolone and cancer risk:

• Preclinical studies looked at the effect of tibolone on oestrogen metabolism in the breast and in breast cancer cells. As it slowed proliferation and increased apoptosis in the breast cancers it was thought to be safer for women at risk of or who had a history of breast cancer. In a small clinical trial it was associated with less mammographic breast density, compared to combined MHT and no different to placebo after six months. (4)
• while there are very few randomized trials of tibolone in women without a history of breast cancer with breast cancer as a secondary endpoint, a systematic review of four studies showed no significant increase in breast cancer (3).
• in contrast, epidemiological studies including the Million Women Study, reported an increase in breast cancer among current users of MHT including tibolone (5, 6), and the LIBERATE study reported increased recurrence of breast cancer in patients taking tibolone (7)
• it is therefore currently recommended that women with a history of breast cancer should not be prescribed tibolone (8).
• a Danish registry study found an increased risk of endometrial malignancy in Tibolone users compared to non-users (9). Importantly though, the Cochrane systematic review which included 8 randomised controlled trials comparing Tibolone with placebo, did not show any difference between the two groups (3).
• there were however, low case number reported in both groups and follow up only to 3 years. It is therefore recommended that women taking Tibolone who experience unexpected post-menopausal bleeding undergo investigation as for women who take conventional MHT
• tibolone may be associated with a reduction in risk of colon cancer (2)

Tibolone and osteoporosis:

• study evidence reveals that tibolone was associated with a reduction in the risk of vertebral fracture in older women with osteoporosis (2)
  • absolute reduction was greater (20.8 per 1000 person-years) among women who had already had a vertebral fracture than among those who had not had such a fracture (4.6 per 1000 person-years)
  • magnitude of the reduction in relative risk was similar to those observed for therapy with oestrogen, bisphosphonates, and raloxifene
  • also associated with a reduction in the risk of nonvertebral fracture, an improvement that was also greater in women who had already had a vertebral fracture
    • a similarly decreased risk of nonvertebral fracture has been demonstrated for oestrogen therapy
    • however the risk of non vertebral fractures has not been shown for not for raloxifene and tamoxifen
  • Tibolone may be considered to prevent vertebral and non-vertebral fractures in younger postmenopausal women, particularly those with menopausal symptoms (10)

Summary of results of the Million Women Study

Type of HRT Use at Recruitment

• figures based on use per 1000 never-users of HRT or current users of tibolone or HRT over a 5 year period.
• based on the values observed for never-users of HRT in the MWS and are expressed over a 5 year period
• *results from a meta-analysis of worldwide data suggest a figure of between 6 and 8 per 1000

The risk of breakthrough bleeding in the earlier months of therapy is 10-15%.

It is recommended that women within a year of their last natural menstrual period should not receive tibolone.

• tibolone is also not suitable for premenopausal women - in both cases it may cause unacceptable irregular bleeding (11)

Tibolone is also contraindicated in women with any history of arterial thromboembolic disease, including stroke, TIA, myocardial infarction and angina (12).

Summary

Tibolone is indicated for the management of vasomotor symptoms associated with the menopause and for the prevention of bone loss. It can be considered an alternative to conventional MHT where improvement in libido is desired. Its effect on lipid metabolism and haemostasis are less certain, while the long-term effects of tibolone on breast cancer and cardiovascular disease remain unknown. It is not recommended for use in women with a history of breast cancer and should be used with caution in women over age 60 because of the increased stroke risk.

Reference:

1. Berning B, Bennink HJ, Fauser BC. Tibolone and its effects on bone: a review. Climacteric. 2001;4(2):120-36

2. Cummings SR et al.The effects of tibolone in older postmenopausal women. N Engl J Med. 2008 Aug 14;359(7):697-78.

3. Formoso G, Perrone E, Maltoni S, Balduzzi S, Wilkinson J, Basevi V, et al. Short-term and long-term effects of tibolone in postmenopausal women. Cochrane Database Syst Rev. 2016;10(10)

4. Lundstrom E, Christow A, Kersemaekers W, Svane G, Azavedo E, Soderqvist G, et al. Effects of tibolone and continuous combined hormone replacement therapy on mammographic breast density. Am J Obstet Gynecol. 2002;186(4):717-22.

5. Beral V, Reeves G, Bull D, Green J, Million Women Study C. Breast cancer risk in relation to the interval between menopause and starting hormone therapy. J Natl Cancer Inst. 2011;103(4):296-305.

6. Brusselaers N, Tamimi RM, Konings P, Rosner B, Adami HO, Lagergren J. Different menopausal hormone regimens and risk of breast cancer. Ann Oncol. 2018;29(8):1771-6.

7. Kenemans P, Bundred NJ, Foidart JM, Kubista E, von Schoultz B, Sismondi P, et al. Safety and efficacy of tibolone in breast-cancer patients with vasomotor symptoms: a double-blind, randomised, non-inferiority trial. Lancet Oncol. 2009;10(2):135-46.

8. Santen RJ, Stuenkel CA, Davis SR, Pinkerton JV, Gompel A, Lumsden MA. Managing Menopausal Symptoms and Associated Clinical Issues in Breast Cancer Survivors. J Clin Endocrinol Metab. 2017;102(10):3647-61.

9. Lokkegaard ECL, Morch LS. Tibolone and risk of gynecological hormone sensitive cancer. Int J Cancer. 2018;142(12):2435-40.

10. SIGN (June 2020). Management of osteoporosis and the prevention of fragility fractures

11. Electronic Medicines Compendium: Tibolone. 2024.

12. NICE 2024: BNF - Drugs, Tibolone. Contra-indications