Tibolone reduces osteoporotic fracture risk and breast cancer risk, but increases the risk of stroke

Tibolone is a synthetic steroid available for prescription in the last two decades in the Europe and other countries, such as Brazil. It has been used for postmenopausal osteoporosis prevention and for treatment of menopausal symptoms.

Tibolone is a progestin that is metabolised in several tissues, forming the metabolites 3α-hydroxytibolone (3α-OH-tibolone) and 3β-hydroxytibolone (3β-OH-tibolone), which bind to the estrogen receptors. These two substances may be sulfated, which inactivates them. The metabolite 3β-OH-tibolone, by its turn, may be transformed into Δ4-isomer, which may be also formed directly from tibolone. The Δ4-isomer presents affinity for progesterone and androgens receptors [1].

This complicated net of esteroidal metabolisation is variable, in accordance with the tissue, depending on the relative concentrations of the enzymes that make such conversions. Thus, for example, in the endometrium, there is predominance of the conversion to Δ4-isomer and, therefore, the progestational action predominates [2].

The beneficial effect of tibolone in the control of the climacteric symptoms had already been demonstrated by some studies, disclosing reduction of the hot flushes, fatigue, insomnia, headache, among others [1].

On the other hand, and in contrast to that observed with the estroprogestative therapy, there are evidences that tibolone would not stimulate the proliferation of the mammary cells [2,3]. Part of this opinion is due to mammographic density studies, which demonstrated that this steroid did not increase the mammary density, in opposition to estrogen and estroprogestative therapies [4–6]. Even with long-term use of tibolone, as much as 10 years, no increase of mammary density has been shown [7].

With regard to bone metabolism, there are demonstrations of bone mineral density increase, reduction of bone turnover with reduction of the bone loss [8–12]. However, the majority of these studies evaluated relatively small populations and demonstration of reduction of fracture risk lacked, which made the substance has indication for prevention of bone loss and not for postmenopausal osteoporosis treatment [1].

This concept changed in August 2008 with the publication of the paper LIFT (Long-term intervention on fractures with tibolone) in the New England Journal of Medicine. It was a multicentric, multinational, randomised, placebo-controlled study which primarily evaluated the effect of tibolone 1.25 mg/day on the risk of vertebral fracture, and had, as secondary objectives, the evaluation of risks of non-vertebral fracture risk breakings, breast cancer, venous thromboembolism and cardiovascular disease [13].

The LIFT study included 4532 postmenopausal women, aging between 60 and 85 years old (average of 68.3 years) with densitometric osteoporosis according to the World Health Organization (t-score ≤ −2.5) or with t-score ≤ −2.0 plus radiological vertebral fracture.

The inclusion of patients was between June 2001 and July 2003, and in October 2005, the data and safety monitoring board of the study communicated a potential increase of risk of stroke. After this information, 496 patients discontinued study treatment. In February 2006, the data and safety monitoring board recommended the interruption of the study because of an increased risk of stroke and because the effect of treatment on vertebral fracture risk had already met the criteria for stopping the trial for efficacy.

According to the published article, the median time of treatment was 34 months, and 91% of the patients had received at least 80% of the doses of the study.

The results of LIFT study confirmed the increase of bone mineral density like previous studies. In this case, the increase for the spine was 4.8% and 3.1% for the femoral neck. However, the most important fact was the finding of 45% reduction of hazard risk for vertebral fracture and 26% reduction of non-vertebral fracture risk. According to the published data, the effect of tibolone in the fracture risk reduction was even greater for patients who presented a previous vertebral fracture.

The reduction observed in the hazard risk of fracture is similar to the one observed with other treatments with proven effectiveness for osteoporosis, such as bisphosphonates. This could place tibolone as a good therapeutical option for osteoporosis.

Another important finding of this study was the decrease in breast cancer risk among tibolone users. This group presented 0.9 cases/1000 person-years, whereas the placebo group had 2.8 cases/1000 person-years, corresponding to a risk reduction of 68%. There was one case of ductal carcinoma in situ in each group.

The hormonal-receptor status for the breast cancer cases was not available, but, probably, this reduction must have been associated with estrogen-receptor-positive cancer, more common among postmenopausal women.

This finding contrasts with Million Women Study (MWS) that showed a 45% increase in the risk of breast cancer among tibolone users, corresponding to a relative risk of 1.45. It should be considered that the number of analysed tibolone users in MWS was 18,186 amongst almost 830,000 postmenopausal women in the entire study [14]. It should also be taken into account that MWS was an observational study, based on questionnaire responders, and at the time of its publication, the question about the possibility of a selection bias emerged, that is, the physicians would have preferred to prescribe tibolone for high-risk for breast cancer postmenopausal women, instead of other hormonal therapies; however, the MWS manuscript informed that the authors had not noticed any significant difference between tibolone users' mammary risk profile and other hormonal therapy users' one.

More recently, a British case–control study did not find an increase in breast cancer risk among women who took tibolone or non-opposed estrogen, but found increased risk among estroprogestative therapy users [15].

On the other hand, LIBERATE (Livial intervention following breast cancer: efficacy, recurrence and tolerability endpoints) study, which intended to show no inferiority of tibolone 2.5 mg/day to placebo in breast cancer relapse among surgically treated women, was interrupted because the safety monitoring board has found higher relapse risk in the steroid study group [16].

LIFT study has also found a 69% reduction in colon cancer incidence in the group that received tibolone. On the other hand, nothing could be concluded about endometrial cancer, because there were four cases in the tibolone group and zero in the placebo one. MWS found greater risk of endometrial cancer among tibolone users, [17] but a randomised study observed no cases of this carcinoma [18]; however, the patients were younger than the LIFT study's ones, which could raise question on the possibility of increase of this risk in older women.

For the purposes of tibolone effect on breast and endometrium cancer risk, it should be considered that the precocious interruption of the study may have impaired a better knowledge of the real effect of the steroid. It is important to remember that for the effect in the breast cancer, the planning was 5 year of follow-up, which did not happen.

LIFT study did not find greater risk of venous thromboembolism or of coronary disease for tibolone users in comparison with placebo; however, it found greater risk for stroke. Tibolone group had 4.3 cases/1000 person-years against 1.9 in the placebo group, corresponding to a hazard risk of 2.19. A greater difference between the study groups' absolute risks was observed for women with 70 years and over. Moreover, the risk seemed to be greater in the first year of treatment.

An increased stroke risk with estrogen therapy has also been described in several studies, such as Women’s Health Initiative [19,20] and Nurses' Health Study [21] for estrogen associated with progestin therapy and also for non-opposed estrogen.

Tibolone may diminish HDL-cholesterol levels, without modifying LDL; thus, the total cholesterol levels diminish. On the other hand, it promotes reduction of triglyceride levels [22]. It is possible that this less favorable lipid profile had contributed for the effect on stroke risk; however, estrogen therapy not only promotes improvement of the lipid profile but it also increases stroke risk.

As there is an exponential increase of stroke risk according to age advance, the authors of LIFT did not recommend the use of tibolone for elderly women, or for those between 50 and 60 years who present other risk factors for stroke, such as blood hypertension, diabetes, smoking and atrial fibrillation [13].

In conclusion, the LIFT study has brought valuable information on tibolone, revealing its effect in reducing the osteoporotic fracture risk when used for postmenopausal women with osteoporosis diagnosis. It also disclosed the risk reduction of breast cancer in this group of women. In counterpart, it should be noted that this finding does not authorise its indication for women who had already had breast cancer, because LIBERATE study was interrupted due to the increase of relapse risk for this specific population. Finally, the LIFT still discloses that tibolone increases the risk of stroke, and this should be taken into account before its prescription.