The Effects of Tibolone in Older Postmenopausal Women  

Steven R. Cummings, M.D., Bruce Ettinger, M.D., Pierre D. Delmas, M.D., Ph.D., Peter Kenemans, M.D., Ph.D., Victoria Stathopoulos, Ph.D., Pierre Verweij, Ph.D., Mirjam Mol-Arts, M.D., Lenus Kloosterboer, Ph.D., Lori Mosca, M.D., Ph.D., M.P.H., Claus Christiansen, M.D., John Bilezikian, M.D., Eduardo Mario Kerzberg, M.D., Susan Johnson, M.D., Jose Zanchetta, M.D., Diederich E. Grobbee, M.D., Ph.D., Wilfried Seifert, Ph.D., Richard Eastell, M.D., for the LIFT Trial Investigators   

ABSTRACT

Background : Tibolone has estrogenic, progestogenic, and androgenic effects.

Although tibolone prevents bone loss, its effects on fractures, breast cancer, and cardiovascular disease are uncertain.

Methods : In this randomized study, we assigned 4538 women, who were between the ages of 60 and 85 years and had a bone mineral density T score of -2.5 or less at the hip or spine or a T score of -2.0 or less and radiologic evidence of a vertebral fracture, to receive once-daily tibolone (at a dose of 1.25 mg) or placebo. Annual spine radiographs were used to assess for vertebral fracture. Rates of cardiovascular events and breast cancer were adjudicated by expert panels.

Results : During a median of 34 months of treatment, the tibolone group, as compared with the placebo group, had a decreased risk of vertebral fracture, with 70 cases versus 126 cases per 1000 person-years (relative hazard, 0.55; 95% confidence interval [CI], 0.41 to 0.74; P<0.001), and a decreased risk of nonvertebral fracture, with 122 cases versus 166 cases per 1000 person-years (relative hazard, 0.74; 95% CI, 0.58 to 0.93; P=0.01). The tibolone group also had a decreased risk of invasive breast cancer (relative hazard, 0.32; 95% CI, 0.13 to 0.80; P=0.02) and colon cancer (relative hazard, 0.31; 95% CI, 0.10 to 0.96; P=0.04). However, the tibolone group had an increased risk of stroke (relative hazard, 2.19; 95% CI, 1.14 to 4.23; P=0.02), for which the study was stopped in February 2006 at the recommendation of the data and safety monitoring board. There were no significant differences in the risk of either coronary heart disease or venous thromboembolism between the two groups.

Conclusions : Tibolone reduced the risk of fracture and breast cancer and possibly colon cancer but increased the risk of stroke in older women with osteoporosis. (ClinicalTrials.gov number, NCT00519857 [ClinicalTrials.gov].) 

COMMENT From Professor Alastair MacLennan:

LIFT was a well conducted quality large placebo controlled randomised trial which had adequate power to examine its primary outcome.

Compared to many long-term RCTs of HRT there was good therapy compliance, low discontinuation and unblinding rates. The primary outcome of a significant reduction in vertebral fractures on 1.25 mg tibolone (half the usual dose) was met at nearly 3 years despite the placebo group also taking calcium and Vitamin D supplements.

There are two important caveats to this trial.

Firstly, as in any RCT, the results apply only to the population studied, which in this case was an osteoporotic elderly population with an average age of 68 at trial entry. Secondly, there is the potential for *Type I statistical error when multiple secondary outcomes are analysed in retrospect and Type II error if the total numbers in the sub-analyses are small. Although all adverse events in general were a secondary safety outcome, stroke was not an a priori defined secondary (or expected) outcome and the expected number of strokes in this age group with osteoporosis over

3 years was around 25-30 in each arm of the trial. Indeed 28 stoke events were recorded in 2,249 tibolone treated women but only 13 in 2,257 women in the placebo group. Thus, the numbers were small and unexpectedly small in the placebo group. We shall never know if this statistically significant relative increase in stroke is real in this population or a chance statistical aberration. The conservative approach is to not prescribe tibolone in elderly osteoporotic women. However, an increase in stroke has not been seen in trials of tibolone in younger postmenopausal women and thus this possible risk cannot be scientifically or clinically applied to the postmenopausal women in their 50's and early 60's when tibolone is usually prescribed.

Long-term RCTS of any therapy are at great risk of early termination if protocols allow multiple sub-analyses of small numbers of secondary adverse outcome events if they are not prespecified in the protocol and the trial is underpowered to examine these outcomes.

*Type I errors are false positives from multiple sub-analyses and Type II errors are false results from small numbers.

COMMENT from the IMS 

Press Statement

ISSUED ON BEHALF OF THE INTERNATIONAL MENOPAUSE SOCIETY BY David Sturdee, President 

 August 14, 2008

The effects of tibolone in older postmenopausal women

The recent report from the LIFT study1, a large, randomized, controlled trial of the hormone replacement therapy (HRT) tibolone in older postmenopausal women with osteoporosis, provides some good news and some bad news. The primary aim of the study was to confirm that tibolone reduces the risk of osteoporotic vertebral fracture. The secondary aims were to evaluate the effects of tibolone on the risks of non-vertebral fractures, breast cancer, deep vein thrombosis and cardiovascular disease over 3-5 years of study. There was a significant reduction in the risk of vertebral fractures, with 70 cases in the treated group compared with 126 cases per 1000 person-years in the placebo group. The absolute reduction was greatest in women with a previous fracture (20.8/1000 person-years (per year)) compared to those who had not had such a fracture (4.6/1000 person-years). There was also a significant reduction (68%) in the risk of invasive breast cancer at 6 cases versus 19 cases/1000 person-years and a reduction of colon cancer (69%) at 4 versus 13/1000 person-years. These very worthwhile benefits have to be considered against an increased risk of stroke at 28 versus 13/1000 person-years, which was the reason for stopping the study earlier than planned at 3 years. However, this risk was much greater in women aged over 70 years, who represented 40% of the study population, who had 3.1 extra cases with stroke/1000 person-years compared to 1.8 extra cases in those aged 60-69 years.

This study has shown that:

• Tibolone reduces the risk of osteoporotic fractures similar to other treatments such as HRT, bisphosphonates and raloxifene
• Tibolone reduces the risk of invasive breast cancer similar to raloxifene and tamoxifen
• The only significant adverse effect was an increased risk of stroke which was greatest in women over the age of 70 years
• Tibolone should be used with caution in elderly women, where the potential benefit/risk ratio may be less than for younger women below the age of 70 years
• The age at which hormone therapy is given is critical, as was also shown in the Women's Health Initiative (WHI) studies with the effects of conventional HRT
• The dose of tibolone in this study (1.25 mg) was half what is generally available and widely used, so the implications for women using the 2.5 mg preparation are not clear, but the risk of stroke may be greater.  

Dr David Sturdee, President of the International Menopause Society, said:

This study confirms that tibolone reduces the risk of osteoporotic fractures and also reduces the incidence of invasive breast cancer. But in older women, or women with an increased risk of stroke, alternative treatments should be considered. As all the major studies over the last few years have shown, HRT is not a ‘one-size fits all' solution, and the age at initiation of treatment is critical. For every woman, therapy needs to be individualized in consultation with her medical adviser, depending on her age and the indications.

Reference

1. Cummings SR, Ettinger B, Delmas PD, et al. for the LIFT Trial investigators. The effects of tibolone in older postmenopausal women. N Engl J Med 2008;359:697-708

Content Updated 26 August, 2008