Tibolone Decreases Fracture, Breast Cancer, but Doubles Stroke Risk

Results of a randomized trial show that tibolone (Livial, Organon), approved for treatment of menopausal symptoms, has positive effects on fracture, breast cancer, and possibly colon cancer in women with osteoporosis over the age of 60 years but more than doubled the risk for stroke. The drug is not currently approved in the United States but is approved in 90 countries to treat menopausal symptoms and in 45 countries to treat osteoporosis.

Results of the study, called the Long-Term Intervention on Fractures with Tibolone (LIFT) trial, are published in the August 14 issue of the New England Journal of Medicine. The trial was supported by Organon.

In an interview, first author Steven R. Cummings, MD, from the San Francisco Coordinating Center and the California Pacific Medical Center Research Institute at the University of California, San Francisco, said that for women in their 50s using the drug for menopausal symptoms, it is probably safe and beneficial. However, he said, "women shouldn't start it or continue it if they're say, 65 or older, and should not start or continue it if they have strong risk factors for stroke such as diabetes or high blood pressure."

Long-Term Effects Unclear

Tibolone, a synthetic selective tissue estrogenic activity regulator (STEAR), has estrogenic, progestogenic, and androgenic effects, the authors write. Although it is known to prevent bone loss, its effects on fractures, breast cancer, and cardiovascular disease are uncertain.

In the LIFT trial, 4538 women between the ages of 60 and 85 years were randomized to receive 1.25 mg daily of tibolone or placebo. All 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. Annual spine radiographs were used to assess vertebral fracture, the primary outcome of the trial, and rates of cardiovascular events and cancer were adjudicated by expert panels.

The study was halted in February 2006 on the recommendation of the data and safety monitoring board when the increased risk for stroke became clear.

During a median of 34 months of treatment, women taking tibolone had a decreased risk for vertebral and nonvertebral fracture, particularly among those who had already had a fracture, as well as breast and colon cancer. However, women on tibolone also had an increase in the absolute risk for stroke of 2.3 per 1000 person-years and a more than doubling in the relative hazard of stroke. There was also a trend to a higher incidence of endometrial cancer in women with a uterus.

LIFT Trial: Outcomes with Tibolone vs Placebo Outcome  Relative Hazard  95% CI  P  
Vertebral fracture  0.55  0.41 – 0.74  < .001  
Nonvertebral fracture  0.74  0.58 – 0.93  .01  
Invasive breast cancer  0.32  0.13 – 0.80  .02  
Colon cancer  0.31  0.10 – 0.96  .04  
Stroke  2.19  1.14 – 4.23  .02  

However, there was no significant difference between the groups in the risk for either coronary heart disease or venous thromboembolism, although it was not powered to look at these outcomes. Other effects were similar to those seen with the combination of estrogen and progestin, including weight gain, vaginal discharge and infection, and breast discomfort.

What makes these results disappointing is the fact that the effects on fracture and breast cancer in particular were "pretty interesting," if not for the increased risk for stroke, Dr. Cummings said. Although any plan by the company to get the drug licensed in the United States is now moot with these results, the positive effect in reducing breast cancer and fractures is worth pursuing to elucidate the mechanism, he added. "If someone investigated that, we might find new ways to reduce the risk of breast cancer," he told Medscape Neurology & Neurosurgery.

Still Searching

In an editorial accompanying the paper, Ghada El-Hajj Fuleihan, MD, from the calcium metabolism and osteoporosis program at the American University of Beirut Medical Center, in Lebanon, writes that based on the LIFT trial results, the use of tibolone should be avoided in older women, those at high risk for stroke, and those who have breast cancer or are at high risk for breast cancer.

"The ideal postmenopausal hormone therapy, which has yet to be identified, should achieve several benefits, minimize risks, and enhance adherence in the individual patient while optimizing cost-effectiveness — a formidable medical and societal challenge," Dr. Fuleihan concludes. "The health risks and needs of a woman vary greatly during her 30 years of expected life after menopause, and health-risk profiles among women also differ. Therein lies the conundrum in searching for an ideal hormonal therapy."

The trial was supported by Organon. Dr. Cummings reports receiving consulting fees from or serving on a paid advisory board for Pfizer, Amgen, Eli Lilly, Procter & Gamble, GlaxoSmithKline, and Organon; disclosures for coauthors appear in the paper. Dr. Fuleihan reports receiving consulting and lecture fees from Eli Lilly, lecture fees from Novartis and Merck, and grants from Novartis and Sanofi-Aventis. No other potential conflict of interest relevant to this article was reported.

N Engl J Med. 2008;359:697-708, 753-755.

Reviewed by Ramaz Mitaishvili, MD

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