Investigational Tibolone Lowers Fracture Rate but Increases Stroke Risk

By Michael Smith
SAN FRANCISCO, 14 aug 2008--The relative risk of vertebral fracture was reduced by 45% by the use of the selective tissue estrogenic activity regulator tibolone, an investigational agent to ease menopause symptoms or prevent osteoporosis, researchers here said.
Tibolone also reduced the risk of non-vertebral fracture and invasive breast cancer in a randomized, double-blind, placebo-controlled study, according to Steven Cummings, M.D., of the California Pacific Medical Center, and colleagues.
But tibolone also was associated with an increased risk of stroke, which led in part to the study being stopped in February 2006, Dr. Cummings and colleagues reported in the Aug. 14 issue of the New England Journal of Medicine.
Tibolone is not approved in the U.S., although it is marketed under the name Livial in 90 other countries. The trial -- Long-Term Intervention on Fractures with Tibolone, or LIFT -- was sponsored by Organon, now part of Schering-Plough, which manufactures the drug.
The study enrolled 4,538 women between ages 60 and 85, who had a bone mineral density T score of no more than minus 2.5 at the hip or spine or a T score of minus 2.0 or less and radiologic evidence of a vertebral fracture.
They were randomized to placebo or once-daily tibolone at a dose of 1.25 milligrams. All patients were also given up to 630 to 1,260 milligrams of calcium citrate and 400 to 800 IU of vitamin D3 daily.
The trial's data safety monitoring board halted the study after a median of 34 months of treatment because the risk of stroke in the tibolone arm was more than twice as high as in the placebo arm, and because the study had met a predetermined stopping point for efficacy, the researchers said.
Analysis of the data found:
A vertebral fracture rate of 70 per 1,000 person-years in the tibolone arm versus 126 among those getting placebo. The relative hazard was 0.55 with a 95% confidence interval from 0.41 to 0.74, which was significant at P<0.001.
A non-vertebral fracture rate of 122 cases per 1,000 person-years for tibolone, compared with 166 cases for placebo. The relative hazard was 0.74 with a 95% confidence interval from 0.58 to 0.93, which was significant at P=0.01.
A decreased risk of invasive breast cancer in the tibolone group. The relative hazard was 0.32 with a 95% confidence interval from 0.13 to 0.80, which was significant at P=0.02.
A lower risk of colon cancer for the tibolone group. The relative hazard was 0.31 with a 95% confidence interval from 0.10 to 0.96, which was significant at P=0.04.
However, the tibolone group had an increased risk of stroke. The relative hazard was 2.19 with a 95% confidence interval from 1.14 to 4.23, which was significant at P=0.02.
The excess risk of stroke was mainly seen in the first year of treatment and in older women, the researchers said.
Overall, the difference in absolute risk of stroke for women in the tibolone group was an increase of 2.3 per 1,000 person-years compared with placebo.
However, for participants 70 or older, the difference in absolute risk was 3.1 per 1,000 person-years, while for those younger than 70, the difference in absolute risk was 1.8 per 1,000 person-years, Dr. Cummings and colleagues found.
The study had limited power to analyze outcomes such as coronary heart disease and endometrial cancer, the researchers noted. Also, longer treatment might change the risk-benefit profile, they said.
The efficacy of the drug in treating menopausal symptoms and preventing bone loss has led to its widespread approval, although its effects on major health outcomes has been "unclear," said Ghada El-Hajj Fuleihan, M.D., of the American University of Beirut Medical Center, in Beirut, Lebanon.
Writing in an accompanying editorial, Dr. El-Hajj Fuleihan said the LIFT study begins to clarify that picture, with clear evidence that the drug should not be used in older women or in those with strong risk factors for stroke (hypertension, smoking, diabetes, and atrial fibrillation).
But the long-term effects of the drug are still unknown, Dr. El-Hajj Fuleihan said.
The study confirms that tibolone reduces both the risk of fractures and the incidence of invasive breast cancer, said David Sturdee, M.D., of Solihull Hospital, in Solihull, England, and the president of the International Menopause Society.
But, he cautioned in a statement, no form of hormone replacement therapy is a "one-size-fits-all solution."
"In older women, or women with an increased risk of stroke, alternative treatments should be considered," Dr. Sturdee said. "For every woman, therapy needs to be individualized in consultation with her medical adviser, depending on her age and the indications."
The study was supported by Organon. Dr. Cummings reported financial links with Amgen, Eli Lilly, Procter & Gamble, GlaxoSmithKline, and Organon.
Dr. El-Hajj Fuleihan reported financial links with Eli Lilly, Novartis, Merck, and sanofi-aventis.
Primary source: New England Journal of MedicineSource reference:Cummings SR, et al "The Effects of Tibolone in Older Postmenopausal Women" N Engl J Med 2008; 359: 697-708. Additional source: New England Journal of MedicineSource reference: El-Hajj Fuleihan G "Tibolone and the Promise of Ideal Hormone-Replacement Therapy" N Engl J Med 2008; 359: 753-55.