Tibolone reduced the risk of vertebral and nonvertebral fractures as well as breast cancer in a large international clinical trial involving older women with osteoporosis, but it also raised the risk of stroke, researchers said.
The drug also appeared to reduce the risk of colon cancer in this study, but tripled the rate of vaginal bleeding and endometrial thickening that required biopsy, reported Dr. Steven R. Cummings and his associates in the Long-Term Intervention on Fractures with Tibolone (LIFT) study.
Tibolone is approved for treating menopausal symptoms in 90 countries and for treating osteoporosis in 45, but is not approved for either indication in the United States.
The LIFT study, sponsored by Organon, compared daily tibolone with placebo in 4,538 osteoporotic women aged 60–85 years who were treated at 80 medical centers in 22 countries. About 26% of these subjects had already had a vertebral fracture.
The trial was halted early, after a median of 34 months of treatment, when an interim analysis showed that the drug doubled the risk of stroke, particularly during the first year of use and in women aged older than 70 years. That analysis also showed that tibolone met the criteria for efficacy in preventing fractures.
At the time the study was stopped, more than 90% of the subjects had received at least 80% of their scheduled doses of tibolone or placebo.
The data showed that tibolone decreased the relative risk of vertebral fracture by 45% and the relative risk of nonvertebral fractures by 26%, said Dr. Cummings of the California Pacific Medical Center Research Institute and the University of California, San Francisco, and his associates.
The drug appeared to be particularly effective at preventing fractures in women who had already had a vertebral fracture, reducing the relative risk of further vertebral fracture by 61% and the relative risk of nonvertebral fracture by 47%, the investigators said (N. Engl. J. Med. 2008;359: 697–708).
The magnitude of these bone effects was similar to that reported for estrogen, bisphosphonate, and raloxifene therapy.
Tibolone also cut the relative risk of breast cancer by 68%, a reduction similar to that reported for tamoxifen or raloxifene.
It is not clear why the drug was found to prevent breast cancer in this study when it was found to raise the risk of the disease in previous observational studies, Dr. Cummings and his colleagues noted.
Compared with placebo, tibolone appeared to decrease the rate of colon cancer. It showed no significant effect on other cancers.
Tibolone more than doubled the risk of stroke. “Among patients 70 years of age or older, the risk of stroke was 6.6 per 1,000 person-years in the tibolone group and 3.4 per 1,000 person-years in the placebo group,” the researchers said.
The drug therefore is contraindicated in women older than 70 and “in women who have strong risk factors for stroke, such as hypertension, smoking, diabetes, and atrial fibrillation.”
Nearly 10% of women receiving tibolone reported abnormal vaginal bleeding, and 499 of them required endometrial biopsy, compared with only 136 women taking placebo.
Four women in the tibolone group developed endometrial cancer, compared with none in the placebo group.
Other adverse effects of tibolone included weight gain, breast pain, vaginal discharge and infection, pelvic pain, and elevations in liver enzymes.
Nineteen percent of the tibolone group discontinued treatment because of adverse events, compared with 13% of the placebo group.
Tibolone did not appear to have a deleterious effect on venous thromboembolism or coronary heart disease events. However, this study was not adequately powered to assess the drug's effects on these cardiovascular outcomes.
Dr. Cummings reported that he has received consulting fees from, or has served on a paid advisory board for, Pfizer, Amgen, Eli Lilly & Co., GlaxoSmith-Kline, Procter & Gamble, and Organon.
It's not clear why the drug was found to prevent breast cancer when it was found to raise the risk in previous studies. DR. CUMMINGS