Alison Palkhivala

September 17, 2008

September 17, 2008 (Montreal, Quebec) — An investigational new selective estrogen-receptor modulator (SERM) is showing promise in the treatment of osteoporosis among postmenopausal women, according to research presented here at the American Society for Bone and Mineral Research 30th Annual Meeting.

"Lasofoxifene, a SERM, has a very high affinity for the estrogen receptor, and previous studies have shown that it decreases bone turnover, increases bone density, and decreases LDL [low-density lipoprotein] cholesterol and all sorts of vulvovaginal [symptoms]," lead author Steven Cummings, MD, told the audience during his presentation. He is founding director of the San Francisco Coordinating Center and a professor of medicine at the University of California at San Francisco.

"Lasofoxifene is really interesting because the development of the selective estrogen-receptor modulators is a very attractive scientific idea." Graham Russell, MD, PhD, told Medscape Medical News. "It's an older idea, and many of us have been very surprised that there's been nothing [new] since raloxifene." Dr. Russell is a professor of musculoskeletal pharmacology at the Nuffield Department of Orthopaedic Surgery, University of Oxford, in England. He moderated the session in which the data on lasofoxifene were presented.

For the Postmenopausal Evaluation and Risk-Reduction with Lasofoxifene (PEAL) trial, 8556 women, aged 59 to 80 years, with T-scores at the lumbar spine or femoral neck between –2.5 and –4.5 were randomly assigned to receive lasofoxifene 0.25 mg once daily, lasofoxifene 0.5 mg once daily, or placebo. All patients also received 1 g of calcium and 400 to 800 IU of vitamin D daily. This was a 3-year trial with a 2-year extension phase.

Dr. Cummings presented data collected after 5 years of therapy based on an intent-to-treat analysis. Overall, 77% of participants remained in the trial for the duration. Those taking the 0.5 mg dose of lasofoxifene, selected as the relevant clinical dose, had average increases in bone mineral density at the spine and femoral neck of about 3%. They also had a 42% reduced risk for vertebral fracture and a 24% reduced risk for nonvertebral fracture, compared with those on placebo (P < .001). Although there was a trend toward reduced hip-fracture rates with 0.5 mg of lasofoxifene, compared with placebo, it did not reach statistical significance.

High-dose lasofoxifene therapy was also associated with an 81% reduced risk for estrogen-receptor positive (ER+) breast cancer (P < .001), a 68% reduced risk for major coronary heart disease (CHD) events (P = .016). Although the risk for stroke was also lower with lasofoxifene, the risk for transient ischemic attacks did not differ from the placebo group.

"The advantage of it over raloxifene is that it has an effect on nonvertebral fractures," said Dr. Russell. "It doesn't reach significance for hip fractures, but it seems to be more potent than raloxifene. And it has other benefits, particularly the cardiovascular benefits and the breast cancer benefits."

There were no differences between the patients on high-dose lasofoxifene and those on placebo with respect to rates of endometrial cancer or hyperplasia. Compared with placebo, the rate of venous thromboembolism (VTE), however, was about double for 0.5 mg of lasofoxifene. Interestingly, mortality rates were slightly higher among those taking the 0.25-mg dose of the drug than among those taking placebo, but there was no difference in mortality rates between those tsaking the high dose of lasofoxifene and those taking placebo.

"Clearly, it has the usually expected safety issues; for instance, venous thromboembolism — the story that is there for all SERMS it seems, and for estrogen as well," said Dr. Russell.

"Lasofoxifene is a new and potent SERM for women with osteoporosis," said Dr. Cummings. "At the 0.5 mg dose, it reduces the risk for vertebral and nonvertebral fractures, ER+ breast cancer, major CHD events, and stroke, but it [also] increases the risk of VTE."

The study was funded by Pfizer, the manufacturer of lasofoxifene, and Dr. Cummings has received funding from Pfizer.

American Society for Bone and Mineral Research (ASBMR) 30th Annual Meeting: Abstract 1288. Presented September 16, 2008.

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