PEARL: High-dose lasofoxifene reduced risk for fracture, breast cancer, coronary events

Postmenopausal women with osteoporosis who received once-daily lasofoxifene at a dose of 0.5 mg experienced decreases in the risks for both vertebral and nonvertebral fractures as well as estrogen receptor-positive breast cancer, coronary heart disease and stroke, according to results of a trial.

However, the nonsteroidal selective estrogen-receptor modulator (Fablyn, Pfizer) was associated with an increased risk for venous thromboembolic events.

Postmenopausal Evaluation and Risk-Reduction with Lasofoxifene, or PEARL, was an international, randomized, placebo-controlled trial. Women were assigned to 1 g calcium and 400 IU to 800 IU vitamin D and placebo during a six- to eight-week run-in period and then randomly assigned to lasofoxifene, at a dose of 0.25 mg (n=1,753) or 0.5 mg per day (n=1,777), or placebo (n=1,820). All women were aged between 59 and 80 years and had a bone mineral density T score of <–2.5 mg at the femoral neck or spine.

The primary endpoint was vertebral fracture at three years, but the trial was extended to five years to include nonvertebral fracture and ER-positive breast cancer as two additional coprimary endpoints.

After five years of treatment, high-dose lasofoxifene (0.5 mg) reduced the risk for vertebral fracture (13.1 cases per 1,000 person-years vs. 22.4 cases per 1,000 person-years; HR=0.58) and nonvertebral fracture (18.7 cases per 1,000 person-years vs. 24.5 cases per 1,000 person-years; HR=0.76) compared with placebo.

Risk was also decreased for ER-positive breast cancer (0.3 cases per 1,000 person-years vs. 1.7 cases per 1,000 person-years; HR=0.19), CHD events (5.1 cases per 1,000 person-years vs. 7.5 cases per 1,000 person-years; HR=0.68) and stroke (2.5 cases per 1,000 person-years vs. 3.9 cases per 1,000 person-years; HR=0.64) compared with placebo.

Women assigned to low-dose lasofoxifene (0.25 mg) also had a decreased risk for vertebral fracture (16 cases per 1,000 person-years vs. 22.4 cases per 1,000 person-years; HR=0.69) and stroke (2.4 cases per 1,000 person-years vs. 3.9 cases per 1,000 person-years; HR=0.61) compared with placebo.

However, the high and low doses of lasofoxifene were associated with an increased risk for venous thromboembolic events when compared with placebo (3.8 cases per 1,000 person-years vs. 2.9 cases per 1,000 person-years vs. 1.4 cases per 1,000 person-years).

According to the researchers, the decreased risk for vertebral fractures is similar to that observed with raloxifene, tibolone, oral bisphosphonates and estrogen therapy, and the decreased risk for nonvertebral fractures is similar to that of other antiresorptive therapies.

Mortality rates per 1,000 person-years were seven in the low-dose lasofoxifene group, 5.7 in the high-dose group and 5.1 in the placebo group.

Five years of treatment with lasofoxifene did not increase the risk for endometrial hyperplasia or cancer. Endometrial cancer was reported in three women in the placebo group, two in the low-dose group and two in the high-dose group. Similar to other selective ER modulators, it was associated with a significant increase in hot flushes and leg cramps.

“The results of the PEARL trial suggest that lasofoxifene offers no major clinically important benefits over raloxifene for the skeleton, breast, heart or reproductive tract” and “seems to offer little, if any, advantage over raloxifene as an agent against osteoporosis,” Carolyn Becker, MD, of Brigham and Women’s Hospital, wrote in an accompanying editorial.

Lasofoxifene is currently available in Europe only.

Becker C. N Engl J Med. 2010;362:8.

Cummings SR. N Engl J Med. 2010;362:686-696.