15 April 2010
In the PEARL study of 8,556 women with postmenopausal osteoporosis, lasofoxifene 0.5mg daily reduced the risk of radiographic vertebral fractures after three years. At the end of five years, lasofoxifene reduced the risk of non-vertebral fractures (mainly forearm/wrist) and oestrogen-positive breast cancer. Lasofoxifene was associated with an increased risk of venous thromboembolic events, as is the currently-marketed selective oestrogen-receptor modulator (SERM) raloxifene
Level of evidence: Level 2 (limited quality patient-oriented evidence) according to the SORT criteria.
There are numerous drugs available for the treatment of osteoporosis and new agents need to show clear benefits over established treatments. If lasofoxifene were to be marketed in the UK then data with clinical endpoints (preferably from well-conducted, large, head-to-head studies against other currently-marketed and widely prescribed treatment options) would ideally be required to determine its place in the management of osteoporosis.
What is the background to this?
Lasofoxifene is a SERM, which was approved in the EU in March 2009 but has not been launched in the UK. Raloxifene, another SERM, is already available for the treatment and prevention of osteoporosis in postmenopausal women. It is recommended by NICE as an option for the secondary prevention of osteoporotic fragility fractures in postmenopausal women who are unable to take certain bisphosphonates and who have a combination of risk factors for fracture. Bazedoxifene is also licensed but not launched.
What does this study claim?
Lasofoxifene 0.5mg reduced the risk of new radiographic vertebral fractures compared to placebo after three years: 13.5 vs. 23.0 fractures per 1,000 person-years, hazard ratio (HR) 0.58, 95% confidence interval (CI) 0.45 to 0.73, P<0.001. At the end of five years, lasofoxifene reduced the risk of non-vertebral fractures, (18.7 vs. 24.5 per 1,000 person-years, HR 0.76, 95%CI 0.61 to 0.91, P=0.002) and oestrogen-positive breast cancer (0.3 vs. 1.7 cases per 1,000, HR 0.19, 95% CI 0.07 to 0.56, P<0.001). There were 2.1 hip fractures per 1,000 person-years in the lasofoxifene group and 2.8 in the placebo group, HR 0.77, 95% CI 0.46 to 1.27, P=0.30.
How does this relate to other studies?
Neither lasofoxifene nor raloxifene have data showing a significant reduction in the incidence of hip fractures. The decreased risk of oestrogen-positive breast cancer is similar to that seen with raloxifene in the MORE study. Secondary endpoints in the PEARL study included major coronary heart disease events and stroke, both of which were reduced in the lasofoxifene 0.5mg group. Raloxifene has been shown to have no effect on cardiovascular outcomes in the large RUTH trial of postmenopausal women with coronary heart disease or risk factors for it.
There are numerous drugs available for the treatment of osteoporosis and new agents need to show clear benefits over established treatments.
Further data from this study were presented to the FDA in the US. These show that the reductions in non-vertebral fractures were mainly due to an affect on wrist and forearm fractures. There was no difference on clinical vertebral fractures at three years, a key secondary endpoint, between lasofoxifene and placebo groups (HR 0.66, 95%CI 0.43 to 1.03, P=0.068). The risk of clinical fracture (defined as vertebral and non-vertebral fractures associated with pain and discomfort) at three years was statistically significant: HR 0.77, 95%CI 0.64 to 0.93, P=0.006.
The European SmPC states that incidence of all clinical fractures at 5 years was 12.1% placebo vs. 9.3% lasofoxifene, P=0.0004 (no CI quoted).
Design: Randomised, placebo-controlled trial. Patients received 1g calcium and 400-800 IU of vitamin D daily during a six to eight week run-in period and those who were compliant were randomised into the trial.
Patients: Women aged 59 to 80 years (mean age 67) with low bone mineral density (BMD) and no evidence suggestive of breast cancer were included. 28% had at least one prevalent baseline radiographically-defined vertebral fracture. Patients on previous bone therapy were excluded, but if annual BMD measurements during the trial decreased significantly patients were referred for an assessment of alternative treatments. One option was to continue with the study drug in conjunction with a bisphosphonate.
Intervention and comparison: All patients received calcium plus vitamin D. Patients were randomised to 0.25mg or 0.5mg lasofoxifene daily or placebo, such that 2,852 participants were in each group. The trial was originally designed to run for three years, but was extended to five.
Outcomes and results: Results here refer to the 0.5mg lasofoxifene group, as that is the strength which is licensed. All results are compared to placebo. At the end of three years, the primary endpoint of radiographic vertebral fractures was reduced in lasofoxifene patients (13.5 vs. 23.0 fractures per 1,000 patient-years in the placebo group, HR 0.58, 95%CI 0.45 to 0.73, P<0.001). At the end of five years, the co-primary endpoints were radiographic non-vertebral fracture and oestrogen-positive breast cancer. Lasofoxifene reduced non-vertebral fractures (confirmed radiographically): 18.7 vs. 24.5 per 1,000 person-years in the placebo group, HR 0.76, 95% CI 0.64 to 0.91, P=0.002. In addition, the incidence of oestrogen-positive breast cancer was reduced by lasofoxifene (0.3 vs. 1.7 cases per 1,000 person-years, HR 0.19, 95%CI 0.07 to 0.56, P<0.001).
A secondary endpoint at five years was the incidence of hip fractures of which 2.1 per 1,000 person-years occurred in the lasofoxifene group and 2.8 in the placebo group, HR 0.77, 95% CI 0.46 to 1.27, P=0.30.
Lasofoxifene was also associated with less major coronary heart disease (5.1 vs. 7.5 per 1,000 person-years, HR 0.68, 95%CI 0.50 to 0.93, P=0.02) and fewer strokes (2.5 vs. 3.9 per 1,000 person-years, HR 0.64, 95%CI 0.41 to 0.99, P=0.04). However, the risk of venous thromboembolic events was increased: 2.9 events per 1,000 person-years for lasofoxifene vs. 1.4 with placebo, HR 2.06, 95%CI 1.17 to 3.61, P=0.01.
Leg cramps and hot flushes were reported more frequently by lasofoxifene patients: leg cramps 56.0 vs. 29.6 per 1,000 person-years, and hot flushes 28.4 vs. 12.3 per 1,000 person-years, both P<0.001 compared to placebo. No increase in the risk of endometrial cancer was seen but endometrial hyperplasia was confirmed in two women taking lasofoxifene 0.5mg and none in the placebo group. Uterine polyps were also more common in lasofoxifene patients (19.8 vs. 2.2 per 1,000 person-years, P<0.001).
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