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What are the benefits and harms of lasofoxifene, a selective estrogen receptor modulator, in osteoporotic postmenopausal women?
Ethical randomized trials require that there be "equipoise" between the treatments -- uncertainty whether the treatment is more effective than the alternative. The authors argue that placebo-controlled trials like this one are ethical because establishing the benefits of selective estrogen receptor modulators (SERMs) requires large trials. However, I would argue that as those benefits have been clarified, a more useful trial would have been a comparison with a bisphosphonate or another SERM (particularly since the vitamin D dose for many patients was too low to prevent fracture). Although there was a modest reduction in breast cancer, heart disease events, and nonvertebral fracture, there was an increase in venous thromboembolism and no difference in all-cause mortality (65 deaths in the placebo group, 90 in the low-dose group, and 73 in the high-dose group). The difference in mortality between placebo and low-dose groups was significant, and caused largely by more cancer deaths in the low-dose group. (LOE = 1b)
Cummings SR, Ensrud K, Delmas PD, et al, for the PEARL Study Investigators. Lasofoxifene in postmenopausal women with osteoporosis. N Engl J Med 2010;362(8):686-696. [PMID:20181970]
Randomized controlled trial (double-blinded)
The researchers recruited women between the ages of 59 years and 80 years with a T score of -2.5 or less at the lumbar spine or femoral neck. Women with a history of breast cancer, venous thromboembolism, thrombophlebitis, or cardiovascular disease were excluded. A total of 8556 women were randomized to receive lasofoxifene 0.25 mg per day, lasofoxifene 0.5 mg per day, or placebo. All women first underwent a run-in period during which they took calcium and vitamin D; those who were adherent to their medications were included in the study, which would create a subtle bias in favor of active treatment. All patients also received 1 g calcium and between 400 IU and 800 IU vitamin D daily. The authors took radiographs regularly for 5 years and regular mammograms, and expert committees adjudicated cardiovascular events and endometrial cancers. The researchers do not tell us whether the committee was masked to treatment assignment. After 5 years, only the higher dose provided benefits that were possibly clinically meaningful. This included a reduction in nonvertebral fracture (24.5 vs 18.7 per 1000 patient years; P = .002). This corresponds to a number needed to treat (NNT) of 34 for 5 years of treatment. The authors also found a reduction in radiographic vertebral fractures (22.4 vs 13.1 per 1000 patient years; P < .001), but do not report the results for clinical vertebral fractures; remember, radiographic fractures are often asymptomatic. There was no significant difference in hip fractures. There was a small but statistically significant reduction in invasive breast cancers (1.6 vs 0.2 per 1000 patient years; P < .001; NNT = 143 over 5 years) but only for the 0.5 mg dose. There was a modest decrease in major coronary heart disease events (7.5 vs 5.1 per 1000 patient years), but an increase in venous thromboembolic events (1.4 vs 2.9 per 1000 patient-years) and pulmonary embolism (0.2 vs 0.7 per 1000 patient years). Most important, there was no difference in all-cause mortality (rate per 1000 patient years = 5.1 for placebo, 7.0 for lasofoxifene 0..5 mg, and 5.7 for lasofoxifene 0.5 mg). Hot flushes, uterine polyps, endometrial hyperplasia, and leg cramps were more common in the treatment groups.