Another Selective Estrogen-Receptor Modulator for

Osteoporosis
Carolyn Becker, M.D

Selective estrogen-receptor modulators are nonsteroidal compounds that act as estrogen

agonists in some tissues and as estrogen antagonists in others. Thus, they are uniquely
suited for postmenopausal women. An ideal selective estrogen-receptor modulator would
offer postmenopausal women the benefits of estrogen therapy (i.e., a reduced risk of
fracture, urologic and vaginal atrophy, and hot flushes) without the risks (i.e., an increased
risk of breast cancer, endometrial cancer, coronary heart disease, stroke, and venous
thromboembolic events).

Tamoxifen and raloxifene, the two selective estrogen-receptor modulators currently

marketed for postmenopausal women in the United States, offer both benefits and
drawbacks. Tamoxifen is associated with a reduced risk of estrogen-receptor (ER)positive
breast cancer but an increased risk of endometrial cancer.1 Raloxifene reduces the risk of
osteoporotic fracture2 and breast cancer,3 has a neutral effect on the risk of endometrial
cancer, and does not reduce the risk of coronary heart disease or stroke.4 Both drugs are
associated with increased risks of venous thromboembolic events and hot flushes, and
neither improves urologic and vaginal atrophy.

In this issue of the Journal, Cummings et al.5 report the results of the Postmenopausal
Evaluation and Risk-Reduction with Lasofoxifene (PEARL) Study (ClinicalTrials.gov
number, NCT00141323 [ClinicalTrials.gov] ), an international, placebo-controlled trial in
which 8556 postmenopausal women with osteoporosis were randomly assigned to
lasofoxifene (at a dose of either 0.25 or 0.5 mg per day) or placebo. The primary end point
after 3 years was vertebral fracture, but the trial was extended for another 2 years to include
two additional coprimary end points nonvertebral fracture and ER-positive breast cancer.
This discussion focuses on the dose of 0.5 mg per day used in the trial, since this dose is
intended for clinical use.

How does lasofoxifene measure up to the other two selective estrogen-receptor modulators,
raloxifene and tamoxifen? As shown in Table 1, at the skeleton, lasofoxifene and raloxifene
have similar effects on bone mineral density.2,5 In the PEARL study, treatment with
lasofoxifene was associated with a 42% relative risk reduction in radiographic vertebral
fracture at 3 years.5 However, according to data submitted to the Food and Drug
Administration (FDA), lasofoxifene did not reduce the risk of new clinical (symptomatic)
vertebral fracture, a key secondary end point at 3 years.6 In contrast, in the Multiple
Outcomes of Raloxifene Evaluation (MORE) trial (NCT00670319 [ClinicalTrials.gov] ),
raloxifene was associated with a significant relative risk reduction in radiographic vertebral
fractures2 and new clinical findings of vertebral fractures.7
In the PEARL study, lasofoxifene had no significant effect on the risk of nonvertebral
fracture at 3 years but was associated with a reduction of 25% in the risk of major
nonvertebral fracture at 5 years.5,6 There were significant reductions in nonvertebral
fractures by 3 years in a subgroup of women with osteoporosis at the spine.6 Raloxifene has
not been associated with a reduction in the risk of nonvertebral fracture, even after 5 to 7
years.2,4,8

A close look at the data from the PEARL study shows that nearly all the reductions in
major nonvertebral fractures appear to be due to a decrease in forearm and wrist fractures.6
At 5 years, there were 112 forearm and wrist fractures in the group of 2852 patients
receiving placebo (3.9%) and 88 forearm and wrist fractures in the group of 2852 patients
receiving lasofoxifene (3.1%), accounting for nearly all the relative risk reduction in major
nonvertebral fractures (absolute risk reduction, 0.8%).6 In short, although lasofoxifene was
associated with a decreased risk of nonvertebral fractures, particularly at the wrist, a
significant effect in the overall group was not evident until 5 years, and absolute risk
reductions were very small. Neither lasofoxifene nor raloxifene is associated with a reduced
risk of hip fracture. On balance, lasofoxifene seems to offer little, if any, advantage over
raloxifene as an agent against osteoporosis.

With regard to nonskeletal outcomes, the relative risk of invasive ER-positive breast cancer
in the PEARL study was reduced by an impressive 85% (P<0.001) among patients
receiving lasofoxifene. Similar reductions have been reported with the use of raloxifene,
which is already approved for the prevention of breast cancer in postmenopausal
women.2,3,4,9

A post hoc analysis of the MORE trial raised hopes that selective estrogen-receptor
modulators in general, and raloxifene in particular, would reduce cardiovascular events in
postmenopausal women.10 The Raloxifene Use for the Heart trial (NCT00190593
[ClinicalTrials.gov] ) directly tested this hypothesis in women at high risk for coronary
heart disease and showed that raloxifene had no effect on cardiovascular outcomes.4
However, the use of raloxifene was associated with an excess risk of fatal strokes,4 almost
exclusively among women with a high risk of stroke at baseline.11

In the PEARL trial, lasofoxifene was associated with a 32% relative risk reduction in major
coronary heart disease (P=0.02) and a 36% relative risk reduction in stroke (P=0.04) at 5
years. There were no differences in the incidence of fatal strokes. Although the
cardiovascular benefits reported in the PEARL trial seem impressive, one would need to
treat 492 patients for 1 year to prevent a single major coronary event.6 Studies suggest that
both raloxifene and lasofoxifene (at a dose of 0.5 mg per day) do not increase the risk of
heart disease or stroke among women with osteoporosis, although raloxifene should be
avoided in women with major risk factors for stroke.4,5 Since lasofoxifene has not been
tested in a cohort of women at high risk for cardiovascular disease, its safety in this
population is unknown.

Similar to estrogen and other selective estrogen-receptor modulators, lasofoxifene more

than doubled the relative risk of venous thromboembolic events and pulmonary embolism,
although the increase in absolute risk was very small. Like raloxifene, lasofoxifene was not
associated with an increased risk of endometrial hyperplasia or endometrial cancer but was
associated with a significant increase in leg cramps and hot flushes. Atrophic vulvovaginitis
was reduced in women who received lasofoxifene, but uterine polyps, endometrial
hypertrophy, and vaginal candidiasis were significantly increased, as compared with
placebo.

Lasofoxifene at a dose of 0.5 mg per day awaits approval from the FDA for treatment of
postmenopausal osteoporosis in women at increased risk for fracture. Given the plethora of
drugs currently available for osteoporosis, studies of new agents should show clear benefits
over existing agents. On the basis of this criterion, 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.

Disclosure forms provided by the author are available with the full text of this article at NEJM.org.

Source Information
From the Division of Endocrinology, Diabetes, and Hypertension, Brigham and Women's Hospital, Boston.

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