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Estrogen or Raloxifene for Postmenopausal Osteoporosis
Therapy?
S.L. Silverman and M. Wong
Depts. of Medicine and Rheumatology, Cedars-Sinai Medical Center, University of California Los
Angeles, Beverly Hills, CA, U.S.A.
*Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, U.S.A.
Summary
Osteoporotic vertebral fractures cause increased morbidity and mortality in
postmenopausal women. Estrogen alone (ERT, estrogen replacement therapy) or
combined with progestin (HRT, hormone replacement therapy), and raloxifene, a
selective estrogen receptor modulator (SERM), are therapeutic options for
osteoporosis. The clinical trial evidence to support fracture efficacy of ERT/HRT
and raloxifene are reviewed.
Introduction
In postmenopausal osteoporosis, declining estrogen levels produce accelerated
bone loss, which lead to decreased bone mass and microarchitectural deterioration,
and an increased risk of fractures, particularly in the vertebrae and hip [1]. Between
20 to 25% of women aged 50 yr and older have one or more vertebral fractures [2].
Clinical hip or spine fractures increases the mortality risk 6.7- and 8.6-fold
respectively [3]. Pre-existing vertebral fractures increases morbidity and mortality
[4] and decreases the quality of life [5]. Women with a pre-existing vertebral
fracture have a 5-fold increased risk of a new vertebral fracture within the
following year [6]. Therefore, the goal of osteoporosis therapy is prevention of new
fractures.
Materials and Methods
For decades, ERT and HRT have been used for management of
postmenopausal symptoms. Observational studies in postmenopausal women are
often cited as evidence to support the use of ERT/HRT for osteoporosis, as there
are very few well-designed clinical trials which examined fracture efficacy. Results
from observational studies are influenced by selection bias and adherence bias, as
women who use ERT/HRT tend to have a better health profile and follow
physicians’ instructions compared to women who do not use these drugs [7].
Currently, demonstration of fracture risk reduction in long-term prospective
double-blind, placebo-controlled, randomized clinical trials is required for
regulatory approval of newer drugs such as raloxifene. These clinical trials last for
at least 3 years, involve large numbers of patients, and require confirmation of
vertebral fractures with radiographs. Such clinical trials are expensive, so many
smaller studies use intermediate markers, such as bone mineral density (BMD).
Low BMD and the presence of existing fractures both predict increased risk of
future fractures, but increase in BMD with antiresorptive agents is a poor predictor
of actual fracture risk reduction with therapy [8]. This review compares the clinical
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trial evidence to support the use of ERT/HRT or raloxifene for reducing the risk of
osteoporotic fractures.
Results
Despite the multitude of published studies on ERT/HRT in postmenopausal
women, only 15 observational studies included fracture as a study endpoint [9].
These trials suggest that postmenopausal women who used ERT/HRT have
reduced fracture risk compared with case-controls. In the Study of Osteoporotic
Fractures, decreased fracture risk was associated with current or prolonged use of
ERT/HRT [10]. The 3-year Postmenopausal Estrogen/Progestin Interventions trial
of 875 women showed significant increases in spinal (5.3%-6.8%) and hip BMD
(3.4%), compared with placebo, but the incidence of fractures was not significantly
different and not assessed in radiographs [11]. Clinical fractures were not
significantly different between HRT and placebo in the Heart and
Estrogen/Progestin Replacement Study of 2673 women at low risk for osteoporosis
[12]. HRT did not significantly reduce the overall nonvertebral fracture risk [13].
In a 1-year clinical trial of 75 women with osteoporosis, the estrogen therapy
significantly decreased the risk of vertebral fractures by 61% when expressed as
events per person-year [14]. This evidence, along with many studies which show
increased BMD, suggest that ERT/HRT may reduce fracture risk.
Raloxifene increased spine BMD by 2.6% compared with placebo at 3 years in
1145 healthy postmenopausal women [15]. In the 3-year randomized, double-blind,
placebo-controlled Multiple Outcomes of Raloxifene Evaluation (MORE) trial of
7705 postmenopausal women with osteoporosis [16], raloxifene 60 mg/d
significantly decreased the risk of painful clinical vertebral fractures by 68% in the
first year [17]. In women without pre-existing vertebral fractures, raloxifene 60
mg/d decreased the risks of new vertebral fractures by 55% [18], and of multiple
(2) new vertebral fractures by 93% [19]. In women with pre-existing vertebral
fractures, who are at greater risk of subsequent fractures, raloxifene 60 mg/d
decreased the risk of new vertebral fractures by 30% at 3 years [16].
Long-term compliance with osteoporosis therapy is necessary to achieve
benefits on fracture prevention. ERT/HRT has beneficial effects on treating
postmenopausal symptoms, such as hot flashes, but the occurrence of breast
tenderness and vaginal bleeding may limit adherence [20]. The occurrence of
breast pain and vaginal bleeding with raloxifene was similar to placebo, while the
incidence of hot flashes was increased [16]. More women discontinued use of
estrogen (72%) compared to raloxifene (50%) after 2 years, with a notable
difference in discontinuation evident at 6 months after the initial prescription [21].
Conclusions
The beneficial effects on postmenopausal symptoms are well-known but the
putative fracture efficacy of ERT and HRT is suggested by several observational
studies. The MORE trial demonstrated that raloxifene decreases vertebral fracture
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risk in postmenopausal women with osteoporosis as early as the first year.
Compliance with raloxifene is superior to that for ERT/HRT.
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