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C620R9095.rtf

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 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 60mg/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 risk in postmenopausal women with osteoporosis as early as the first year. Compliance with raloxifene is superior to that for ERT/HRT.

References

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