Raloxifene reduces risk of vertebral fractures and breast cancer in postmenopausal women regardless of prior hormone therapy

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Original Research

Raloxifene reduces risk of vertebral fractures and breast cancer in postmenopausal women regardless of prior hormone therapy

J Fam Pract. 2004 October;53(10):789-796

By

Olof Johnell, MD

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References

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4. Bren L. The estrogen and progestin dilemma: New advice, labeling and guidelines. FDA Consumer 2003;37:10-11.

5. Haas JS, Kaplan CP, Gerstenberger EP, Kerlikowske K. Changes in the use of postmenopausal hormone therapy after the publication of clinical trial results. Ann Intern Med 2004;140:184-188.

6. Gallagher JC, Rapuri PB, Haynatzki G, Detter JR. Effect of discontinuation of estrogen, calcitriol, and the combination of both on bone density and bone markers. J Clin Endocrinol Metab 2002;87:4914-4923.

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11. Ettinger B, Black DM, Mitlak BH, et al. Reduction of verte-bral fracture risk in postmenopausal women with osteo-porosis treated with raloxifene: Results from a 3-year randomized clinical trial. JAMA 1999;282:637-645.

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Practice recommendations

Consider prescribing raloxifene 60 mg/d for postmenopausal women, regardless of whether they have used hormone therapy, to reduce the incidence of vertebral fractures and breast cancer (SOR:B).

ABSTRACT

Objective: We examined whether past use of hormone therapy influences the effects of raloxifene on the risk of new vertebral fracture, cardiovascular events, or breast cancer.
Study Design: The Multiple Outcomes of Raloxifene Evaluation (MORE) trial examined vertebral fracture incidence as the primary endpoint, breast cancer incidence as a secondary endpoint. Cardiovascular events were collected as secondary safety endpoints.
Population: The MORE trial enrolled 7705 postmenopausal women. Of the 7682 women who reported their previous HT use status, 29% used HT before screening.
Outcomes Measured: Separate logistic regression models analyzed the relationships between prior HT use and the risk of vertebral fracture, cardiovascular events, or breast cancer. Interaction terms with P<.10 were considered to be statistically significant. Confidence intervals for relative risks (RR) were calculated using the Mantel-Haenszel method.
Results: Raloxifene 60 mg/d, the clinically approved dose for osteoporosis prevention and treatment, reduced the risk of vertebral fractures by 54% (RR=0.46) and 29% (RR=0.71) in women with and without prior HT use, respectively (interaction P=.05). A lower incidence of invasive breast cancer in women with prior HT use (RR=0.23) and in women without prior HT use [RR=0.31; interaction P=.60] was observed in women receiving raloxifene (pooled doses). Irrespective of prior HT use, women treated with raloxifene (pooled doses) had no change in incidence of cardiovascular events (interaction P=.56).
Conclusions: The risk of vertebral fractures was lower in women treated with raloxifene, regardless of prior HT use, but there was a suggestion that the effect was greater in women who had used HT. Women randomized to receive raloxifene exhibited a decreased incidence of invasive breast cancer, compared with women receiving placebo. No change occurred in the incidence of cardiovascular events, regardless of prior HT use.

Estrogen-containing hormone therapies (HT) have been used to alleviate menopausal symptoms and to prevent chronic diseases common to postmenopausal women, including osteoporosis and cardiovascular disease.^1,2 In this analysis, we use the abbreviation “HT” to refer to postmenopausal hormone therapies, either estrogen alone or combined with progestin.

Based on the findings of the randomized, double-blind Women’s Health Initiative (WHI) study involving estrogen-progestin,³ the Food and Drug Administration (FDA) recommends using HT to treat moderate to severe symptoms of vulvar and vaginal atrophy and vasomotor symptoms associated with the menopause, and to prevent post-menopausal osteoporosis.⁴ When HT is prescribed only to prevent osteoporosis in women without menopausal symptoms, the FDA recommends that other approved, non-estrogen therapies be considered and that HT be used at the lowest dose for the shortest duration to achieve treatment goals.⁴ Many postmenopausal women have chosen to discontinue HT in light of these recommendations.⁵ However, discontinuing HT may increase bone resorption and accelerate bone loss,^6,7 which, if untreated, places women at risk for osteoporotic fractures.

The serum estrogen receptor modulator (SERM) raloxifene is not an estrogen, a progestin, or a hormone,⁸ but it binds to the estrogen receptor to exert effects in the skeletal and cardiovascular systems and in breast tissue.⁹ In the 4-year Multiple Outcomes of Raloxifene Evaluation (MORE) osteoporosis treatment trial of postmenopausal women, raloxifene 60 mg/d, the approved dose for post-menopausal osteoporosis prevention and treatment, increased bone mineral density (BMD) and significantly reduced the risk for new vertebral fractures with sustained efficacy.¹⁰ With the declining use of long-term HT,⁵ it is clinically relevant and important to determine whether a history of HT use has any influence on the effects of other antiresorptive agents, such as raloxifene, which may be subsequently used for postmenopausal osteoporosis prevention and treatment. The objective of this analysis is to determine the effects of raloxifene on BMD, and the risks of vertebral fractures, cardiovascular events, and breast cancer in post-menopausal women who did or did not use HT prior to screening for the MORE osteoporosis study.

Materials and methods

Subjects and treatment

Details on subject recruitment and follow-up, and complete inclusion and exclusion criteria, were previously described for the MORE study.¹¹ The trial examined the incidence of osteoporotic fractures as a primary endpoint and the incidence of breast cancer as a prespecified secondary endpoint, and it collected reports of cardiovascular events as a secondary safety endpoint.

Researchers enrolled 7705 women up to 80 years of age who were at least 2 years post-menopausal, and who had osteoporosis as defined by radiographically apparent vertebral fractures at baseline or BMD criteria. Women were randomly assigned to receive raloxifene 60 or 120 mg/d, or an identically appearing placebo.¹¹ All women received daily supplements of calcium (500 mg) and vitamin D (400 to 600 IU). An ethical review board at each site approved the MORE study protocol. All women gave written informed consent to participate in the study in accordance with the ethical principles stated in the Declaration of Helsinki.