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

Discussion

This analysis examined the effects of raloxifene in women who reported their use of postmenopausal hormone therapies before enrolling in the MORE osteoporosis trial. Compared with placebo, women treated with raloxifene experienced significant decreases in the risks for new vertebral fractures and the incidence of breast cancer, without significant changes in the incidence of cardiovascular events, regardless of previous HT use. These analyses provide further information on the effects of raloxifene on the risks of vertebral fractures,¹⁰ cardiovascular events,¹⁴ and breast cancer¹⁶ seen in the overall MORE study population at 4 years.

This analysis found a differential reduction in vertebral fracture risk with raloxifene between women who did and did not have prior HT use, which may result from possible differences in women who chose to use HT before participating in MORE. In women with previous HT use, a greater proportion had a family history of osteo-porosis and a lower proportion had prevalent ver-tebral fractures at baseline, compared with women who had not used HT. Other unidentified confounding factors, such as the “healthy user” bias commonly associated with women who chose to use HT,¹⁷ may also contribute to the differential vertebral fracture risk reduction with raloxifene treatment. The Study of Osteoporotic Fractures showed that women with current estrogen use had significantly decreased fracture risks, but the risk reduction waned in women who discontinued estrogen.¹⁸ After HT discontinuation, BMD loss resumes at a rate similar to that seen in women shortly after menopause, suggesting that prior HT use may have limited residual effects on maintaining BMD.^7,19 Such findings raise the urgency of evaluating the risk for osteoporosis in women who discontinue HT.

Women treated with raloxifene had no significant changes in the incidence of cardiovascular events, with no differential treatment effect based on prior HT use. In the HERS²⁰ and WHI³ trials, which studied the outcomes of estrogen-progestin therapy in postmenopausal women, similar analyses did not show any significant differential effects of prior HT use on the incidence of cardiovascular events with estrogen-progestin during the respective trials.

In this analysis, women treated with raloxifene had a significantly lower incidence of breast cancer compared with those who received placebo, and this incidence was comparable between women with and without prior HT use. In contrast, women who had used HT before the WHI study had a significant increase in the risk of breast cancer with estrogen-progestin therapy during the study, compared with those who had not used HT.³

A limitation of our analysis that a history of HT use was based on participants’ self-report, which depended on their ability to recall medication they may have taken years earlier. Also, no information was obtained on therapy duration and the doses and formulations of HT. Since the MORE trial was conducted in 25 countries, the patterns and types of HT regimens are expected to be different. The strength of our analysis is that the MORE population was large enough to prospectively collect data on multiple clinical outcomes.

In summary, postmenopausal women treated with raloxifene experienced a significant risk reduction for vertebral fractures, regardless of prior HT use, but women who had used HT may exhibit greater reductions. Women who used raloxifene had no change in the incidence of cardiovascular events and a lower incidence of breast cancer, compared with placebo, regardless of their history of HT use. Since HT is becoming increasingly limited to short-term use for menopausal symptoms, women and their physicians may consider several other therapeutic options to address postmenopausal health concerns.

Acknowledgments

The authors acknowledge the contributions of Leo Plouffe Jr., MD, and Somnath Sarkar, PhD, for suggestions on manuscript content, and Sharon Xiaohan Zou, MS, for statistical programming. A complete list of all investigators in the MORE trial is found in J Clin Endocrinol Metab 2002; 87:3609–3617. Portions of this work were presented at the following meetings: Third European Symposium on Clinical and Economic Aspects of Osteoporosis and Osteoarthritis, Barcelona, Spain, 2002; International Society for Clinical Densitometry (ISCD), Los Angeles, USA,2003; European Calcified Tissue Society (ECTS), Rome, Italy, 2003; International Bone and Mineral Society (IBMS), Osaka, Japan, 2003; European Menopause and Andropause Society (EMAS), Bucharest, Romania, 2003; Ninth Bath Conference on Osteoporosis, Bath, UK, 2003. Eli Lilly and Company sponsored the Multiple Outcomes of Raloxifene Evaluation (MORE) Trial.

Corresponding author
Olof Johnell, MD, PhD, Department of Orthopedics, Universitetssjukhuset MAS, Malmo, SE-20502, Sweden. E-mail: olof.johnell@orto.mas.lu.se.