What can be learned from the levormeloxifene experience?

Levormeloxifene is a selective estrogen receptor modulator that was developed as an alternative to estrogen replacement therapy for the treatment and prevention of postmenopausal bone loss. In animal models, levormeloxifene prevented increased bone turnover and vertebral bone loss following ovariectomy. Studies of healthy postmenopausal women showed that levormeloxifene 1.25 - 20 mg/day decreased bone turnover and increased bone mineral density to a comparable extent to that observed during conventional hormone replacement therapy. However, in the phase II and III studies, the effect on bone turnover and bone mineral density was similar for each dose of levormeloxifene and the minimal effective dose was never established. The development of levormeloxifene was discontinued during the phase III trial due to a significant incidence of gynecologic adverse events in the levormeloxifene-treated groups. This article reviews the preclinical and clinical studies of levormeloxifene and the circumstances for the premature termination of the development of the drug. Other selective estrogen receptor modulators such as tamoxifen and raloxifene and the perspectives for selective estrogen receptor modulators in development are furthermore discussed.