Raloxifene and Bone

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Beall and coworkers162 published the first report of the actions of a nonsteroidal antiestrogen clomiphene on bone maintenance in ovariectomized rats. Unfortunately, these studies were flawed, as clomiphene is a mixture of the antiestrogenic E isomer and the estrogenic Z isomer. Clearly, it was possible that one isomer produced a dominant estrogenic effect in bone but the other isomer produced a dominant antiestrogenic effect in uterus and breast. The uncertainty was clarified with the finding that tamoxifen, the antiestrogenic pure isomer of a triphenylethylene, and raloxifene, a chemically stable antiestrogen, were both estrogen-like in bone but antiestrogenic in uterus and breast.96

The 1995 patent and the December 10, 1997 FDA approval of raloxifene for the treatment and prevention of osteoporosis were based, in part, on earlier studies performed in 1987 by Jordan and coworkers96 which showed that raloxifene preserved bone density in ovariectomized rats (Figure 4a) and prevented rat mammary carcinogenesis (Figure 4b).91 The discovery that raloxifene and related compounds might prevent osteoporosis96 laid the foundation for subsequent confirmation of bone data in animals.97-99,163 These discoveries also led to clinical trials that demonstrated maintenance of bone density in postmenopausal women at risk for osteoporosis.78 These data were remarkably similar to those observed with tamoxifen.144 However, the actual proof that raloxifene could be useful to treat osteoporosis was obtained in the MORE trial (Figure 5), which was a multicenter, randomized, blinded, placebo-controlled osteoporosis treatment trial. A total of 7705 women aged 31-80 years in 25 countries who had been postmenopausal for at least 2 years and who met World Health Organization criteria for having osteoporosis were included in the study. The study began in 1994 and had up to 36 months of follow-up for primary efficacy measurements and nonserious adverse events and up to 40 months of follow-up for serious adverse events. Participants were randomized to raloxifene (60 or 120 mg day_ 1) or placebo. Results from this study79,164 showed that raloxifene at

0.75

0.70

0.65

lOVX

Bone

Mammary cancer

4 months

4 months

Ral E2B

Ral E2B

Mammary cancer

Control Low raloxifene

High

Control Low raloxifene

High

Figure 4 A comparison of the effects of raloxifene (Ra1) on (a) femur ash density in ovariectomized (OVX) rats96 and (b) the incidence of rat mammary tumors91 after the administration of N-nitrosomethylurea (NMU). For bone density studies, ovariectomized rats (8 per group) were treated daily with raloxifene (100 mg), estradiol-3-benzoate (25 mg), or with a combination of raloxifene and estradiol-3-benzoate for 4 months. One group of 8 ovariectomized rats received only the vehicle (0.2 ml peanut oil). For tumor incidence studies, virgin female Sprague-Dawley rats were injected with 5mg NMU, and 2 weeks after the injection rats were randomized into three groups of 25 animals and were given injections daily for 10 weeks with 100 (low) and 500 mg (high) raloxifene. The control group received peanut oil alone.

MORE trial

Randomized (n = 7705)

Follow-up radiographs

Follow-up radiographs

Required 24 months: 2263

Required 24 months: 4472

Required 36 months: 1957

Required 36 months: 4039

Any follow-up radiograph: 2292

Any follow-up radiograph: 4536

Placebo (n = 2576) All received standard intervention

Raloxifene hydrochloride (n = 5129) All received standard intervention

Figure 5 Study design of the Multiple Outcomes of Raloxifene Evaluation (MORE) trial. The MORE trial is a multicenter, randomized, blinded, placebo-controlled trial which was undertaken primarily to examine the effect of raloxifene on the skeleton. A total of 7705 postmenopausal women with osteoporosis and ranging in age from 31 to 80 years participated in this study. The women were divided into two study groups and were then randomized to receive either placebo or 60 or 120 mg day-1 of raloxifene. Study group 1 included those whose femoral neck or lumbar spine bone density t score was below - 2.5. Study group 2 included women who had low bone density and one or more moderate or severe vertebral fractures or two or more mild vertebral fractures. Incident vertebral fracture was determined radiographically at baseline and at scheduled 24- and 36-month visits. Bone mineral density was determined annually by dual-energy x-ray absorptiometry.

Bones

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