Osteocalcin and N-telopeptide significantly decreased at all BZA-estrogen dosages, compared with placebo, and at most BZA-estrogen dosages, compared with raloxifene.
WHAT THIS EVIDENCE MEANS FOR PRACTICE
Bazedoxifene is a potential therapeutic agent for menopausal women that may protect the endometrium while preventing bone loss in a population at higher risk of osteoporosis. It is not yet approved for this indication; further investigation is needed.
The combination of an estrogen and a selective estrogen receptor modulator to potentially relieve vasomotor symptoms, prevent vulvovaginal atrophy, and preserve bone mass without stimulating the endometrium or increasing the risk of breast cancer or venous thromboembolism is very exciting—and just might revolutionize treatment of menopausal women
Another SERM bites the dust
Bolognese M, Krege JH, Utian WH, et al. Effects of arzoxifene on bone mineral density and endometrium in postmenopausal women with normal or low bone mass. J Clin Endocrinol Metab. 2009;94:2284–2289.
The benzothiophene derivative arzoxifene, which has been in development for the prevention and treatment of osteoporosis, as well as for reduction of the risk of invasive breast cancer in postmenopausal women, has been pulled from the regulatory approval process by its manufacturer, Eli Lilly.
This move is somewhat surprising because, in a phase 3 trial, arzoxifene significantly increased bone mineral density at the lumbar spine (2.9%) and total hip (2.2%), compared with placebo. It also decreased levels of biochemical markers of bone metabolism.
In the trial, Bolognese and associates randomly assigned 331 postmenopausal women who had normal or low bone mass to receive 20 mg of arzoxifene or placebo daily for 2 years.
The trial also found that changes in breast density were neutral or slightly decreased in the arzoxifene group, and there was no evidence of endometrial hyperplasia or carcinoma, based on central review of baseline and follow-up endometrial biopsies. Nor were there any significant differences between groups in endometrial thickness, as assessed by transvaginal ultrasonography, or in the incidence of uterine polyps, vaginal bleeding, and hot flushes.
Nevertheless, Lilly issued a press release in late August announcing that arzoxifene would not be submitted to the FDA for regulatory review.5 It appears that, although initial results from the “pivotal” 5-year, phase 3 GJAD “Generations” trial indicated that the drug had met the primary endpoints of significantly reducing the risk of vertebral fracture and invasive breast cancer in postmenopausal women, “the study failed to demonstrate a statistically significant difference in key secondary efficacy endpoints, such as nonvertebral fractures, clinical vertebral fractures, cardiovascular events, and cognitive function, compared with placebo.”
The release went on to say: “In addition, certain adverse events, including venous thromboembolic events, hot flushes, and gynecological-related events, were reported more frequently in the arzoxifene group, compared with placebo.”5
Arzoxifene therefore joins an expanding list of selective estrogen receptor modulators (SERMs) that did not make it out of clinical trials: idoxifene, droloxifene, levormeloxifene, and lasofoxifene (approved in Europe, however), to name a few. The fall of arzoxifene again underscores the notion that “not all SERMs are created equal.”6