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Arzoxifene for Prevention of Osteoporosis
Abstract & Commentary
By Leon Speroff, MD, Editor, Professor of Obstetrics and Gynecology, Oregon Health and Science University, Portland, is Editor for OB/GYN Clinical Alert.
Synopsis: Arzoxifene increases bone density in postmenopausal women.
Source: Bolognese M, 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 Apr 7; Epub ahead of print.
Arzoxifene is being developed by Eli Lilly and Co. to prevent bone loss and treat osteoporosis. A 2-year, randomized trial compared the bone density responses in 331 postmenopausal women treated with either arzoxifene (20 mg/day) or placebo. Bone density was slightly increased in the spine and the hip in the treated group compared with placebo. There was no evidence of endometrial stimulation in the treated group either on biopsied specimens or by measurement of endometrial thickness by transvaginal ultrasonography. Three patients in the placebo group and none in the treated group developed breast cancer. There were no cases of venous thrombosis, and hot flushing was equally prevalent in the two groups.
Arzoxifene is an estrogen agonist-antagonist similar to raloxifene, originally studied for the treatment of breast cancer. Preclinical studies indicated that arzoxifene is an estrogen agonist in bone and on lipids, but an estrogen antagonist in endometrial and breast tissue. Arzoxifene, therefore, had the potential to be as effective as tamoxifen but be free of the risk of endometrial stimulation, and perhaps, venous thrombosis.
A phase III clinical trial comparing arzoxifene and tamoxifen for the treatment of advanced local breast cancer or metastatic tumors was disappointing.1 The trial was terminated when it became apparent that the results with arzoxifene were inferior to tamoxifen with regard to survival times and treatment failure times. Two other members of this drug family, droloxifene and idoxifene, have also failed to yield superior results to tamoxifen for the treatment of breast cancer. For this reason, attention was turned to another use for these agents. Clinical trials assessing the efficacy and safety of arzoxifene for prevention of fractures and breast cancer are now under way.
Various drug companies are pursuing members of this drug family, such as arzoxifene, lasofoxifene, and basedoxifene, hoping to develop a patent-protected drug that would compete with raloxifene. Keep two important points in mind as new data emerge in this slow and expensive process:
1. Comparison phase III clinical trials are essential. Preclinical studies indicate potential, but only head-to-head comparisons tell us if a new drug is any better than what we already have. The comparison of these agonist-antagonist drugs with tamoxifen is a good example. Hoped-for superiority of the new drugs failed to emerge. In addition, the new drugs will have to perform better than the aromatase inhibitors. Comparison data are also required to determine whether one of the new drugs is superior in avoiding hot flushing and venous thrombosis.
2. Fracture data for both hip and spine are necessary. These drugs differ in potency as measured by bone density and biochemical markers of bone metabolism. Preclinical studies suggested that arzoxifene was more potent in regard to preventing bone loss compared with raloxifene, and the clinical trial data support this conclusion. Greater potency, therefore, of arzoxifene gives some hope that one of these new drugs will overcome the serious drawback of raloxifene treatment, a lack of effect in preventing hip fractures. Bazedoxifene has demonstrated about a 50% reduction in hip fractures in a phase III clinical trial.2