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Idoxifene: A Selective Estrogen Receptor Modulator that Prevents Bone Loss in Ovariectomized rats

Idoxifene: A Selective Estrogen Receptor Modulator that Prevents Bone Loss in Ovariectomized rats. Nuttall, M., Bradbeer, J.N., Stroup, G.B., Nadeau, D.P., Hoffman, S.J., Zhao, H., Rehm, S., and Gowen, M. 1998. Endocrinology. 139(12): 5224-5234.

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Idoxifene: A Selective Estrogen Receptor Modulator that Prevents Bone Loss in Ovariectomized rats

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  1. Idoxifene: A Selective Estrogen Receptor Modulator that Prevents Bone Loss in Ovariectomized rats Nuttall, M., Bradbeer, J.N., Stroup, G.B., Nadeau, D.P., Hoffman, S.J., Zhao, H., Rehm, S., and Gowen, M. 1998. Endocrinology. 139(12): 5224-5234.

  2. Introduction/Background • Accelerated bone loss secondary to decreased estrogen levels at menopause is a major risk factor for Osteoporotic fractures. • Postmenopausal bone loss can be prevented by estrogen replacement therapy (ERT).

  3. Reduced onset of Alzheimers Disease Reduced incidence of colon cancer Reduced incidence of osteoarthritis decreased incidence of macular degeneration Uterine bleeding Uterine cancer Increased risk of thrombosis Increased risk of breast cancer with long term use Benefits vs. Risks of ERT

  4. Ideal Therapy • Because of the risks of ERT, it is estimated that in the US less than 40% of women who begin estrogen replacement therapy will continue treatment beyond one year. • Retain bone mineral density • lack estrogenic activity on endometrium • retain cardiovascular effects of estrogen • reduce incidence of breast cancer

  5. Idoxifene • One of many compounds known as selective estrogen receptor modulators (SERMs) • A SERM is defined as a compound that has estrogen agonism on one or more desired tissues such as bone or liver and has antagonistic effects on reproductive tissue such as breast or uterus

  6. Idoxifene (continued) • Idoxifene is a novel SERM that has a 2.5 to 5 fold greater affinity for the estrogen receptor alpha than other SERMs studied. • Has fewer side effects than tamoxifen, raloxifene, droloxifene, etc.

  7. Rationale for experiments • To determine whether or not idoxifene acts as an estrogen agonist on the bone following estrogen withdrawal • investigated using ovariectomized rats (Ovx) • Action of idoxifene on cell types in culture compared to the natural hormone estrogen • use the classical estrogen response element (ERE) to measure effects of estrogen agonist/antagonist on gene expression.

  8. Conslusion • Idoxifene prevented bone loss by suppressing the increase in bone turnover that occurs upon estrogen withdrawal • Provided direct evidence that idoxifene is working as an estrogen agonist in osteoblalsts in culture, and that the profile of induction of transcription through the ERE in osteoblasts by idoxifene is similar to that of estrogen.

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