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Journal of American Medical Association
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Cardiovascular Disease Outcomes During 6.8 Years of Hormone Therapy
Heart and Estrogen/Progestin Replacement Study Follow-up (HERS II)
»ONGOING STUDIES
Author:
S. Palacios
Gynaecologist
Last Review: 21/02/2003
In the few years, since the term SERMs (selective estrogen receptor modulators) was coined, the studies and the uses of these molecules has accelerated at a speed that we should never have imagen.
SERMs are a class of compounds that have been developed with the aim to retain the beneficial effects of hormone replacement therapy (HRT) on bone tissue and cardiovascular system, but not their stimulating effects on breast and uterus.
Right know we have two quimically different SERMs, that had been aproved for clinical use, tamoxifen and raloifene.
Each SERM produces different structural changes in the alfa and beta estrogenic receptors, which are really encharge to stimulate or to inhibit the transcription genic activity of the estrogens. This is the reason why each SERM has an specific estrogenic or antiestrogenic activity.
The European and American Health Authorities, had approved to use SERMs in the treatment of breast cancer (Tamoxifen and Toremifen), for the quimioprevention of the breast cancer (tamoxifen) and also for the osteoporosis (Raloxifene). nevertheless they have also secundary effects. The tamoxifen increases the endometrial cancer and the tamoxifen, toremifen and also the raloxifen increases the tromboembolic accidents.
The search of new SERMs has to go in a depth knowledge of the SERMs that we have now and by this way to get an ideal selective estrogen, wich will be the one with a positive effect on bone, regulate lipid metabolism resulting in a cardiovascular positive HDL:LDL ratio, and relieve vasomotor instability while also not estimulating the uterine endometrium or the breast.
Phisicians, have already accepted the term SERM, and identify some indications and hoping to find new. That is why we have a great expectation for the results of the clinical researchs that are ongoing with the actual SERMs, and for the development of new SERMs. There are two SERMs currently in phase 3 of their clinical developement, basedoxifene acetate and lasofoxifene.
Actual SERMs
Tamoxifen
It is the first SERM accepted for the treatment of breast cancer. It is more effective in premenopausic and postmenopausic women with breast cancer with positive estrogenic receptors. Since 1998, it was also used for the quimioprevention of breast cancer. However, it has also some secondary effects as the tromboembolic accidents, the encrease the risk of endometrial cancer and the cataractas.
Indeed, several studies have shown that tamoxifen has estrogenic agonist action on the skeleton and on lipoprotein metabolism in postmenopausal women. However, because its long term use is associated with an increased risk of endometrial cancer, tamoxifen can not be widely used in healthy postmenopausal women, which has lead to the developement of new molecules devoid of this side effect.
Raloxifene
A benzothiophene non steroidal molecule which has been extensively studied in phase II and III trials. It is used for the prevention and for the treatment of postmenopausal osteoporosis. It has estrogenic effects on bone and cholesterol metabolism but behaves as a complete antiestrogen on mammary gland and endometrium tissue.
In the prevention of postmenopausal bone loss and vertebral fractures, the effects of raloxifen have been established in several randomized, double-blind studies against placebo.
Common side effects considered with the use of raloxifene include hot flushes and leg cramps. The most serious side effect associated with the use of raloxifene is venous thromboembolism.
The multiple outcomes of raloxifene evaluation (MORE) study, was a trial involving postmenopausal women with osteoporosis treated with placebo or raloxifene 60 mgs/day (n= 2.576 2557). Finding in the four year results that raloxifene significantly decrease the risk of vertebral fractures in a 34% of the women with osteoporosis and previous vertebral fractures and in a 49% in women with osteoporosis but without previous vertebral fractures. This effect was accompanied by a decrease in markers of bone turnover. This study has been extended into a new study called CORE.
Ongoing studies with raloxifeno
Ruth trial ( The Raloxifene Use for the Heart)
Ruth is an international, multicenter, randomized, double-blind placebo-controlled trial of 10.101 postmenopausal women with 55 years or more from 26 countries.
The end of the trial will be almost on the year 2006. The study objective is to determine the effect of raloxifene 60 mgs, compared with placebo, on major cardiovascular events and breast cancer. It is a study on phase III, ongoing.
Star trial ( The study of Tamoxifen and Raloxifene)
It is a phase III ongoing study of tamoxifen and raloxifene for the prevention of breast cancer is one of the largest breast cancer prevention trials ever. A total of 22.000 postmenopausal women between 35 and 59 years at high-risk of breast cancer will be enrolled at approximately 400 sites in the United States, Puerto Rico and Canada.
The primary objective of the study is to determine whether raloxifene 60 mgs/day is more or less effective than tamoxifen 20 mgs/day in significantly reducing the incidence rate of invasive breast cancer in postmenopausal women at high risk of breast cancer.
Toxicity, side effects, and the quality of life effects of the two requirements that will be also assessed.
New SERMs ongoing
Droloxifene
It is similar to the tamoxifen. It is a potent antiestrogenic for the mammary gland. The results of studies on phase II, done on women with advanced breast cancer had find an answer of 17-31%, 30-44% and 31-42% depending if the dose is 20, 40 or 100 mg/day of draloxifene. The secondary effects in these studies were hot flashes, vaginal dryness, pulmonary embolism and deep vein thrombosis.
Idoxifene
It is a new SERM with a less estrogenic power and a better antiestrogenic activity than the tamoxifene.
Arzoxifene
It is a new analog of the benzotiofen similar to the raloxifen. Preclinic studies have found an antiestrogenic effect over breast and uterus and an estrogenic effect over bone and lipids. On the studies on phase I, hot flashes was the most common secondary effect. Actually they are ongoing studies on phase II and III.
Basedoxifene
A third generation SERM, that has also shown on the preclinic studies to be an estrogenic SERM over skeletal and cardiovascular systems and antiestrogenic over mammary tissue and uterus.
Preclinical data from student studies demostrate that bazedoxifene selectively acts as an estrogen agonist on the skelton and cardiovascular system while exhibiting little to no effect on the uterus.
Lasofoxifen
It is a very hopeful SERM with positive effects on bone and lipidic metabolism without effects on the uterus. Actually they are ongoing studies on phase III.
Ospemifene
Is a new SERM developed for the prevention and treatment of the osteoporosis. We have right now the results of three clinic researchs, two in phase I and one in phase II.
It has show on healthy postmenopausic women a good effect on bone also lowering the LDL cholesterol and a similar effect over endometric tissue as the raloxifene.
The future
The SERMs do not displace in the next years the estrogenic power of the HRT, but they are an alternative for the women in wich the HRT is contraindicated, the one who can not tolerate the secondary effects, or the one who has been take in it for more than four years. Since the WHY study SERMs will be the election for the postmenopausal women wich has been taking HRT for more than four years. We continue believing that SERMs will be very important not only in the prevention and treatment of the osteoporosis but also for the prevention of the breast cancer and of the cardiovascular desease. We are expectant for the effects of the SERMs over the central nervous system.
Where possible, the treatment should also be individualised to optimise the treatment for each individual woman.
REFERENCES
1. Osborne CK, Zhao H and Fuqua SAW. Selective estrogen receptor modulators: structure, function and clinical use. J Clin Oncol, 2000; 18:3172-3186.
2. Early Breast Cancer Trialist´s Collaborative Group. Tamoxifen for early breast cancer: an overview of the randomized trials. Lancet, 1998; 351:1451-1467.
3. Eajtell R, Adadri J, Harper K et al. The effects of raloxifene on incidence vertebral fractures in postmenopausal women with osteoporosis. 4 years results from the MORE trial. J Bone Mineral res 2000; 15: 5229.
4. Mosca L. Rationale and overview of raloxifene use for the Heart (RUTH) trial. Ann NY Acad Sci, 2001; 949:181-185.
5. Writing Group for the Women´s Health Initiative Investigators. Risks and benefits of estrogen plus progestin in healthy postmenopausal women. Principal results from the women´s health initiative randomized controlled trial. JAMA 2002, Vol 288: 321- 333.
6. Barret-Connor G, Grady D, Sashegyi A, Anderson P.Cox, et al. Raloxifene and cardiovascular events in women with osteoporosis. A 4 years results from the MORE trial. JAMA 2002;287:847-857.
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