| Selective Estrogen Receptor Modulators (SERMs) |

Category: Practitioners

INTRODUCTION
SERMs are a new category of therapeutic agents available for the prevention and treatment of osteoporosis. They are distinct from pure estrogen agonists and antagonist by displaying selective agonism or antagonism in different tissue types.

The first available SERM, tamoxifen is therapeutically used as an antagonist of breast cancer tissue but is limited by partial uterine agonism,causing endometrial hyperplasia.

Raloxifene,a new SERM, was registered in South Africa in February 1999 for the prevention of postmenopausal osteoporosis.Registration was preceded by several placebo-controlled multi centric international trails involving over 9000 postmenopausal patients.As this is the only SERM presently available for use in osteoporosis, the rest of the discussion will focus on results obtained in these studies.

BONE EFFECTS
Raloxifene acts as an estrogen agonist on bone with antiresorptive effects on bone metabolism.Compared with placebo,raloxifene decreased serum and urine concentrations of several markers of bone turnover and increased bone density of the spine and hip by 2.5% and 2% over 2 years.In the MORE study, 2 years of treatment decreased the risk of radiographically and clinically diagnosed vertebral fractures by 38% to 52%.This effect is greater than the predicted changes based on bone density alone and on par with that achieved by estrogen or alendronate.The MORE study, in the initial period of reporting,has not yet proved fracture prevention at the hip.

CARDIOVASCULAR EFFECTS
Favorable agonistic effects on surrogate markers for the prevention of miocardial infarction have consistently been reported. Raloxifene decreases total serum cholesterol,low density lipoprotein-C,apolipoprotein-B and fibrinogen levels. Triglyceride levels are unaffected.High density lipoprotein-C is not raised as with estrogen,except for the high density lipoprotein 2 subfraction.The possible prevention of miocardial infarction is being addressed in the ongoing RUTH study.

UTERINE EFFECTS
Raloxifene has consistenly displayed antagonistic effects on the uterine endometrium as measured by transvaginal ultrasound,when compared to placebo. This results in the absence of uterine bleeding and the elimination of the risk of endometrial hyperplasia and cancer as associated with tamoxifen and unopposed estrogen therapy.

BREAST EFFECTS
Raloxifene acts as an antagonist in breast tissue. The clinical result is a lack of mastalgia and breast enlargement as often experienced with estrogen. The latest report from the MORE study indicates that among postmenopausal woman with osteoporosis,the risk of invasive breast cancer was decreased by 76% during 3 years of treatment with raloxifene ,when compared to placebo.Raloxifene reduced the risk of invasive estrogen receptor-positive breast cancer by 90% without influencing receptor-negative tumors.

SAFETY PROFILE
Raloxifene has a very good safety profile in postmenopausal women at risk for osteoporotic fracture.The only significant serious side effect is a threefold increase in the risk of venous thromboembolism, when compared to controls.The risk is modest in absolute terms and comparable to that seen with estrogen.

Hot flushes were reported by more patients receiving raloxifene(8.7%) compared to placebo(5.4%).The majority of women reported the flushes as mild to moderate in nature and rarely resulted in discontinuation from the study.

Leg cramps likewise occurred more often in raloxifene patients but rarely resulted in discontinuation.

MECHANISM OF ACTION
The molecular mechanism by which raloxifene produces estrogen antagonistic effects,is most likely classical competition for receptor binding.

The estrogen agonistic activity appears to involve novel post-receptor pathways and non-classical estrogen response elements.After high affinity binding with the ligand-binding domain of the estrogen receptor,raloxifene evokes a conformational change in the receptor structure and dimerizes the receptor.The receptor dimer now associates with DNA-response elements and receptor –associated proteins.The ability of raloxifene to elicit tissue selective responses is likely related to the diversity of receptor- associated proteins in different tissues,the differential distribution of estrogen receptor subtypes,and the activation of multiple-response elements in different genes.

CLINICAL SIGNIFICANCE
The exact positioning of raloxifene in the clinical pharmacological arena will only be clear as more results become available.Endpoint cardiovascular effects are addressed in the RUTH study and continuation of the MORE study will addres longterm effects on breast cancer.This is important as longterm resistance to tamoxifen has been reported.

The effect of raloxifene on the central nervous system needs to be defined in future studies,especially any effect on dementia(Alzheimers)

The effects on the urogenital epithelium(bladder and vagina) needs to be defined as studies on droloxifene had to be terminated because of an increased incidence of uterovaginal prolapse and incontinence.

Estrogen hormone replacement therapy remains the gold standard for the prevention of menopausal related conditions.Poor patient compliance to estrogen therapy may jeopardize the longterm beneficial effects.The most common reasons for discontinuation of estrogen therapy are uterine bleeding,mastalgia,perceived weight gain and fear of breast cancer.A recent meta analysis does indeed demonstrate a slightly higher risk of breast cancer after 5 and 10 years of estrogen treatment.

CONCLUSION
Considering presently available data,raloxifene can already be regarded as an important new tool in the hands of the physician treating menopausal women,especially women who can not,will not or should not take estrogen.

Published on 2005-06-08