Download Evidence-Based Clinical Effects of Selective Estrogen Receptor

Evidence-Based Clinical Effects of Selective Estrogen
Receptor Modulators (SERMS)
M.W. Draper
Lilly Research Laboratories
a division of Eli Lilly and Company, Indianapolis. IN, U.S.A.
Over the past decade, it has become increasingly evident that hormone replacement therapy
(HRT) has benefits in the postmenopausal woman, which extend beyond symptom relief.
Prevention of the postmenopausal loss of skeletal mass has been shown to be a clear benefit
of proper estrogen replacement. In addition, evidence has accumulated which shows positive
effects of HRT on serum lipid levels and probably on the incidence of coronary artery disease
in this population, although the solid, prospective data to substantiate this assumption remain
to be gathered. It may be that other benefits of HRT administration in the postmenopausal
woman will yet be clearly documented. In this setting, the current low level of acceptance and
use of HRT, particularly in certain countries of the world, is surprising. Contributing to this
problem is the fact that awareness of the benefits of HRT among postmenopausal women is
still far from optimal. Another important reason for lower-than-expected use of HRT has been
the undesirable effects, both real and perceived, which are associated with HRT use. Side
effects of both estrogens and progestins are limiting for some women. Perhaps the most
serious limitation of all, however, is the fear of the enhancement of cancer risk associated
with estrogen replacement.
In this setting, there has been an intense search for therapies related to estrogen which might
provide the significant benefits of HRT, but which would avoid some or all of the negative
aspects of this therapy. This pursuit has been stimulated recently by observations that
tamoxifen, a therapeutic agent which clearly acts through the estrogen receptor may have
“selective” actions. Positive skeletal and cardiovascular benefits of tamoxifen have been
demonstrated in women who receive the drug either as primary or adjuvant therapy for breast
cancer. The uterine effects of tamoxifen, however, may not conform to the ideal pattern of
“selectivity”, and other side effects may also be of concern.
Research efforts have now succeeded in giving us the first example of a compound acting
through the estrogen receptor (ER), but in which the pattern of clinical action is selective for a
particular patient population, in this case the asymptomatic postmenopausal woman.
Raloxifene is a benzothiophene derivative, originally developed at Lilly Research Labs with an
intended application in breast cancer. Extensive clinical evaluation of raloxifene has now
established that this compound may, indeed, be able to deliver many of the very positive
benefits of long-term HRT, but without the most serious effects which limit the chronic use of
HRT in postmenopausal women.
The most extensively-documented clinical effect of raloxifene is its action as a skeletal
antiresorptive. Bone turnover is decreased by therapy with this compound, in a manner
similar to that seen with various estrogen treatments. In clinical trials involving over 10,000
postmenopausal women, many treated for over 3 years with raloxifene, it has been
established that this compound decreases bone turnover to the point that bone loss is halted,
with 2-3% increases in bone mineral density at all skeletal sites .In addition, in a 3-year study
of nearly 8000 osteoporotic women, a 40-50% decrease in vertebral fracture rate has been
achieved by daily therapy with raloxifene.
Raloxifene has also been shown in these studies to have a substantial and consistent effect
to lower LDL cholesterol levels, without concomitant increases in serum triglycerides. Other
evidence for potential cardiovascular benefit has also been demonstrated in both preclinical
and clinical models. Very large, prospective studies are currently underway with both HRT
and raloxifene, in order to document the fact that positive effects on surrogate markers will be
manifest in the prevention of cardiovascular disease and a decrease the incidence of
myocardial infarctions in postmenopausal women.
In marked contrast to both estrogen and tamoxifen, however, all evidence on raloxifene
supports the view that this drug is a competitive antagonist of estrogen action in the uterus.
Uterine bleeding is not seen in raloxifene-treated patients. In addition, the long-established
antiproliferative action of raloxifene in mammary tissue has now been validated in these large
clinical trials. It has recently been reported in a 3 year treatment study with raloxifene, that
osteoporotic postmenopausal patients experienced a highly-significant 76% decrease (versus
placebo) in incidence of newly-diagnosed breast cancer.
It is now clear that selective action through the estrogen receptor can be achieved.
Furthermore, a particular compound, raloxifene, has been developed which delivers
antiresorptive skeletal action sufficient to prevent osteoporotic fractures. This compound also
has positive effects on the serum lipid profile. In reproductive tissues, however, raloxifene
appears to behave as a very effective estrogen antagonist. Thus, the first significant step has
been taken in bringing targeted, ER-active agents to specific groups of patients. This new
therapy will help us to make significant strides in permitting women to enjoy long and
productive lives, without the ravages resulting from untreated postmenopausal health risks.