Some of the views expressed in the following notes on newly approved products should be regarded as preliminary, as there may have been limited published data at the time of publication, and little experience in Australia of their safety or efficacy. However, the Editorial Executive Committee believes that comments made in good faith at an early stage may still be of value. Before new drugs are prescribed, the Committee believes it is important that more detailed information is obtained from the manufacturer's approved product information, a drug information centre or some other appropriate source.


Evista (Eli Lilly)
60 mg tablets
Approved indication: prevention of bone loss
Australian Medicines Handbook Section 10.4

The Australian National Consensus Conference on the Prevention and Management of Osteoporosis1 recommended oestrogen therapy for postmenopausal women with a low bone mass. Oestrogens have a beneficial effect, but they increase the risk of endometrial cancer. Research efforts have therefore been directed at finding a drug with oestrogenic effects which is selective for bone.

Raloxifene acts on oestrogen receptors. It produces different effects in different tissues because of the way it binds with the receptors. Raloxifene has an agonist effect on bone, but does not stimulate the endometrium. Experimentally, it inhibits the growth of breast cancer cells.

A multinational study enrolled 601 postmenopausal women with low or normal bone density.2 They were randomised to take 30 mg, 60 mg or 150 mg of raloxifene or placebo daily for two years. The response to treatment was evaluated by measurement of bone density and biochemical markers of bone metabolism. Bone density increased in women given raloxifene while it decreased in those given placebo. There was a significant decrease in bone turnover in the women who took raloxifene. The greatest increase in bone density at the hip occurred in women taking 60mg raloxifene. This is now the recommended daily dose.

Postmenopausal women taking oestrogens may also benefit from the effect of treatment on the risk of cardiovascular disease. Like oestrogen, raloxifene alters the lipoprotein profile. In the efficacy study,2 raloxifene significantly decreased the concentration of total and LDL cholesterol. Another study compared these findings with hormone replacement therapy (HRT).3 The reductions in LDL cholesterol were similar, but raloxifene did not 'significantly' change the HDL cholesterol which was increased 11% by HRT. Raloxifene significantly lowered fibrinogen while HRT had no effect.

The bioavailability of raloxifene is only 2%. This is because only 60% of the dose is absorbed and this undergoes first-pass metabolism. The daily dose may be taken with or without food. Raloxifene is highly protein bound and it mainly circulates as glucuronide metabolites. The plasma elimination half-life is approximately 28 hours with excretion mainly in the faeces.

Raloxifene is not recommended for patients with liver disease. As there is an increased risk of thromboembolism, raloxifene is contraindicated in women with a history of venous thrombosis. Compared with women taking placebo, women taking raloxifene are significantly more likely to experience leg cramps, peripheral oedema and vasodilatation.

While raloxifene provides another option for preventing osteoporosis in postmenopausal women, its role in therapy needs to be elucidated. More research is needed to see if it reduces fractures or protects against cardiovascular disease. Tamoxifen may also protect against osteoporosis, but it can increase the incidence of endometrial cancer. While raloxifene does not cause endometrial proliferation,2 it is not as effective as oestrogen in reducing hot flushes. There are no data on using raloxifene and oestrogens in combination. Recent results are encouraging,4 but further studies will be needed to discover how raloxifene affects the long-term risk of breast cancer.

References

  1. The Australian National Consensus Conference on the Prevention and Management of Osteoporosis 1996. Aust Prescr 1997;20 (3 Suppl).
  2. Delmas PD, Bjarnason NH, Mitlak BH, Ravoux A, Shah AS, Huster WJ, et al. Effects of raloxifene on bone mineral density, serum cholesterol concentrations, and uterine endometrium in postmenopausal women. N Engl J Med 1997;337:1641-7.
  3. Walsh BW, Kuller LH, Wild RA, Paul S, Farmer M, Lawrence JB, et al. Effects of raloxifene on serum lipids and coagulation factors in healthy postmenopausal women. JAMA 1998;279:1445-51.
  4. Cummings SR, Eckert S, Krueger KA, Grady D, Powles TJ, Cauley JA, et al. The effect of raloxifene on risk of breast cancer in postmenopausal women. JAMA 1999;281:2189-7.