, Volume 60, Issue 2, pp 379-411
Date: 17 Sep 2012

Raloxifene

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Summary

Abstract

Raloxifene is a selective estrogen receptor modulator that partially mimics the effects of estrogens in bone and the cardiovascular system, while functioning as an antiestrogen in endometrial and breast tissue.

In randomised placebo-controlled studies involving postmenopausal women or patients with osteoporosis, raloxifene 60 to 150 mg/day was effective in increasing bone mineral density (BMD) over 12-to 36-month periods. At the 60 mg/day recommended dosage, increases of 1.6 to 3.4%, 0.9 to 2.3% and 1.0 to 1.6% were reported in lumbar spine, femoral neck and total hip, respectively, versus ≤0.5% with placebo.

Raloxifene 60 or 120 mg/day decreased the risk of vertebral fractures over a 36-month period in postmenopausal patients with osteoporosis. Significant reductions in radiographic fracture risk versus placebo (30 and 50%) occurred regardless of whether patients had existing fractures at baseline. Although raloxifene did not affect the overall incidence of nonvertebral fractures, a reduction in the incidence of ankle fracture was reported in comparison with placebo. In postmenopausal women, raloxifene 60 mg/day significantly reduced serum levels of total and low density lipoprotein cholesterol from baseline, compared with placebo. High density lipoprotein cholesterol and triglyceride levels were unaffected.

Raloxifene 60 or 120 mg/day reduced the risk of invasive breast cancer by 76% during a median of 40 months’ follow-up in postmenopausal patients with osteoporosis and no history of breast cancer. A relative risk reduction of 90% was reported for estrogen-receptor positive invasive breast cancers; estrogen-receptor negative cancer risk was unaffected by raloxifene.

Raloxifene was generally well tolerated in clinical trials at dosages up to 150 mg/day. Adverse events thought to be related to raloxifene treatment were hot flushes and leg cramps. Venous thromboembolism was the only serious adverse event thought to be related to raloxifene treatment and a relative risk of 3.1 compared with placebo treatment was reported in patients with osteoporosis. Vaginal bleeding occurred in ≤6.4% of raloxifene-treated women but was reported by 50 to 88% of those receiving estrogens or hormone replacement therapy (HRT). Raloxifene treatment was not associated with stimulatory effects on the endometrium.

Conclusions: Raloxifene significantly increases BMD in postmenopausal women and reduces vertebral fracture risk in patients with osteoporosis. In clinical trials, raloxifene was generally well tolerated compared with placebo and HRT, although its propensity to cause hot flushes precludes use in women with vasomotor symptoms. In particular, the lack of stimulatory effects on the endometrium and the reduction in invasive breast cancer incidence indicate raloxifene as an attractive alternative to HRT for the management of postmenopausal osteoporosis.

Pharmacodynamic Properties

Raloxifene is a selective estrogen receptor modulator that partially mimics the effects of estrogens in bone and the cardiovascular system and has estrogen antagonist properties in endometrial and breast tissue.

Mechanism of Action: Raloxifene appears to influence gene transcription, via the intermediary of estrogen receptors (ER), through interactions with the estrogen response element (ERE) and a distinct DNA target, the raloxifene response element (RRE). However, the precise mechanism of action of this agent remains to be elucidated.

Bone Remodelling: Raloxifene modulates bone cell homeostasis in vitro, through actions on the proliferation and activity of osteoclasts and osteoblasts. Effects include inhibition of osteoclast pit formation and increases in the expression of bone matrix proteins such as alkaline phosphatase, osteonectin, osteocalcin and collagen.

In postmenopausal women and patients with osteoporosis, raloxifene 30 to 150 mg/day consistently and significantly reduced serum and urinary markers of bone turnover compared with placebo treatment. The effects of raloxifene 60 mg/day on bone turnover were less than those of conjugated equine estrogens 0.625 mg/day in a 6-month study. Raloxifene 60 mg/day plus alendronate 10 mg/day appeared to have greater effects on markers of bone turnover over a 12-month period than either agent alone.

Histomorphometric analysis of iliac crest biopsies indicated that 6 months’ treatment with raloxifene 60 mg/day maintained bone architecture and had no adverse effects on mineralisation rate or bone quality in postmenopausal women. These effects were similar to those of conjugated equine estrogens 0.625 mg/day. Cardioprotective Potential: Antiatherogenic properties have been reported in animal models and in in vitro studies.

Pharmacokinetic Properties

Raloxifene is rapidly absorbed from the gastrointestinal tract (approximately 60%) and undergoes extensive first-pass glucuronidation. Peak plasma concentrations (Cmax) of raloxifene and its metabolites typically occur 6 hours after oral administration and a median absolute bioavailability of 2% has been reported. After multiple doses, Cmax and area under the plasma concentration-time curve (AUC) values of raloxifene were 1.36 µg/L per mg/kg and 24.2 µg · h/L per mg/kg.

Raloxifene is extensively distributed after oral administration and an apparent volume of distribution of 2348 L/kg has been reported. In vitro, raloxifene is >95% bound to human plasma proteins. The plasma elimination half-life of raloxifene is 27.7 hours.

Raloxifene is metabolised by glucuronidation and unchanged drug accounts for 1% of circulating concentrations. Excretion is predominantly via the faecal route and occurs within 5 days of administration; approximately 5% of the administered dose is excreted in urine as glucuronide conjugates.

Coadministration of warfarin with raloxifene produced small but significant reductions in clearance and volume of distribution of the warfarin enantiomers. Maximum prothrombin response and prothrombin time AUC were reduced by 10 and 8%, respectively. Warfarin administration did not affect the pharmacokinetic properties of raloxifene. A 60% reduction in the absorption and enterohepatic recirculation of raloxifene was reported after a single dose of the anion exchange resin cholestyramine.

Therapeutic Use

During the clinical trials programme for raloxifene, therapeutic efficacy in terms of prevention of bone loss in postmenopausal women and treatment of postmenopausal patients with osteoporosis has been evaluated on the basis of changes in bone mineral density (BMD) and fracture incidence. Raloxifene, at dosages of 60 to 150 mg/day, was administered as an oral once daily regimen.

In postmenopausal women and patients with osteoporosis enrolled in randomised multicentre trials, raloxifene (generally in the presence of calcium and vitamin D3 supplementation) consistently increased lumbar spine, femoral neck, otal hip and total body BMD relative to baseline values over 12-to 36-month treatment periods. Significant increases versus placebo in BMD were evident within 12 months and were maintained for the remainder of treatment. At the 60 mg/day therapeutic dosage, increases of 1.6 to 3.4%, 0.9 to 2.3% and 1 to 1.6% were reported in the lumbar spine, femoral neck and total hip, respectively. Mean BMD values were reduced compared with baseline or increased by ≤0.5% in individuals receiving placebo.

In a 12-month study, treatment with raloxifene 60 mg/day plus alendronate 10 mg/day significantly increased lumbar spine and proximal femur BMD to a greater extent than either agent alone or placebo. Alendronate tended to increase BMD at both sites to a greater extent than raloxifene, although this difference was not significant.

In a large randomised double-blind placebo-controlled study involving 7705 patients with postmenopausal osteoporosis, the relative risk of vertebral fractures was reduced by raloxifene 60 or 120 mg/day. Over a 36-month treatment period, significant reductions in radiographic fracture risk (30 and 50%) relative to placebo occurred regardless of whether patients had pre-existing fractures at baseline.Moreover, the risk of clinical (painful) vertebral fractures was reduced by 60% during raloxifene treatment. Raloxifene significantly reduced the incidence of ankle fracture compared with placebo treatment (0.7 vs 1.1%, p < 0.05), although there was no difference between groups for hip, wrist or total nonvertebral fractures.

Tolerability

Raloxifene at dosages up to 150 mg/day has been generally well tolerated in clinical trials in postmenopausal women. Adverse events thought to be related to raloxifene treatment were hot flushes and leg cramps. No clinically important changes in haematological, renal or hepatic laboratory variables were observed during 3-year raloxifene treatment.

Hot flushes occurred in 24.6% of postmenopausal women treated for up to 30 months with raloxifene, compared with 18.3% receiving placebo (p < 0.001) and were more frequent (p < 0.05) during treatment with raloxifene than with HRT or conjugated equine estrogens. In the large osteoporosis treatment study, 9.7 and 11.6% of patients receiving raloxifene 60 and 120 mg/day, respectively, experienced hot flushes, compared with 6.4% in the placebo group. Most episodes of hot flush were mild or moderate in intensity and tended to occur more commonly in the first 6 months of treatment. The occurrence of other vasomotor symptoms such as daytime and night sweats and sleep disorders did not differ between raloxifene, placebo, HRT and estrogen treatment.

Leg cramps occurred more commonly in individuals receiving raloxifene than in the placebo group (5.5 vs 1.9%), although the incidence of this event was not significantly different between raloxifene, HRT and estrogen treatment. Similarly, leg cramps occurred in 7.0, 6.9 and 3.7% of patients receiving raloxifene 60 or 120 mg/day or placebo, respectively, in the large osteoporosis treatmentstudy. In this trial, the incidence of peripheral oedema was also more common (p < 0.01) with raloxifene treatment (5.2 and 6.5%) than with placebo (4.4%). Breast pain was rare during raloxifene treatment and occurred less frequently than during treatment with HRT or estrogens.

Few episodes of vaginal bleeding occurred during treatment with raloxifene (<6.4%) and the incidence was similar to that reported among individuals receiving placebo. In contrast, vaginal bleeds were reported by 50 to 88.5% of postmenopausal women receiving estrogens or HRT. In a 3-year study involving 7705 patients, endometrial carcinoma occurred in 4, 2 and 4 patients receiving raloxifene 60 or 120 mg/day or placebo, respectively.

The only serious adverse events considered related to raloxifene treatment were venous thromboembolic episodes. Although the incidence was low (1% in each of 60 and 120 mg/day groups vs 0.3% with placebo) a relative risk of thromboembolic events of 3.1 was reported. The greatest risk of thromboembolism occurred within the first 4 months of therapy.

Dosage and Administration

Oral raloxifene is indicated for the treatment and prevention of postmenopausal osteoporosis at a dosage of 60 mg/day, and may be administered without respect to mealtimes. Supplemental calcium and/or vitamin D should be added to the diet if the daily intake is inadequate.

Raloxifene is contraindicated in patients with known hypersensitivity to raloxifene and in those with a history of thromboembolic events. Raloxifene should be discontinued ≥72 hours prior to and during prolonged immobilisation, and should be resumed only after the patient is fully ambulatory.

Concomitant use of raloxifene with systemic estrogens or cholestyramine is not recommended and raloxifene should be used with caution in patients taking highly protein-bound drugs such as diazepam, diazoxide and lidocaine (lignocaine). In patients taking concomitant warfarin or other coumarin derivatives, prothrombin times should be closely monitored when starting or stopping raloxifene treatment.