Over the past decade, this new family of compounds has emerged. SERMs are defined as compounds that produce estrogen agonism in 1 or more desired target tissues (eg, bone, liver) together with estrogen antagonism and/or minimal agonism (ie, clinically insignificant) in reproductive tissues, such as the breast or uterus.[14] Raloxifene and its hydrochloride salt form are benzothiophene derivatives that were initially investigated as a treatment for advanced breast cancer.[15,16] Raloxifene was also shown to inhibit the hypertrophy of the uterus in response to estrogens,[17,18] to reduce serum cholesterol levels, and to increase BMD.[19] In light of this unique pharmacologic profile, extensive investigations of raloxifene were promptly undertaken to evaluate its skeletal properties.Characterization of Raloxifene: Preclinical Studies

On a molecular basis, raloxifene activates the gene encoding transforming growth factor beta (TGF beta3), which, together with other growth factors and cytokines, induces production of osteoblasts and inhibits the activity of osteoclasts and shortens their life span.[20,21] In vitro, raloxifene and estrogen inhibit — with similar potency and magnitude — interleukin (IL)-6-induced differentiation and resorptive activity of mammalian osteoclasts.[22] In the human-female-derived SaOS-2 osteoblast-like cell line, raloxifene dose dependently stimulated creatine kinase activity, a marker of cell division.[20]

Beneficial estrogen agonist-like effects of raloxifene have been characterized extensively in ovariectomized (OVX) rats. As an in vivo correlate of in vitro experiments, raloxifene and estrogens produce parallel reductions of serum IL-6 levels in OVX rats to levels observed in sham controls.[23] In the same model, oral administration of raloxifene (0.1-10.0 mg/kg per day) or oral ethinylestradiol (0.1 mg/kg per day) for 5 weeks induced similar effects — namely, preservation of BMD in the distal femur and proximal tibia.[17] Noteworthy in this experiment was the lack of significant estrogenic effect on uterine tissue in raloxifene-treated animals. The effects of ovariectomy on 6-month-old rats’ spinal BMD, femoral moment of inertia, femoral dry weight and volume, and, to a lesser extent, femoral BMD were similarly inhibited in an indistinguishable fashion by 17-beta estradiol (100 mcg/kg per day, subcutaneously) and raloxifene hydrochloride (1 mg/kg per day, orally) with a half-maximally effective dose of raloxifene on L1-L4 BMD between 0.1 and 1.0 mg/kg per day.[24]

When these animals were examined by peripheral computed tomography, the proximal tibia showed a 17% reduction in BMD 31 days after ovariectomy with a progressive increase in the cross-sectional area of the proximal tibiae, loss of cancellous bone, widening of marrow spaces, and thinning of the cortical bone wall opposite the fibula. Regression analysis of the dose-dependent protective effects of raloxifene showed half-maximal efficacy on the tibial BMD at 0.4 mg/kg per day. By comparison, 17alpha-ethinylestradiol showed dose-dependent effects with ED50 = 0.013 mg/kg per day.[25] After 6 months of oral administration, raloxifene and ethinylestradiol produced equivalent beneficial effects on the biomechanical properties of the vertebra (load to fracture) and the femoral neck (shear to failure) compared with OVX controls, with a significant correlation between vertebral strength and vertebral BMD.[26]Characterization of Raloxifene: Studies in Postmenopausal Women

In early postmenopausal women who were randomly assigned to raloxifene (60 mg/day), estrogen (0.625 mg/day conjugated equine estrogens plus 5 mg medroxyprogesterone/day for the first 2 weeks of each month), or no treatment, both raloxifene and estrogen produced a significant positive calcium balance shift, assessed by using calcium tracer kinetic methods, for up to 31 weeks of therapy. At this time point, resorption was reduced by both agents, although to a greater extent with estrogens; formation was reduced by estrogens but not by raloxifene, so that the general pattern of bone remodeling was similarly affected by the 2 agents.[27] In healthy postmenopausal women, an 8-week regimen of raloxifene hydrochloride (200-600 mg/day) and conjugated equine estrogens (0.625 mg/day) decreased to a similar extent biochemical markers of bone remodeling, ie, serum alkaline phosphatase (range, 10% to 11%), serum osteocalcin (range, 21% to 26%), urinary pyridinoline cross-links (range, 20% to 26%), and urinary calcium excretion (range, 45% to 72%).[28]

This estrogen agonist-like effect of raloxifene on bone turnover translated into significant increases in BMD of the lumbar spine, hip, and total body when a group of postmenopausal women aged 45-60 years and within 2-8 years of menopause, with T-scores for BMD of the lumbar spine between -2.5 and +2.0, were randomized for 24 months to receive placebo or 30, 60, or 150 mg/day of raloxifene for 24 months. At 24 months, the mean (with standard deviation) difference in the change in BMD between the women receiving 60 mg raloxifene and those receiving placebo was 2.4% (0.4%) for the lumbar spine, 2.4% (0.4%) for the total hip, and 2.0% (0.4%) for the total body. A subgroup analysis demonstrated that during therapy, the increases in BMD in lumbar spine and hip were similar regardless of the initial BMD, level of bone turnover (as assessed by baseline biochemical determinations), age, body mass index, and history of estrogen or thiazide therapy.[29]

Raloxifene (60 or 120 mg/day) was also administered to postmenopausal women with at least 1 prevalent vertebral fracture and compared in a 2-year, double-blind, placebo-controlled, prospective, randomized study to a control group receiving 750 mg of calcium and 400 IU vitamin D daily. With raloxifene (60 mg/day), biochemical markers of bone remodeling were significantly decreased — serum bone-specific alkaline phosphatase [-24% (6%)], osteocalcin [-36% (6%)], and urinary C-telopeptide fragment of type I collagen/creatinine [-36% (8%)], and there was a nonsignificant trend of an increase over controls in BMD for lumbar spine, total body, and total hip.[30] Similar results for biochemical markers of bone resorption and BMD were obtained in studies involving European[31] and Asian[32] populations.The Multiple Outcomes of Raloxifene Evaluation (MORE) Trial

The MORE trial was a randomized, placebo-controlled study of raloxifene 60 or 120 mg/day vs placebo (all women received calcium 500 mg and vitamin D 400 IU/day) involving 7705 women who were at least 2 years postmenopause.[33] This study was conducted at multiple centers throughout 25 countries. The primary end point of MORE was the determination of the percentage of women taking raloxifene who had at least 1 new vertebral fracture, as compared with the control group. Secondary end points were the relative risk (RR) of nonvertebral fractures, breast cancer, and cardiovascular events.

All women enrolled met the World Health Organization (WHO) criteria for osteoporosis (T-score = -2.5). Approximately one third had prevalent vertebral fractures. The average age was 65 years in patients without prevalent fractures and 69 years in those with prevalent fractures, with body mass indices of 25 and 26, respectively.

Evaluable radiographs were available for 6828 women. A central laboratory assessed vertebral fractures in the spinal radiographs. This procedure was carried out by radiologists blinded to treatment group assignment but not to the temporal sequence of the radiograph. Women were grouped according to the presence or absence of an adjudicated vertebral fracture at baseline. An adjudicated fracture was confirmed by at least 2 of 3 determinations, consisting of 2 independent semiquantitative (SQ) assessments and 1 quantitative morphometric (QM) measurement. Normal vertebrae (grade 0) had minimal deformity, with 40%, respectively. Vertebral fractures were also identified using QM criteria, consisting of a decrease in anterior, middle, and posterior vertebral height of >/= 20% and >/= 4 mm.

In clinical trials of osteoporosis therapies, the standard method used to define incident vertebral fractures from radiographs consists of a combination of SQ and QM assessment criteria.[34] Incident vertebral fractures were described as new fractures in vertebrae that were not fractured at baseline.

At 36 months, of the evaluable radiographs in 6828 women, 503 (7.4%) had at least 1 new vertebral fracture, including 10.1% of women receiving placebo, 6 hondrocream krema.6% of those receiving 60 mg/day of raloxifene, and 5.4% of those receiving 120 mg/day of raloxifene. Risk of vertebral fracture was reduced in both study groups receiving raloxifene (for 60 mg/day group: RR = 0.7; 95% confidence interval [CI] = 0.5-0.8; for 120 mg/day group: RR = 0.5; 95% CI = 0.4-0.7). Frequency of vertebral fracture was reduced in women who did not have prevalent fracture. In women with prevalent vertebral fractures who received 60 mg/day of raloxifene, the relative risk of new vertebral fracture was 0.7 (95% CI = 0.6-0.9); it was 0.5 (95% CI = 0.4-0.8) in those with low BMD but no prevalent vertebral fractures at inclusion. Compared with placebo, the 60-mg/day and 120-mg/day dosages of raloxifene increased BMD in the femoral neck by 2.1% and 2.4%, respectively, and in the spine by 2.6% and 2.7%, respectively (P At 1 year, raloxifene 60 mg/day decreased the risk for new clinical vertebral fractures by 68% (95% CI = 20% to 87%) compared with placebo in the overall study population and by 66% (95% CI = 23% to 89%) in women with prevalent vertebral fractures, who are at greater risk for subsequent fracture. The risk for clinical vertebral fractures in the raloxifene 60-mg/day group was decreased by 46% (95% CI = 14% to 66%) at 2 years and by 41% (95% CI = 17% to 59%) at 3 years. The cumulative incidence of new clinical vertebral fractures was lower in the group receiving raloxifene 60 mg/day compared with placebo (P In the overall cohort, the risk of nonvertebral fractures for raloxifene (60 mg/day and 120 mg/day) vs placebo did not differ significantly (RR = 0.9, 95% CI = 0.8-1.1).[35] However, when assessing separately women whose fracture severity grades, at baseline, corresponded to an estimated decrease in vertebral height of > 40% (grade 3), raloxifene 60 mg/day significantly decreased the risk of new vertebral fracture (RR = 0.73, 95% CI = 0.54-0.99) and nonvertebral fracture (RR = 0.53, 95% CI = 0.29-0.99) at 3 years.

Thirteen cases of breast cancer were confirmed among the 5129 women assigned to raloxifene vs 27 among the 2576 women assigned to placebo (RR = 0.24, 95% CI = 0.13-0.44; P An additional annual mammogram, at 4 years, reflected 3004 additional patient-years of follow-up. At this follow-up, 61 invasive breast cancers had been reported and were confirmed by the adjudication board, resulting in a 72% risk reduction with raloxifene (RR = 0.28, 95% CI = 0.17-0.46). These data indicate that 93 osteoporotic older postmenopausal women would need to be treated with raloxifene for 4 years to prevent 1 case of invasive breast cancer. Raloxifene reduced the risk of estrogen receptor-positive invasive breast cancer by 84% (RR = 0.16, 95% CI = 0.09-0.30).[37]

Raloxifene also significantly reduced the risk of cardiovascular events in a subset of women with increased cardiovascular risk (determined by the presence of multiple cardiovascular risk factors or prior coronary events or revascularization procedure). In the overall cohort, there were no significant differences between treatment groups in the number of combined coronary and cerebrovascular events: 96 (3.7%) with placebo, 82 (3.2%) with 60 mg/day of raloxifene, and 94 (3.7%) with 120 mg/day of raloxifene. RRs were 0.86 (95% CI = 0.64-1.15) and 0.98 (95% CI = 0.74-1.30) for 60 mg/day and 120 mg/day of raloxifene, respectively. Similar results were obtained when coronary and cerebrovascular events were analyzed separately.

Among the subset of 1035 women with increased cardiovascular risk at baseline, however, those assigned to raloxifene had a significantly lower risk of cardiovascular events compared with placebo (RR = 0.60, 95% CI = 0.38-0.95). The number of cardiovascular events during the first year was not significantly different across groups in the overall cohort (P = .94) or among women at increased cardiovascular risk (P = .86) or with evidence of established coronary heart disease (P = .60).[38] Hot flashes were the most common nonserious adverse event, prompting withdrawal in 0.1%, 0.7%, and 0.5% of the women in the placebo, raloxifene 60 mg, and raloxifene 120 mg groups, respectively. Leg cramps were also reported more frequently in the women given raloxifene (7.0% in the 60 mg and 6.9% in the 120 mg groups) than in the placebo group (3.7%).

After 3 years, raloxifene increased the risk of venous thromboembolic disease (RR = 3.1, 95% CI = 1.5-6.2) but did not increase the risk of endometrial cancer (RR = 0.8, 95% CI = 0.2-2.7).[36]

From a cost-utility analysis of a Swedish database, it appears that raloxifene can be targeted cost-effectively to postmenopausal women with osteopenia with a risk for hip fracture (relative risk 2.6) and to women aged 65 or older or at high risk (relative risk 3.0) for hip fracture.[39]

Rate this post