Selective Estrogen Receptor Modulators

1. Efficacy of SERMs in clinical trials

The multiple outcomes for raloxifene evaluation (MORE) study was a multicenter, randomized, blinded, placebo-controlled clinical trial, conducted for over three years for participants on raloxifene. The trial was able to demonstrate the effectiveness of raloxifene in maintaining BMD and minimizing bone loss in both the spine and femur neck for the study participants. Postmenopausal women with osteoporosis achieved a reduction of 30% in vertebral fractures with raloxifene. However, for non-vertebral fractures, there was no reduction with raloxifene use [6]. For lasofoxifene, another SERM, the randomized, double-blind, placebo-controlled study Postmenopausal Evaluation and Risk Reduction with Lasofoxifene (PEARL) clinical trial for vertebral fracture risk in postmenopausal women showed a 42% reduction [7]. In another study, for the bazedoxifene 20 mg group and the raloxifene 60 mg group compared with the placebo group, there was a significant effect on maintaining BMD and reducing annual new vertebral fractures [8].

Many clinical trials with postmenopausal osteoporotic women examining various SERM preparations have shown that SERMs can maintain BMD and reduced incidence of vertebral fractures, but did not reduced fracture risk in non-vertebral cases, indicating that their benefit for fractures is anatomically limited.

2. Extra-skeletal effects

The potential cardiovascular effects for raloxifene were studied by looking at the blood lipid profile changes for participants taking the medication, and a reduction in the high dose lipoprotein cholesterol was seen, but without a triglyceride increasing effect. The MORE study found an increased risk of a cardiovascular event in women [9]; however, the Raloxifene Use for the Heart (RUTH) indicated cardiovascular disease risk changes compared to placebo that were not statistically significant [9].

For breast cancer risk for participants taking raloxifene, the MORE study found that over a period of four years, there was 62% reduction in incidence of breast cancer. In the RUTH study, there was also a reduction of risk of invasive breast cancer by 44% relative risk reduction when used for an average of 5.6 years [9]. The continuing outcomes relevant to evista study, which took place over an eight-year period, found a 66% relative risk reduction [10].

In the case of tamoxifen and the endometrial effects on the vaginal mucosa, the endometrial cancer risk was found to be 2.5 times higher if raloxifene was used. Bazedoxifene has been found to have no net effect on endometrial cancer occurrence and does not increase its risk. For lasofoxifene, it has a slightly positive effect on the increase of endometrial thickness, but has a low endometrial cancer incidence [3]. Thus, the key difference between these SERMs is their endometrial safety. A tissue selective estrogen complex (TSEC) was developed in accordance with the endometrial effect, and it is combined with the presence or absence of the estrogen conjugate (Table 1).

Table 1

Tissue selective estrogen complex

3. Raloxifene vs. bazedoxifene

According to a bazedoxifene 20 mg, bazedoxifene 40 mg, raloxifene 60 mg per day after 36 months and placebo-controlled study, vertebral fracture risk was significantly lower in the study population of postmenopausal women with osteoporosis, as compared to placebo. For the bazedoxifene versus raloxifene arms, there were no statistically significant differences in efficacy. However, for the high risk group with the femoral neck T-score < or= -3.0, and the group with T-score >or= 1 with one or more moderate or severe vertebral fractures, the bazedoxifene 20 mg group had a significant reduction in risk of non-vertebral fractures as well compared to the other arms [3]. A randomized, double blind, placebo-active controlled study to compare the cost-effectiveness of bazedoxifene and raloxifene, bazedoxifene was more cost effective [11]. In addition to breast studies, there appears to be similar effects for raloxifene and bazedoxifene in terms of endometrial safety and blood lipid profiles.

4. Patient compliance

Many osteoporosis drugs have reported improvements in BMD and prevention of fractures in osteoporosis cases, but it is difficult to maintain patient compliance for dosing on schedule. Due to the chronic and progressive nature of osteoporosis, the patient cannot see the direct benefits of taking these medications. SERM drug are usually taken with BP and compliance is low due to gastrointestinal problems and other side effects [12]. However, by using BP in a weekly or monthly basis, better compliance has been reported. According to Licata [13], at seven months of being on these medications, the hormone replacement treatment discontinuation rate was at its highest at 26% for medications with BP formulations, while the SERM discontinuation rate was lower at 19%. From the survey by Huas et al. [14], monthly BP had the best compliance, followed by BP taken weekly and then taken on a daily basis. SERM compliance was also similar. Sambrook et al. [15] showed that weekly and monthly usage, rather than daily usage, had better compliance for BP and BP SERM combinations.

5. Use in the elderly population

As vertebral fractures frequently occur in relatively young patients, as compared to hip fractures, SERMs, which have marginal benefits in decreasing frequency of non-vertebral fractures, have been recommended as the first-line of defense for patients between the ages of 60 and 65. As serious complications from long-term BP use, such as occurrence of femoral atypical fractures and osteonecrosis of the jaw, have recently been reported, using SERMs instead is thought to be more appropriate for patients at approximately 60 years of age. It should be noted that most previous clinical trials on SERM for osteoporosis studies have used cohorts of postmenopausal women at approximately 65 years of age or older [16].

According to Cummings et al. [17], who examined the efficacy of administrating raloxifene to patients with an average age of 85.3 years (range, 75–99 years), a significant change of biochemical markers was also observed in cases of such elderly patients. Jacobsen et al. [18] also reported from a randomized, double-blinded and placebo-controlled study that significant BMD improvement and decreases in vertebral fracture rates were observed among female patients over age 70, compared to the placebo group.

6. Adverse effects and long-term safety

Clinical usage of SERM medications can have several side effects. Representative side effects of raloxifene include hot flashes and leg cramps. As such Davies et al. [19] reported that the occurrence frequency of hot flashes was significantly higher among postmenopausal healthy women under 60 who used raloxifene, as compared to the control group. Also, the study reported that no increase in hot flash frequency was observed at six months after beginning of the treatment. Davies et al. [19] argued that leg cramp occurrence was only a mild symptom of raloxifene use and that it was not significant enough to suspend its use. Raloxifene use has also been linked to rare, but serious side effects, such as venous thromboembolism, including deep vein thrombosis (DVT), pulmonary embolism (PE) and retinal vein thrombosis [17].

Higher frequency and extent of menopausal symptoms, including hot flashes and atrophic vaginitis, are the most commonly observed side effects from tamoxifen use. Increased occurrence of vaginal discharge and irregular menses has also been reported among women who use tamoxifen. Retinopathy has also been observed among women who use high-dose tamoxifen, but a less extensive retinal change can occur from time to time in cases of normal dose usage. However, an impact on vision is known to be very rare [20]. Use of tamoxifen has also been linked to a higher occurrence of cataracts. According to Fisher et al., women on tamoxifen experienced cataracts surgery 57% more often than for the control group [21]. Similar to raloxifene, tamoxifen has been reported to increase the risk of thromboembolic events, including DVT and PE [22].

Unlike BP, SERMs do not continue to impact bones and the effects on BMD cannot be expected to continue once the medication is suspended. Hence, long-term use of SERM medication is required for the prevention of osteoporosis. Messalli and Scaffa [23] reported a good overall risk-benefit profile for raloxifene, although it increases the risk of venous thromboembolism and fatal strokes. They argued that a guarded and careful use of the medication is required, accounting for an individual's specific risk factors.

From a sampling of postmenopausal women, Siris et al. [24] compared the skeletal effects of raloxifene with placebo and reported that a decrease in non-vertebral fracture risk was unlikely to persist over eight years. They recommended switching to other anti-osteoporosis agents after an eight-year use of raloxifene.