Selective estrogen receptor modulators for prevention and treatment of osteoporosis

INTRODUCTION — The selective estrogen receptor modulators (SERMs) bind with high affinity to the estrogen receptor and have estrogen agonist and antagonist properties that vary depending upon the individual target organ [1,2]. The factors that determine the variable estrogen receptor agonist and antagonist activity of SERMs are not fully defined but are under active study. (See "Mechanisms of action of selective estrogen receptor modulators and down-regulators".)

Some SERMs, such as raloxifene and bazedoxifene, have estrogen activity in bone and, therefore, prevent bone loss, improve bone mineral density (BMD), and decrease the risk of vertebral fracture. The use of SERMs for the prevention and treatment of osteoporosis will be discussed here. Their role in breast cancer prevention is discussed in detail elsewhere. (See "Selective estrogen receptor modulators and aromatase inhibitors for breast cancer prevention" and "Adjuvant endocrine and targeted therapy for postmenopausal women with hormone receptor-positive breast cancer".)

An overview of the approach to therapy of osteoporosis in postmenopausal women and the prevention of bone loss are also reviewed separately. (See "Overview of the management of low bone mass and osteoporosis in postmenopausal women".)

CANDIDATES FOR THERAPY — Patients with the highest risk of fracture are the ones most likely to benefit from drug therapy. Fracture risk is determined by a combination of bone mineral density (BMD) and clinical risk factors. Selecting patients at high risk of fracture for osteoporosis therapy is reviewed in detail separately. (See "Overview of the management of low bone mass and osteoporosis in postmenopausal women", section on 'Patient selection'.)

CHOICE OF DRUG — For postmenopausal women who are candidates for and desire pharmacologic therapy for prevention of bone loss, bisphosphonates or raloxifene are reasonable options. There are nonskeletal considerations with raloxifene that may play an important role in the selection of postmenopausal women for therapy: a reduction in breast cancer risk, but an increase in thromboembolic events and hot flashes, and no apparent effect on heart disease or the endometrium. Raloxifene inhibits bone resorption and reduces the risk of vertebral fracture, and it is our selective estrogen receptor modulator (SERM) of choice because it has eight-year safety and efficacy data and also reduces the risk of breast cancer. Raloxifene is usually chosen for osteoporosis prevention when there is an independent need for breast cancer prophylaxis. (See "Overview of the management of low bone mass and osteoporosis in postmenopausal women".)

Bazedoxifene (available in Europe and Japan) has similar efficacy as raloxifene in preventing and treating postmenopausal osteoporosis. However, there are few long-term safety data, and it has not been adequately studied for breast cancer prevention.

Bazedoxifene-conjugated equine estrogen is a combination drug available in some countries for the treatment of hot flashes and the prevention of bone loss in postmenopausal women with an intact uterus. Although this combination is an option for menopausal women who have bothersome hot flashes (prohibiting the use of bazedoxifene alone or raloxifene) and who are not candidates for or are intolerant of bisphosphonates, the absence of long-term fracture and safety data tempers our enthusiasm for bazedoxifene-conjugated equine estrogen. In addition, the effect of bazedoxifene-conjugated equine estrogen on breast cancer risk is unknown.

We favor bisphosphonates over SERMs for the treatment of osteoporosis because they have greater efficacy than SERMs in reducing nonspine and hip fractures [3]. Raloxifene is a reasonable alternative to bisphosphonates for postmenopausal women with osteoporosis (low bone mineral density [BMD, T score <-2.5] and no fragility fractures) who cannot tolerate or are not candidates for any bisphosphonates or for postmenopausal women with osteoporosis who are also at high risk for invasive breast cancer. We prefer raloxifene to bazedoxifene because it has long-term safety and efficacy data and because it has been shown to reduce the risk of breast cancer. (See "Overview of the management of low bone mass and osteoporosis in postmenopausal women", section on 'Choice of initial therapy'.)

RALOXIFENE — Raloxifene inhibits bone resorption and reduces the risk of vertebral fracture, and it is our selective estrogen receptor modulator (SERM) of choice for postmenopausal women who are candidates for and desire pharmacologic therapy for prevention of osteoporosis because it has eight-year safety and efficacy data and also reduces the risk of breast cancer. Raloxifene is also an option for the treatment of osteoporosis in postmenopausal women who cannot tolerate bisphosphonates or who are at high risk for invasive breast cancer.

Bone mineral density — There are several trials demonstrating a beneficial effect of raloxifene on bone mineral density (BMD) (figure 1) [4-9]. In a meta-analysis of seven trials (four treatment, three prevention) examining the effects of raloxifene versus placebo on BMD, raloxifene increased BMD of the lumbar spine (weighted mean difference [WMD] 1.8, 95% CI 1.5-2.1) and hip (WMD 2.1, 95% CI 1.7-2.5) after two years of treatment [10].

In the largest trial, the Multiple Outcomes of Raloxifene Evaluation (MORE) trial, 7705 postmenopausal women with osteoporosis were randomly assigned to raloxifene (60 or 120 mg) or placebo daily [11]. Lumbar spine and femoral neck BMD increased from 2 to 2.7 percent in the raloxifene groups compared with placebo.

Smoking, which reduces the efficacy of estrogen by accelerating its metabolism, did not interfere with the anti-osteoporotic effect of raloxifene [12].

Fracture — Raloxifene reduces the risk of vertebral fracture [7,8,13-15]; however, it has not been shown to reduce nonvertebral fractures. As an example, in a meta-analysis of trials comparing raloxifene with placebo, raloxifene consistently reduced the risk of vertebral fracture in postmenopausal women (odds ratio [OR] 0.6, 95% CI 0.5-0.7) [13]. In the largest trial, the MORE trial, a subset of 6828 of the women had lumbar spine radiographs at baseline and after 36 months of treatment [7,8]. Among the women receiving 60 mg and 120 mg raloxifene, 6.6 and 5.4 percent, respectively, had new vertebral fractures, compared with 10.1 percent in the placebo group (figure 2); the risk of nonvertebral fractures was similar in the three groups.

Potency — Raloxifene appears to be a less potent antiresorptive agent than alendronate or estrogen [16-20]. As examples:

●In a one-year study of 331 postmenopausal women with osteoporosis, alendronate (10 mg/day) increased BMD more than raloxifene (60 mg/day) [16].

●In a three-year trial of 619 hysterectomized, postmenopausal women randomly assigned to raloxifene 60 mg/day, conjugated estrogen 0.625 mg/day, or placebo, beneficial effects on BMD were seen with both drugs, although the effect of estrogen was more marked (4.6 percent increase in spine BMD versus no change and 2 percent decrease with raloxifene and placebo, respectively) [19]. Hot flashes and leg cramps were more common in the raloxifene group, while breast tenderness was more common with estrogen.

It is not known if the greater efficacy in increasing BMD with alendronate and estrogen translates into greater fracture reduction. There are no fracture trials directly comparing raloxifene with a bisphosphonate.

Combination therapy — We do not suggest combination therapy (eg, bisphosphonate-raloxifene), as the additional BMD benefits are small, the reduction in fracture risk above that with either agent alone is unknown [16], and there are additional costs and side effects of taking two agents.

Some trials have reported that raloxifene (either taken concurrently or prior to parathyroid hormone [PTH]) does not suppress the BMD response to PTH as much as alendronate. Patients previously treated with raloxifene have a good BMD response to PTH, but the optimal management (continue versus discontinue raloxifene) is unclear. This topic is reviewed in more detail elsewhere.

Duration of therapy — In women who are tolerating raloxifene well and who are having a good response (improvement or stable BMD), we suggest not stopping therapy. Safety and efficacy data from clinical trials extend for eight years [14] and, therefore, some clinicians prefer to discontinue raloxifene after eight years and switch to an alternative anti-osteoporosis agent.

Unlike bisphosphonates, SERMs do not have a prolonged duration of action in the skeleton, and there is no residual benefit on BMD after discontinuation of therapy (see "Bisphosphonate therapy for the treatment of osteoporosis", section on 'Duration of therapy'). In one trial, women who had completed a five-year course of raloxifene experienced significant decreases in lumbar spine and femoral neck BMD (2.4 and 3 percent, respectively) one year after discontinuation of raloxifene [21]. The rate of bone loss was similar to that of placebo-treated patients.

Effects in premenopausal women — Raloxifene is not effective for the prevention or treatment of osteoporosis in premenopausal women. In a two-year study of 37 premenopausal women at risk for breast cancer, raloxifene significantly decreased lumbar spine BMD by 3.5 percent and total hip BMD by 1 percent [22]. The decrease in BMD was associated with an increase in all markers of bone turnover. After stopping raloxifene for one year, BMD increased by 1.4 percent and 1.7 percent in the spine and hip, respectively. Therefore, raloxifene, like tamoxifen, has opposite effects on bone in pre- and postmenopausal women. (See 'Tamoxifen' below.)

Adverse effects

General — In clinical trials, hot flushes, leg cramps, and peripheral edema were more common with raloxifene than with placebo, occurring in 8 to 25, 5 to 10, and 5 to 14 percent of patients, respectively [4,6,7,11,15]. There was no difference in endometrial thickness or in complaints of breast pain or vaginal bleeding between the active treatment and placebo groups.

In the MORE trial, raloxifene therapy was not associated with an increased risk of either gallbladder disease or cataracts (risks that are increased with estrogen and tamoxifen use, respectively) [23,24]. However, an increased risk of gallbladder disease was seen with raloxifene in the Raloxifene Use for The Heart (RUTH) trial, described below [15]. (See 'Coronary heart disease' below.)

Venous thromboembolism — Raloxifene increases the risk of venous thromboembolic (VTE) events, as has been described for both estrogen and tamoxifen therapy [7,11,15,24]. The magnitude of this effect is illustrated by the results of a meta-analysis of nine trials (24,523 postmenopausal women), in which therapy with raloxifene was associated with an increase in the risk of deep venous thrombosis (DVT) and pulmonary embolism (ORs 1.5, 95% CI 1.1-2.1 and 1.9, 95% CI 1.0-3.5, respectively) [25]. The magnitude of the relative risk appears similar to that reported with estrogen-progestin use. (See "Menopausal hormone therapy and cardiovascular risk", section on 'Venous thromboembolism'.)

In one of the largest trials, the RUTH trial, 10,101 postmenopausal women (mean age 67 years) with coronary heart disease (CHD) or risk factors for CHD were randomly assigned to raloxifene (60 mg/day) or placebo [15]. The two primary outcomes were coronary events and invasive breast cancer. Raloxifene was associated with an increased risk of VTE (103 versus 71 events, hazard ratio [HR] 1.44, 95% CI 1.1-1.9, absolute risk increase 1.2 per 1000). (See 'Coronary heart disease' below.)

In the Study of Tamoxifen and Raloxifene (STAR) trial, which compared raloxifene with tamoxifen for the prevention of breast cancer, the risk of thromboembolic events (DVT, pulmonary embolism) was lower with raloxifene than with tamoxifen [23]. This trial is reviewed separately. (See "Selective estrogen receptor modulators and aromatase inhibitors for breast cancer prevention", section on 'Raloxifene'.)

Stroke — In the RUTH trial, raloxifene was not associated with an increased risk in overall stroke risk but was associated with an increased risk of fatal stroke (59 versus 39 events, HR 1.49, 95% CI 1.0-2.2, absolute risk increase 0.7 per 1000 woman-years) compared with placebo [15]. In a post hoc analysis, the increased risk of fatal stroke was greater in women who had a high baseline risk of stroke [26]. In the STAR trial, stroke risk was similar in the raloxifene and tamoxifen groups [23]. (See 'Coronary heart disease' below and "Selective estrogen receptor modulators and aromatase inhibitors for breast cancer prevention", section on 'Choice of agent'.)

Other effects

Coronary heart disease — Although raloxifene decreases serum concentrations of total and low-density lipoprotein (LDL) cholesterol [4,27], it does not decrease the risk of CHD [15,28,29]. In the RUTH trial, 10,101 postmenopausal women (mean age 67 years) with CHD or its risk factors were randomly assigned to raloxifene (60 mg/day) or placebo [15]. The two primary outcomes were coronary events and invasive breast cancer. After a mean treatment period of 5.6 years, the following results were seen:

●Raloxifene had no significant effect on the risk of coronary events when compared with placebo (HR 0.95). In a post hoc analysis of the original dataset, the incidence of coronary events among women <60 years of age was significantly lower in the raloxifene group compared with placebo [30]. However, these data should be interpreted with caution as they were based upon a post hoc subgroup analysis and a small number of events (50 versus 84).

●The absolute rates of events that were decreased (vertebral fractures and breast cancer) were similar to the absolute rates of events that were increased (VTE events and fatal stroke).

In the STAR trial, the risk of CHD was similar in the raloxifene and tamoxifen groups [23]. This trial is reviewed separately. (See "Selective estrogen receptor modulators and aromatase inhibitors for breast cancer prevention", section on 'Choice of agent'.)

In a study of raloxifene therapy in 12 postmenopausal women with a history of hypertriglyceridemia while on oral estrogen, 3 of the 12 developed severe hypertriglyceridemia (≥1000 mg/dL [≥11.3 mmol/L]) while taking raloxifene [31]. This subset of susceptible women should be monitored closely if raloxifene is subsequently prescribed.

Breast cancer — The MORE trial showed that raloxifene was associated with a substantially reduced risk of invasive breast cancers, a secondary endpoint of the study [11]. In the RUTH trial described above, raloxifene reduced the risk of invasive breast cancer (HR 0.56; absolute risk reduction 1.2 cases per 1000 women per year). The benefit was primarily due to a decreased risk of estrogen receptor (ER)-positive breast cancers. This topic is reviewed in more detail separately. (See "Selective estrogen receptor modulators and aromatase inhibitors for breast cancer prevention".)

Mortality — In the MORE/CORE (Continuing Outcomes Relevant to Evista) trial, which recruited postmenopausal women with osteoporosis, mortality was recorded as an adverse event [7]. Overall mortality was lower among patients in the raloxifene group (45 versus 65 deaths, HR 0.68, 95% CI 0.46-0.99) [32]. In the RUTH trial, which recruited postmenopausal women with CHD or its risk factors, overall mortality was a secondary endpoint, and coronary death was a component of the primary composite endpoint [15]. There was no difference in overall or coronary mortality rates between the raloxifene and placebo groups (554 versus 595 deaths, HR for overall and coronary mortality 0.92, 95% CI 0.82-1.03 and 0.78-1.09, respectively). However, there was a significant increase in cerebrovascular mortality (59 versus 39 deaths, HR 1.49 [95% CI 1.00-2.24]). In a post hoc pooled analysis of mortality data from MORE/CORE and RUTH, overall mortality was lower among women receiving raloxifene (HR 0.9, 95% CI 0.8-1.0), primarily due to a lower rate of noncardiovascular deaths [32].

These data suggest that treatment with raloxifene has the most favorable risk-benefit profile in postmenopausal women at high risk for vertebral compression fractures and breast cancer but a less favorable profile in women at high risk for thromboembolic disease and stroke. When considering raloxifene therapy, the individual's risk of disease and personal preference are important for weighing the potential benefits and risks.

Cognitive function — An analysis of data from the MORE trial showed that the risk of cognitive decline was no different with raloxifene versus placebo [33].

Genitourinary effects — Unlike estrogen and tamoxifen, raloxifene is not associated with vaginal bleeding, and unlike estrogen, it does not increase the risk of endometrial hyperplasia or cancer [2,23,24,34,35]. In a secondary analysis of the MORE trial, neither endometrial hyperplasia nor endometrial cancer risk was increased with raloxifene compared with placebo (relative risk [RR] 1.3, 95% CI 0.4-5.1 and RR 0.9, 95% CI 0.3-2.7, for endometrial hyperplasia and cancer, respectively) [24].

In the STAR trial, the lower number of endometrial cancers in the raloxifene as compared with tamoxifen groups (23 of 4712 versus 36 of the 4732) was not statistically significant (risk ratio 0.62, 95% CI 0.35-1.08) [23]. However, more than one-half of enrolled women had undergone hysterectomy and were not at risk for endometrial cancer. Fewer women receiving raloxifene underwent hysterectomy for noncancer reasons (111 versus 244). (See "Selective estrogen receptor modulators and aromatase inhibitors for breast cancer prevention", section on 'Choice of agent'.)

In addition, raloxifene does not appear to affect vaginal symptoms (dryness or dyspareunia) [36], nor does it have any effect on urinary incontinence symptoms [37].

BAZEDOXIFENE — Bazedoxifene is available in Europe and Japan for the treatment of postmenopausal osteoporosis in women at increased risk for fracture. It is not available as a stand-alone drug in the United States; however, it is available in combination with conjugated estrogen (see 'Bazedoxifene-conjugated estrogen' below). Bazedoxifene has similar efficacy in preventing and treating postmenopausal osteoporosis as raloxifene. Although the short-term adverse effects of the two drugs appear to be similar (hot flashes, leg cramps, deep vein thrombosis [DVT]), there are few long-term safety data with bazedoxifene, and it has not been adequately studied for breast cancer prevention.

Efficacy in preventing and treating osteoporosis is illustrated by the following trials:

●In a two-year, randomized trial of bazedoxifene, raloxifene, or placebo in 1583 postmenopausal women with osteopenia (T-score of the lumbar spine or femoral neck between -1.0 and -2.5 or other risk factors), women randomly assigned to bazedoxifene or raloxifene similarly maintained spine and hip bone mineral density (BMD), whereas women in the placebo group had significant bone loss at both sites (between-group differences of approximately 1.5 and 1.6 percent, respectively) [38].

●In a three-year, randomized trial in 6847 postmenopausal women with osteoporosis, the cumulative incidence of new vertebral fractures was significantly lower in women randomly assigned to bazedoxifene (20 or 40 mg daily) or raloxifene (60 mg daily) versus placebo (fracture rates of 2.3, 2.5, 2.3 versus 4.1 percent) [39]. The risk of nonvertebral fractures was not decreased in the raloxifene or bazedoxifene groups compared with controls.

In a two-year extension of the trial (4216 postmenopausal women), the incidence of new vertebral fractures remained lower in the bazedoxifene groups than placebo group (4.5 and 3.9 versus 6.8 percent with placebo) [40]. The incidence of nonvertebral fractures was similar among groups.

In both trials, hot flashes and leg cramps were the most common adverse events, occurring in up to 24 and 12 percent of subjects, respectively. The incidence of hot flashes was significantly higher in the bazedoxifene and raloxifene groups than in the placebo group. The rates of endometrial hyperplasia, cancer, and polyps were low and similar among the groups [41,42], but the rate of DVT was slightly but significantly higher in the raloxifene and bazedoxifene groups compared with placebo [39]. In one of the trials, 753 of 6847 women underwent periodic transvaginal ultrasonography to assess endometrial safety and 444 had mammography to assess breast density [41,43]. After two years, the following findings were noted:

●There were no between-group differences in mean endometrial thickness (2.26, 2.51, 2.56, and 2.26 mm in the bazedoxifene 20 mg, bazedoxifene 40 mg, raloxifene 60 mg, and placebo groups, respectively) or mean change from baseline in endometrial thickness (-0.07, 0.10, 0.16, and -0.08 mm, respectively).

●The incidence of ovarian cancer was low. There was evidence of a significant increase in the incidence of ovarian cancer with bazedoxifene 20 mg (five cases). However, there were no cases with bazedoxifene 40 mg, which seems to make a causal relationship unlikely.

●Changes in breast density were low and not significantly different among the four groups.

In cellular and animal models of advanced breast cancer, bazedoxifene inhibited the growth of both tamoxifen-sensitive and resistant breast cancer cells [44,45]. There are insufficient breast cancer prevention data in women.

BAZEDOXIFENE-CONJUGATED ESTROGEN — A combination of bazedoxifene-conjugated equine estrogen (20 mg/0.45 mg) is available in the United States for the treatment of postmenopausal vasomotor symptoms and prevention of osteoporosis in women with an intact uterus [46]. In Europe, it is available for the treatment of postmenopausal vasomotor symptoms in women with an intact uterus for whom treatment with progestins is not appropriate [47].

A theoretical advantage of combination of bazedoxifene-conjugated equine estrogen would be to relieve estrogen deficiency symptoms and prevent bone loss, while avoiding withdrawal bleeding and estrogen-induced breast tenderness. This combination is an option, therefore, for women with an intact uterus who have hot flashes (prohibiting the use of bazedoxifene alone or raloxifene) and who are not candidates for or are intolerant of bisphosphonates, who have breast tenderness with standard estrogen-progestin therapy, or who cannot tolerate any type of progestin therapy because of side effects. However, the absence of long-term fracture and safety data tempers our enthusiasm for bazedoxifene-conjugated equine estrogen. In addition, the effect of bazedoxifene-conjugated equine estrogen on breast cancer risk is unknown.

Estrogen prevents bone loss and fracture. The protective effect has been documented for all types of postmenopausal hormone therapy (unopposed estrogen, combined estrogen-progestin, different estrogen and progestin formulations, different routes of administration [oral versus transdermal], and different patterns of administration [cyclic versus continuous]). These studies are reviewed in detail separately. (See "Menopausal hormone therapy in the prevention and treatment of osteoporosis".)

Although we no longer consider estrogen a first-line therapy for osteoporosis prevention in older postmenopausal women (over age 60 years), since data from the Women's Health Initiative suggest that estrogen-progestin therapy reduces fracture risk at a cost of increases in the incidence of breast cancer, coronary heart disease (CHD), stroke, and venous thromboembolism (VTE), the benefit/risk profile of hormone replacement therapy may vary for women based upon their time since menopause. Estimates of the absolute risks and benefits of estrogen (either alone or combined with progestin) in women starting treatment between ages 50 to 59 years and the variety of estrogen and progestin combinations are reviewed separately. (See "Menopausal hormone therapy: Benefits and risks", section on 'Estimates of risk in women 50 to 59 years' and "Preparations for menopausal hormone therapy", section on 'Dosing'.)

The treatment of postmenopausal hot flashes is reviewed in more detail separately. (See "Menopausal hot flashes".)

Efficacy — Conjugated estrogen and bazedoxifene individually have been shown to prevent vertebral fracture [39,48] (see 'Bazedoxifene' above). The combination of bazedoxifene-conjugated equine estrogen has been shown to improve bone density [49,50]; however, there are no fracture prevention data for combination therapy. As an example, in a two-year trial of bazedoxifene-conjugated equine estrogen (in varying doses), raloxifene, or placebo in 3397 postmenopausal women with bone mineral density (BMD) T-scores between -1 and -2.5, BMD of the lumbar spine and total hip increased significantly with bazedoxifene-conjugated equine estrogen and raloxifene compared with placebo [49]. The greatest improvement in BMD was seen with the formulation of bazedoxifene-conjugated equine estrogen that contained the lowest dose of bazedoxifene (10 mg) combined with the highest dose of conjugated estrogen (0.625 mg). These results are not surprising, given the known beneficial effects of conjugated estrogen on BMD; the lowest dose of bazedoxifene did not negate these effects.

In women who were more than five years postmenopause, formulations of bazedoxifene-conjugated equine estrogen containing bazedoxifene 10 or 20 mg with conjugated estrogen 0.45 or 0.625 mg resulted in greater increases in lumbar spine BMD than raloxifene (between-group difference 1.2 to 1.6 percent). Without fracture prevention data, this is of uncertain clinical significance.

In addition, combinations with the lower doses (10 or 20 mg) of bazedoxifene with either 0.45 or 0.625 mg of conjugated estrogen significantly improved indices of vaginal atrophy and reduced the daily number of hot flushes (mean change -9 versus -2.4 and -5.3 for placebo and raloxifene groups, respectively) [51]. The incidence of VTE events was low and similar among the groups. The incidence of endometrial hyperplasia was not increased in the groups taking at least 20 mg of bazedoxifene [52].

Adverse effects — Common adverse effects (incidence >5 percent) of combination bazedoxifene-conjugated equine estrogen include muscle cramps, nausea, abdominal pain, dyspepsia, diarrhea, oropharyngeal pain, dizziness, and neck pain [53]. Bazedoxifene inhibits the stimulatory activity of conjugated estrogens in the uterus, and therefore, it does not cause endometrial hyperplasia [54]. It also inhibits the activity of conjugated estrogen in breast tissue, but the effect of bazedoxifene-conjugated equine estrogen on breast cancer risk is unknown. The effect of bazedoxifene-conjugated equine estrogen on the risk of ovarian cancer is also unknown.

This combination drug contains conjugated equine estrogen, and therefore, it has similar risks as other estrogen-containing medications, including an increased risk of stroke and deep vein thrombosis (DVT). Whether the combination drug bazedoxifene-conjugated equine estrogen has a higher risk of thromboembolic disease than either drug alone is uncertain. (See 'Bazedoxifene' above and "Menopausal hormone therapy: Benefits and risks".)

Contraindications — Bazedoxifene-conjugated estrogen is contraindicated in women who have a history of thromboembolic disease, history of breast or uterine cancer, have unusual vaginal bleeding, or liver disease.

TAMOXIFEN — Despite reasonable data to suggest efficacy, tamoxifen is not considered a first-line selective estrogen receptor modulator (SERM) for the prevention or treatment of osteoporosis, primarily due to a greater number of endometrial adverse effects with tamoxifen compared with raloxifene. Unlike tamoxifen, raloxifene is not associated with vaginal bleeding or an increased risk of endometrial hyperplasia or cancer. We therefore do not use tamoxifen for the prevention or treatment of osteoporosis. However, if a postmenopausal woman is taking tamoxifen for the prevention or treatment of breast cancer, it may lower her risk of osteoporosis.

In postmenopausal women with estrogen-dependent breast cancer, tamoxifen provides some protection against postmenopausal bone loss, presumably due to its partial agonist activity (figure 3) [55-58] (see "Evaluation and treatment of premenopausal osteoporosis", section on 'Indications for concomitant pharmacologic treatment'). The increase in bone density with tamoxifen (approximately 1.2 percent in the lumbar spine at two years) is substantially less than that with estrogen or a bisphosphonate such as alendronate (5 to 7 percent at two years). In contrast, net bone loss is reported in many studies in which tamoxifen was administered to premenopausal women [57,58]. In premenopausal women, tamoxifen, like raloxifene, blocks estrogen action on bone and causes a decrease in bone density. Thus, premenopausal women who are taking tamoxifen for the prevention or treatment of breast cancer require monitoring of bone mineral density (BMD). (See "Evaluation and treatment of premenopausal osteoporosis", section on 'Indications for concomitant pharmacologic treatment'.)

Tamoxifen prevents fracture in postmenopausal women, as illustrated by the following studies:

●The National Surgical Adjuvant Breast and Bowel Project (NSABP) P-1 Trial is the only prospective study of tamoxifen in which fracture risk was examined. In this study, 13,328 women were randomly assigned to tamoxifen (20 mg/day) or placebo, with the primary objective to determine whether tamoxifen reduced the incidence of invasive breast cancer in high-risk women. In the latest report, with seven years of follow-up, women receiving tamoxifen had significantly fewer fractures of the hip, radius, and spine (80 versus 116 in the placebo group, combined relative risk [RR] 0.68, 95% CI 0.51-0.92) [55]. (See "Selective estrogen receptor modulators and aromatase inhibitors for breast cancer prevention".)

●In a population-based analysis, women aged 50 years or older who were diagnosed with an osteoporotic fracture (vertebral, wrist, hip) in Manitoba, Canada from 1996 to 2004 were each compared with three controls without fracture, matched for age, ethnicity, and comorbidity [59]. Current tamoxifen use, which was identified in 105 fracture cases and 459 controls, was associated with lower osteoporotic fracture rates (odds ratio [OR] 0.68, 95% CI 0.55-0.84). Past tamoxifen use was unrelated to osteoporotic fracture risk.

LASOFOXIFENE — Lasofoxifene is available in some countries (but not the United States) for the treatment and prevention of postmenopausal osteoporosis [60,61]. It has been shown to act as a skeletal agonist and breast and uterine antagonist [62,63]. In the Postmenopausal Evaluation and Risk-Reduction With Lasofoxifene (PEARL) trial, over 8500 postmenopausal women with osteoporosis (T-score below -2.5) were randomly assigned to lasofoxifene (0.25 or 0.5 mg daily) versus placebo [64]. All subjects received calcium (1000 mg) and vitamin D (400 to 800 international units) daily. The primary endpoint for the first three years of the five-year trial was radiographic vertebral fractures. Nonvertebral fracture and estrogen receptor (ER)-positive breast cancer were coprimary endpoints through five years. The following summarizes the major observations [64,65]:

●After three years, patients treated with either dose of lasofoxifene had fewer vertebral fractures (13.5 versus 23 per 1000 patient-years in the 0.5 mg and placebo groups, respectively, hazard ratio [HR] 0.58, 95% CI 0.45-0.73). After five years, the reduction in vertebral fracture was similar, and patients randomly assigned to 0.5 mg daily also had significantly fewer nonvertebral fractures (18.7 versus 24.5 per 1000 person-years, HR 0.76, 95% CI 0.64-0.91). There was no effect on the incidence of hip fracture.

●After five years, there was a reduction in the incidence of ER-positive breast cancer (0.3 versus 1.7 per 1000 person-years in the 0.5 mg and placebo groups, respectively, HR 0.19, 95% CI 0.07-0.56). (See "Selective estrogen receptor modulators and aromatase inhibitors for breast cancer prevention".)

●After five years, there was a reduction in major coronary heart disease (CHD) (5.1 versus 7.5 cases per 1000 person-years in the 0.5 mg and placebo groups, respectively, HR 0.68, 95% CI 0.50-0.93) and in stroke (2.5 versus 3.9 cases per 1000 person-years, HR 0.64, 95% CI 0.41-0.99), and there was no difference in the incidence of fatal strokes, which occurred in seven and five patients in the lasofoxifene 0.5 mg and placebo groups, respectively.

●There was an increase in venous thrombotic (VTE) events (HR 2.1, 95% CI 1.2-3.6). There was also an unexplained small (just reaching statistical significance) increase in all-cause mortality in the 0.25 mg group but not in the 0.5 mg group, which seems to make a causal relationship unlikely.

●Leg cramps, hot flushes, endometrial hypertrophy, uterine polyps, and vaginal candidiasis were significantly more common in women assigned to lasofoxifene than placebo.

There are no trials directly comparing lasofoxifene and raloxifene. Compared with raloxifene trials, the lasofoxifene trial showed similar reductions in vertebral fractures and risk of ER-positive breast cancer and similar increases in the risk of thromboembolic events, hot flashes, and leg cramps. After five years, lasofoxifene was associated with a decrease in nonvertebral fractures, whereas raloxifene has not been shown to have any effect. Neither selective estrogen receptor modulator (SERM) reduces the risk of hip fracture [66].

Although lasofoxifene decreased the risk of major CHD and stroke, the number of events in these categories was small and the confidence intervals wide, suggesting that studies in a high-risk group (larger number of CHD events) are warranted to confirm these findings. Lasofoxifene has not been studied in women with CHD or its risk factors. In the Raloxifene Use for The Heart (RUTH) trial, raloxifene was associated with an increased risk of fatal stroke, an increase that was greater in women who had a high baseline risk of stroke [15,26]. (See 'Coronary heart disease' above.)

Neither drug significantly increases endometrial hyperplasia or endometrial cancer. However, lasofoxifene may have more endometrial side effects. In the lasofoxifene trials, endometrial hyperplasia was confirmed in more women in the lasofoxifene group (six versus none in the placebo group) [67]. The mean increase in endometrial thickness was approximately 1.5 mm, compared with 0.01 mm in raloxifene trials [11,67]. In addition, lasofoxifene use was associated with a significant increase in cystic echotexture on transvaginal ultrasound (due to benign cystic atrophy), endometrial hypertrophy, vaginal bleeding, and uterine polyps. In contrast, raloxifene has not been shown to increase endometrial thickness or vaginal bleeding.

Thus, lasofoxifene appears to have similar or better skeletal and cardiovascular benefits but worse endometrial risks than raloxifene. The uterine adverse effects of lasofoxifene require further investigation with long-term follow-up.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Osteoporosis".)

SUMMARY AND RECOMMENDATIONS — A selective estrogen receptor modulator (SERM) is a therapeutic option for the prevention and treatment of osteoporosis. Candidates for pharmacologic therapy and other pharmacologic options are discussed elsewhere. (See "Overview of the management of low bone mass and osteoporosis in postmenopausal women", section on 'Patient selection' and "Overview of the management of low bone mass and osteoporosis in postmenopausal women", section on 'Choice of initial therapy'.)

●Candidates for therapy – For the majority of postmenopausal women, we suggest not using pharmacologic therapy for prevention of osteoporosis (Grade 2B). (See "Overview of the management of low bone mass and osteoporosis in postmenopausal women".)

●Choice of drug

•Prevention of osteoporosis in postmenopausal women – For postmenopausal women who are candidates for and desire pharmacologic therapy for prevention of osteoporosis, we suggest bisphosphonates or raloxifene as first-line choices (Grade 2B). (See 'Choice of drug' above and "Overview of the management of low bone mass and osteoporosis in postmenopausal women".)

-Raloxifene – There are nonskeletal considerations with raloxifene that may play an important role in the selection of patients for therapy: a reduction in breast cancer risk, but an increase in thromboembolic events and hot flashes, and no apparent effect on heart disease or the endometrium. Raloxifene is usually chosen for osteoporosis prevention when there is an independent need for breast cancer prophylaxis. (See 'Adverse effects' above and 'Other effects' above.)

-Bazedoxifene – Bazedoxifene (available in Europe and Japan) has similar efficacy as raloxifene in preventing postmenopausal osteoporosis. However, there are few long-term safety data, and it has not been adequately studied for breast cancer prevention. (See 'Choice of drug' above and 'Bazedoxifene' above.)

-Bazedoxifene-conjugated equine estrogen – Combination bazedoxifene-conjugated equine estrogen is an option for women with an intact uterus who have hot flashes (prohibiting the use of bazedoxifene alone or raloxifene) and who are not candidates for or are intolerant of bisphosphonates, who have breast tenderness with standard estrogen-progestin therapy, or who cannot tolerate any type of progestin therapy because of side effects. However, the absence of long-term fracture and safety data tempers our enthusiasm for bazedoxifene-conjugated equine estrogen. In addition, the effect of bazedoxifene-conjugated equine estrogen on breast cancer risk is unknown. (See 'Choice of drug' above and 'Bazedoxifene-conjugated estrogen' above.)

-Tamoxifen – Tamoxifen is not a first-line SERM for the prevention or treatment of osteoporosis. However, if a postmenopausal woman is taking tamoxifen for the prevention or treatment of breast cancer, it should decrease her risk of osteoporosis. (See 'Tamoxifen' above.)

•Treatment of osteoporosis in postmenopausal women – For the treatment of osteoporosis in postmenopausal women, we suggest bisphosphonates over SERMs as first-line therapy (Grade 2B). (See "Overview of the management of low bone mass and osteoporosis in postmenopausal women", section on 'Choice of initial therapy'.)

We favor bisphosphonates over SERMs for the treatment of osteoporosis because they have greater efficacy than SERMs in reducing nonspine and hip fractures. Raloxifene is a reasonable alternative to bisphosphonates for postmenopausal women with osteoporosis (low bone mineral density [BMD, T score <-2.5] and no fragility fractures) who cannot tolerate or are not candidates for any bisphosphonates or for postmenopausal women with osteoporosis who are also at high risk for invasive breast cancer. We prefer raloxifene to bazedoxifene (alone or as part of combination therapy) because it has long-term safety and efficacy data and because it has been shown to reduce the risk of breast cancer. (See "Overview of the management of low bone mass and osteoporosis in postmenopausal women", section on 'Choice of initial therapy' and "Selective estrogen receptor modulators and aromatase inhibitors for breast cancer prevention".)

•Premenopausal women – In premenopausal women, raloxifene blocks estrogen action on bone and causes a decrease in bone density, and therefore, it should not be used for the prevention or treatment of osteoporosis. Tamoxifen similarly decreases bone density in premenopausal women. Thus, premenopausal women who are taking tamoxifen require monitoring of BMD. (See 'Effects in premenopausal women' above and 'Tamoxifen' above and "Evaluation and treatment of premenopausal osteoporosis", section on 'Indications for concomitant pharmacologic treatment'.)