Approaching the ideal selective estrogen receptor modulator for prevention and treatment of postmenopausal osteoporosis

Key Points

Abstract

Postmenopausal osteoporosis is a worldwide health concern associated with significant complications including fracture, disability, and mortality. The economic burden of this disease is substantial and is expected to increase significantly as the population ages. It is becoming increasingly important to identify patients who will benefit from available and emerging therapies for the prevention and/or treatment of osteoporosis. Although raloxifene is the only selective estrogen receptor modulator (SERM) currently approved for postmenopausal osteoporosis, several third-generation SERMs are undergoing clinical evaluation. Each investigational SERM has a unique clinical profile, with the overarching goal of developing an ideal SERM that provides the beneficial effects of estrogens without the associated risks and side effects. It is doubtful that any single SERM will have all of these characteristics, but novel SERMs such as bazedoxifene are likely to provide significant patient benefits that may translate to lower overall healthcare costs. (Formulary. 2010;45:52-61.)

Age-related bone loss places postmenopausal women at increased risk for osteoporosis and its potential complications, including fracture, disability, and mortality. Osteoporosis is a worldwide health concern, with approximately 200 million individuals affected, including one-third of women between the ages of 60 and 70 and two-thirds of women older than 80 years.¹ The Third National Health and Nutrition Examination Survey (NHANES III) estimated that 13% to 18% of US women 50 years and older have osteoporosis (bone mineral density [BMD] T-score –2.5 or less), and 37% to 50% have osteopenia (BMD T-score between –1.0 and –2.5).²

As the population ages, osteoporosis will have an even greater impact on the healthcare system. Thus it is becoming increasingly important to identify patients who will benefit from treatment, particularly those at high risk for fracture. The fracture risk assessment tool (FRAX) designed by the World Health Organization to calculate the 10-year probability of hip fracture and major osteoporotic fracture (clinical vertebral, hip, forearm, or humerus fracture) based on femoral neck BMD and easily obtained clinical risk factors, will be an important tool for this purpose.⁶ This algorithm, which uses Poisson regression to derive hazard functions, can be calibrated for different countries. The probability of fracture is determined using age, body mass index, and dichotomized risk factors, including prior fragility fracture, parental history of hip fracture, current tobacco smoking, and long-term oral glucocorticoid use. It is believed that this tool will help identify women who may be candidates for pharmacologic therapy.

Several agents are commercially available for the prevention and/or treatment of postmenopausal osteoporosis, including bisphosphonates, hormone therapy, calcitonin, parathyroid hormone, strontium ranelate (outside the United States), and the selective estrogen receptor modulator (SERM) raloxifene.⁷

IDEAL SERM FOR POSTMENOPAUSAL OSTEOPOROSIS

CLINICAL PROFILES OF COMMERCIALLY AVAILABLE SERMS

Each SERM has unique pharmacologic properties and should be evaluated on an individual basis to determine its benefit-risk profile for the prevention and/or treatment of postmenopausal osteoporosis. Two SERMs, tamoxifen and raloxifene, are commercially available in the United States.

Tamoxifen. Tamoxifen, a first-generation SERM, is commonly used for the treatment of estrogen-responsive breast cancer because of its antiestrogenic effects in breast tissue. Tamoxifen also maintains BMD and decreases low-density lipoprotein (LDL) cholesterol levels.^10-12 A clear association exists between tamoxifen and endometrial cancer, however, limiting its use to the postmenopausal breast cancer population.^13,14 Tamoxifen is also associated with an increased risk of venous thromboembolic events (VTEs), hot flushes, and stroke.^15-17

Raloxifene. A second-generation SERM, raloxifene is the only SERM currently approved for the treatment and prevention of postmenopausal osteoporosis. It is also approved for the reduction of invasive breast cancer risk in postmenopausal women with osteoporosis and in postmenopausal women at high risk for invasive breast cancer. Based on the results of large, multicenter, double-blind trials, raloxifene has demonstrated beneficial effects on BMD and significant reductions in vertebral fracture risk compared with placebo.^18,19 No studies, however, have shown a significant positive effect on the overall risk of nonvertebral fracture.^19,20 Although post-hoc subgroup analyses have reported a significant reduction in nonvertebral fracture risk at 6 common sites (clavicle, humerus, wrist, pelvis, hip, and lower leg) in women with severe baseline fractures treated with raloxifene, there was no treatment effect on the risk of all nonvertebral fractures.^21,22 Regarding its effects on the lipid profile, raloxifene has been shown to significantly decrease LDL cholesterol levels and significantly increase high-density lipoprotein cholesterol levels compared with placebo, but there is no evidence of any reduction in adverse cardiac events.^18,23 In a large, randomized, double-blind trial of more than 19,000 postmenopausal women (the National Surgical Adjuvant Breast and Bowel Project Study of Tamoxifen and Raloxifene [STAR] P-2 trial), raloxifene was as effective as tamoxifen in reducing invasive breast cancer risk.²⁴

Regarding safety and tolerability, raloxifene has been associated with several class effects commonly observed with SERMs. In a large phase 3 trial of 7,705 women (Multiple Outcomes of Raloxifene Evaluation [MORE]), those receiving raloxifene had a small but significant increase in endometrial thickness versus placebo, but no increased risk of endometrial cancer.²⁵ Raloxifene has also been associated with VTEs, stroke, and an increased incidence or worsening of hot flushes.^23,26,27 In a recently published analysis from a randomized, placebo-controlled trial of 10,101 postmenopausal women with or at increased risk of coronary heart disease, incidences of VTEs and fatal stroke, but not all strokes, were significantly higher in patients receiving raloxifene than in those receiving placebo.²⁸ Taken together, the benefits of tamoxifen and raloxifene for reducing the risk of vertebral fracture and invasive breast cancer must be weighed against the increased risks of VTEs, stroke, and uterine cancer (tamoxifen only).

THIRD-GENERATION SERMS

Third-generation SERMs are being developed in an effort to create drugs that are structurally distinct from first- and second-generation SERMs to improve efficacy while reducing some of the unfavorable side effects associated with these agents. Ideally these novel SERMs should retain the favorable qualities of raloxifene, but with increased efficacy for enhancing BMD, reducing vertebral and nonvertebral fracture risk, and improving serum lipid levels (Table 2).

Bazedoxifene. Bazedoxifene is a novel SERM under investigation for the prevention and treatment of postmenopausal osteoporosis (recently approved in the European Union for the treatment of postmenopausal osteoporosis in women at increased risk of fracture and under regulatory review in the United States), with clinical data available from 2 large phase 3 studies and worldwide clinical data from more than 10,000 women. In phase 2 studies of healthy postmenopausal women, bazedoxifene showed statistically significant reductions in markers of bone remodeling, without adverse effects on the breast or endometrium.^29-31 In a phase 3 prevention study of 1,583 postmenopausal women with normal or low BMD, bazedoxifene 10 mg, 20 mg, and 40 mg daily and raloxifene 60 mg daily significantly increased BMD at the lumbar spine and total hip relative to placebo, and significantly reduced levels of bone turnover markers from baseline versus placebo.³² Favorable effects on lipid profile also were observed.

In a second phase 3 treatment study of 7,492 postmenopausal women with osteoporosis, the risk of new vertebral fracture was significantly reduced with bazedoxifene 20 mg and 40 mg daily and raloxifene 60 mg daily versus placebo.³³ Bazedoxifene also significantly increased BMD and decreased levels of bone turnover relative to placebo. Although there were no differences among treatment groups in the incidence of nonvertebral fractures in the overall population, a post-hoc subgroup analysis of 1,772 women considered at higher risk for fracture based on known risk factors was performed; bazedoxifene 20 mg per day showed a significant reduction in the risk of all nonvertebral fractures versus both placebo and raloxifene 60 mg daily. Moreover, independent analyses were performed evaluating fracture data for all patients receiving bazedoxifene or placebo (not just those at high risk for fracture; n=5,643). These data were consistent with the previous subgroup analysis, showing that bazedoxifene significantly decreased the risk of all clinical fractures and morphometric vertebral fractures in women at or above a FRAX-based fracture probability threshold, confirming that the efficacy of bazedoxifene increases with increasing fracture probability.³⁴ The results of this analysis coupled with those from a similar analysis of women treated with an oral bisphosphonate reinforce the validity of the FRAX algorithm in identifying patients who will benefit from osteoporosis treatment.^34,35

In both phase 3 trials, all doses of bazedoxifene were generally safe and well tolerated.^32,33 The incidence of adverse events and discontinuations caused by adverse events were generally similar among treatment groups.^32,33 Hot flushes occurred with similar frequency among the bazedoxifene and raloxifene treatment groups, but occurred significantly more often than with placebo; however, these events typically did not result in treatment discontinuation.^32,33 No cardiovascular safety concerns were seen in the bazedoxifene treatment groups in the prevention trial, and cardiovascular events were infrequent and evenly distributed among groups in the osteoporosis treatment study.^32,33 The incidence of VTEs, primarily deep vein thrombosis, was higher in the active bazedoxifene and raloxifene treatment groups versus placebo.^32,33 Bazedoxifene was associated with favorable effects on endometrial and breast tissue, similar to that observed with placebo and raloxifene.^32,33,36,37

In addition to the clinical studies, bazedoxifene is being evaluated in combination with conjugated estrogens for the treatment of menopausal symptoms (hot flushes and vulvar-vaginal atrophy) and for the prevention of postmenopausal osteoporosis.^38-41 This represents a new class of therapeutics, known as tissue selective estrogen complex (TSEC), with the goal of achieving an optimal combination of estrogen receptor agonist and antagonist effects.^42,43 Recent evidence from phase 3 studies showed that a TSEC that pairs bazedoxifene with conjugated estrogens significantly increased BMD and provided relief of hot flushes and improvement in measures of vulvar-vaginal atrophy with no evidence of endometrial or breast stimulation in postmenopausal women with a uterus.^38-41 To date, bazedoxifene is the only SERM that can be combined with estrogens to produce this balance of agonist and antagonist effects.

Lasofoxifene. Lasofoxifene has been evaluated in postmenopausal women for the prevention and treatment of osteoporosis and for the treatment of vaginal atrophy. In the United States, lasofoxifene received a favorable vote from the FDA panel for the treatment of postmenopausal osteoporosis, but additional information was requested prior to approval; non-approvable letters have been received by the manufacturers for the prevention of postmenopausal osteoporosis and the treatment of vaginal atrophy. Lasofoxifene was recently approved by the European Commission for the treatment of postmenopausal osteoporosis in women at increased risk for fracture. In a 2-year phase 2 study of 410 postmenopausal women, lasofoxifene .25 mg and 1.0 mg per day significantly increased lumbar spine BMD versus raloxifene 60 mg daily or placebo, and increases in total hip BMD were similar in all treatment groups.⁴⁴ Both lasofoxifene and raloxifene significantly decreased levels of bone turnover markers relative to placebo. In terms of lipid effects, reductions in LDL cholesterol were significantly greater with lasofoxifene than with raloxifene or placebo. The phase 3 Postmenopausal Evaluation And Risk-reduction with Lasofoxifene (PEARL) study enrolled 8,556 women with osteoporosis; 3-year results (published only in abstract format to date) showed that lasofoxifene significantly reduced vertebral and nonvertebral fracture risk, increased BMD, and decreased levels of bone marker turnover relative to placebo.^45,46 Moreover, lasofoxifene significantly decreased the risk of breast cancer.⁴⁵ In addition to its efficacy in bone, early data suggest that lasofoxifene improves the signs and symptoms of vaginal atrophy, including discomfort during sexual intercourse.^47-49

The safety and tolerability profile of lasofoxifene appears similar to that of raloxifene, but discontinuation rates due to adverse events were higher with lasofoxifene in the phase 2 study.⁴⁴ Incidences of hot flushes and leg cramps were similar with lasofoxifene and raloxifene and higher than those observed with placebo.^44,45 Lasofoxifene treatment has been associated with an increase in endometrial thickness and the incidence of endometrial polyps and vaginal bleeding compared with placebo.^44,45,50

In the PEARL study, lasofoxifene was shown to increase the number of diagnostic uterine procedures versus placebo, although there was no evidence of an increased risk of endometrial carcinoma or hyperplasia.⁵⁰ Lasofoxifene was also associated with an increased risk of VTEs compared with placebo.⁴⁵

Ospemifene. The efficacy and safety of ospemifene have been evaluated for the treatment of osteoporosis and vaginal atrophy. Phase 2 studies have shown that ospemifene 30 mg, 60 mg or 90 mg daily has similar effects on bone turnover markers compared with raloxifene and significantly greater changes from baseline versus placebo.^51,52 Phase 1 and 2 studies also indicate an estrogenic effect of ospemifene on the vaginal epithelium.^53-55 These findings led to a recently completed phase 3 study of ospemifene for the treatment of vulvar-vaginal atrophy in postmenopausal women (clinical trial NCT00276094). Similar to lasofoxifene and raloxifene, evidence suggests a link between ospemifene therapy and increased endometrial thickness and uterine volume.⁵⁴

Clinical data suggest that ospemifene may exhibit both favorable and unfavorable characteristics distinct from other third-generation SERMs currently under investigation. For example, unlike many SERMs, ospemifene does not appear to have pro-estrogenic (ie, favorable) effects on the lipid profile.⁵⁵ Also noteworthy is that ospemifene does not increase the incidence of climacteric symptoms, including hot flushes, versus placebo.^53-55

Its overall clinical profile appears promising, but longer-term trials with larger patient numbers are needed to definitively determine the benefit–risk profile of ospemifene for osteoporosis prevention and treatment.

Arzoxifene (LY353381). Arzoxifene is structurally similar to raloxifene, with increased antiestrogenic effects.⁵⁶ Initial trials evaluated arzoxifene for the prevention and treatment of breast cancer.^57-60

A phase 3 breast cancer trial of arzoxifene compared with tamoxifen, however, was stopped early when an interim analysis suggested that arzoxifene was statistically inferior to tamoxifen.⁶¹ Nevertheless, phase 3 studies evaluating arzoxifene for the prevention and treatment of osteoporosis have been conducted (clinical trials NCT00088010, NCT00383422), based on phase 1 and 2 data in breast cancer patients showing that arzoxifene decreases bone turnover.^58-60 Two-year results from a recently published phase 3 study of 331 postmenopausal women with normal to low bone mass showed that arzoxifene significantly increased lumbar spine and total hip BMD and decreased markers of bone turnover versus placebo, with neutral effects on the uterus and endometrium.⁶² However, the manufacturer of arzoxifene has recently discontinued its development based on initial results from a large phase 3 study (clinical trial NCT00088010) showing that arzoxifene did not significantly reduce nonvertebral or clinical fractures or cardiovascular events relative to placebo despite achieving significant reductions in vertebral fracture and invasive breast cancer.⁶³

Moreover, several adverse events were more common with arzoxifene than with placebo, including VTEs, hot flushes, and gynecologic-related events.

OTHER SERMS

In addition to third-generation SERMs in various phases of clinical investigation, others are currently in the preclinical stages of development and include Y134, LSN2120310, and RAD-1901. Evaluation of some third-generation SERMs for osteoporosis has been recently discontinued (eg, idoxifene and levormeloxifene), in part because of their adverse uterine effects, including increased endometrial thickness.

OTHER CURRENT TREATMENT OPTIONS

DXA SCANS DURING OSTEOPOROSIS THERAPY

The National Osteoporosis Foundation recommends that patients on any type of pharmacologic therapy for osteoporosis undergo a dual-energy x-ray absorptiometry (DXA) scan 2 years after initiating therapy and every 2 years thereafter.⁷⁸ The guidelines further state that more frequent testing may be warranted in certain clinical situations. Based on personal clinical experience, however, physicians should obtain DXA scans 1 year after initiating any drug if the intent is to preserve or to treat bone density.

COST-EFFECTIVENESS CONSIDERATIONS

Data are limited on the cost-effectiveness of SERMs for the prevention and/or treatment of postmenopausal osteoporosis, particularly given that raloxifene is the only SERM currently approved in the United States for this indication. Data suggest that targeting osteoporosis treatment to appropriate at-risk populations can be cost-effective for managed care, with savings from fracture prevention compensating for treatment costs.⁷⁹ For example, 2 cost-effectiveness analyses based on data from the MORE study showed that raloxifene was cost-effective in the treatment of postmenopausal women at increased risk for vertebral fracture.^80,81 Similarly, an analysis of bazedoxifene utilizing the FRAX algorithm showed that bazedoxifene was cost-effective in women aged ≥60 years with prior fracture and at the threshold of osteoporosis (T-score of –2.5).⁸² Bazedoxifene was also found to be cost-effective in women with strong risk factors and with a T-score above the threshold for osteoporosis. Thus preliminary pharmacoeconomics data suggest that SERMs may be a cost-effective treatment option for postmenopausal women at increased risk for osteoporotic fracture.

CONCLUSION

Given the substantial burden of osteoporosis on health systems, it is important to have a range of treatment options available to meet the needs of individual patients. Each SERM evaluated to date offers a unique clinical profile, which may result in differences in clinical outcomes and have a potential impact on both direct and indirect costs to managed care organizations, patients, and the healthcare system. Ideally, a single SERM would be able to reproduce all the beneficial effects of estrogens (ie, pro-estrogenic effects on bone and lipids) without the estrogen-associated risks or side effects (ie, neutral or antiestrogenic effects on breast and endometrium). Although there is a large body of literature demonstrating the overall tolerability and efficacy of third-generation SERMs for the prevention and treatment of osteoporosis, data translating these effects into reduced fracture rates are limited. In the short term, it is unlikely that a single SERM will have all the characteristics of an ideal SERM; however, novel SERMs such as bazedoxifene are likely to provide significant benefit to postmenopausal women for the prevention and treatment of osteoporosis with a favorable safety and tolerability profile. Moreover, these benefits in terms of efficacy and safety may translate to lower overall healthcare costs. Common class side effects of SERMs, such as hot flushes and VTEs, and other potential safety concerns require additional study to further clarify the benefit-risk profiles of these new agents.

Dr Taylor is professor of obstetrics, gynecology and reproductive sciences, and director of reproductive endocrinology and infertility, division of reproductive endocrinology, Yale University School of Medicine, New Haven, Conn.

Disclosure Information: Editorial support was provided by Bo Choi, PhD, and was funded by Wyeth Pharmaceuticals, Collegeville, Pa., which was acquired by Pfizer, Inc., in October 2009. The author was not compensated and retained full editorial control over the contents.

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