Abstract
Bazedoxifene is a new drug that belongs to the group of selective estrogen-receptor modulators (SERMs), a class of medication that acts selectively on estrogen receptors. A characteristic that distinguishes SERMs from pure receptor agonists and antagonists is that their action is different in various tissues. In some tissues, SERMs can selectively inhibit while in other tissues they can stimulate estrogen-like action [1,2]. Bazedoxifene has been developed by Wyeth Pharmaceuticals, NJ, USA, and is currently undergoing clinical evaluation for possible use in prevention and treatment of osteoporosis, particularly in post-menopausal women. When approved, bazedoxifene is planned to be sold by Wyeth under the trade name Viviant•. Another drug that is undergoing final clinical trials for approval by the US FDA is Aprela• (Wyeth, NJ, USA), which contains a combination of bazedoxifene with conjugated estrogens.
Estrogen has several physiological functions, both at the level of the genital and nongenital systems, for example, bone, blood vessels and brain. Excess estrogen can cause, or at least be linked to, several disorders, both reproductive, for example, endometriosis, uterine fibroids and endometrial hyperplasia, and nonreproductive, for example, thrombosis and blood clots, as well as other serious disorders such as breast and uterine cancer. On the other hand, estrogen deficiency has been associated with other major health problems such as osteoporosis, an epidemic that is anticipated, according to the National Osteoporosis Foundation, to affect nearly 41 million postmenopausal women in the USA by the year 2020 [101]. In addition, worldwide estimates predict that more than 75 million people in the Western hemisphere, including the USA, Europe and Japan, will suffer from osteoporosis, with the International Osteoporosis Foundation expecting that the number of persons affected will double in the next 50 years [102].
Osteoporosis
Osteoporosis is a common debilitating, and progressive disorder characterized by significantly low bone mass that leads to diminished bone strength and results in skeletal fragility and susceptibility to fracture [101,102]. Osteoporosis is well established as a growing epidemic of significant public health concern worldwide, particularly in developed countries. This increases the risk for fracture, disability and mortality. Approximately 70–90% of hip, spine or forearm fractures occurring among white women who are 45–84 years of age are related to osteoporosis [3,103]. The current direct cost of treating osteoporotic fractures in the USA has been calculated to be between US$10 billion and $15 billion annually. Other indirect costs associated with lost wages and productivity are difficult to estimate, but are likely to add billions of dollars to the total cost of osteoporosis complications [4].
Role of estrogen in osteoporosis
The fundamental role played by estrogen in bone metabolism and prevention of osteoporosis has been well established. Declining estrogen levels are believed to be a principal cause of osteoporosis in menopausal women [5]. The major role played by estrogen in preventing osteoporosis and osteoporosis-related risk has been established in the National Osteoporosis Risk Assessment study, when fracture risk reduction associated with estrogen use was lost almost immediately after estrogen discontinuation [6].
While systemic estrogen products have been US FDA-approved for osteoporosis ‘prevention’, but not treatment, both parathyroid hormone (teriparatide) and calcitonin are approved for the ‘treatment’ of women with postmenopausal osteoporosis, but not prevention. On the other hand, the efficacy of several other pharmacological agents for ‘prevention and treatment’ of osteoporosis has been established, including the bisphosphonates alendronate, risedronate and ibandronate, as well as the SERM raloxifene [7].
Despite the availability of several options for the prevention and treatment of osteoporosis, such options might not be suitable for clinical use in all women who could have clinical situations that raise safety concerns. In addition to pharmacological therapy, evidence supports the importance of lifestyle modifications such as increased calcium and vitamin D intake, as well as weight-bearing exercise, to prevent or slow the progress of osteoporosis.
Role of SERMs in osteoporosis
As mentioned earlier, SERMs function as both agonists and antagonists to estrogen receptors selectively, depending on the tissue. Since SERMs are different in their agonistic and antagonistic activities at various estrogen receptors throughout the body, their indications would be different. The primary goal of the development of various SERMs in clinical practice for preventing and treating osteoporosis is to maximize the drugs' agonistic activity where needed (bone tissue), while avoiding adverse effects by minimizing estrogenic agonistic activities in other tissues, such as the endometrium, breast and blood [2,8].
Currently, there are two SERMs that have been approved by the FDA for clinical use: raloxifene and tamoxifen [8]. Another approved drug in Europe, strontium ranelate, is pending FDA approval. Tamoxifen is approved for treating breast cancer in both pre- and post-menopausal women, as well as for preventing breast cancer in women at high risk for its development [8,104], and raloxifene is approved for preventing and treating osteoporosis in postmenopausal women, as well as reducing the risk of invasive breast cancer in postmenopausal women with osteoporosis and women at high risk for invasive breast cancer [9].
Several other SERMs, including bazedoxifene, are currently in development for preventing and treating osteoporosis, and other potential indications such as prevention and treatment of breast cancer, while reducing the risk of osteoporosis [2].
Bazedoxifene
Bazedoxifene is a chemically distinct member of the SERMs that was developed to fulfill the requirements for favorable effects on both bone and lipid metabolism (estrogenic agonistic activities) while demonstrating breast and uterine safety (lack of estrogenic agonist activity or even antagonistic activity at the level of breast and endometium tissues) [10–12].
Pharmacology of bazedoxifene
The oral bioavailability of bazedoxifene capsules and tablets was determined in healthy postmenopausal women [13]. Doses were given on an empty stomach and had an absolute bioavailability of approximately 6% irrespective of the formulation (capsules or tablets). This bioavailability of bazedoxifene is approximately threefold higher than that of the other SERM, raloxifene. Moreover, the concentration–time profiles for the oral formulations were superimposable, indicating that tablet and capsule formulations are bioequivalent [13]. Maximum concentration is reached 1–2 h after oral administration with an elimination half-life of approximately 28 h. Protein binding has been found to be greater than 99%, achieving a steady-state plasma concentration by day 7 of administration. Linear pharmacokinetics are attained after doses ranging from 5 to 40 mg, without unexpected accumulation [14]. The major route of excretion of bazedoxifene (85%) is via the feces, while only a minor amount (<1%) is excreted in the urine. Glucuronidation is the major metabolic pathway, and bazedoxifene-5-glucuronide is the most prevalent metabolite (40–95%) with little to no cytochrome P450-mediated metabolism [15].
The optimum dosage of bazedoxifene is currently being established. Doses reported in Phase II trials have ranged from 2.5 to 40 mg daily. The daily dose of 40 mg has been demonstrated to have the least incidence of breast tenderness and endometrial thickening, while having consistent positive effects on bone mass [16].
Effect of bazedoxifene on various body tissues
The mechanism of action of SERMs is through binding to two types of estrogen receptors: estrogen receptor-α and estrogen receptor-β. As explained earlier, SERMs are unique because they possess both agonist and antagonistic properties at the same time depending on the type of tissue. This is explained in part by the availability of different estrogen receptor subtypes in different tissues. An optimal SERM for the prevention and treatment of osteoporosis is the one that possesses agonistic effect at the level of the bone, while not stimulating breast or uterine tissues. This would achieve the favorable effects of preventing bone loss whilst having a low incidence of breast pain and endometrial stimulation with its resulting endometrial proliferation, hyperplasia and bleeding or even endometrial cancer. Agonistic activity at the level of the vaginal tissue is a favorable effect that reduces problems of vaginal dryness. In addition, beneficial effects at the level of the vascular tissue and lipid metabolism are significant advantages [17].
Bazedoxifene has demonstrated affinity for both estrogen receptors-α and -β, with a dissociation constant for the estrogen receptor-α of approximately 0.1 nM and for the estrogen receptor-β of approximately 0.3 nM. This indicates that bazedoxifene has slightly more affinity for estrogen receptor-α than estrogen receptor-β. Bazedoxifene acts as a competitive inhibitor of estradiol at both estrogen receptors, which indicates antagonistic effect in the presence of high estradiol levels while having agonistic activity with low estradiol levels [16].
Studies in animal models found bazedoxifene treatment to increase, or at least maintain, bone mineral density and improve bone compressive strength, while reducing total cholesterol levels. At the level of the breast tissue, bazedoxifene did not stimulate the proliferation of the MCF-7 breast tissue cell line. In addition, it inhibited the estradiol-induced proliferation effect on this cell line. At the level of the uterine tissue, bazedoxifene exhibited little or no uterotropic activity in an immature rat model [11,12].
Bone
Removal of the ovaries in rats results in significant loss of trabecular bone. In a model of ovarictomized rats, bone loss could be prevented by the administration of bazedoxifene over a course of 6 weeks at doses of 0.1, 0.3, 1.0 and 3.0 mg/kg/day. The dose that was found to be associated with the most optimum outcome (preventing bone loss while having favorable uterine and vasomotor end points) was 0.3 mg/kg/day [16].
Uterus
The immature rat uterine wet weight is an accepted animal model for measuring the agonistic effect on estrogen and its agonists. An increase in uterine wet weight indicates either a response to estrogen or stimulation of the uterus. Bazedoxifene was found to have a paradoxical effect on the uterine tissues. Doses of 0.5 and 5 mg/kg were studied in an immature rat uterine model [18]. At the 0.5 mg/kg dose, there was a 35% increase in uterine wet weight while at the 5 mg/kg dose, paradoxically, there was no significant difference in weight. The 0.5 mg/kg dose of bazedoxifene increased uterine wet weight and was not associated with luminal epithelial cell hypertrophy or hyperplasia, myometrial hypertrophy or luminal distention. This indicates that the increase in uterine weight was not accompanied by hypertrophy or hyperplasia. Bazedoxifene may be considered to be nonstimulatory at the uterine estrogen receptors at a dose of 0.5 mg/kg while being an antagonist at a dose of 5 mg/kg in the rat animal model [16,18].
Vasomotor
The animal model for assessing vasomotor changes includes measuring the tail temperature in morphine-addicted rats. Naloxone administration to morphine-addicted rats causes a rise in tail temperature. Estrogen-receptor agonists inhibit the naloxone-induced rise in the tail temperature while estrogen-receptor antagonists exaggerate such temperature rises. Bazedoxifene 0.3 mg/kg/day (the dose that is needed to prevent bone loss) has not been shown to inhibit or exacerbate the naloxone-induced temperature rise. Although such data may support the hypothesis that bazedoxifene may not have vasomotor effects in postmenopausal women, clinical trials in postmenopausal women are needed to confirm such a hypothesis [18].
Available evidence from clinical trials
At daily oral doses up to 40 mg/day, randomized, double-blind, controlled studies in healthy postmenopausal women found bazedoxifene to have a safety profile similar to placebo. In these studies, bazedoxifene produced statistically significant reductions (p < 0.05–0.001) in markers of bone remodeling without increasing the incidence of breast pain or having a stimulatory effect on the endometrium [19–21].
Effect on the endometrium
In a Phase II clinical trial with the end point of evaluating effects on the endometrium, 497 postmenopausal women who had an intact uterus with increased bone turnover were randomized to receive bazedoxifene at one of four doses (2.5, 5, 10 or 20 mg orally per day), placebo or a combination of estrogen–progestin for a treatment period of 6 months. In addition to the study treatments, patients were also instructed to take calcium 600 mg daily. All women had baseline and follow-up ultrasound examinations to assess endometrial thickness. While patients who received bazedoxifene (all four doses) had no difference in endometrial thickness compared with placebo. There was a small but significant increase in endometrial thickness in the group that received estrogen–progestin in comparison with the placebo group (p < 0.05). In the second phase of the same study that was a 6-month follow-up in a double-blind, randomized, active- and placebo-controlled design, which included a total of 497 healthy postmenopausal women, bazedoxifene at doses of 20, 30 and 40 mg/day was evaluated in comparison with placebo. High doses of bazedoxifene (30 and 40 mg) were associated with significant decreases in endometrial thickness. The inhibition of the endometrium was found to be dose-dependant [22].
Effect on bone
In another study with the end point to evaluate the effect of bazedoxifene on bone metabolism in postmenopausal women, doses of 5, 10 or 20 mg/day were studied [23]. Bazedoxifene was administered for 3 months in a randomized, double-blind, placebo-controlled design. The study had another active control group that received raloxifene 60 mg/day. All patients participating in the study in all treatment groups received calcium 600 mg/day. When compared with placebo, both bazedoxifene 5 mg and raloxifene treatment produced statistically significant decreases in bone metabolism indices (p < 0.05). The reduction in bone turnover markers was found to be dose-dependent, with the greatest effect noted at higher doses of bazedoxifene. In agreement with an earlier Phase II clinical trial that studied the effect of bazedoxifene on the endometrium, treatment with bazedoxifene 20 or 40 mg was associated with a 20–25% decrease in bone turnover without endometrial hyperplasia [16,22].
Effect on breast pain
To determine the incidence of breast pain, 351 postmenopausal women who were randomized to receive one dose of four possible doses (2.5, 5, 10 or 20 mg) of bazedoxifene per day or a conjugated estrogen/medroxyprogesterone combination, or placebo. The conjugated estrogen/medroxyprogesterone served as an active control. All women filled out daily diary cards to report breast pain. Women who received the conjugated estrogen/medroxyprogesterone combination had a statistically significant increase in the incidence of breast pain compared with the placebo group. In contrast, women receiving bazedoxifene (all tested four doses) did not have an increased incidence of breast pain compared with those taking placebo. The study was extended to study the effect of bazedoxifene 20 or 40 mg versus placebo on the incidence of breast pain, including an additional 236 postmenopausal women. While the 20 mg dose was again found to have no differences in the incidence of breast pain compared with placebo; interestingly, the 40 mg dose did have a significantly lower incidence of breast pain compared with placebo, indicating that high doses of bazedoxifene might decrease breast pain, possibly due to an antagonistic effect [24]. A more recent study that had a follow-up of 2 years confirmed those findings [25].
Phase III clinical trials
There are several Phase III clinical trials currently looking at the efficacy and safety of bazedoxifene for the prevention and treatment of osteoporosis in postmenopausal women. In one study, primary outcomes included reduction of new vertebral fractures and comparison of the safety profile of bazedoxifene monotherapy for the treatment of osteoporosis in postmenopausal women [105]. The study, which began in October 2001 and is expected to enroll 7500 females aged 55–80 years who were at least 2 years post-menopausal was randomized, double-blind, and placebo-controlled.
A second study, which is evaluating the dose-response of bazedoxifene in Japanese women with postmenopausal osteoporosis, has completed recruiting subjects, but is ongoing in Japan. The study began in August 2003 and aimed to enrol approximately 375 patients; the trial is a randomized, placebo-controlled, double-blind, parallel-assignment, safety/efficacy study. The primary outcome is bone mineral density of the lumbar spine at 2 years of treatment. Secondary outcomes include bone metabolic markers, bone mineral density of the hip, lipid parameters, height and adverse effects [106].
Other Phase III studies include three trials that are currently recruiting patients to evaluate the use of bazedoxifene in combination with conjugated equine estrogens (CEEs) for alleviating menopausal symptoms. The hypothesis behind combining bazedoxifene with CEEs is to provide a hormone-replacement option that does not include progestin for women with an intact uterus, to offset any adverse events seen with traditional hormone-replacement therapy, in particular uterine or breast stimulation, and to have decreased stimulation of the vasomotor system [107–109].
A recent study evaluated the safety and efficacy of various doses of bazedoxifene (10, 20 and 40 mg/day) compared with placebo and another SERM (60 mg/day of raloxifene) in preventing bone loss in postmenopausal women. The study was initiated to evaluate the efficacy and safety of the various bazedoxifene doses in preventing bone loss in healthy post-menopausal women with normal/low bone mineral density. The 2-year results showed a significant protective effect on the bone, as demonstrated by increasing bone mineral density at multiple skeletal sites and a reduced rate of bone turnover. Bazedoxifene 20 and 40 mg were associated with a significant increase in bone mineral density relative to placebo observed after 6 months of treatment and preserved through 24 months. The bone mineral density and bone turnover marker effects of bazedoxifene were comparable to those of raloxifene. The percentage changes in bone mineral density from baseline in the bazedoxifene 20 and 40 mg treatment groups were significant compared with the placebo group at all time points assessed. In this study there was not a dose-response effect with bazedoxifene. However, the 20 and 40 mg doses were consistently more effective in protecting against bone loss than the 10 mg dose, particularly at the femoral neck, a skeletal site that is known to be rich in cortical bone. Compared with raloxifene 60 mg, bazedoxifene 20 and 40 mg provided comparable skeletal protection. In the placebo group, calcium supplementation did not prevent bone loss, indicating that calcium supplementation alone is ineffective in preserving bone mass early after menopause.
Interestingly, the same study demonstrated favorable changes with bazedoxifene treatment in serum concentrations of total cholesterol, LDL- and HDL-cholesterol relative to placebo. However, whether the observed changes in lipid profile with bazedoxifene treatment have any clinical relevance remains to be determined.
Bazedoxifene was also found to be well tolerated in this population of healthy postmenopausal women who were at risk for osteoporosis-related fracture. The incidences of adverse events, serious adverse events and withdrawals because of adverse events were similar among all treatment groups. No statistically significant differences were observed among the treatment groups for any cardiovascular events [25].
Concerns about bazedoxifene
Despite the encouraging initial data from the currently available clinical trials regarding efficacy and safety, bazedoxifene is an investigational product, with its safety and efficacy profile not yet fully elucidated. The safety and efficacy data reported from the limited Phase I studies have revealed a good tolerability and favorable adverse event profile without any clinically significant abnormal laboratory values with bazedoxifene doses up to 80 mg [16].
Adverse effects
Being one of the SERMs, bazedoxifene would be expected to have a profile of adverse effects similar to those encountered with SERMs. The most serious of those adverse effects include increased risk of deep venous thrombosis, thromboembolism and thrombophlebitis. Other adverse effects such as nausea, dyspepsia, peripheral edema, hypertriglyceridemia, migraine and arthralgia are also expected secondary to the estrogenic properties of SERMs. The lack of serious adverse effects in preclinical development studies is encouraging, particularly in light of the absence of stimulatory effects on the endometrium and lack of vasomotor symptoms that are frequently encountered with most SERMs [8,16].
Dose adjustment with age
There are currently no available data on the use of bazedoxifene in children. This group may need protection against osteoporosis in situations such as hypogonadism and premature ovarian failure. Bazedoxifene has been studied in women during the early years of menopause. There are no data on its use in advanced postmenopausal age. However, it is not expected that using bazedoxifene in the advanced age group will require dose adjustment. Bazedoxifene is not metabolized via Phase I oxidative reactions, which are reduced in the geriatric population, it is metabolized through glucuronidation, which is a Phase II conjugation reaction that is unaffected by age [14].
Drug interactions
An important adverse event has been suggested by one of the studies, including the possibility of a drug–drug interaction between bazedoxifene and ibuprofen. This has been thought to be due to both drugs being metabolized via the same pathway (glucuronidation). However, when a single oral dose of bazedoxifene 20 mg and ibuprofen 600 mg were administered concomitantly in healthy, postmenopausal women, analysis for both drugs' concentrations did show significant changes. The authors concluded that the two medications can be safely administered concomitantly with no dosage adjustment necessary [109].
Adverse events associated with different doses of bazedoxifene compared with placebo.
All adverse events.
Data taken with permission from [25].
Conclusion
Bazedoxifene is a third-generation, nonsteroidal, SERM being approved and developed for use alone or in combination with estrogen for prevention and treatment of osteoporosis in postmenopausal women. Preliminary clinical trials are encouraging. Bazedoxifene has been found efficacious in reducing bone loss in early postmenopausal women. The antagonistic effects at the breast tissue and absence of stimulatory action on the endometrium, while having an estrogenic stimulation on bone tissues, all confirm the clinical efficacy of bazedoxifene. The lack of vasomotor effects compared with raloxifene was thought of as a unique advantage. However, Phase III studies have confirmed an increase in vasomotor symptoms, similar to raloxifene, in women treated with bazedoxifene. The completion of ongoing clinical trials should elucidate the differences between bazedoxifene and other SERMs and define the clinical value of bazedoxifene in osteoporosis management.
Future perspective
In the next decade, the epidemic of osteoporosis is expected to affect a growing number of people worldwide. Thus, the need for effective and safe treatment of osteoporosis will obviously increase. SERMs are a promising medication that can fulfill such a need for effective anti-osteoporosis agents. While the two currently approved SERMs (tamoxifene and raloxifene) suffer from significant clinical problems, bazedoxifene appears to offer promising advantages over both drugs. Bazedoxifene does not appear to have the adverse effects that tamoxifene has at the level of the endometrium (endometrial proliferation, hyperplasia and carcinoma) or at the level of thromboemolism risk. Compared with raloxifene, bazedoxifene does not appear to cause vasomotor symptoms as raloxifene dose. However, the short and limited experience with bazedoxifene prevent us from drawing firm conclusions. Only time and further clinical experience with more patients for longer periods of treatment will confirm the speculations for the success of bazedoxifene as an optimum agent for osteoporosis prevention and treatment.
Osteoporosis is an epidemic that affects a growing number of people worldwide. Treating complications associated with osteoporosis, including various fractures, constitutes a significant economic burden.
Selective estrogen-receptor modulators are promising medications that can provide an exciting option for the prevention and treatment of osteoporosis.
Bazedoxifene is a third-generation, nonsteroidal, selective estrogen-receptor modulator that is being approved and developed for use alone or in combination with estrogen for osteoporosis management in postmenopausal women. It has shown promise in preliminary clinical trials.
Bazedoxifene has been found to be efficacious in reducing bone loss in early postmenopausal women. This favorable effect on the bone tissue was not associated with the drawbacks of stimulating the endometrium or the breast tissue. The lack of vasomotor effects compared with raloxifene is a unique advantage.
Currently, the short and limited experience with bazedoxifene prevents us from drawing firm conclusions regarding the advantages of bazedoxifene compared with other selective estrogen-receptor modulators. However, the encouraging preliminary results from clinical trials support trying it as a promising agent for the prevention and treatment of osteoporosis.
Footnotes
The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
No writing assistance was utilized in the production of this manuscript.