Continuing Education Activity

Bazedoxifene is a medication used in the treatment and management of osteoporosis. First approved by the FDA in 2013 as a combination drug, this drug primarily targets postmenopausal women, the population most susceptible to bone loss defects. Bazedoxifene belongs to a family of drug compounds known as selective estrogen receptor modulators. This activity reviews the indications, mechanism of action, route of administration, adverse events, and other key elements (e.g., off-label uses, dosing, pharmacodynamics, pharmacokinetics, monitoring, and relevant interactions) pertinent to healthcare providers in the management of patients with osteoporosis and related menopausal symptoms.

Objectives:

• Highlight the indicated use for bazedoxifene.
• Describe the mechanism of action of bazedoxifene.
• Identify the potential adverse effects associated with bazedoxifene.
• Discuss the importance of interprofessional communication amongst healthcare team members and its relevance in enhancing patient outcomes following the administration of bazedoxifene for osteoporosis.

Indications

Bazefoxifene is a selective estrogen receptor modulator (SERM) used primarily in managing osteoporosis in postmenopausal women.[1] Osteoporosis has become increasingly prevalent in society as the population over 65 is one of the fastest-growing demographics. This condition is characterized by progressive degeneration of overall bone density, leaving the patient increasingly susceptible to proximal fractures.

Osteoporosis is medically defined by a bone density T score of 2.5 standard deviations below the mean. While age represents the most significant risk factor, menopause leads to rapid bone resorption due to a remarkable decrease in estrogen levels. It remains one of the biggest contributors to debilitating physical health for women.[2]

Bazedoxifene first gained general acceptance for osteoporosis when approved by the FDA in 2013. As part of a combination drug incorporating conjugated estrogens and bazedoxifene, this medication aims to prevent osteoporotic-induced fractures for high-risk women that may have contraindications to other conventional therapeutics.[3]

Before late 2013, the standard clinical treatment for osteoporosis included bisphosphonates like alendronate or IV zoledronic acid, but these were administered with caution, as they are contraindicated in pregnant women and patients with chronic kidney disease.[4] 

Bazedoxifine's therapeutic benefits and efficacy were thoroughly tested through two global, randomized, double-blind, placebo- and active-controlled, phase III studies. As part of the inclusion criteria, the study encompassed 1583 healthy postmenopausal women at risk for osteoporosis who were randomly assigned to one of five groups: bazedoxifene 10 mg, 20 mg, or 40 mg a day; raloxifene 60 mg/day; placebo. The study's principal objective was reinforced by the results of the clinical trials, as it was determined that improvements in lumbar bone mineral density (BMD) scores were dose-dependent and significantly elevated from baseline. The mean percentage elevation in lumbar BMD in the 40 mg bazedoxifene group and raloxifene 60 mg group, compared with the placebo group, was 1.49% in both groups.[3]

Other general indications for bazedoxifene include the prevention of glucocorticoid-induced osteoporosis.[5] As part of a randomized clinical trial targeting postmenopausal women diagnosed with osteopenia and patients using low-dose corticosteroids for rheumatoid arthritis, it was found that bone mineral density outcomes in the treatment group significantly reduced the probability of long-term osteoporosis complications, in contrast with the control group. Along with targeting bone density, the bazedoxifene/conjugated estrogens combination is also therapeutically used to manage moderate to severe vasomotor symptoms associated with menopause in women with an intact uterus.[6]

FDA Approved Use

• Prevention of osteoporosis and management of vasomotor symptoms in postmenopausal women

Non-FDA Approved Indication

• Anti-proliferative effects that inhibit the progression of breast cancer

Mechanism of Action

Classified as a SERM, bazedoxifene is part of the interleukin-6 family of cytokines. Depending on the tissue or estrogen receptor being targeted, it functions as a competitive antagonist that yields anti-proliferative effects in cases of breast cancer or uterine carcinoma/endometrial hyperplasia and as an agonist that stimulates lipid metabolism and proper regulation of bone turnover.[7] 

The biomolecular antagonistic effects result from a pro-apoptotic signal that allows bazedoxifene to inhibit STAT3 and MAPK signaling pathways and effectively destroy cancer cells.[8] This drug has an oral bioavailability of around 6%, exhibiting a linear increase in serum concentration in response to ascending dosage levels. While the specific molecular mechanism of how an estrogen agonist like bazedoxifene modulates bone regulation and remodeling, current hypotheses include reductions in osteoclastogenesis via mitochondrial and ER-mediated mechanisms along with underlying effects on regulating serum calcium levels.[9]

Administration

Conjugated estrogen and bazedoxifene is a combination drug regimen strongly considered, in parallel with bisphosphonates, as the first line of treatment for postmenopausal women at risk of osteoporosis, hot flashes, or night sweats. The recommended dosage for this medication consists of 20 mg bazedoxifene, and 0.45 mg conjugated estrogen consumed via oral administration once daily. This pharmaceutical agent is usually available as a 30-day supply, with the average treatment duration lasting around two years.

In most cases, women are instructed to take this medication with supplemental calcium 600 mg or vitamin D. It is strongly advised not to exceed the dosage threshold, which constitutes not taking more than one tablet within 24 hours. If the patient missed a previous dose, the clear instructions are to take the oral medication as soon as possible, without regard to the timing of meals.[10]

Adverse Effects

Based on results analyzed in placebo-controlled trials, the most common adverse effects associated with the combination of conjugated estrogens and bazedoxifene include:

• Muscle spasms 
• Nausea
• Diarrhea
• Dyspepsia
• Abdominal pain 
• Oropharyngeal pain
• Neck pain 
• Dizziness

While there were other side effects and complications associated with bazedoxifene/conjugated estrogens, the probability of exhibiting those symptomatic adverse effects was not significantly different from what was seen in the placebo group.[11] Bazedoxifene/conjugated estrogens treatment is associated with an increased risk of venous thromboembolism.

Contraindications

Like most in the selective estrogen receptor modulator class of drugs, bazedoxifene, combined with conjugated estrogens, presents various contraindications. The most notable is pregnancy, as bazedoxifene/conjugated estrogens is a notable FDA Pregnancy Category X drug, though bazedoxifene as a drug itself is not classified as a potential teratogen.

Other notable contraindications include abnormal uterine bleeding, hypersensitivity allergic reactions to exogenous estrogen, and certain cardiovascular complications such as any prior or current history of deep vein thrombosis, stroke, pulmonary embolism, or myocardial infarction. Usage of the drug is strongly advised against in patients with hepatic and renal impairment, as ineffective metabolism by CYP3A4 and clearance of the drug can lead to unintended pharmacological effects.

Drug-drug interactions are still limited in research analysis regarding bazedoxifene/conjugated estrogens. However, some clinical trials have demonstrated that both CYP3A4 inhibitors and inducers pose a risk for potential adverse reactions following the intake of the combination drug.[10] 

Monitoring

Before initiating any treatment with bazedoxifene and conjugated estrogens, it is important to get a quantitative understanding of bone health and better assess any potential osteoporosis risks. The ideal diagnostic tool for measuring bone mineral density (BMD) is dual-energy X-ray absorptiometry (DEXA). A DEXA scan is an imaging device that uses spectral imaging to determine BMD scores and analyze the long-term probability of developing a vertebral or hip fracture. Following initiation of bazedoxifene/conjugated estrogens treatment, it is vital to continue monitoring BMD scores via DEXA every one to two years, which can later be curtailed based on the overall progress of bone strength.[12]

Following initiation of bazedoxifene/conjugated estrogen therapy, it is integral for both the patient and healthcare provider to monitor for any cardiovascular adverse effects. It has been documented that long-term usage of estrogen agonists/antagonists amongst postmenopausal women has led to an increased risk of stroke, pulmonary embolism, and deep vein thrombosis.

Should the patient suspect any symptoms characteristic of a cardiovascular anomaly, it is integral for her to immediately discontinue the drug and report the symptoms to her primary healthcare provider or a cardiologist. If there is a family history of cardiovascular complications, in that case, the patient needs to report that to her primary care physician to determine if necessary to either consider alternative drug regimens or strictly monitor for symptoms in a healthcare setting. Other adverse effects that require monitoring but are not of immediate danger to a patient include abdominal pain, nausea, muscle spasms, and light-headedness.[10]

Another potential long-term concern of unopposed estrogen therapy is endometrial cancer. Clinical trials have demonstrated a slightly increased risk of endometrial hyperplasia following treatment with 20 mg BZA/0.625 mg CE, as opposed to the treatment group with only 20 mg BZA/0.45 mg CE. There were no reported cases of endometrial hyperplasia in the placebo group. While the risk of endometrial cancer for postmenopausal women taking conjugated estrogens/bazedoxifene is quite low, it is important not to supplement this drug with any additional estrogen therapy and to ensure proper clinical surveillance during drug therapy.[13]

Toxicity

Potential symptoms of an overdose of bazedoxifene/Conjugated estrogens include severe muscle spasms and classic gastrointestinal symptoms, including abdominal pain, vomiting, and nausea. Current research hasn't found a prescribed antidote or first-line treatment to reverse a potentially toxic dose of this combination drug. Patients are advised to seek services of an emergency room or contact Poison control should they suspect an overdose. It's been clinically demonstrated that as a pharmaceutical agent alone, bazedoxifene has a relatively wide therapeutic index. While it is FDA approved as a 20 mg dose in conjunction with conjugated estrogens, bazedoxifene showed no toxicity effects up to 80 mg.[7] 

While bazedoxifene is a relatively safe drug compound with minimal risks of overdose toxicity or long-term adverse effects, conjugated estrogen has elevated risks. While trying to determine the optimal ratio of bazedoxifene to conjugated estrogens, a double-blind, randomized, placebo-controlled clinical study found that 0.625 mg of conjugated estrogen significantly increases endometrial thickness. It was determined that at least 20 mg of bazedoxifene was necessary to counter the CE-induced hyperplasia effects to minimize the probability of endometrial carcinoma developing in the long run.[14]

In addition, there are significant risks associated with bazedoxifene/conjugated estrogens due to the teratogenic effects on fetal development, and thus is classified as a Pregnancy Category X drug. Should a patient become aware that they are pregnant while currently on bazedoxifene/conjugated estrogen drug therapy, it is recommended to immediately discontinue the drug and consult with her primary care physician or obstetrician. 

Enhancing Healthcare Team Outcomes

Bazedoxifene is a selective estrogen receptor modulator used in conjunction with conjugated estrogen to treat osteoporosis and hot flashes in post-menopausal women. Following its FDA approval in late 2013, this drug has gained greater clinical acceptance over the years by the physician community. Yet while this drug is touted for its efficacy, using it requires a great deal of interprofessional communication between a patient's healthcare management team as it is targeted at a specific population with a particular set of symptoms.

In a previous phase 3, randomized and double-blind studies were conducted to evaluate the efficacy of conjugated estrogens/bazedoxifene on post-menopausal women. Most data have shown the drug to be effective for women between the age of 40 and 65. Still, the drug is contraindicated in women over 75.[15]

Within the spectrum of possible clinicians a woman might want to consult before taking this drug includes her primary care physician, gynecologist, rheumatologist, endocrinologist, and, depending on the severity of osteoporosis or accompanying fractures, an orthopedic surgeon. Working with different physicians can provide a greater depth of understanding to the patient regarding the benefits of the drug and notable contraindications.

Without proper management and care coordination by health providers, it is possible the patient could experience adverse effects following the usage of this drug. Should an overdose or significant adverse effect occur that brings the patient to the emergency room, the ER clinician must be able to communicate with at least the patient's primary care physician and possibly one other specialist who either had the most frequent visits with the patient or prescribed her bazedoxifene/conjugated estrogens.[15]

The primary care physician must educate a patient on the importance of integrating behavioral modifications with the patient's pharmaceutical regimen. For a post-menopausal woman, it is essential that she exercises regularly and eats nutritious food that promotes a healthy weight that is less susceptible to brittle bones and compounding fractures; in addition, it is pivotal that the patient avoids alcohol, smoking, and spicy foods that may exacerbate hot flash symptoms.

Lifestyle changes work in synergy with bazedoxifene/conjugated estrogens, and a team of medical providers must be able to facilitate necessary lifestyle changes alongside a focused drug treatment plan that would enhance patient-centered care and improve overall outcomes.