A Comprehensive Clinical and Pharmacological Monograph on Raloxifene (DB00481)

1.0 Executive Summary and Drug Profile

1.1 Overview of Raloxifene as a Second-Generation SERM

Raloxifene is a non-steroidal, second-generation selective estrogen receptor modulator (SERM) that belongs to the benzothiophene chemical class.[1] Marketed primarily under the brand name Evista®, it is a cornerstone therapy for specific conditions in postmenopausal women.[3] The defining characteristic of Raloxifene is its tissue-selective pharmacology. It exhibits estrogen-agonistic effects in certain tissues, notably bone and the systems governing lipid metabolism, while simultaneously acting as a potent estrogen-antagonist in reproductive tissues such as the breast and uterus.[3] This dual-action profile allows Raloxifene to confer many of the protective benefits of estrogen, particularly the preservation of bone mineral density, without incurring the proliferative risks associated with estrogenic stimulation of breast and endometrial tissues.[6]

Its primary clinical applications are the prevention and treatment of osteoporosis in postmenopausal women and the reduction of risk for developing invasive breast cancer in postmenopausal women who are either osteoporotic or otherwise at high risk.[3] It is available as a generic medication and is administered as a standard 60 mg oral tablet taken once daily, with or without food.[3] In 2020, it was a widely prescribed medication in the United States, with over 1 million prescriptions filled, underscoring its established role in clinical practice.[3]

1.2 Developmental History and Regulatory Milestones

The clinical trajectory of Raloxifene is a quintessential example of successful drug repurposing. Originally developed under the code name Keoxifene (LY 139481), its initial focus was as a therapeutic agent for established breast cancer, an indication in which it ultimately failed to demonstrate sufficient efficacy.[1] However, during these early investigations, translational studies revealed its unique and complex effects on bone, breast, and uterine tissues. This led to a strategic "reinvention" of the compound, pivoting away from cancer treatment and toward prevention and management of other postmenopausal conditions.[10]

This new direction culminated in its first major regulatory approval in December 1997, when the U.S. Food and Drug Administration (FDA) approved Raloxifene, under the brand name Evista® (manufactured by Eli Lilly), for the prevention of postmenopausal osteoporosis.[3] This was followed by approval from the European Medicines Agency (EMA) in 1998.[11] The FDA expanded its indication in 1999 to include the

treatment of established postmenopausal osteoporosis.[12]

A landmark label expansion occurred in September 2007. Based on compelling evidence from large-scale, long-term clinical trials—including the MORE (Multiple Outcomes of Raloxifene Evaluation), CORE (Continuing Outcomes Relevant to Evista), and RUTH (Raloxifene Use for The Heart) trials—the FDA approved Raloxifene for the reduction in risk of invasive breast cancer.[5] This approval was specifically granted for two populations: postmenopausal women with osteoporosis and postmenopausal women determined to be at high risk for invasive breast cancer.[5] This history is crucial to understanding its clinical placement; it is a prophylactic agent, not a treatment for active disease, a distinction explicitly noted on its label.[9]

1.3 Chemical Structure and Physicochemical Properties

Raloxifene is chemically classified as a member of the 1-benzothiophene family, a structure that distinguishes it from both endogenous steroidal estrogens like estradiol and first-generation SERMs like tamoxifen, which is a triphenylethylene derivative.[1]

Its formal IUPAC name is [6-hydroxy-2-(4-hydroxyphenyl)-1-benzothiophen-3-yl]-[4-(2-piperidin-1-ylethoxy)phenyl]methanone.[1] The molecule has the chemical formula

C28​H27​NO4​S and a molecular weight of approximately 473.58 g/mol.[2] Physically, it is a solid substance, appearing as light-yellow crystals when derived from acetone.[1] A critical physicochemical property is its very low solubility in water, a factor that influences its formulation and pharmacokinetic profile.[1] It is typically administered as a hydrochloride salt (CAS Number 82640-04-8) to improve its properties for pharmaceutical formulation.[1]

The following table consolidates the key identifiers and profile characteristics of Raloxifene, providing a foundational reference for research and regulatory purposes.

Table 1: Raloxifene Drug Profile and Identifiers

Attribute	Value	Source(s)
Drug Name	Raloxifene	3
DrugBank ID	DB00481	1
Type	Small Molecule	5
CAS Number (Base)	84449-90-1	1
CAS Number (HCl Salt)	82640-04-8	1
IUPAC Name	[6-hydroxy-2-(4-hydroxyphenyl)-1-benzothiophen-3-yl]-[4-(2-piperidin-1-ylethoxy)phenyl]methanone	1
Molecular Formula	C28​H27​NO4​S	1
Average Weight	473.583 Da	2
Drug Class	Selective Estrogen Receptor Modulator (SERM); Estrogen Agonist/Antagonist; Hormones/Antineoplastics	3
Brand Names	Evista®, Optruma®	3
Synonyms/Code Names	Keoxifene, LY 139481, LY-156758	1
ChEMBL ID	CHEMBL81	1
PubChem CID	5035	11

2.0 Molecular Pharmacology: A Dual-Action Modulator

2.1 The Selective Estrogen Receptor Modulator (SERM) Concept

Selective Estrogen Receptor Modulators (SERMs) are a sophisticated class of pharmaceutical agents designed to interact with estrogen receptors (ERs) in a highly nuanced manner. Unlike endogenous estrogen, which functions as a universal agonist across all tissues, SERMs exhibit tissue-specific pharmacology, acting as either an agonist or an antagonist depending on the cellular context.[3] The fundamental therapeutic goal of a SERM is to selectively harness the beneficial effects of estrogen—such as maintaining bone density and favorable lipid profiles—while simultaneously avoiding or actively blocking its potentially detrimental effects, such as the stimulation of cell proliferation in the breast and uterus.[4] Raloxifene, a second-generation SERM, is the first agent from the benzothiophene class to be designated as such, representing a structural and functional evolution from the first-generation triphenylethylene SERM, tamoxifen.[1]

2.2 Receptor Binding Dynamics: ERα, ERβ, and GPER

Raloxifene's complex activity begins at the receptor level. It binds with high affinity to the two principal isoforms of the nuclear estrogen receptor, ERα and ERβ.[3] Its dissociation constant (

Kd​) for ERα is approximately 50 pM, an affinity comparable to that of estradiol, the body's primary estrogen.[3] However, its interaction is not uniform. Evidence indicates that Raloxifene functions as a partial agonist at the ERα isoform, which is predominantly associated with activating estrogenic pathways, and as a pure antagonist at the ERβ isoform, which often has an inhibitory or opposing role.[3] This differential activity across receptor isoforms is a foundational element of its tissue-selective effects. Adding another layer of complexity, recent pharmacological studies have identified Raloxifene as an agonist of the G protein-coupled estrogen receptor (GPER), a membrane-bound receptor that mediates rapid, non-genomic estrogen signaling. This interaction may contribute to its broader pharmacological profile beyond classical nuclear receptor activity.[3]

2.3 Tissue-Specific Gene Regulation and Conformational Change

The molecular mechanism underpinning the "selective" nature of SERMs is rooted in the unique three-dimensional conformational change that the estrogen receptor undergoes upon binding to the ligand.[4] When Raloxifene occupies the ligand-binding pocket of the ER, its distinct structure, particularly a bulky and inflexible side-chain, physically obstructs a critical surface on the receptor. This protrusion prevents the receptor from properly aligning with essential co-activator proteins, specifically by blocking the interaction with the Activation Factor-2 (AF-2) domain.[6] The AF-2 domain is indispensable for initiating gene transcription in response to estrogen in tissues like the breast and endometrium. This physical blockade of AF-2 is considered the key molecular event responsible for Raloxifene's antagonist effects in these tissues.[6]

Conversely, in other cellular environments, such as bone cells, the story is different. The Raloxifene-ER complex, despite its altered conformation, can recruit a different set of tissue-specific co-regulatory proteins. This reconfigured complex is then capable of binding to a distinct DNA sequence known as the Raloxifene Responding Element (RRE), which is different from the classic Estrogen Response Element (ERE) that mediates estrogen's primary effects.[6] This interaction with the RRE initiates the transcription of a different suite of genes, ultimately producing an estrogen-agonist effect in that tissue.[6] A prime example of this is the specific activation of the transforming growth factor-β3 (TGF-β3) gene, a potent regulator of bone remodeling and a key mediator of Raloxifene's bone-protective effects.[4] This elegant mechanism—involving a combination of receptor isoform preference, unique conformational changes, and the recruitment of tissue-specific co-regulators to alternative gene promoters—is what allows Raloxifene to be beneficial in one tissue while being protective in another.

2.4 Detailed Pharmacodynamics

2.4.1 Estrogen-Agonist Effects: Bone and Lipid Metabolism

Bone: In skeletal tissue, Raloxifene functions as a potent estrogen agonist. It effectively mimics the bone-preserving actions of endogenous estrogen by inhibiting the activity of osteoclasts, the cells responsible for bone resorption, and supporting the function of osteoblasts, the cells responsible for bone formation.[5] This net anti-resorptive effect leads to a significant decrease in the levels of biochemical markers of bone turnover, such as serum alkaline phosphatase and osteocalcin, bringing them down to levels typical of premenopausal women.[4] Mechanistically, this is achieved in part through the upregulation of anti-resorptive factors like TGF-β3 and osteoprotegerin (OPG), and the downregulation of pro-resorptive cytokines, including interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α).[6] The clinical result of these actions is a measurable increase in bone mineral density (BMD) and a reduced risk of vertebral fractures.[12]

Lipid Metabolism and Coagulation: Raloxifene's agonistic activity extends to the liver, where it beneficially modulates lipid metabolism. It has been consistently shown to lower serum levels of total cholesterol and low-density lipoprotein (LDL) cholesterol, often referred to as "bad cholesterol".[21] However, its profile is distinct from that of estrogen, as it has a neutral or negligible effect on high-density lipoprotein (HDL) cholesterol and triglyceride levels.[21] The estrogen-agonist effect in the liver is also responsible for its most significant adverse effect. By activating hepatic estrogen receptors, Raloxifene influences the liver's production of various coagulation factors and decreases fibrinogen levels, leading to a procoagulatory state.[3] This mechanistic link between its desired metabolic effects and its thrombotic risk is critical; the risk of venous thromboembolism (VTE) is not an idiosyncratic reaction but an inherent consequence of the drug's intended mechanism of action in the liver.

2.4.2 Estrogen-Antagonist Effects: Breast and Uterine Tissue

Breast: In mammary tissue, Raloxifene functions as a pure estrogen antagonist.[3] It competitively binds to estrogen receptors on mammary epithelial cells, effectively blocking endogenous estrogen from exerting its proliferative effects.[5] This anti-proliferative action is clinically manifested as a reduction in breast density, which is itself a known risk factor for breast cancer.[3] This mechanism forms the basis for its FDA-approved indication in reducing the risk of developing invasive, estrogen receptor (ER)-positive breast cancer in high-risk postmenopausal women.[5]

Uterus: One of the most important pharmacodynamic features of Raloxifene, and a key differentiator from tamoxifen, is its purely antagonistic effect on the uterus.[1] Unlike tamoxifen, which has partial agonist activity that can stimulate the endometrium, Raloxifene does not promote endometrial proliferation. Consequently, its use is not associated with an increased risk of endometrial thickening, abnormal vaginal bleeding, endometrial hyperplasia, or endometrial cancer.[3] This superior uterine safety profile is a major clinical advantage and a primary reason for its selection over other SERMs in certain patient populations.

3.0 Clinical Pharmacokinetics: Absorption, Distribution, Metabolism, and Excretion (ADME)

3.1 Absorption and Bioavailability

Raloxifene is administered orally and is absorbed rapidly from the gastrointestinal tract, with approximately 60% of an oral dose being absorbed.[23] Despite this high rate of absorption, the drug is subject to extensive and rapid first-pass metabolism. As it passes through the gut wall and liver for the first time, it is heavily conjugated into glucuronide metabolites.[21] This presystemic clearance is so efficient that the absolute bioavailability of active, unchanged Raloxifene is extremely low, estimated to be only about 2%.[23] This means that for every 60 mg tablet administered, only about 1.2 mg of the active drug reaches the systemic circulation. The standard dosage regimen is designed to achieve therapeutic concentrations despite this low bioavailability. While co-administration with a high-fat meal can increase the peak plasma concentration (

Cmax​) and area under the curve (AUC), the effect is not considered clinically critical for chronic therapy, and the FDA label permits administration without regard to meals.[9]

3.2 Distribution

Once in the systemic circulation, Raloxifene is distributed extensively throughout the body. This is reflected by its very large apparent volume of distribution, which is approximately 2348 L/kg.[5] This value indicates that the drug does not remain confined to the bloodstream but partitions extensively into tissues. Furthermore, Raloxifene is highly bound to plasma proteins, with over 95% of the drug complexed with albumin and, to a lesser extent, alpha-1-acid glycoprotein.[2] This high degree of protein binding has significant clinical implications, as it creates the potential for displacement interactions with other concurrently administered drugs that are also highly protein-bound, such as warfarin.[9]

3.3 Metabolism and Elimination

A key feature of Raloxifene's metabolic profile is that it does not significantly involve the cytochrome P450 (CYP450) enzyme system.[4] This is a major clinical advantage, as it minimizes the risk of drug-drug interactions with the vast number of medications that are substrates, inhibitors, or inducers of CYP enzymes. Instead, the primary metabolic pathway for Raloxifene is Phase II conjugation, specifically glucuronidation, which occurs in the liver and gut wall to form several inactive glucuronide metabolites.[21]

The elimination of Raloxifene is characterized by a long plasma elimination half-life, which ranges from approximately 27 to 33 hours.[4] This long half-life is a result of extensive enterohepatic recycling and is the pharmacokinetic basis for the convenient once-daily dosing schedule. Excretion occurs predominantly via the biliary system into the feces, which accounts for over 93% of the eliminated dose, mostly in the form of glucuronide conjugates.[21] A negligible amount of the drug, less than 0.2%, is excreted unchanged in the urine. This excretion profile indicates that hepatic function is far more critical to its clearance than renal function, and dose adjustments for renal impairment are generally not required.[21]

3.4 Table 2: Summary of Pharmacokinetic Parameters of Raloxifene

The pharmacokinetic properties of Raloxifene dictate its clinical use, including dosing frequency and potential for interactions. The table below summarizes these key parameters and their clinical implications.

Parameter	Value / Description	Clinical Implication / Notes	Source(s)
Absorption	~60% of oral dose absorbed	Rapid absorption from the GI tract.	23
Bioavailability	Absolute bioavailability is ~2%	Extensive first-pass glucuronidation severely limits systemic exposure of the active drug. Dosing is established based on this low value.	21
Distribution	Volume of Distribution: 2348 L/kg	Extensively distributed into tissues rather than remaining in plasma.	5
Protein Binding	>95% (to albumin and α1-acid glycoprotein)	High potential for displacement interactions with other highly protein-bound drugs (e.g., warfarin, diazepam).	9
Metabolism	Extensive first-pass glucuronidation. Not significantly metabolized by CYP450 pathways.	Low risk of interactions with the many drugs metabolized by the CYP450 system, a significant clinical advantage.	4
Elimination Half-life	27.7 to 32.5 hours	Long half-life supports convenient once-daily dosing.	4
Excretion	Primarily in feces (>93%); minimal in urine (<0.2%)	Hepatic impairment is a greater concern for drug clearance than renal impairment.	21

The pharmacokinetic profile of Raloxifene presents both advantages and potential challenges. Its lack of reliance on the CYP450 system for metabolism is a significant benefit, reducing the likelihood of many common drug-drug interactions. However, its extremely low bioavailability means that any factor altering its first-pass glucuronidation could theoretically lead to large relative changes in systemic drug exposure. Similarly, its high degree of plasma protein binding creates a specific vulnerability to displacement interactions. While the common CYP-mediated interactions are largely avoided, clinicians must remain vigilant for interactions involving glucuronidation pathways or competition for protein binding sites.

4.0 Evidence-Based Clinical Applications and Efficacy

4.1 Indication 1: Treatment and Prevention of Postmenopausal Osteoporosis

Raloxifene is firmly established and FDA-approved for both the prevention and treatment of osteoporosis in postmenopausal women.[3] The physiological basis for this indication is the decline in estrogen production following menopause, which triggers an imbalance in bone remodeling. Bone resorption by osteoclasts begins to outpace bone formation by osteoblasts, leading to a progressive loss of bone mass and a deterioration of bone microarchitecture.[23] Raloxifene directly counteracts this process through its estrogen-agonist effects in skeletal tissue, effectively mimicking the bone-protective role of estrogen.[23] The standard dosage for both prevention and treatment is a 60 mg tablet administered orally once per day.[3]

The clinical efficacy of Raloxifene is supported by extensive evidence from large-scale, randomized, placebo-controlled trials. These studies have consistently demonstrated that Raloxifene produces statistically significant increases in bone mineral density (BMD) at key skeletal sites, including the lumbar spine, total hip, and femoral neck, as well as in total body BMD, when compared with placebo.[4] In parallel with these BMD improvements, treatment with Raloxifene leads to a significant reduction in the levels of biochemical markers of bone turnover, returning them to the normal premenopausal range.[4]

The ultimate goal of osteoporosis therapy is the prevention of fractures. The pivotal MORE (Multiple Outcomes of Raloxifene Evaluation) trial provided definitive evidence in this regard, showing that Raloxifene significantly reduces the risk of new vertebral fractures by 30-50% in postmenopausal women with osteoporosis.[6] This protective effect was observed in women both with and without prevalent fractures at baseline and was sustained over four years of treatment.[12] Despite these benefits, Raloxifene is generally considered a second-line agent to bisphosphonates for the broad treatment of osteoporosis.[3] A primary reason for this is its failure to demonstrate a statistically significant reduction in the risk of

non-vertebral fractures, most notably hip fractures, in the overall study populations of its major trials.[30] This distinction is critical, as hip fractures are associated with the greatest morbidity and mortality.

Raloxifene has also been studied in sequential therapy regimens. Clinical trials have shown that following a course of treatment with an anabolic agent like teriparatide, which actively builds new bone, subsequent therapy with the anti-resorptive Raloxifene can effectively maintain or even augment the gains in BMD.[31]

4.2 Indication 2: Reduction of Invasive Breast Cancer Risk

In 2007, the FDA approved a second major indication for Raloxifene: the reduction of risk of invasive breast cancer.[12] This approval is targeted at two specific groups of postmenopausal women: 1) those with diagnosed osteoporosis, and 2) those without osteoporosis but who are at high risk for developing invasive breast cancer, as determined by risk assessment models like the Gail model.[5] The therapeutic rationale is its potent estrogen-antagonist activity in breast tissue, which blocks the proliferative signals of estrogen that can drive the development of hormone-sensitive cancers.[8]

The dosage for this indication is the same as for osteoporosis: 60 mg once daily.[9] While clinical trials often employed a five-year treatment duration, the optimal duration of therapy for risk reduction has not been definitively established.[9]

The efficacy of Raloxifene for chemoprevention is supported by robust clinical trial data:

• The MORE trial and its 4-year extension, the CORE trial, provided a total of 8 years of follow-up data. This long-term analysis demonstrated that Raloxifene reduced the risk of invasive breast cancer by 56% compared to placebo. Critically, this risk reduction was almost entirely confined to estrogen receptor (ER)-positive tumors (a 63% reduction), with no significant effect on the incidence of ER-negative cancers.[14]
• The RUTH trial, which enrolled women at risk for cardiovascular disease, corroborated these findings, showing a 44% overall reduction in invasive breast cancer, again driven by a 55% reduction in ER-positive tumors.[14]
• The STAR (Study of Tamoxifen and Raloxifene) trial provided a direct, head-to-head comparison with tamoxifen. It concluded that Raloxifene was approximately 76% as effective as tamoxifen in reducing the risk of invasive breast cancer.[34]

It is essential to recognize the specific limitations of this indication, which are clearly stated on the FDA label. Raloxifene is not indicated for the treatment of active or established breast cancer, for reducing the risk of cancer recurrence in women who have already had breast cancer, or for reducing the risk of non-invasive breast cancers like ductal carcinoma in situ (DCIS).[9]

4.3 Indication 3: Corticosteroid-Induced Osteoporosis

In addition to postmenopausal osteoporosis, Raloxifene is also approved for the prevention and treatment of osteoporosis induced by the chronic use of glucocorticoids.[3] This provides an important therapeutic option for postmenopausal patients who require long-term steroid therapy for other medical conditions and are consequently at high risk for significant bone loss.

The dual indications of Raloxifene create a unique clinical niche. While it may not be the most potent agent for either osteoporosis or breast cancer prevention when considered in isolation, it is the only single agent FDA-approved to address both conditions simultaneously.[5] This makes it an ideal therapeutic choice for a specific patient archetype: the postmenopausal woman who presents with both osteopenia or osteoporosis and a concurrent high risk for developing ER-positive breast cancer. For this patient, Raloxifene offers an elegant solution that can "kill two birds with one stone".[12] For a patient with severe osteoporosis and minimal breast cancer risk, a bisphosphonate would likely be preferred due to its proven efficacy in preventing hip fractures. Conversely, for a patient at very high risk of breast cancer but with normal bone density, tamoxifen might be chosen for its superior chemopreventive efficacy. The primary value of Raloxifene lies precisely at the intersection of these two common and serious health concerns of postmenopausal women.

5.0 Comprehensive Safety Profile and Risk Management

5.1 Analysis of the FDA Boxed Warning: Venous Thromboembolism and Stroke

Raloxifene's prescribing information includes a Black Box Warning, the FDA's most stringent warning, highlighting two major cardiovascular risks that are central to its safety profile.[9]

Venous Thromboembolism (VTE): Treatment with Raloxifene is associated with a significantly increased risk of venous thromboembolic events, including deep vein thrombosis (DVT), pulmonary embolism (PE), and the less common retinal vein thrombosis.[9] Clinical trial data indicate that the relative risk of VTE is increased approximately threefold compared to placebo (relative risk ≈ 3.1).[3] The risk appears to be highest during the initial months of therapy. Due to this substantial risk, Raloxifene is strictly contraindicated in women with an active or past history of any VTE event.[3] To manage this risk in all patients, it is recommended that therapy be discontinued at least 72 hours prior to and during any period of prolonged immobilization, such as major surgery or extended bed rest, when the baseline risk of thrombosis is already elevated.[9]

Death from Stroke: The second component of the boxed warning relates to an increased risk of death from stroke. This risk was identified in the RUTH trial, which specifically enrolled postmenopausal women who either had documented coronary heart disease (CHD) or were at increased risk for major coronary events. In this high-risk population, Raloxifene was associated with an increased incidence of fatal stroke.[3] Consequently, the FDA label explicitly states that Raloxifene should not be used for the primary or secondary prevention of cardiovascular disease.[9]

5.2 Profile of Common and Serious Adverse Events

Beyond the boxed warnings, Raloxifene has a well-characterized profile of other adverse events.

Common Side Effects: The most frequently reported adverse effects in clinical trials are vasomotor symptoms, specifically hot flashes, and leg cramps.[3] Hot flashes can affect up to 28% of patients (compared to 21% on placebo) and are most prominent during the first six months of treatment; they can be a significant cause of treatment discontinuation.[2] Other common effects include peripheral edema (swelling of the ankles, hands, or feet), arthralgia (joint pain), increased sweating, and flu-like symptoms.[3]

Serious Adverse Events: Aside from the thromboembolic and stroke risks, other rare but serious adverse events have been reported. These include transient elevations in liver enzymes, requiring periodic monitoring of hepatic function, and thrombocytopenia (a low number of blood platelets), which can lead to an increased risk of bruising or bleeding.[8]

Favorable Uterine and Breast Profile: A key aspect of Raloxifene's safety profile is its antagonistic effect on reproductive tissues. This translates into significant clinical advantages. Unlike tamoxifen, Raloxifene does not stimulate the endometrium and is not associated with an increased incidence of vaginal bleeding, endometrial hyperplasia, or endometrial cancer.[3] This is one of its most important safety features. Any new-onset vaginal bleeding in a patient taking Raloxifene is not expected to be caused by the drug and warrants a prompt and thorough gynecological workup to identify the underlying cause.[23] Similarly, it does not increase the incidence of breast pain or tenderness.[3]

5.3 Table 3: Summary of Adverse Events by Frequency

The following table provides a structured overview of Raloxifene's adverse event profile, categorized by system organ class and frequency, to aid in clinical assessment and patient counseling.

System Organ Class	Common (≥1/100 to <1/10)	Uncommon (≥1/1,000 to <1/100)	Rare (≥1/10,000 to <1/1,000)
Vascular Disorders	Hot flashes, Peripheral edema	Venous Thromboembolism (DVT, PE)	Retinal vein thrombosis
Nervous System		Headache, Migraine	Fatal Stroke (in high-risk CVD patients)
Musculoskeletal	Leg cramps, Arthralgia, Muscle spasms
General Disorders	Flu-like symptoms, Increased sweating
Reproductive System	Vaginal itching, Increased white discharge	Mild breast pain/tenderness
Blood & Lymphatic			Thrombocytopenia
Hepatobiliary			Liver enzyme changes

5.4 Contraindications, Warnings, and Precautions

The safe use of Raloxifene requires adherence to specific contraindications and precautions.

Contraindications:

• Active or past history of venous thromboembolic events (DVT, PE, retinal vein thrombosis).[3]
• Pregnancy (FDA Pregnancy Category X), women who may become pregnant, and nursing mothers. Raloxifene can cause fetal harm and its use is strictly contraindicated in these populations.[3]

Warnings and Precautions:

• Cardiovascular Risk: Caution should be exercised in patients with a history of stroke, transient ischemic attack (TIA), atrial fibrillation, hypertension, or who are active smokers, due to the increased risk of fatal stroke.[1]
• Hepatic and Renal Impairment: Raloxifene should be used with caution in patients with significant hepatic or renal impairment, as these conditions may lead to increased systemic concentrations of the drug.[9]
• Premenopausal Use: Use in premenopausal women is not recommended.[9]
• Concomitant Estrogen Use: Co-administration with systemic estrogens is not recommended as the safety of this combination has not been established.[9]
• Hypertriglyceridemia: Caution is advised for patients with a history of marked hypertriglyceridemia (triglycerides > 500 mg/dL) in response to oral estrogen therapy.[16]

The safety profile of Raloxifene exemplifies a critical clinical concept: therapeutic trade-offs. It successfully avoids the significant uterine risks associated with tamoxifen, which is a major advantage. However, it introduces its own distinct and serious cardiovascular risks, namely VTE and fatal stroke in at-risk individuals. This means the clinical decision is not about identifying a universally "safer" drug, but about carefully matching a drug's specific risk profile to an individual patient's baseline health status and risk factors.

6.0 Clinically Significant Drug and Disease Interactions

6.1 Pharmacokinetic Interactions

Raloxifene's pharmacokinetic profile, characterized by extensive glucuronidation and high protein binding but minimal CYP450 metabolism, dictates its interaction potential.

• Cholestyramine: Co-administration with cholestyramine or other anion exchange resins is not recommended. These agents can bind to Raloxifene in the gastrointestinal tract, significantly reducing its absorption and interfering with its enterohepatic recycling, which could lead to a substantial decrease in systemic exposure and efficacy.[23]
• Levothyroxine: Raloxifene may decrease the absorption of levothyroxine. To avoid this interaction, patients should be advised to separate the administration of these two medications by several hours.[23]
• Ampicillin/Amoxicillin: The prescribing information suggests that concomitant use with ampicillin or amoxicillin is not recommended, as some data suggest these antibiotics may reduce the absorption of Raloxifene by altering the gut flora involved in its enterohepatic circulation.[23]
• Cytochrome P450 (CYP450) System: As Raloxifene is not metabolized to a clinically significant degree by CYP450 enzymes, it is not expected to have major interactions with the numerous drugs that are substrates, inhibitors, or inducers of this system.[4] This is a notable clinical advantage. Some in vitro data suggest it may be a weak inhibitor of certain isoenzymes like CYP2C8 and CYP2B6, but this is not considered to be clinically relevant at standard doses.[44]

6.2 Pharmacodynamic Interactions

• Warfarin: A minor pharmacodynamic interaction with warfarin has been reported. Raloxifene may cause a small decrease in prothrombin time. While the effect is generally not large, it is prudent to monitor the International Normalized Ratio (INR) more closely when initiating or discontinuing Raloxifene in patients receiving long-term warfarin therapy.[9] The mechanism is thought to involve competition for binding sites on plasma proteins.[23]
• Systemic Estrogens: The safety of using Raloxifene concurrently with systemic estrogen-containing products (e.g., hormone replacement therapy) has not been established, and this combination is not recommended.[9]
• Ospemifene: Ospemifene is another SERM used for dyspareunia. Co-administration with Raloxifene is not recommended due to the potential for additive or synergistic effects, which could increase the risk of adverse events like VTE.[23]

6.3 Considerations in Comorbid Conditions (Disease Interactions)

A patient's underlying medical conditions can significantly influence the safety and appropriateness of Raloxifene therapy.

• Thromboembolism: A personal history of any venous thromboembolic event is an absolute contraindication to the use of Raloxifene.[41]
• Cardiovascular Disease: Due to the increased risk of fatal stroke in high-risk women, Raloxifene should not be used for primary or secondary prevention of cardiovascular disease. Extreme caution and a careful risk-benefit assessment are required for patients with a history of stroke, TIA, atrial fibrillation, uncontrolled hypertension, or who are smokers.[1]
• Hepatic or Renal Impairment: Raloxifene should be used with caution in patients with significant hepatic or renal disease, as these conditions can impair its metabolism and clearance, potentially leading to higher systemic drug concentrations and an increased risk of toxicity.[9]
• Hypertriglyceridemia: Caution is warranted in patients with a known history of developing severe hypertriglyceridemia during treatment with oral estrogen, as a similar reaction could potentially occur with Raloxifene.[16]

An examination of drug interaction databases reveals a notable contradiction regarding the severity of Raloxifene's interactions. Some sources, like RxList, classify its interaction profile as relatively benign, with "no known serious interactions" apart from with other SERMs.[38] In stark contrast, other databases, such as Drugs.com, list as many as 18 "major" interactions, a classification implying that the combination should be avoided.[41] This discrepancy highlights the inherent challenge in relying on a single source and the different criteria used by various platforms to classify risk. From a clinical standpoint, this does not mean one source is right and the other is wrong, but rather that a cautious approach is necessary. Instead of relying solely on a label like "major" or "minor," it is more prudent for the clinician to understand the mechanistic basis of the potential interactions—such as interference with absorption (cholestyramine, levothyroxine) or competition for protein binding (warfarin)—and to implement appropriate monitoring plans for any patient on concomitant therapy.

7.0 Comparative Assessment: Raloxifene versus Tamoxifen

The clinical positioning of Raloxifene is best understood through a direct comparison with tamoxifen, the first-generation SERM and the historical benchmark for both breast cancer treatment and chemoprevention.

7.1 Efficacy in Breast Cancer Chemoprevention: Insights from the STAR Trial

The STAR (Study of Tamoxifen and Raloxifene) trial was a landmark, prospective, randomized, double-blind study designed specifically to compare the two drugs head-to-head. Involving nearly 20,000 high-risk postmenopausal women, it provides the highest level of evidence for this comparison.[34]

• Invasive Breast Cancer: The primary endpoint of the STAR trial was the incidence of invasive breast cancer. The results showed that tamoxifen was statistically more effective. Over a median follow-up of nearly 7 years, Raloxifene was found to be approximately 76% as effective as tamoxifen in reducing the risk of invasive breast cancer.[34] While both drugs were significantly better than placebo, tamoxifen retained an efficacy advantage.
• Non-invasive Breast Cancer: A similar pattern was observed for non-invasive breast cancers, such as ductal carcinoma in situ (DCIS) and lobular carcinoma in situ (LCIS). Tamoxifen reduced the risk by approximately 50%, whereas Raloxifene was about 78% as effective as tamoxifen in this regard.[34]

7.2 Comparative Safety and Tolerability Profiles

While tamoxifen holds an edge in efficacy, Raloxifene demonstrates a more favorable safety profile in several critical areas.

• Uterine Health: This is the most significant point of differentiation. Tamoxifen's partial agonist effect on the endometrium leads to a two- to threefold increased risk of endometrial hyperplasia and uterine cancer.[35] In stark contrast, Raloxifene acts as a uterine antagonist and does not increase this risk.[3] The STAR trial confirmed this, reporting significantly fewer cases of uterine cancer and hyperplasia in the Raloxifene group compared to the tamoxifen group.[34]
• Thromboembolic Events: Both drugs carry a risk of VTE, which is a class effect for SERMs. However, the risk is demonstrably lower with Raloxifene. The STAR trial reported that women taking Raloxifene had 28% fewer DVTs and 20% fewer pulmonary embolisms than those taking tamoxifen.[34]
• Cataracts: The development of cataracts is a known side effect of tamoxifen. The STAR trial found that the risk of requiring cataract surgery was approximately 20% lower in the Raloxifene group.[34]
• Bone Health: Raloxifene is FDA-approved for the treatment and prevention of osteoporosis and has proven efficacy in reducing vertebral fractures.[35] While tamoxifen also preserves BMD in postmenopausal women, it is not approved for this indication, and its uterine risks make it an undesirable choice for bone health alone.[30]
• Common Side Effects: While both drugs can cause vasomotor symptoms like hot flashes, their profiles of other common side effects differ. Tamoxifen is more frequently associated with vaginal discharge, whereas Raloxifene is more commonly linked to leg cramps and arthralgia.[35]

7.3 Table 4: Head-to-Head Comparison of Raloxifene and Tamoxifen

This table distills the complex trade-offs between the two leading SERMs, providing a clear, comparative framework for clinical decision-making.

Feature	Raloxifene	Tamoxifen	Source(s)
Patient Population	Postmenopausal women only	Premenopausal and Postmenopausal women	35
BC Risk Reduction Efficacy	~76% as effective as Tamoxifen	The benchmark for SERM chemoprevention (~50% risk reduction vs. placebo)	34
Effect on Uterus	Antagonist	Agonist	3
Endometrial Cancer Risk	No increased risk; potentially protective	Increased risk (2-3 fold)	3
VTE Risk (DVT/PE)	Increased risk, but lower than Tamoxifen	Increased risk, higher than Raloxifene	34
Cataract Risk	Lower risk than Tamoxifen	Higher risk than Raloxifene	34
Bone Health	Approved for osteoporosis treatment/prevention	Preserves BMD but not approved for this use	30
Common Side Effects	Leg cramps, joint pain	Vaginal discharge	35

The choice between Raloxifene and tamoxifen is a classic exercise in clinical risk-benefit analysis, pivoting on the trade-off between absolute breast cancer prevention efficacy and uterine safety. Tamoxifen is statistically superior at preventing breast cancer, but Raloxifene is statistically superior in its safety profile concerning the uterus, VTE, and cataracts. Therefore, the decision cannot be based on a single metric. For a postmenopausal woman with an intact uterus, the significantly safer uterine profile of Raloxifene often makes it the preferred agent for chemoprevention, despite its slightly lower efficacy. Conversely, for a woman who has had a hysterectomy (and thus has no endometrial cancer risk), the superior efficacy of tamoxifen might make it the more logical choice, assuming her VTE and cataract risks are acceptable. This nuanced, individualized decision-making process is the essence of modern personalized medicine in this therapeutic area.

8.0 Emerging Research and Future Directions

8.1 Investigational Uses and Drug Repurposing

The unique and complex mechanism of action of Raloxifene has spurred significant interest in its potential application beyond its approved indications, a process known as drug repurposing.[22] This research explores whether its estrogen receptor-modulating effects can be leveraged in other disease states.

• Schizophrenia: A particularly intriguing area of investigation is the use of Raloxifene as an adjunctive therapy for postmenopausal women with schizophrenia. Several studies and ongoing trials are exploring this possibility, with some preliminary reports suggesting promising results in improving negative symptoms and cognitive function, which are notoriously difficult to treat with standard antipsychotics.[23] This line of inquiry suggests that estrogen receptor modulation may play a significant role in neurobiology and psychiatric disorders.
• Antiviral Activity: Preclinical, in vitro research has indicated that Raloxifene may possess efficacy against a range of RNA viruses, including Ebola virus, Influenza A virus, and Hepatitis C virus.[22] This unexpected finding has led to its investigation as a potential therapeutic for viral illnesses. For instance, clinical trials have been initiated to evaluate its efficacy in treating mild-to-moderate COVID-19 and to assess its impact on the immune response to SARS-CoV-2 vaccination.[52]
• Other Investigational Areas: The scope of research extends further. Clinical trials have also explored Raloxifene's potential role in managing acromegaly, treating perimenopausal depression, and its use in combination with structured exercise programs to improve bone health and quality of life in breast cancer survivors.[52]

The exploration of Raloxifene for central nervous system (CNS) disorders like schizophrenia and depression is particularly noteworthy. It implies that estrogen receptors are not only present but also functionally important in the brain regions that regulate mood, cognition, and psychosis. The fact that a selective modulator is being tested, rather than simple estrogen replacement, suggests that a nuanced approach—harnessing some estrogenic effects while avoiding others—may offer a therapeutic window. This opens a potential new frontier for SERM research, moving beyond traditional women's health indications and into the realm of neuropsychiatry, where it could address sex-specific or hormonal components of various CNS conditions.

8.2 Long-Term Safety Data and Post-Marketing Surveillance

The long-term safety and efficacy of Raloxifene are well-documented, thanks to several large-scale, multi-year clinical trials. The combined data from the MORE and CORE trials provide a robust dataset covering up to 8 years of continuous use, which is among the longest and most comprehensive for any SERM.[33] Similarly, long-term follow-up from the

STAR trial has continued to refine the comparative risk-benefit profiles of both Raloxifene and tamoxifen, strengthening the evidence base for their use in chemoprevention.[55]

Despite this wealth of positive data, a significant challenge remains: the clinical uptake of SERMs for breast cancer chemoprevention is persistently low.[49] This "prevention gap" suggests that significant barriers exist among both physicians and patients. These barriers are often related to a lack of awareness of the potential benefits, an overestimation of the risks, or concerns about managing side effects like hot flashes.[29]

8.3 The Future of SERMs in Clinical Practice

The development of Raloxifene was a pivotal step in endocrine therapy, paving the way for newer, potentially more refined agents. This includes third-generation SERMs like bazedoxifene and lasofoxifene, as well as the novel class of tissue-selective estrogen complexes (TSECs), which combine a SERM with an estrogen.[2]

Future research is likely to focus on several key areas. One is the development of molecules with even greater tissue selectivity, aiming to maximize the benefits on bone and cardiovascular markers while further minimizing risks like VTE. This could potentially be achieved by designing drugs that more specifically target the interactions with tissue-specific co-regulator proteins or that selectively modulate downstream signaling pathways, such as the OPG/RANK/RANKL system in bone, which is known to be influenced by Raloxifene.[6] The ongoing exploration of Raloxifene for repurposed uses in CNS and infectious diseases suggests that the full therapeutic potential of modulating the estrogen receptor system is still being uncovered and will likely be a fertile ground for discovery for years to come.

9.0 Synthesis and Concluding Recommendations

9.1 Integrated Risk-Benefit Analysis

Raloxifene is a medication defined by its nuanced and highly specific risk-benefit profile. Its primary clinical value stems from its unique ability to offer two distinct benefits simultaneously: the prevention of osteoporotic vertebral fractures and the reduction of invasive, estrogen receptor-positive breast cancer risk in postmenopausal women. This dual action makes it an attractive option for a specific patient demographic.

However, these benefits must be carefully weighed against its significant and mechanistically-linked risks. The FDA Black Box Warning for an increased incidence of venous thromboembolism and fatal stroke in women with or at high risk for cardiovascular disease is the most critical consideration. The decision to initiate Raloxifene therapy, therefore, cannot be generalized. It requires a highly individualized assessment that integrates the patient's menopausal status, bone mineral density, calculated breast cancer risk (e.g., via the Gail model), uterine status (i.e., intact uterus or post-hysterectomy), and a thorough evaluation of her personal and family history of cardiovascular and thromboembolic disease.

9.2 Summary of Raloxifene's Role in Modern Therapeutics

In the landscape of modern therapeutics, Raloxifene occupies a valuable but distinct niche. It is not the universal first-line treatment for uncomplicated postmenopausal osteoporosis; agents like bisphosphonates are often preferred due to their proven efficacy in reducing the risk of hip fractures, a key clinical outcome that Raloxifene has not demonstrated. Similarly, for pure breast cancer chemoprevention, it is not the most potent agent available; tamoxifen offers greater risk reduction.

Raloxifene's primary and enduring value lies at the intersection of these two major fields of postmenopausal health. For the specific patient who presents with both significant osteoporotic risk and a high risk of developing ER-positive breast cancer, Raloxifene offers an elegant and compelling therapeutic solution. It allows a clinician to address both major health concerns with a single, once-daily oral agent that also carries the significant advantage of a favorable uterine safety profile compared to its main SERM competitor. While ongoing research into its potential repurposed uses in CNS and infectious diseases is promising and may one day expand its clinical utility, its current role is that of a specialized tool, expertly applied to the right patient for whom the unique combination of benefits clearly outweighs the known risks.

Works cited

1. Raloxifene | C28H27NO4S | CID 5035 - PubChem, accessed August 7, 2025, https://pubchem.ncbi.nlm.nih.gov/compound/Raloxifene
2. Raloxifene | 84449-90-1 - ChemicalBook, accessed August 7, 2025, https://www.chemicalbook.com/ChemicalProductProperty_EN_CB1290431.htm
3. Raloxifene - Wikipedia, accessed August 7, 2025, https://en.wikipedia.org/wiki/Raloxifene
4. Raloxifene: A Selective Estrogen Receptor Modulator - AAFP, accessed August 7, 2025, https://www.aafp.org/pubs/afp/issues/1999/0915/p1131.html
5. Raloxifene: Uses, Interactions, Mechanism of Action | DrugBank ..., accessed August 7, 2025, https://go.drugbank.com/drugs/DB00481
6. Raloxifene: Mechanism of Action, Effects on Bone Tissue, and Applicability in Clinical Traumatology Practice - PMC, accessed August 7, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC2687107/
7. Raloxifene (Evista®) - Bone Health & Osteoporosis Foundation, accessed August 7, 2025, https://www.bonehealthandosteoporosis.org/patients/treatment/medicationadherence/raloxifene-evista/
8. Raloxifene | Cancer information, accessed August 7, 2025, https://www.cancerresearchuk.org/about-cancer/treatment/drugs/raloxifene
9. Evista Labeling - accessdata.fda.gov, accessed August 7, 2025, https://www.accessdata.fda.gov/drugsatfda_docs/label/2007/022042lbl.pdf
10. The Discovery and Development of Selective Estrogen Receptor ..., accessed August 7, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC3624793/
11. raloxifene | Ligand page - IUPHAR/BPS Guide to PHARMACOLOGY, accessed August 7, 2025, https://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2820
12. Recommendations for raloxifene use in daily clinical practice in the Swiss setting - PMC, accessed August 7, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC3508239/
13. center for drug evaluation and - accessdata.fda.gov, accessed August 7, 2025, https://www.accessdata.fda.gov/drugsatfda_docs/nda/2007/022042s000_MedR_P1.pdf
14. Annotation of FDA Label for raloxifene and ESR1, ESR2 - PharmGKB, accessed August 7, 2025, https://www.pharmgkb.org/labelAnnotation/PA166185194
15. Raloxifene Hydrochloride - NCI, accessed August 7, 2025, https://www.cancer.gov/about-cancer/treatment/drugs/raloxifenehydrochloride
16. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda, accessed August 7, 2025, https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/020815s034lbl.pdf
17. RALOXIFENE - gsrs, accessed August 7, 2025, https://gsrs.ncats.nih.gov/ginas/app/beta/substances/YX9162EO3I
18. Raloxifene Hydrochloride | C28H28ClNO4S | CID 54900 - PubChem, accessed August 7, 2025, https://pubchem.ncbi.nlm.nih.gov/compound/54900
19. Raloxifene (Evista®) | OncoLink, accessed August 7, 2025, https://www.oncolink.org/cancer-treatment/oncolink-rx/raloxifene-evista-r
20. Raloxifene Uses, Side Effects & Warnings - Drugs.com, accessed August 7, 2025, https://www.drugs.com/mtm/raloxifene.html
21. What is the mechanism of Raloxifene Hydrochloride? - Patsnap Synapse, accessed August 7, 2025, https://synapse.patsnap.com/article/what-is-the-mechanism-of-raloxifene-hydrochloride
22. Raloxifene's mechanism of action. | Download Scientific Diagram - ResearchGate, accessed August 7, 2025, https://www.researchgate.net/figure/Raloxifenes-mechanism-of-action_fig2_26283059
23. Raloxifene - StatPearls - NCBI Bookshelf, accessed August 7, 2025, https://www.ncbi.nlm.nih.gov/books/NBK544233/
24. Long-term safety and efficacy of raloxifene in the prevention and treatment of postmenopausal osteoporosis: an update - PMC, accessed August 7, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC2971719/
25. Raloxifene (oral route) - Side effects & dosage - Mayo Clinic, accessed August 7, 2025, https://www.mayoclinic.org/drugs-supplements/raloxifene-oral-route/description/drg-20065760
26. Study Details | Raloxifene on Coagulation System in the Postmenopausal Women, accessed August 7, 2025, https://www.clinicaltrials.gov/study/NCT04454775
27. medlineplus.gov, accessed August 7, 2025, https://medlineplus.gov/druginfo/meds/a698007.html#:~:text=Raloxifene%20is%20in%20a%20class,density%20(thickness)%20of%20bone.
28. Raloxifene: A review of its use in postmenopausal osteoporosis - ResearchGate, accessed August 7, 2025, https://www.researchgate.net/publication/12338034_Raloxifene_A_review_of_its_use_in_postmenopausal_osteoporosis
29. Continued breast cancer risk reduction in postmenopausal women treated with raloxifene: 4-year results from the MORE trial. Multiple outcomes of raloxifene evaluation | Request PDF - ResearchGate, accessed August 7, 2025, https://www.researchgate.net/publication/12070676_Continued_breast_cancer_risk_reduction_in_postmenopausal_women_treated_with_raloxifene_4-year_results_from_the_MORE_trial_Multiple_outcomes_of_raloxifene_evaluation
30. SERMs for Osteoporosis: Raloxifene (Evista) - WebMD, accessed August 7, 2025, https://www.webmd.com/osteoporosis/serms
31. Raloxifene Completed Phase 4 Trials for Postmenopausal Osteoporosis Treatment | DrugBank Online, accessed August 7, 2025, https://go.drugbank.com/drugs/DB00481/clinical_trials?conditions=DBCOND0030339&phase=4&purpose=treatment&status=completed
32. Study Details | Sequential Use of Teriparatide and Raloxifene HCl in the Treatment of Postmenopausal Women With Osteoporosis | ClinicalTrials.gov, accessed August 7, 2025, https://clinicaltrials.gov/study/NCT00035256
33. Continuing Outcomes Relevant to Evista: Breast Cancer Incidence in Postmenopausal Osteoporotic Women in a Randomized Trial of Raloxifene | JNCI - Oxford Academic, accessed August 7, 2025, https://academic.oup.com/jnci/article/96/23/1751/2521073
34. The Study of Tamoxifen and Raloxifene (STAR): Questions and Answers - NCI, accessed August 7, 2025, https://www.cancer.gov/types/breast/research/star-trial-results-qa
35. Raloxifene vs. Tamoxifen: 6 Similarities and Differences - GoodRx, accessed August 7, 2025, https://www.goodrx.com/classes/estrogen-agonist-antagonists/raloxifene-vs-tamoxifen
36. Raloxifene | Saint Luke's Health System, accessed August 7, 2025, https://www.saintlukeskc.org/health-library/raloxifene
37. Label: RALOXIFENE HYDROCHLORIDE tablet, film coated - DailyMed, accessed August 7, 2025, https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=c9b60ef1-c88b-4363-9a28-5854b7ff8a50
38. Raloxifene: Side Effects, Uses, Dosage, Interactions, Warnings - RxList, accessed August 7, 2025, https://www.rxlist.com/raloxifene/generic-drug.htm
39. Raloxifene (Evista): Uses & Side Effects - Cleveland Clinic, accessed August 7, 2025, https://my.clevelandclinic.org/health/drugs/20931-raloxifene-tablets
40. Impact of Raloxifene or Tamoxifen Use on Endometrial Cancer Risk: A Population-Based Case-Control Study, accessed August 7, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC2654370/
41. Evista Interactions Checker - Drugs.com, accessed August 7, 2025, https://www.drugs.com/drug-interactions/raloxifene,evista.html
42. Raloxifene (Evista): Uses, Side Effects, Interactions, Pictures, Warnings & Dosing - WebMD, accessed August 7, 2025, https://www.webmd.com/drugs/2/drug-5191/raloxifene-oral/details
43. Raloxifene (Evista): Uses, Side Effects, Alternatives & More - GoodRx, accessed August 7, 2025, https://www.goodrx.com/raloxifene/what-is
44. Showing BioInteractions for Raloxifene (DB00481) | DrugBank Online, accessed August 7, 2025, https://go.drugbank.com/drugs/DB00481/biointeractions
45. Raloxifene Interactions Checker - Drugs.com, accessed August 7, 2025, https://www.drugs.com/drug-interactions/raloxifene.html
46. Tamoxifen vs Raloxifene vs Exemestane for Chemoprevention - PMC, accessed August 7, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC3744245/
47. Study of Tamoxifen and Raloxifene (STAR) for the Prevention of Breast Cancer in Postmenopausal Women | ClinicalTrials.gov, accessed August 7, 2025, https://clinicaltrials.gov/study/NCT00003906
48. Raloxifene and tamoxifen had similar efficacy for preventing invasive breast cancer in women at increased risk - ACP Journals, accessed August 7, 2025, https://www.acpjournals.org/doi/10.7326/ACPJC-2006-145-3-072
49. Use of Tamoxifen and Raloxifene for Breast Cancer Chemoprevention in 2010 - PMC, accessed August 7, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC3771085/
50. Research table: Tamoxifen and raloxifene to reduce breast cancer risk - Susan G. Komen, accessed August 7, 2025, https://www.komen.org/breast-cancer/facts-statistics/research-studies/topics/use-of-tamoxifen-and-raloxifene-to-reduce-the-risk-of-breast-cancer/
51. Drug Repurposing for Atopic Dermatitis by Integration of Gene Networking and Genomic Information - PMC, accessed August 7, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC8548825/
52. Search for Raloxifene - Clinical Trials register, accessed August 7, 2025, https://www.clinicaltrialsregister.eu/ctr-search/search?query=Raloxifene
53. Raloxifene and Rimostil for Perimenopause-Related Depression - ClinicalTrials.gov, accessed August 7, 2025, https://clinicaltrials.gov/study/NCT00030147
54. Raloxifene With or Without Exercise Compared With Exercise Alone in Women Who Have Been Previously Treated for Breast Cancer | ClinicalTrials.gov, accessed August 7, 2025, https://clinicaltrials.gov/study/NCT00031811
55. Regulatory Approval of Cancer Risk-reducing (Chemopreventive) Drugs: Moving What We Have Learned into the Clinic - PubMed Central, accessed August 7, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC3059243/