BONMAX TABLETS

Indications

• Prevention of osteoporosis in postmenopausal women
• Treatment of osteoporosis in postmenopausal women
• Reduction of risk of invasive breast cancer in postmenopausal women with osteoporosis

Dosage

Children: Raloxifene is

Adults: The usual adult dose for the treatment and prevention of osteoporosis is 60 mg once daily.

Mechanism of action

Raloxifene acts as both an estrogen agonist and antagonist through its selective binding to estrogen receptors (ERα and ERβ). Upon binding, it induces a conformational change in the receptor, leading to dissociation from Heat Shock Protein 90 (Hsp90), dimerization, and subsequent translocation to the nucleus. Here, it binds to estrogen response elements (EREs) in the DNA, modulating gene expression. In bone, it stimulates osteoblast activity and inhibits osteoclast activity, thereby enhancing bone mineral density and reducing bone resorption.

Pharmacodynamics

Raloxifene exhibits estrogenic effects on bone and lipid metabolism, while exerting anti-estrogenic effects on the endometrium and breast tissue. It has been shown to increase bone mineral density in postmenopausal women and reduce the incidence of vertebral fractures, demonstrating its efficacy in osteoporosis management. Clinical trials have indicated significant increases in bone mineral density at various skeletal sites in women treated with raloxifene compared to placebo.

Pharmacokinetics

Raloxifene is well absorbed after oral administration, with a bioavailability of approximately 60%. It is extensively bound to plasma proteins, primarily albumin. The drug undergoes hepatic metabolism via cytochrome P450 enzymes, mainly CYP3A4, leading to multiple metabolites. The elimination half-life is about 27 hours, and it is primarily excreted in feces. Renal clearance is minimal, as less than 6% is excreted unchanged in urine.

Contra-indications

• Pregnancy
• Active or past venous thromboembolism
• Hypersensitivity to raloxifene or any of its components

Adverse effects

• Hot flashes
• Leg cramps
• Lipid changes
• Increased risk of venous thromboembolism
• Nausea
• Headache
• Fatigue
• Skin rash

Interactions

• Cholestyramine (may reduce the absorption of raloxifene)
• Warfarin (may increase anticoagulant effect; monitor INR)
• Estrogen-containing medications (may diminish the effect of raloxifene)

Precautions

• Monitor for signs of thromboembolism
• Evaluate liver function before initiation
• Use with caution in patients with a history of hyperlipidemia

Pregnancy

Raloxifene is contraindicated in pregnancy due to potential harm to the fetus.

Breast-feeding

The safety of raloxifene during breastfeeding has not been established; caution is advised.

Storage

Store in a cool, dry place, away from direct light. Keep out of reach of children.

Formulations

• Tablets: 60 mg

Indications

• Prevention and treatment of osteoporosis in postmenopausal women
• Reduction in the risk of invasive breast cancer in postmenopausal women with osteoporosis or at high risk for breast cancer

Dosage

Adults: For the treatment of osteoporosis, the recommended dosage of raloxifene is 60 mg once daily, with or without food. For breast cancer risk reduction, the same dosage applies. It is important to assess individual patient needs and consider potential contraindications or drug interactions.

Mechanism of action

Raloxifene exerts its effects by binding to estrogen receptors, which leads to a modulation of estrogenic activity in various tissues. In bone tissue, it activates estrogen receptors to inhibit bone resorption and turnover, ultimately increasing bone mineral density. In breast tissue, it acts as an antagonist, which helps to reduce the risk of estrogen-dependent cancers.

Pharmacodynamics

Raloxifene demonstrates a favorable pharmacodynamic profile by selectively activating estrogen receptors in bone and acting as an antagonist in breast and uterine tissues. This selective action helps to maintain bone density and reduce fracture risk while minimizing the risk of endometrial hyperplasia and breast cancer, which are commonly associated with estrogen therapy. Its effects on bone metabolism are evidenced by increased bone mineral density and reduced biochemical markers of bone turnover.

Pharmacokinetics

Raloxifene is well-absorbed following oral administration, with peak plasma concentrations occurring approximately 6 hours post-dose. It has a high bioavailability due to extensive enterohepatic recirculation. The drug is highly protein-bound (approximately 95%) and is metabolized primarily in the liver via glucuronidation. The elimination half-life is about 27 hours, allowing for once-daily dosing. Renal excretion is minimal, and the drug does not require dosage adjustment in patients with renal impairment.

Contra-indications

• Hypersensitivity to raloxifene or any excipients
• Current or history of venous thromboembolism (VTE)
• Pregnancy
• Lactation

Adverse effects

• Hot flashes
• Leg cramps
• Peripheral edema
• Increased risk of thromboembolic events
• Nausea
• Fatigue
• Headache
• Mood changes

Interactions

• Estrogen-containing therapies (increased risk of VTE)
• Warfarin (may affect INR levels)
• Bile acid sequestrants (decreased absorption of raloxifene)
• Tamoxifen (may reduce efficacy of raloxifene)

Precautions

• Monitor for signs of VTE
• Use with caution in patients with a history of liver disease
• Consider alternative therapies in patients with a history of breast cancer
• Assess risk factors for stroke

Pregnancy

Raloxifene is contraindicated in pregnancy due to potential risks to the fetus.

Breast-feeding

Raloxifene is not recommended during breastfeeding; effects on breastfed infants are unknown.

Storage

Store at room temperature, away from moisture and heat. Keep out of reach of children.

Formulations

• Tablets: 60 mg

Mechanism of action

Raloxifene is a selective estrogen receptor modulator that acts as both an estrogen agonist and antagonist via differential effects on the tissue-specific estrogen receptors. Based on the findings of competitive binding assays, raloxifene displays binding affinity that is similar to that of [estradiol], the predominant circulating estrogen. Estrogens play variable roles at different tissues in females, including the bone, breasts, uterus and liver, by binding to the steroid nuclear hormone receptors, Estrogen Receptor alpha (ERα) or Estrogen Receptor beta (ERβ). These receptors are normally bound to the Heat Shock Protein 90 (Hsp90) when unbound to the ligand. Ligand binding induces a conformational change in the receptor that promotes dissociation of the receptor from Hsp90, dimerization and translocation into the nucleus. This movement into the nucleus allows the receptor to bind to genomic locations based on sequence recognition of the DNA binding domain, also known as the Estrogen Response Elements (EREs). In bones, endogenous estrogens normally modulate multiple DNA response elements, including the gene-encoding transforming growth factor-β3 (TGF-β3), which is a cytokine embedded in the bone matrix. TGF-β3 plays an important role in bone remodelling by working with other cytokines to induce production of osteoblasts, such as IL-6, and attenuate the activity of osetoclasts. Estrogens typically maintain the bone integrity by inhibiting the cytokines that recruit osteoclasts and oppose the bone-resorbing, Ca2+-mobilizing action of parathyroid hormone. In contrast, estrogens promote osteoblast proliferation, augment the production of TGF-β3 and bone morphogenic proteins, and inhibit apoptosis. Mimicking the action of endogenous estrogen in bone tissues, raloxifene binds to the estrogen receptor to influence gene transcription through interactions with the estrogen response element (ERE) and a distinct DNA target, the raloxifene response element (RRE). It occupies the same ER ligand binding site as estrogen. Upon binding, raloxifene induces a conformational change of the receptor, allowing mediation of direct binding to transcriptional elements by accessory proteins. Increased expression of bone matrix proteins, such as alkaline phosphatase, osteonectin, osteocalcin and collagen may be seen. The agonistic or antagonistic action of raloxifene depends on the extent of recruitment of coactivators and corepressors to estrogen receptor (ER) target gene promotors. In breast tissues, raloxifene acts as an estrogen receptor antagonist to attenuate the estrogen-dependent proliferative effects of epithelial cell expansion. In addition to the antiproliferative effects, raloxifene prevents the production of cytokines and recruitment of macrophages and lymphocytes into tumor mass. Bone remodeling is controlled by the actions of bone-degrading osteoclasts and bone-forming osteoblasts (OBs). Aging and loss of estrogen after menopause affects bone mass and quality. Estrogen therapy, including selective estrogen receptor modulators (SERMs), can prevent bone loss and increase bone mineral density in post-menopausal women. Although investigations of the effects of estrogen on osteoclast activity are well advanced, the mechanism of action of estrogen on OBs is still unclear. The proline-rich tyrosine kinase 2 (Pyk2) is important for bone formation and female mice lacking Pyk2 (Pyk2-KO) exhibit elevated bone mass, increased bone formation rate and reduced osteoclast activity. Therefore, in the current study, we examined the role of estrogen signaling on the mechanism of action of Pyk2 in OBs. As expected, Pyk2-KO OBs showed significantly higher proliferation, matrix formation, and mineralization than WT OBs. In addition we found that Pyk2-KO OBs cultured in the presence of either 17beta-estradiol (E2) or raloxifene, a SERM used for the treatment of post-menopausal osteoporosis, showed a further robust increase in alkaline phosphatase (ALP) activ

Pharmacodynamics

Raloxifene belongs to the selective estrogen receptor modulator (SERM) drug class that exhibits estrogenic effects on bone and lipid metabolism while mediating anti-estrogenic effects on uterine endometrium and breast tissues. On skeletal tissues, raloxifene stimulates bone-depositing osteoblasts and inhibits bone-resorbing osteoclasts to augument bone mineral density. Raloxifene produces estrogen-like effects on bone, reducing the resorption of bone and increasing bone mineral density in postmenopausal women, thus slowing the rate of bone loss. In three randomized, placebo-controlled trials in Europe, postmenopausal women receiving raloxifene at variable doses of 30 to 150 mg daily demonstrated significant increases in bone mineral density in the lumbar spine, total hip, femoral neck and total body compared to placebo. In the MORE and RUTH trials, there were fewer incidences of vertebral fractures in postmeopausal women receiving raloxifene compared to placebo. In a eight-week study evaluating short-term effects of raloxifene in healthy postmenopausal women, there was a decrease in the bone turnover markers, such as serum alkaline phosphatase level, serum osteocalcin level and urinary calcium excretion. Raloxifene was shown to inhibit estrogen-dependent proliferation of human breast cancer cells _in vitro_ and development of induced mammary tumors in rats _in vivo_. In adult female rats, raloxifene produced a greater regression of the mammary gland than [tamoxifen]. The MORE trial was a multicenter, randomized, double-blind clinical trial that investigated the long-term effects of the drug therapy in European and American postmenopausal women receiving raloxifene for 40 months. Additionally, a reduction in the incidence of invasive breast cancer was also demonstrates in the CORE and RUTH trials. Study findings demonstrated that compared to placebo, the risk of invasive breast cancer was decreased by 76% among postmenopausal women with osteoporosis. There was a decrease in the risk of estrogen receptor-positive breast cancer by 90% but there was no increase in the risk of endometrial cancer. Unlike hormone replacement therapy, raloxifene does not mediate proliferative or stimulatory effects on endometrial tissue. Findings from both animal and human studies demonstrated no significant changes in the histologic appearance of the endometrium. Raloxifene promotes estrogen-like effects on lipid metabolism. In a European trial that evaluated lipid profiles following raloxifene therapy over the 24-month period, there were significant decreases in the serum concentrations of total and low-density lipoprotein (LDL) cholesterol over a 24-month period of raloxifene therapy. Raloxifene is not associated with causing alterations in the serum levels of HDL cholesterol or triglycerides. As the HDL choesterol level is considered a strong inverse predictor of cardiovascular disease in women, the cardioprotective effects of raloxifene were questioned. Due to limited data on the long-term trials, it is not possible to determine whether the small lipid effects produced by raloxifene correlate with a smaller degree of cardioprotective activity compared with hormone replacement therapy.