What is the mechanism of action and proper use of Fosamax (alendronate)?

Fosamax (Alendronate): Mechanism of Action and Proper Use

Fosamax (alendronate) is a potent bisphosphonate that binds to bone hydroxyapatite and specifically inhibits osteoclast-mediated bone resorption, and must be taken on an empty stomach with a full glass of water while remaining upright for at least 30 minutes to avoid esophageal irritation. 1

Mechanism of Action

Alendronate works by preferentially localizing to sites of active bone resorption, specifically under osteoclasts, where it inhibits their bone-resorbing activity without interfering with osteoclast recruitment or attachment. 1 The drug binds to bone surfaces for prolonged periods and is incorporated into the bone matrix, where it remains pharmacologically inactive until released during bone remodeling. 2

Cellular Effects

• Alendronate prevents osteoclasts from forming the ruffled border that is characteristic of active bone resorption, thereby reducing bone turnover without directly affecting bone formation. 1
• The drug shows approximately 10-fold higher uptake on osteoclast surfaces compared to osteoblast surfaces. 1
• Because bone resorption and formation are coupled processes, reducing resorption ultimately leads to reduced formation, but bone formation exceeds resorption at remodeling sites, resulting in progressive gains in bone mass. 1

Biochemical Effects

• Alendronate reduces urinary markers of bone resorption (deoxypyridinoline and N-telopeptides) by approximately 50-70% within one month, reaching levels similar to healthy premenopausal women. 1
• Markers of bone formation (osteocalcin, bone-specific alkaline phosphatase) decrease by approximately 40-50% after 6-12 months of treatment. 1

Proper Administration

Critical Dosing Instructions

To minimize the risk of esophageal irritation, alendronate must be taken with very specific precautions: 2

• Take on an empty stomach with a full glass (6-8 oz) of plain water only—no other beverages, food, or medications. 2
• Remain upright (sitting or standing) for at least 30 minutes after taking the medication. 2
• Do not eat or drink anything for at least 30 minutes after administration. 2
• Swallow the tablet whole—do not chew, crush, or suck on it. 2

Dosing Regimens

Standard dosing options include: 2, 3

• 10 mg once daily 2
• 70 mg once weekly (therapeutically equivalent to daily dosing) 2, 3
• 5 mg daily or 35 mg weekly for prevention 2

The once-weekly 70 mg formulation provides continuous inhibition of bone resorption because osteoclast-mediated bone resorption is a slow process requiring 2-3 weeks for completion, and alendronate remains at active remodeling sites for sustained periods. 3

Clinical Efficacy

Alendronate produces sustained increases in bone mineral density (BMD) at all skeletal sites including spine, femoral neck, and trochanter, with progressive increases of approximately 2.5% in total body BMD. 2, 4

Most importantly, alendronate reduces fracture risk: 2

• 48% reduction in vertebral fractures 2
• 47-56% reduction in radiographic vertebral fractures in postmenopausal women with existing fractures 4
• Reduction in hip fractures in high-risk populations 4

Pharmacokinetics

Alendronate has extremely poor oral bioavailability of less than 2%, with systemically available drug either taken up by bone or excreted renally. 5

• Renal excretion is the only route of elimination, with 30-50% recovered in urine within 24 hours. 5
• Drug not excreted within 24 hours is sequestered in the skeleton, from which it is slowly released over approximately 12 years in humans. 5
• Food, beverages (including orange juice and coffee), and calcium significantly reduce absorption, which is why fasting administration is mandatory. 2

Important Safety Considerations

Esophageal Precautions

The most critical safety concern is esophageal irritation, which can lead to esophagitis or esophageal ulceration if dosing instructions are not followed precisely. 2 This risk is minimized by strict adherence to the upright positioning and fasting requirements described above.

Contraindications

Alendronate is contraindicated in patients with: 2

• Abnormalities of the esophagus that delay esophageal emptying
• Inability to stand or sit upright for at least 30 minutes
• Hypocalcemia (must be corrected before starting therapy)

Pre-Treatment Requirements

Vitamin D deficiency must be corrected prior to initiating bisphosphonate therapy, particularly intravenous formulations, to prevent bisphosphonate-related hypocalcemia and ensure optimal efficacy. 2 The goal is to achieve 25(OH)D levels >32 ng/mL. 2

Patients requiring dental work should complete procedures and allow adequate healing time before starting bisphosphonates, as osteonecrosis of the jaw (though very rare at <1 case per 100,000 person-years) is most consistently associated with recent dental surgery. 2

Duration of Therapy

Given the prolonged skeletal retention of bisphosphonates and concerns about long-term suppression of bone turnover, some experts recommend discontinuation after 5 years with careful observation, though 10-year data with alendronate showed continued BMD increases without increased fracture risk. 2