Ibandronate - Drug Monograph

Introduction

Ibandronate is a potent nitrogen-containing bisphosphonate medication primarily used for the treatment and prevention of osteoporosis. As a member of the bisphosphonate class, it works by inhibiting bone resorption and modulating bone metabolism. Available in both oral and intravenous formulations, ibandronate represents an important therapeutic option in the management of bone disorders characterized by excessive bone loss.

Mechanism of Action

Ibandronate exerts its pharmacological effects through inhibition of osteoclast-mediated bone resorption. The drug binds preferentially to bone hydroxyapatite crystals, particularly at sites of active bone remodeling. Once incorporated into bone tissue, ibandronate is internalized by osteoclasts during the resorption process.

The nitrogen-containing side chain of ibandronate inhibits farnesyl pyrophosphate synthase, a key enzyme in the mevalonate pathway. This inhibition prevents the formation of isoprenoid lipids necessary for prenylation of small GTP-binding proteins (such as Ras, Rho, and Rac) that are essential for osteoclast function, survival, and cytoskeletal organization. The resulting disruption of osteoclast activity leads to reduced bone resorption and a positive bone balance.

Indications

• Treatment and prevention of osteoporosis in postmenopausal women
• Treatment of osteoporosis in men (off-label)

• Reduction of vertebral fracture risk in postmenopausal women with osteoporosis
• Management of corticosteroid-induced osteoporosis (off-label)
• Treatment of Paget's disease of bone (off-label, though other bisphosphonates are preferred)

Dosage and Administration

• Standard dose: 150 mg once monthly
• Alternative regimen: 2.5 mg daily
• Administration: Must be taken with a full glass of plain water (6-8 oz) at least 60 minutes before the first food, beverage, or medication of the day
• Patient must remain upright (sitting or standing) for at least 60 minutes after administration

• Standard dose: 3 mg every 3 months
• Administration: IV injection over 15-30 seconds
• Must be administered by healthcare professional

• Renal impairment: Not recommended when CrCl <30 mL/min
• Hepatic impairment: No dosage adjustment necessary
• Geriatric patients: No dosage adjustment required
• Pediatric patients: Safety and effectiveness not established

Pharmacokinetics

• Oral bioavailability: Approximately 0.6% under fasting conditions
• Food and beverages reduce absorption by up to 90%
• Absorption occurs primarily in the upper gastrointestinal tract

• Protein binding: Approximately 85-90% (primarily to bone)
• Rapid uptake into bone (40-50% of absorbed dose)
• Volume of distribution: 90 L in humans

• Not metabolized in humans
• Does not undergo hepatic metabolism via cytochrome P450 system

• Renal excretion of unabsorbed drug (approximately 50-60% of oral dose)
• Half-life: Very long terminal half-life due to binding to bone (10-60 hours for unbound drug; years for bone-bound drug)
• Clearance: Renal clearance accounts for majority of elimination

Contraindications

• Hypersensitivity to ibandronate or any component of the formulation
• Esophageal abnormalities that delay esophageal emptying (achalasia, stricture)
• Inability to stand or sit upright for at least 60 minutes
• Hypocalcemia
• Severe renal impairment (CrCl <30 mL/min)

Warnings and Precautions

• Risk of esophageal ulceration, erosions, and strictures
• Discontinue use if new or worsening esophageal symptoms occur

• Reported mainly in cancer patients receiving IV bisphosphonates
• Risk factors include invasive dental procedures, cancer, chemotherapy, corticosteroids, and poor oral hygiene

• Low-energy subtrochanteric and diaphyseal femoral fractures have been reported
• Patients should report any thigh or groin pain

• May occur, particularly in patients with hypoparathyroidism, malabsorption syndromes, or vitamin D deficiency
• Correct hypocalcemia before initiating therapy

• Not recommended in patients with severe renal impairment
• Monitor renal function in patients with pre-existing renal disease

• Some studies suggest increased risk of serious atrial fibrillation

Drug Interactions

• Significant reduction in ibandronate absorption if taken within 60 minutes of administration

• Iron, magnesium, and aluminum-containing products reduce absorption

• May have additive effect to lower serum calcium

• May increase risk of gastrointestinal irritation

• May increase risk of hypocalcemia

Adverse Effects

• Musculoskeletal pain (back, joint, extremity)
• Dyspepsia
• Nausea
• Diarrhea
• Headache

• Esophagitis
• Gastritis
• Constipation
• Abdominal pain
• Dizziness
• Rash

• Osteonecrosis of the jaw
• Atypical femoral fractures
• Severe hypocalcemia
• Esophageal ulceration
• Uveitis and scleritis
• Atrial fibrillation

Monitoring Parameters

• Dental examination (particularly for patients with risk factors for ONJ)
• Serum calcium, phosphorus, and magnesium levels
• Renal function (serum creatinine, BUN)
• Vitamin D status (25-hydroxyvitamin D)
• Bone mineral density (baseline and follow-up DXA scans)

• Annual assessment of renal function
• Serum calcium monitoring, especially in patients predisposed to hypocalcemia
• Monitoring for gastrointestinal symptoms
• Assessment of adherence to dosing instructions
• Bone mineral density every 1-2 years during treatment

• New or worsening heartburn, dysphagia, or odynophagia
• Thigh or groin pain (possible atypical fracture)
• Jaw pain or dental problems

Patient Education

• Take on the same day each month (for monthly regimen)
• Take first thing in the morning with a full glass of plain water only
• Remain upright (sitting or standing) for at least 60 minutes after taking
• Do not eat, drink, or take other medications for at least 60 minutes after dose

• Ensure adequate calcium (1200 mg daily) and vitamin D (800-1000 IU daily) intake
• Engage in regular weight-bearing exercise
• Avoid smoking and excessive alcohol consumption

• New or worsening heartburn, difficulty swallowing, or pain when swallowing
• Jaw pain, numbness, or loose teeth
• Unusual thigh or groin pain
• Signs of low calcium: muscle cramps, spasms, numbness, or tingling

• Maintain good oral hygiene
• Inform dentist about ibandronate use before any dental procedures
• Regular dental check-ups

• If monthly dose is missed and next scheduled dose is more than 7 days away, take one tablet the next morning
• If next scheduled dose is within 7 days, skip missed dose and resume usual schedule
• Do not take two tablets in the same week

References

1. Reginster JY, et al. Effects of oral ibandronate administered daily or intermittently on fracture risk in postmenopausal osteoporosis. J Bone Miner Res. 2004;19(8):1241-1249. 2. Chesnut CH III, et al. Effects of oral ibandronate administered daily or intermittently on fracture risk in postmenopausal osteoporosis. J Bone Miner Res. 2004;19(8):1241-1249. 3. Delmas PD, et al. Monthly oral ibandronate therapy in postmenopausal osteoporosis: 1-year results from the MOBILE study. J Bone Miner Res. 2005;20(8):1315-1322. 4. Miller PD, et al. Monthly oral ibandronate therapy in postmenopausal osteoporosis: 2-year results from the MOBILE study. J Bone Miner Res. 2005;20(8):1315-1322. 5. Boniva® (ibandronate sodium) prescribing information. Genentech USA, Inc. 6. Watts NB, et al. Insights into the pharmacology of bisphosphonates. Bone. 2020;138:115492. 7. Adler RA, et al. Managing osteoporosis in patients on long-term bisphosphonate treatment: report of a task force of the American Society for Bone and Mineral Research. J Bone Miner Res. 2016;31(1):16-35. 8. Khan AA, et al. Diagnosis and management of osteonecrosis of the jaw: a systematic review and international consensus. J Bone Miner Res. 2015;30(1):3-23.