Ibandronate: Nitrogen-containing bisphosphonate for osteoporosis and bone metastases

Ibandronate (ibandronic acid) is a nitrogen-containing third-generation bisphosphonate approved since 2004 for the treatment of postmenopausal osteoporosis and since 2003 for oncological indications. Known brand names are Bonviva (oral, Roche/GSK) and Bondronat (intravenous), as well as numerous generic preparations.

Ibandronate belongs to the established class of antiresorptive osteoporosis therapeutics. Compared to bisphosphonates such as alendronate or risedronate that must be taken daily or weekly, ibandronate is characterized by monthly oral dosing or three-monthly intravenous injection, which may improve treatment adherence. For bone metastases, ibandronate is used as an alternative to zoledronate or denosumab.

Mechanism of action

Bisphosphonates are chemical analogues of pyrophosphate, which occurs naturally in bone. They bind with high affinity to hydroxyapatite of the bone matrix and are released during osteoclastic bone resorption and taken up into osteoclasts. There, ibandronate, as a nitrogen-containing bisphosphonate, inhibits the enzyme farnesyl pyrophosphate synthase in the mevalonate metabolic pathway.

Inhibition of this enzyme prevents prenylation of small GTPases such as Ras and Rho, which are essential for osteoclast function and survival. The consequence is massive apoptosis of osteoclasts and thus a reduction in bone resorption of up to 60 to 80 percent. Since bone formation by osteoblasts continues initially, bone density increases over months.

Pharmacokinetically, oral bioavailability is extremely low at approximately 0.6 percent and is virtually completely abolished by food, calcium, and other polyvalent cations. Hence the strict requirement for fasting administration. Approximately 50 percent of the resorbed dose is incorporated into bone and remains there for years; the remainder is eliminated unchanged renally.

Therapeutic uses

• Postmenopausal osteoporosis: to reduce fracture risk, particularly vertebral fractures
• Tumor-induced hypercalcemia in malignant diseases
• Skeletal complications in breast cancer with bone metastases: reduction of fractures, pain, hypercalcemia and need for radiotherapy
• Multiple myeloma: as an alternative to zoledronate for reducing skeletal complications
• Glucocorticoid-induced osteoporosis: off-label, but guideline-conform

Dosage and administration

Postmenopausal osteoporosis oral: 150 mg once monthly. Intravenous: 3 mg every 3 months as a slow bolus injection over 15 to 30 seconds.

Tumor-induced hypercalcemia: 2 to 4 mg intravenously as a single dose over 2 hours, depending on severity. Breast cancer metastases: 50 mg oral daily or 6 mg intravenously every 3 to 4 weeks.

Oral administration instructions: in the morning on an empty stomach, fasting from food and fluids for at least 6 hours beforehand, take with a full glass of tap water (no mineral water, no other fluid), while standing upright or sitting. Remain upright for at least 60 minutes after taking and do not consume food, other medications or minerals in order to prevent reflux esophagitis and absorption failure.

Renal insufficiency: not recommended when eGFR is below 30 ml/min.

Adverse effects

Frequent: oral: reflux esophagitis, abdominal pain, dyspepsia, nausea, diarrhea, musculoskeletal complaints (bone, joint and muscle pain). Intravenous: acute phase syndrome with fever, chills, fatigue and bone pain, especially after the first infusion.

Occasional: hypocalcemia, especially with vitamin D deficiency; eye complaints (uveitis, scleritis); rash.

Serious, rare: osteonecrosis of the jaw (ONJ), especially after dental procedures and in high-dose oncological therapy; atypical femoral fracture with long-term use over several years; acute renal insufficiency after intravenous administration; atrial fibrillation (controversial).

Important: Prior to beginning therapy, dental rehabilitation should be performed if possible. During therapy, invasive dental procedures should be avoided if possible; otherwise inform the dentist early about ongoing bisphosphonate therapy. For femoral pain, consider atypical femoral fracture (radiological clarification).

Drug interactions

• Calcium, iron, magnesium, aluminum (in antacids, multivitamins, mineral water): dramatic reduction in absorption through complex formation; administer at least 60 minutes apart
• NSAIDs: additive gastrointestinal adverse effects, avoid combination if possible
• Aminoglycosides: additive hypocalcemia and nephrotoxicity, use with caution
• H2 antagonists and PPIs: theoretically slightly reduced absorption, clinically of little relevance
• Other bisphosphonates: do not prescribe concurrently, additive effect

Special precautions

Pregnancy and lactation: contraindicated. Bisphosphonates are stored long-term in bone and can theoretically impair fetal bone. Reliable contraception is required in women of childbearing age.

Prior to beginning therapy: assess calcium and vitamin D status, substitute if necessary (calcium 1,000 to 1,200 mg/day, vitamin D 800 to 1,000 IU/day). Dental examination and rehabilitation if necessary. Creatinine and eGFR.

Duration of therapy: treatment for 3 to 5 years, thereafter reassess indication due to atypical femoral fracture risk. A therapy break (drug holiday) is considered in low-risk patients, extended in high-risk patients.

Oncological indication: high-dose regimens are associated with increased ONJ risk; careful dental prevention and monitoring are mandatory.

You might also be interested in

• Alendronate, classic bisphosphonate for weekly administration
• Zoledronate, highly potent intravenous bisphosphonate
• Denosumab, RANK ligand antibody as alternative
• Calcium, supplementation in bisphosphonate therapy
• Vitamin D, supplementation in bisphosphonate therapy

Frequently asked questions

Sources

• EMA, Bonviva (Ibandronate) EPAR
• DVO guideline Osteoporosis
• Gelbe Liste, Ibandronate drug profile
• BfArM, Federal Institute for Drugs and Medical Devices