Ibandronic Acid
Monthly bisphosphonate in osteoporosis and bone metastases
Ibandronic acid is a nitrogen containing bisphosphonate noted primarily for the option of monthly oral intake and quarterly intravenous administration. Roche and GlaxoSmithKline launched the substance in 2003 under the brand names Bondronat and Bonviva; numerous generics are now available. The range of indications covers postmenopausal osteoporosis as well as prevention of skeletal events in breast cancer with bone metastases.
Compared with bisphosphonates that must be taken daily or weekly, such as alendronic acid and risedronic acid, ibandronic acid offers markedly greater adherence through monthly oral and quarterly intravenous dosing. The monthly oral formulation (Bonviva 150 mg once monthly) is particularly well established in patients who find daily dosing regimens burdensome. Quarterly intravenous dosing (3 mg every 3 months) is the alternative in case of gastrointestinal complaints or insufficient oral compliance.
Mechanism of Action
Like all nitrogen containing bisphosphonates, ibandronic acid accumulates in the bone matrix, is taken up by osteoclasts during resorption and intracellularly inhibits farnesyl pyrophosphate synthase in the mevalonate pathway. The consequence is impaired prenylation of small GTPases; the cytoskeleton assembly of osteoclasts collapses and these cells undergo apoptosis. Bone resorption decreases, bone mass and mineralisation rise, and fracture risk is reduced.
Clinical efficacy was documented in the BONE study: with 2.5 mg orally daily over 3 years, vertebral fracture risk in postmenopausal osteoporosis was reduced by 62 percent compared with placebo. The MOBILE study confirmed equivalence of the 150 mg monthly dose. The DIVA study demonstrated non inferiority of quarterly 3 mg intravenous administration. The effect on non vertebral fractures and hip fractures is less clear cut than with alendronic acid and zoledronic acid.
Oral bioavailability of ibandronic acid is less than one percent; food reduces it practically to zero. Strict fasting intake is therefore obligatory. After absorption, about half binds to bone, the remainder is excreted renally unchanged. Residence time in bone is many years.
Indications
- Postmenopausal osteoporosis with increased fracture risk, as oral or intravenous use
- Prevention of skeletal events in patients with breast cancer and bone metastases
- Tumour induced hypercalcaemia as intravenous acute therapy (4 mg once)
Use in men with osteoporosis is off label practice in some European countries; in Germany, however, approval is limited to postmenopausal women and the oncological indications above. For men, alendronic acid, risedronic acid, zoledronic acid and denosumab are available.
Dosage and Administration
Bonviva 150 mg orally once monthly: on the same calendar day each month, fasting at least 1 hour before the first meal or fluid (apart from tap water). The tablet is swallowed with a full glass of tap water (not mineral water); the patient must remain upright (sitting or standing) for at least 1 hour to avoid esophagitis.
Bondronat 2.5 mg orally daily: identical intake rules as the monthly form. This dosage is now less commonly used. Bondronat 3 mg intravenously every 3 months: short infusion over 15 to 30 seconds, also possible as a bolus if the approval allows. Bondronat 6 mg intravenously every 3 to 4 weeks in oncological indications: in combination with antitumour chemotherapy or hormone therapy.
Renal impairment: ibandronic acid is contraindicated in the osteoporosis indication at a creatinine clearance below 30 ml/min. Hepatic impairment: no dose adjustment required because hepatic metabolism is minimal. Calcium and vitamin D: supplementation with 1000 mg calcium and 800 to 1000 IU vitamin D daily is standard. Before starting therapy, correct vitamin D deficiency to avoid hypocalcaemia.
Side Effects
Common: musculoskeletal pain (arthralgia, myalgia), headache, dyspepsia, nausea, abdominal pain, diarrhoea, constipation, influenza like acute phase reaction especially after intravenous administration with fever and muscle pain.
Uncommon: hypocalcaemia, anaemia, esophagitis, dysphagia, reflux, increased urinary urgency, skin rash, asthma exacerbation in asthmatics.
Rare and clinically relevant: osteonecrosis of the jaw (medication related osteonecrosis of the jaw, MRONJ), atypical femur fractures, severe hypocalcaemia with neurological symptoms, dizziness at first infusion, uveitis, scleritis.
Osteonecrosis of the jaw: risk is markedly higher with oncological high dose administration (6 mg every 4 weeks) than with osteoporosis dosing. Risk factors are invasive dental procedures, poor oral hygiene, smoking, glucocorticoids and immunosuppressants. A dental check up before therapy is strongly recommended.
Interactions
- Calcium, magnesium and aluminium salts, multivalent cations: reduce absorption of the oral form, keep at least 1 hour apart
- Milk and dairy products: also reduce absorption
- Aminoglycosides, cisplatin, loop diuretics: additive nephrotoxicity, especially with intravenous administration
- NSAIDs: caution due to additive renal strain, especially with oncological high dose therapy
- Other antiresorptive substances (denosumab, other bisphosphonates): combination not useful
Special Notes
Strictly follow intake rules: oral ibandronic acid only works if taken fasting, with plain tap water and in upright position. Failure to remain upright can lead to severe esophagitis with ulceration. The oral form is contraindicated with feeding tubes or swallowing disorders; use the intravenous alternative instead.
Dental check up: before starting therapy, a dental review with removal of decayed teeth, root canal treatment and adjustment of dentures should take place. During therapy, avoid invasive procedures (tooth extraction, implants) where possible, or carry them out under strict hygiene and, if needed, with antibiotic prophylaxis.
Duration of therapy and drug holiday: in postmenopausal osteoporosis reassessment is recommended after 3 to 5 years of therapy to rebalance the benefit risk ratio. With stable bone density and low fracture risk a drug holiday of 1 to 2 years can be considered.
Pregnancy and lactation: ibandronic acid is contraindicated. The substance remains in bone for years and may be released during a later pregnancy. Women of childbearing age are usually excluded from therapy or require reliable contraception; approval applies to postmenopausal patients.
Monitoring: creatinine before every intravenous administration, serum calcium in at risk patients, vitamin D level, annual bone density measurement (DXA), dental review, clinical assessment of upper and lower leg pain because of atypical femur fractures.
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Frequently Asked Questions
Why do I have to stand for 1 hour after intake?
Bisphosphonates adhere on contact with the esophageal mucosa and can cause severe inflammation, ulcers and strictures. An upright posture and a full glass of water ensure that the tablet passes rapidly into the stomach and the esophagus is spared. After 1 hour the first meal may be taken.
Can I take ibandronic acid with milk?
No. Milk, mineral water, calcium and magnesium products as well as coffee or tea reduce the bioavailability of ibandronic acid practically to zero. Only tap water is suitable. After the 1 hour waiting period, dairy products and other drinks may be consumed.
What do I do if I miss the monthly tablet?
If the tablet has been forgotten for less than 1 week, take it fasting the next morning and then continue in the usual monthly rhythm. With more than 1 week of delay, skip the missed tablet and take the next one at the next regular date. Do not double the dose.
When should I take a drug holiday?
Reassessment is recommended after 3 to 5 years of therapy. With low fracture risk, stable bone density and no prior fracture, a drug holiday of 1 to 2 years may be useful to lower the risk of atypical femur fractures and jaw osteonecrosis. The individual decision lies with the treating physician; special caution applies in high risk patients.
Sources
- EMA, Bonviva (ibandronic acid) EPAR
- AWMF, S3 Guideline Osteoporosis DVO
- Gelbe Liste, Ibandronic acid active substance profile
- BfArM, Federal Institute for Drugs and Medical Devices
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