- Oral bisphosphonates can cause upset stomach and inflammation and erosions of the esophagus, which is the main problem of oral ''N''-containing preparations. This can be prevented by remaining seated upright for 30 to 60 minutes after taking the medication.
- Intravenous bisphosphonates can give fever and flu-like symptoms after the first infusion, which is thought to occur because of their potential to activate human γδ T cells. These symptoms do not recur with subsequent infusions.
- There is a slightly increased risk for electrolyte disturbances, but not enough to warrant regular monitoring.
- In chronic renal failure, the drugs are excreted much more slowly, and dose adjustment is required.
- Bisphosphonates have been associated with osteonecrosis of the jaw; with the mandible twice as frequently affected as the maxilla and most cases occurring following high-dose intravenous administration used for some cancer patients. Some 60% of cases are preceded by a dental surgical procedure (that involve the bone), and it has been suggested that bisphosphonate treatment should be postponed until after any dental work to eliminate potential sites of infection (the use of antibiotics may otherwise be indicated prior to any surgery).
- A number of cases of severe bone, joint, or musculoskeletal pain have been reported, prompting labeling changes
- Recent studies have reported bisphosphonate use (specifically zoledronate and alendronate) as a risk factor for atrial fibrillation in women. The inflammatory response to bisphosphonates or fluctuations in calcium blood levels have been suggested as possible mechanisms.
- Matrix metalloproteinase 2 may be a candidate gene for bisphosphonate-associated osteonecrosis of the jaws, since it is the only gene known to be associated with bone abnormalities and atrial fibrillation, both of which are side-effects of bisphosphonates.
- There are concerns that long-term bisphosphonate use can result in severe or over-suppression of bone turnover especially at the femur sub-trochanteric region. It is thought that micro-cracks in the bone are unable to heal and eventually unite and propagate, resulting in atypical fractures. Such fractures tend to heal poorly and often require some form of bone stimulation, for example bone grafting as a secondary procedure. This complication is not common, and the benefit of overall fracture reduction still holds.
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