Dosing regimens and main adverse events of bisphosphonates

Abstract

The bisphosphonates pamidronate and clodronate are most often used in oncology. Newer, more potent compounds under study are ibandronate and zoledronate. The main route of administration is by intravenous infusion (1-2 hours for pamidronate) but oral formulations are or soon will be available for some bisphosphonates (clodronate, ibandronate) and shorter infusion times are being studied (zoledronate, ibandronate). After oral administration of aminobisphosphonates, the main adverse event can be epigastric pain and esophagitis for which the current recommendations include swallowing 180 to 240 mL of water and remaining upright for 30 minutes after tablet ingestion. After intravenous administration, the main adverse events are injection site reaction and flu-like syndrome. Injection site reactions are seen in up to 6% of patients given pamidronate, and this figure is likely to be lower with ibandronate and zoledronate. Flu-like syndrome is seen in up to one third of patients given pamidronate, less with ibandronate, and no figure is yet available for zoledronate. Adverse effects on kidney function were only seen when using a high dose of zoledronate (8 mg over 5-15 minutes) and the current recommended dose is 4 mg given as a 15-minute infusion. Disadvantages of the oral route are poor absorption (<5%) and occasional digestive side effects. With protracted use the size and number of tablets required can reduce compliance. The advantage of oral administration is use on an outpatient basis and it may thus be the preferred route for patients on hormonal therapy and in the adjuvant setting. The main route of administration, however, is currently a 1- to 2-hour intravenous pamidronate infusion, often preferred for patients receiving chemotherapy. The disadvantage of the latter is the need for an appropriate hospital environment. Shorter infusion times are being studied with newer compounds. Intravenous administration is the preferred route for patients receiving chemotherapy. Equivalent intravenous doses to achieve similar success rates in normalizing serum calcium levels are approximately 90 mg, 4 mg, and 2 mg for pamidronate, ibandronate, and zoledronate, respectively. The expectation from the new, more potent compounds is for more convenient therapeutic schemes leading to increased patient compliance and improvements in the reduction of the skeletal morbidity rate and hopefully increase in survival rate.