Administration routes and delivery systems of bisphosphonates for the treatment of bone resorption

Geminal bisphosphonates (BPs) are a class of drugs considered to be stable analogs of pyrophosphate (P–O–P), a physiological regulator of calcification and bone resorption. A number of BPs have been approved for clinical use in Paget’s disease, hypercalcemia of malignancy, and osteoporosis. The major disadvantage of the clinically utilized BPs is their poor oral absorption from the GI tract, typically less than 1% is absorbed. In addition, the BPs have been associated with adverse gastrointestinal effects in humans. The challenge for novel drug delivery systems is to achieve improved bioavailability and safety. In the first part of this review, we discuss the bioavailability of BPs, the effect of food on the absorption of BPs, the mechanism of BPs’ absorption and the adverse gastrointestinal effects. In the second part of the review, various methods that have been used for improving the bioavailability of BPs are described. Dosage form strategies reviewed include the use of particular formulations for increasing oral absorption as well as decreasing adverse gastrointestinal effects, absorption enhancers, BP compounds and the solubility of their calcium complex/salts, and the prodrug approach. Because of the poor GI absorption, attempts have been made to enhance the bioavailability of BPs by several parenteral routes other than i.v. injections. Description of nasal administration, s.c. and i.m. injections, BP implants and targeted osteotropic delivery systems are reviewed.