Experimental Evaluation of Bisphosphonates: Basic and Regulatory Aspects

Abstract

Pharmacodynamic evaluation of bisphosphonates has been -and still is- highly prolific in animals and in vitro models to generate evidences that give support to their therapeutic use in different clinical situations under different administration routes or schedules and, also, to explain their mechanisms of action. As part of the requirements of health authorities, and even in the case of drugs like bisphosphonates which have highly specific actions, safety pharmacology and conventional toxicological studies (acute toxicity, repeated-dose studies and special toxicity studies) are necessary for the preliminary identification of skeletal and non-skeletal target organs of toxicity, for the estimation of safe human-equivalent doses, and to identify monitoring parameters during different stages of clinical investigation. Highlighting the differences between basic and regulatory aspects, this article will provide a general review of the following issues: • Mechanistic pathways such as the ones related to the inhibition of farnesyl-pyrophosphate synthase. • Pharmacodynamic effects in different models of generalized or localized osteopenias (estrogenic depletion, drug-induced, associated to PTHrpproducing tumors, periodontitis, peri-implant osteolysis, among others), and the necessary tools: bone densitometry, histomorphometry, biomechanics, clinical chemistry, etc. • Evidence arising from conventional toxicology or safety pharmacology studies and the importance of their conduction under good laboratory practice standards. • Potential new uses (including non-skeletal uses) and different delivery systems (liposomes, conjugates, local administration).