Pharmacology: Mechanism of Action of Bisphosphonates

Bisphosphonates (BPs) are the most widely used and effective anti-resorptive agents for the treatment of diseases in which there is an increase in osteoclastic resorption, including post-menopausal osteoporosis, Paget’s disease, and tumor-associated osteolysis. BPs are chemical analogs of inorganic pyrophosphate (PPi) and, although they share many pharmacological features with PPi, there are important biochemical differences, particularly in the way in which they bind to bone mineral and their effect on bone resorption. BPs are preferentially incorporated into sites of active bone remodeling, as commonly occurs in conditions characterized by accelerated skeletal turnover. These drugs can be grouped in three different classes: first-generation, non-nitrogen containing BPs (e.g., clodronate and etidronate), second-generation nitrogencontaining BPs (N-BPs, e.g., pamidronate and alendronate) and third-generation N-BPs (e.g., ibandronate and zoledronate) and the phosphonocarboxylate analogue 3-PEHPC. BPs have several common properties, including poor intestinal absorption, high affinity for bone mineral, inhibitory effects on osteoclastic bone resorption, prolonged bone retention, and elimination in the urine. They are generally well tolerated, even if side effects have been described.