Extra-skeletal effects of bisphosphonates.

Bisphosphonates (BPs) are pyrophosphate analogues widely used in diseases related to bone loss and increased bone turnover. Their high affinity for bone hydroxyapatite makes them ideal agents for bone diseases, while preventing them from reaching other cells and tissues. Data of the last decade, however, have demonstrated extra-skeletal tissue deposition and a variety of non-skeletal effects have been recently recognized. As such, BPs have been shown to exert anti-tumor, immunomodulatory, anti-inflammatory and anti-diabetic effects. In addition, new delivery systems (liposomes, nanoparticles, hydrogels) are being developed in an effort to expand BPs clinical application to extra-skeletal tissues and enhance their overall therapeutic spectrum and effectiveness. In the present review, we outline current data on extra-skeletal actions of bisphosphonates and attempt to unravel the underlying pathophysiological mechanisms.