Introduction to bisphosphonates. History and functional mechanisms

The development of bisphosphonates is based on our studies in the 1960s on the mechanism of mineralization. It was shown that biological fluids contained mineralization inhibitors which we identified as inorganic pyrophosphate. Pyrophosphate, which, along with longer polyphosphates, has long been known as a water softener due to its inhibition of calcium carbonate formation, also has the ability to inhibit calcium phosphate crystal formation as well as dissolution. When given parenterally (but not orally), they also inhibit experimentally induced mineralization in vivo in animals. Their lack of effectiveness on oral application, as well as for bone destruction, is due to enzymatic cleavage in the body. We therefore sought analogues which had similar properties but were not biologically degraded. The bisphosphonates, which have a P-C-P instead of a P-O-P bond, fulfilled these criteria. They have been known since the middle of the 19th century and have also been used industrially as water softeners. We discovered that they bind to calcium phosphate crystals in the same way as pyrophosphate and inhibit calcium phosphate binding as well as its dissolution. In vivo, they inhibit mineralization as well as bone destruction. While the first process can be explained by a physicochemical mechanism, the second is cellular and involves the inhibition of the formation, lifespan and activity of osteoclasts. The molecular mechanism is dependent on the structure of the bisphosphonate. The structurally more simple molecules without nitrogen incorporate the P-C-P bond in ATP containing molecules and become toxic to the osteoclasts. The more active nitrogen containing bisphosphonates inhibit mevalonate metabolism due to the specific inhibition of farnesyl pyrophosphate synthase. This leads to a reduction in geranylgeranyl pyrophosphate, which is necessary for osteoclast survival.