Preclinical history

About 100 years ago German chemists discovered that inorganic pyrophosphate could prevent deposition of calcium salts from solution. This observation was the basis of the industrial use of polyphosphates for prevention of calcium carbonate deposition in pipes.

The first biological effect of a pyrophosphate analog was demonstrated in 1968 when Fleisch and his associates in Switzerland found that these agents could inhibit vitamin D-induced aortic calcification in rats (Schibler et al., 1968). Subsequent collaboration of the Swiss investigators with Dr M. D. Francis and his colleagues at Procter and Gamble resulted in the development of bisphosphonates which could be applied to the treatment of a variety of human disorders, the most common of which is osteoporosis.

Chemistry

The bisphosphonates, which were initially termed diphosphonates, are compounds which have two C—P bonds. The compounds are referred to as geminal bisphosphonates if the two bonds are found on the same carbon atom (P—C—P), although this class of compounds is usually simply termed bisphosphonates.

The bisphosphonates are analogs of inorganic pyrophosphate whose core structure has a P—O—P structure. The substitution of an alkyl group confers resistance to hydrolysis to the bisphosphonates whereas inorganic pyrophosphate is highly susceptible to hydrolysis by pyrophosphatases such as alkaline phosphatase.