Discovery, clinical development, and therapeutic uses of bisphosphonates.
OBJECTIVE
To review the literature concerning the history, development, and therapeutic uses of bisphosphonates.


METHODS
English-language articles were identified through a search of MEDLINE (through December 2004) using the key word bisphosphonate. Reference lists of pivotal studies, reviews, and full prescribing information for the approved agents were also examined.


METHODS
Selected studies included those that discussed the discovery and initial applications of bisphosphonates, as well as their historical development, pharmacokinetic and pharmacodynamic properties, and current therapeutic uses.


RESULTS
Bisphosphonates structurally resemble pyrophosphates (naturally occurring polyphosphates) and have demonstrated similar physicochemical effects to pyrophosphates. In addition, bisphosphonates reduce bone turnover and resist hydrolysis when administered orally. The information gained from initial work with etidronate generated a considerable scientific effort to design new and more effective bisphosphonates. The PCP moiety in the general bisphosphonate structure is essential for binding to hydroxyapatite and allows for a number of chemical variations by changing the 2 lateral side chains (designated R(1) and R(2)). The R(1) side chain determines binding affinity to hydroxyapatite, and the R(2) side chain determines antiresorptive potency. Accordingly, each bisphosphonate has its own characteristic profile of activity.


CONCLUSIONS
The bisphosphonates reduce bone turnover, increase bone mass, and decrease fracture risk and therefore have a significant place in the management of skeletal disorders including osteoporosis, Paget's disease, bone metastases, osteogenesis imperfecta, and heterotopic ossification.
Licata
Angelo A
AA
Metabolic Bone Center; Research Department of Endocrinology, The Cleveland Clinic Foundation, 1063 Kirtland Ln., Lakewood, OH 44107-1423, USA. LICATAA@ccf.org
D001847:Bone Diseases / Q000188:drug therapy; D004164:Diphosphonates / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D013678:Technology, Pharmaceutical / Q000379:methods*
D004164:Diphosphonates