Original ArticlesBisphosphonates: from the laboratory to the clinic and back again
Introduction
The discovery and development of the bisphosphonates (BPs) as a major class of drugs for the treatment of bone diseases has been a fascinating story that has extended over three decades. As the title of this presentation implies, the tale starts with laboratory studies31, 32 related to mechanisms of biological calcification, followed by the clinical exploitation of bisphosphonates as inhibitors of bone resorption, and has recently returned to laboratory studies that are helping to unravel how these drugs work at a cellular level.
There are several recent books and reviews available that describe the chemistry, pharmacology, and clinical applications of bisphosphonates.10, 22, 27, 28, 37, 41, 43, 47, 73, 79, 93
Section snippets
The early days
In the early 1960s, Neuman and Fleisch30 were studying mechanisms of calcification induced by collagen, and showed that body fluids such as plasma and urine contained inhibitors of calcification. Since it had been known since the 1930s that trace amounts of polyphosphates were capable of acting as water softeners by inhibiting the crystallization of calcium salts, such as calcium carbonate, they proposed that compounds of this type might be natural regulators of calcification under
Clinical applications
Exploration of bisphosphonates as inhibitors of calcification showed some promise, and early applications of etidronate included use in myositis ossificans and in patients who had undergone total hip replacement surgery to prevent subsequent heterotopic ossification and to improve mobility.10, 27 It should be emphasized that these effects required very high doses of etidronate, and that inhibition of skeletal mineralization is not a significant clinical problem when etidronate is used at the
The relationship between the chemical structure of bisphosphonates and their biological activity
Bisphosphonates differ from pyrophosphate in that a carbon rather than an oxygen atom bridges the two phosphate residues, which renders bisphosphonates chemically stable and able to withstand incubation in acids or with hydrolytic enzymes (Figure 1). The P-C-P moiety is responsible for the strong affinity of the bisphosphonates for the skeleton and allows for a number of variations in structure based on substitution in the R1 and R2 positions on the carbon atom (Figure 2). The ability of the
Mechanisms of action
Bisphosphonates probably inhibit bone resorption by being selectively taken up and adsorbed to mineral surfaces in bone, whence they are internalized by osteoclasts. Bisphosphonates affect osteoclast-mediated bone resorption in a variety of ways, which include effects on osteoclast recruitment, differentiation, and resorptive activity.44, 45, 57, 82, 84 Once internalized within osteoclasts, bisphosphonates perturb cellular metabolism and induce apoptosis (Figure 3). Given the structural
Future prospects
It has taken over 30 years since the discovery of the profound effects of the bisphosphonates on calcium metabolism for them to become well established as clinically successful antiresorptive agents, and their availability has enabled new approaches to the therapy of bone diseases.
There have now been many years of mostly favorable experience with the use of bisphosphonates in diseases such as Paget’s disease of bone, myeloma, and bone metastases. Bisphosphonates represent an important class of
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