PMID: 15995133

Issn Print: 0021-9355

Publication Date: 2005/07/01


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BISPHOSPHONATES IN ORTHOPAEDIC SURGERY

CAROL D. MORRIS; THOMAS A. EINHORN

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Author Information: morrisc@mskcc.org

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Excerpt

Bisphosphonates are the most clinically important class of antiresorptive agents available to treat diseases characterized by osteoclast-mediated bone resorption such as osteoporosis, Paget disease, and tumor-associated bone diseases. They are synthetic, metabolically stable analogues of inorganic pyrophosphate in which the P-O-P bond has been replaced with a non-hydrolyzable P-C-P bond (Fig. 1). The diphosphate configuration of both P-O-P and P-C-P contributes to a three-dimensional structure capable of binding divalent ions such as Ca2+ and is the basis for the bone-targeting property of these compounds. This feature led to their use as bone-scanning agents when coupled with a radioisotope such as technetium-991. Because the P-O-P compound is rapidly metabolized, it is safe to label with radioactive isotopes for bone-scanning. However, there is no known enzyme capable of metabolizing the P-C-P bond of bisphosphonates, which allows considerable longevity of these compounds after they are administered.
More than three decades of research and development have produced a wide range of molecules that vary on the basis of the side-chain substituents (−R1, −R2) attached to the carbon compound; this leads to variable clinical efficacy for a given bone-resorptive condition based on the stereochemistry of that side chain (Table I). Since bisphosphonates were described more than a century ago, more than 1000 have been synthesized and more than a dozen have been investigated in humans. Currently, seven bisphosphonates have been approved by the United States Food and Drug Administration (FDA) for use for various skeletal indications (Table I). As a result of intense clinical interest and a number of compelling preclinical investigations, several bisphosphonates are being used in an off-label fashion for a variety of skeletal disorders. In addition, bisphosphonates that have not yet gained FDA approval are presently under clinical investigation and have shown promise in a number of therapeutic applications.
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