Nbx

rised róñate zoledronate o oh o o oh o

"O —p —c—p—O" "O—p —c—p—O"

III III

oh ch2oh oh ch2oh n' xn

figure 61-8 Structures of pyrophosphate and bisphosphonates. The substituents (R1 and R2) on the central carbon of the bisphosphonate parent structure are shown in blue.

Based on their side chains, the bisphosphonates are grouped into first-, second-, and third-generation drugs. First-generation drugs (e.g., medronate, clodronate, and etidronate) contain minimally modified side-chains or a chlorophenyl group (e.g., tiludronate) and are the least potent agents. Second-generation aminobisphosphonates (e.g., pamidronate, alendronate, and ibandronate) contain an N-atom in the side chain and are 10-100 times more potent than the first-generation drugs. Third-generation drugs (e.g., risedronate and zoledronate) contain an N-atom within a heterocyclic ring and are up to 10,000 times more potent than first-generation drugs.

Bisphosphonates concentrate at sites of active remodeling and are incorporated into the bone matrix. When the bone is remodeled, they are released in the acid environment of the resorption lacunae and induce apoptosis in the osteoclasts.

Available Bisphosphonates

Several bisphosphonates are available in the U.S. (Figure 61-8). Etidronate (didronel) is used for the treatment of Paget's disease but largely has been supplanted by pamidronate and zoledronate for hypercalcemia. Pamidronate (aredia) is approved in the U.S. for parenteral treatment of hypercalcemia (60-90 mg infused over 4 hours), and also is used for Paget's disease.

Several bisphosphonates are approved for the treatment of Paget's disease, including tiludronate (skelid), alendronate (fosamax), and risedronate (actonel), typically at higher doses than those employed in osteoporosis. Zoledronate (zometa) also appears to be quite effective as a single infusion of 4 mg.

ABSORPTION, FATE, AND EXCRETION

All oral bisphosphonates have very limited bioavailability. They should be administered with a full glass of water following an overnight fast and at least 30 minutes before breakfast. They are excreted primarily by the kidneys and are not recommended for patients with a creatinine clearance of less than 30 mL/min.

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