The bisphosphonates are analogs of pyrophosphate in which the P-O-P bond has been replaced with a nonhydrolyzable P-C-P bond (Figure 42–4). Currently available bisphosphonates include etidronate, pamidronate, alendronate, risedronate, tiludronate,
OHOH OH Etidronate: ethane-1-hydroxy-1,
OHOH OH Pamidronate: 3-Amino-1-hydroxy-
OHOH OH Alendronate: 4-Amino-1-hydroxy-butylidene
FIGURE 42–4 The structure of pyrophosphate and of the first three bisphosphonates—etidronate, pamidronate, and alendronate—that were approved for use in the United States.
ibandronate, and zoledronate. With the development of the more potent bisphosphonates, etidronate is seldom used.
Results from animal and clinical studies indicate that less than 10% of an oral dose of these drugs is absorbed. Food reduces absorption even further, necessitating their administration on an empty stomach. A major adverse effect of oral forms of the bisphosphonates (risedronate, alendronate, ibandronate) is esophageal and gastric irritation, which limits the use of this route by patients with upper gastrointestinal disorders. This complication can be circumvented with infusions of pamidronate, zoledronate, and ibandronate. Intravenous dosing also allows a larger amount of drug to enter the body and markedly reduces the frequency of administration (eg, zoledronate is infused once per year). Nearly half of the absorbed drug accumulates in bone; the remainder is excreted unchanged in the urine. Decreased renal function dictates a reduction in dosage. The portion of drug retained in bone depends on the rate of bone turnover; drug in bone often is retained for months to years.
The bisphosphonates exert multiple effects on bone mineral homeostasis, which make them useful for the treatment of hypercalcemia associated with malignancy, for Paget’s disease, and for osteoporosis (see Box: Newer Therapies for Osteoporosis). They owe at least part of their clinical usefulness and toxicity to their ability to retard formation and dissolution of hydroxyapatite crystals within and outside the skeletal system. Some of the newer bisphosphonates appear to increase bone mineral density well beyond the 2-year period predicted for a drug whose effects are limited to slowing bone resorption. This may be due to their other cellular effects, which include inhibition of 1,25(OH)2D production, inhibition of intestinal calcium transport, metabolic changes in bone cells such as inhibition of glycolysis, inhibition of cell growth, and changes in acid and alkaline phosphatase activity.