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Mechanism of Action, Pharmacokinetic and Pharmacodynamic Profile, and Clinical Applications of Nitrogen-containing Bisphosphonates

Department of Molecular Endocrinology and Bone Biology, WP26A-1000, Merck Research Laboratories, West Point, PA 19486, USA; donald_kimmel{at}merck.com

View larger version (9K): [in this window] [in a new window]   Figure 1. Bisphosphonates used most frequently in the clinic today have a characteristic structure. All have a hydroxyl group on the carbon atom that confers high affinity for calcium and the skeleton. They vary only at the R-group, which always contains a nitrogen atom that is in either an alkyl or a heterocyclic structure.

View larger version (19K): [in this window] [in a new window]   Figure 2. Nitrogen-containing bisphosphonates inhibit farnesyl diphosphate (FPP) synthase, an enzyme in the mevalonate pathway. FPP synthase is responsible for isoprenylation of small GTPases that promote an array of activities in the osteoclasts that control bone resorption. Without this activity, bone resorption is slowed.

View larger version (19K): [in this window] [in a new window]   Figure 3. Artists’ depiction of trabecular bone and location of nBP as affected by time and bone remodeling activity. This Fig. attempts to put theory into pictures. (a) A bone multicellular unit (BMU) with an osteoclast and osteoblasts is at the lower right. At six hours after administration of a bolus dose of an nBP, the drug is found at all surfaces. The concentration is lowest at resting surfaces, highest at resorption surfaces, and in between at formation surfaces. (b) At three days after nBP administration of a bolus dose, the nBP concentration at resting surfaces has declined significantly. nBP under osteoblasts has become buried by ongoing bone formation activity, and diffuse deposits in newly formed bone from recirculated nBP are appearing. The concentration remains high under osteoclasts and in their brush border. (c) At ten days after nBP administration, the nBP concentration at resting surfaces has declined further from the three-day level, and now is markedly lower than at six hours. nBP under osteoblasts has become more deeply buried by ongoing bone formation activity, with diffuse deposits accumulating in newly forming bone, from recirculated nBP. The concentration remains high under osteoclasts, but the brush border has started to become disorganized, and the osteoclast is aging. (d) At 30 days after nBP administration, the nBP concentration at resting surfaces has declined further, with little remaining. The BMU has completed its work, leaving a bone structural unit (BSU). Note that the completed BSU has buried nBP where osteoblasts have finished, with a line from the initial deposit and diffuse nBP closer to the surface that came from recirculation. While the nBP at resting surfaces is still available for exchange to fluids, the buried nBP will not be removed and become biologically active, until resorption associated with a new BMU begins work in the area. The buried nBP is biologically inert. A new BMU has begun resorption in the upper left. (e) A new bolus dose of nBP is given. At 60 days after nBP administration, the nBP concentration at resting surfaces is minimal. The BMU at the upper left has completed its work, leaving another BSU with a concentrated line and diffuse deposit. The nBP in the BSU at the lower right is stable. (f) At 60 days after nBP, the picture of nBP location after weekly dosing is somewhat different, with no concentrated line visible, but more diffuse deposits to BSUs that were forming bone along the way. The nBP in the BSU at the lower right, even during weekly dosing, is stable. With less frequent, but equal, cumulative dosing, new BMUs will encounter fewer deposits of old nBP, but the ones they encounter are likely to be more concentrated, as compared with more frequent dosing.

Journal of Dental Research, Vol. 86, No. 11, 1022-1033 (2007)
DOI: 10.1177/154405910708601102


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