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Five nBPs are currently approved in the United States. The primary indications are for treatment of osteoporosis (alendronate, ibandronate, and risedronate) and treatment\/prevention of skeletal-related events (SREs) in multiple myeloma and breast and prostate cancer patients (ibandronate, pamidronate, and zoledronic acid). nBPs are the most efficacious drugs available for these diseases, reducing osteoporotic fracture risk by 50\u201360% in persons with low bone mass or prior osteoporotic fracture, and SREs by one-third in cancer patients. The absorbed nBP dose for cancer patients is from seven to ten times that in osteoporosis patients. nBPs are unique in that they first exert profound pharmacodynamic effects long after their blood levels reach zero. Current pharmacokinetic studies indicate that approximately half of any nBP dose reaches the skeleton, with an early half-life of ten days, and a terminal half-life of about ten years. Practical study design limitations and theoretical considerations suggest that both the half-life and the amount of nBP retained in the skeletons of patients on long-term nBP therapy are substantially overestimated by extrapolation directly from current pharmacokinetic data. In fact, the amount of nBP being released from skeletal tissues of long-term-treated patients, particularly in osteoporosis patients, becomes insufficient to maintain full pharmacodynamic efficacy relatively soon after dosing is interrupted.<\/jats:p>","DOI":"10.1177\/154405910708601102","type":"journal-article","created":{"date-parts":[[2009,1,8]],"date-time":"2009-01-08T19:39:42Z","timestamp":1231443582000},"page":"1022-1033","source":"Crossref","is-referenced-by-count":199,"title":["Mechanism of Action, Pharmacokinetic and Pharmacodynamic Profile, and Clinical Applications of Nitrogen-containing Bisphosphonates"],"prefix":"10.1177","volume":"86","author":[{"given":"D.B.","family":"Kimmel","sequence":"first","affiliation":[{"name":"Department of Molecular Endocrinology and Bone Biology, WP26A-1000, Merck Research Laboratories, West Point, PA 19486, USA;"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"179","published-online":{"date-parts":[[2007,11,1]]},"reference":[{"key":"ADAMI-ETAL-1987","doi-asserted-by":"publisher","DOI":"10.1007\/BF02556671"},{"key":"ALAKANGAS-ETAL-2002","doi-asserted-by":"publisher","DOI":"10.1007\/s002230010047"},{"key":"ALI-ETAL-2001","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2001.19.14.3434"},{"key":"AMIN-ETAL-1992","doi-asserted-by":"publisher","DOI":"10.1016\/S0022-2275(20)41388-4"},{"key":"ARIKOSKI-ETAL-2004","doi-asserted-by":"publisher","DOI":"10.1016\/j.bone.2003.11.019"},{"key":"BARRETT-ETAL-2004","doi-asserted-by":"publisher","DOI":"10.1177\/0091270004267594"},{"key":"BAUSS-AND-RUSSELL-2004","doi-asserted-by":"publisher","DOI":"10.1007\/s00198-004-1612-7"},{"key":"BENFORD-ETAL-1999","doi-asserted-by":"publisher","DOI":"10.1124\/mol.56.1.131"},{"key":"BERENSON-ETAL-1998","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.1998.16.2.593"},{"key":"BERENSON-ETAL-2002","unstructured":"Berenson JR, Ravera C, Ma P -2002- Population pharmacokinetics of zoledronate -abstract- Proc Am Soc Clin Oncol 23:209."},{"key":"BERKHOUT-ETAL-1996","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.271.24.14376"},{"key":"BLACK-ETAL-1996","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(96)07088-2"},{"key":"BLACK-ETAL-2006","doi-asserted-by":"publisher","DOI":"10.1001\/jama.296.24.2927"},{"key":"BLACK-ETAL-2007","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa067312"},{"key":"BODY-ETAL-2003","doi-asserted-by":"crossref","unstructured":"Body JJ, Diel LJ, Lichinitser MR, Kreuser ED, Dornoff W, Gorbunova VA,\n                      et al.\n                      -2003- Intravenous ibandronate reduces the incidence of skeletal complications in patients with breast cancer and bone metastases. 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