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14-September-2008 11:27:25 - Bisphosphonate Redirected from Bisphosphonates In pharmacology, bisphosphonates also called: diphosphonates are a class of drugs that inhibit osteoclast action and the resorption of bone. Its uses include the prevention and treatment of osteoporosis, osteitis deformans Paget's disease of bone, bone metastasis with or without hypercalcaemia, multiple myeloma and other conditions that feature bone fragility. Contents 1 History 2 Chemistry and classes 3 Pharmacokinetics 4 Mechanism of action 4.1 Non-nitrogenous 4.2 Nitrogenous 5 Uses 6 Side-effects 7 Footnotes 8 External links History Bisphosphonates were developed in the 19th century, but were first investigated in the 1960s for use in disorders of bone metabolism. Their non-medical use included water softening in irrigation systems used in orange groves. The initial rationale for their use in humans was their potential in preventing the dissolution of hydroxylapatite, the principal bone mineral, and hence arresting bone loss. Only in the 1990s was their actual mechanism of action demonstrated.1 Chemistry and classes All bisphosphonate drugs share a common P-C-P backbone: basic structure of bisphosphonates The two PO3 phosphonate groups covalently linked to carbon determine both the name bisphosphonate and the function of the drugs. The long side chain R2 in the diagram determines the chemical properties, the mode of action and the strength of bisphosphonate drugs. The short side chain R1, often called the 'hook', mainly influences chemical properties and pharmacokinetics. Pharmacokinetics Of the bisphosphonate that is resorbed from oral preparation or infused for intravenous drugs, about 50% is excreted unchanged by the kidney. The remainder has a very high affinity for bone tissue, and is rapidly absorbed onto the bone surface. Mechanism of action Bisphosphonates, when attached to bone tissue, are ingested by osteoclasts, the bone cell that breaks down bone tissue. There are two classes of bisphosphonate: the N-containing and non-N-containing bisphosphonates. The two types of bisphosphonates work differently in killing osteoclast cells. side chains of bisphosphonate molecules Non-nitrogenous Non-N-containing bisphosphonates: Etidronate Didronel - 1 potency relative to that of etidronate Clodronate Bonefos, Loron - 10 Tiludronate Skelid - 10 The non-nitrogenous bisphosphonatesdisphosphonates are metabolised in the cell to compounds that replace the terminal pyrophosphate moiety of ATP, forming a nonfunctional molecule that competes with adenosine triphosphate ATP in the cellular energy metabolism. The osteoclast initiates apoptosis and dies, leading to an overall decrease in the breakdown of bone.2 Nitrogenous N-containing bisphosphonates: Pamidronate APD, Aredia - 100 Neridronate - 100 Olpadronate - 500 Alendronate Fosamax - 500 Ibandronate Boniva - 1000 Risedronate Actonel - 2000 Zoledronate Zometa - 10000 Nitrogenous bisphosphonates act on bone metabolism by binding and blocking the enzyme farnesyl diphosphate synthase FPPS in the HMG-CoA reductase pathway also known as the mevalonate pathway.3 HMG-CoA reductase pathway HMG-CoA reductase pathway Disruption of the HMG CoA-reductase pathway at the level of FPPS prevents the formation of two metabolites farnesol and geranylgeraniol that are essential for connecting some small proteins to the cell membrane. This phenomenon is known as prenylation, and is important for proper sub-cellular protein trafficking see lipid anchored protein for the principles of this phenomenon.4 While inhibition of protein prenylation may affect many proteins found in an osteoclast, disruption to the lipid modification of Ras, Rho, Rac proteins has been speculated to underlie the effects of bisphosphonates. These proteins can affect both osteoclastogenesis, cell survival, and cytoskeletal dynamics. In particular, the cytoskeleton is vital for maintaining the ruffled border that is required for contact between a resorbing osteoclast and a bone surface. Statins are another class of drugs that inhibit the HMG-CoA reductase pathway. Unlike bisphosphonates, statins do not bind to bone surfaces with high affinity, and are thus not specific for bone. Nevertheless, some studies have reported a decreased rate of fracture an indicator of osteoporosis and/or an increased bone mineral density in statin users. The overall efficacy of statins in the treatment osteoporosis remains controversial. Uses Bisphosphonates are used clinically for the treatment of osteoporosis, osteitis deformans Paget's disease of the bone, bone metastasis with or without hypercalcaemia, multiple myeloma and other conditions that feature bone fragility. In osteoporosis and Paget's, alendronate and risedronate are the most popular first-line drugs. If these are ineffective or the patient develops digestive tract problems, intravenous pamidronate may be used. Alternatively, strontium ranelate or teriparatide are used for refractory disease, and the SERM raloxifene is occasionally administered in postmenopausal women instead of bisphosphonates. High-potency intravenous bisphosphonates have shown to modify progression of skeletal metastasis in several forms of cancer, especially breast cancer. Other bisphosphonates, medronate R1, R2 = H and oxidronate R1 = H, R2 = OH are mixed with radioactive technetium and are injected for imaging bone and detecting bone disease. More recently, bisphosphonates have been used to reduce fracture rates in children with osteogenesis imperfecta. Side-effects Oral bisphosphonates can give stomach upset and inflammation and erosions of the esophagus, which is the main problem of oral N-containing preparations. This can be prevented by remaining seated upright for 30 to 60 minutes after taking the medication. Intravenous bisphosphonates can give fever and flu-like symptoms after the first infusion, which is thought to occur because of their potential to activate human γδ T cells. Notably, these symptoms do not recur with subsequent infusions. There is a slightly increased risk for electrolyte disturbances, but not enough to warrant regular monitoring. In chronic renal failure, the drugs are excreted much more slowly, and dose adjustment is required. Bisphosphonates have been associated with osteonecrosis of the jaw; with the mandible twice as frequently affected as the maxilla and most cases occurring following high-dose intravenous administration used for some cancer patients. Some 60% of cases are preceded by a dental surgical procedure and it has been suggested that bisphosphonate treatment should be postponed until after any dental work to eliminate potential sites of infection.5 A number of cases of severe bone, joint, or musculoskeletal pain have been reported, prompting labeling changes6 Recent studies have reported bisphosphonate use specifically zoledronate and alendronate as a risk factor for atrial fibrillation in women.789 The inflammatory response to bisphosphonates or fluctuations in calcium blood levels have been suggested as possible mechanisms.8 One study estimated that 3% of atrial fibrillation cases might have been due to alendronate use.8 Until now however, the benefits of bisphosphonates generally outweigh this possible risk, although care needs to be taken in certain populations at high risk of serious adverse effects from atrial fibrillation such as patients with heart failure, coronary artery disease or diabetes.8 Footnotes ^ Fleisch H 2002. Development of bisphosphonates. Breast Cancer Res 4 1: 30-4. doi:10.1186/bcr414. PMID 11879557. ^ Frith J, Mönkkönen J, Blackburn G, Russell R, Rogers M 1997. Clodronate and liposome-encapsulated clodronate are metabolized to a toxic ATP analog, adenosine 5'-beta, gamma-dichloromethylene triphosphate, by mammalian cells in vitro. J Bone Miner Res 12 9: 1358-67. doi:10.1359/jbmr.1997.12.9.1358. PMID 9286751. ^ van Beek E, Cohen L, Leroy I, Ebetino F, Löwik C, Papapoulos S Nov 2003. Differentiating the mechanisms of antiresorptive action of nitrogen containing bisphosphonates. Bone 33 5: 805-11. doi:10.1016/j.bone.2003.07.007. PMID 14623056. ^ van beek E, Löwik C, van der Pluijm G, Papapoulos S 1999. The role of geranylgeranylation in bone resorption and its suppression by bisphosphonates in fetal bone explants in vitro: A clue to the mechanism of action of nitrogen-containing bisphosphonates. J Bone Miner Res 14 5: 722-9. doi:10.1359/jbmr.1999.14.5.722. PMID 10320520. ^ Woo S, Hellstein J, Kalmar J 2006. Narrative corrected review: bisphosphonates and osteonecrosis of the jaws. Ann Intern Med 144 10: 753-61. PMID 16702591. ^ Wysowski D, Chang J 2005. Alendronate and risedronate: reports of severe bone, joint, and muscle pain. Arch Intern Med 165 3: 346-7. doi:10.1001/archinte.165.3.346-b. PMID 15710802. ^ Black DM, Delmas PD, Eastell R, et al May 2007. Once-yearly zoledronic acid for treatment of postmenopausal osteoporosis. N. Engl. J. Med. 356 18: 1809-22. doi:10.1056/NEJMoa067312. PMID 17476007. ^ a b c d Heckbert SR, Li G, Cummings SR, Smith NL, Psaty BM April 2008. Use of alendronate and risk of incident atrial fibrillation in women. Arch. Intern. Med. 168 8: 826-31. doi:10.1001/archinte.168.8.826. PMID 18443257. ^ Cummings SR, Schwartz AV, Black DM May 2007. Alendronate and atrial fibrillation. N. Engl. J. Med. 356 18: 1895-6. doi:10.1056/NEJMc076132. PMID 17476024. External links International Myeloma Foundation article on bisphosphonates v d e Drugs for treatment of bone diseases M05 Bisphosphonates Nitrogenous Pamidronic acid, Alendronic acid, Ibandronic acid, Risedronic acid, Zoledronic acid - Non-nitrogenous Etidronic acid, Clodronic acid, Tiludronic acid, Incadronic acid Bone morphogenetic proteins Dibotermin alfa - Eptotermin alfa Other Ipriflavone - Aluminium chlorohydrate - Strontium ranelate - Odanacatib Retrieved from http://en..org/wiki/Bisphosphonate Categories: Bisphosphonates Views Article Discussion this page History Personal tools Log in / create account Navigation Main page Contents Featured content Current events Random article Search Go Search Interaction Community portal Recent changes Contact Donate to Help Toolbox What links here Related changes Upload file Special pages Printable version Permanent link Cite this page Languages Deutsch Français Italiano Polski SlovenÅ¡Ä?ina Svenska This page was last modified on 7 September 2008, at 12:35
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