Bisphosphonate 619733 222906993 2008-07-01T18:09:20Z DOI bot 6652755 Citation maintenance. Formatted: title. You can [[WP:DOI|use this bot]] yourself! Please [[User:DOI_bot/bugs|report any bugs]]. In [[pharmacology]], '''bisphosphonates''' (also called: '''diphosphonates''') are a class of drugs that inhibit [[osteoclast]] action and the [[bone resorption|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. ==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.<ref>{{cite journal | author = Fleisch H | title = Development of bisphosphonates | journal = Breast Cancer Res | volume = 4 | issue = 1 | pages = 30–4 | year = 2002 | pmid = 11879557 | doi = 10.1186/bcr414}}</ref> == Chemistry and classes == All bisphosphonate drugs share a common P-C-P "backbone": [[Image:Bisphosphonate_basic_structure.png|||basic structure of bisphosphonates]] The two PO<sub>3</sub> ([[phosphate]]) groups [[covalent]]ly linked to [[carbon]] determine both the name "bis''phospho''nate" and the function of the drugs. The long ''[[side chain]]'' ('''R<sub>2</sub>''' in the diagram) determines the chemical properties, the mode of action and the strength of bisphosphonate drugs. The short ''side chain'' (R<sub>1</sub>), 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 [[osteoclast]]s, the bone cell that breaks down bone tissue. There are two classes of ''bisphosphonate'': the ''[[nitrogen|N]]''-containing and non-''N''-containing bisphosphonates. The two types of bisphosphonates work differently in killing osteoclast cells. [[Image:Bisphosphonate side chains.png|350px|right|side chains of bisphosphonate molecules]] === Non-nitrogenous === Non-''N''-containing bisphosphonates: * [[Etidronic acid|Etidronate]] (Didronel) - 1 (potency relative to that of etidronate) * [[Clodronate]] (Bonefos, Loron) - 10 * [[Tiludronate]] (Skelid) - 10 The non-nitrogenous bisphosphonates(disphosphonates) are [[metabolism|metabolised]] in the [[cell (biology)|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.<ref>{{cite journal | author = Frith J, Mönkkönen J, Blackburn G, Russell R, Rogers M | title = Clodronate and liposome-encapsulated clodronate are metabolized to a toxic ATP analog, adenosine 5'-(beta, gamma-dichloromethylene) triphosphate, by mammalian cells in vitro | journal = J Bone Miner Res | volume = 12 | issue = 9 | pages = 1358–67 | year = 1997 | pmid = 9286751 | doi = 10.1359/jbmr.1997.12.9.1358}}</ref> === 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).<ref>{{cite journal | author = van Beek E, Cohen L, Leroy I, Ebetino F, Löwik C, Papapoulos S | title = Differentiating the mechanisms of antiresorptive action of nitrogen containing bisphosphonates | journal = Bone | volume = 33 | issue = 5 | pages = 805–11 | year = 2003 | month = Nov | pmid = 14623056 | doi = 10.1016/j.bone.2003.07.007}}</ref> [[Image:HMG-CoA reductase pathway.png|thumb|right|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).<ref>{{cite journal | author = van beek E, Löwik C, van der Pluijm G, Papapoulos S | title = 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 | journal = J Bone Miner Res | volume = 14 | issue = 5 | pages = 722–9 | year = 1999 | pmid = 10320520 | doi = 10.1359/jbmr.1999.14.5.722}}</ref> 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. [[Statin]]s 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 (bone)|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 (R<sub>1</sub>, R<sub>2</sub> = H) and oxidronate (R<sub>1</sub> = H, R<sub>2</sub> = 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 [[esophagitis|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 [[gamma/delta T cells|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.<ref>{{cite journal | author = Woo S, Hellstein J, Kalmar J | title = Narrative [corrected] review: bisphosphonates and osteonecrosis of the jaws | journal = Ann Intern Med | volume = 144 | issue = 10 | pages = 753–61 | year = 2006 | pmid = 16702591}}</ref> * A number of cases of severe bone, joint, or musculoskeletal pain have been reported, prompting labeling changes<ref>{{cite journal | author = Wysowski D, Chang J | title = Alendronate and risedronate: reports of severe bone, joint, and muscle pain | journal = Arch Intern Med | volume = 165 | issue = 3 | pages = 346–7 | year = 2005 | pmid = 15710802 | doi = 10.1001/archinte.165.3.346-b}}</ref> * Recent studies have reported bisphosphonate use (specifically [[zoledronate]] and [[alendronate]]) as a risk factor for [[atrial fibrillation]] in women.<ref name="HORIZON">{{cite journal |author=Black DM, Delmas PD, Eastell R, ''et al'' |title=Once-yearly zoledronic acid for treatment of postmenopausal osteoporosis |journal=N. Engl. J. Med. |volume=356 |issue=18 |pages=1809–22 |year=2007 |month=May |pmid=17476007 |doi=10.1056/NEJMoa067312 |url=http://content.nejm.org/cgi/pmidlookup?view=short&pmid=17476007&promo=ONFLNS19}}</ref><ref name="ArchIntMed2008">{{cite journal |author=Heckbert SR, Li G, Cummings SR, Smith NL, Psaty BM |title=Use of alendronate and risk of incident atrial fibrillation in women |journal=Arch. Intern. Med. |volume=168 |issue=8 |pages=826–31 |year=2008 |month=April |pmid=18443257 |doi=10.1001/archinte.168.8.826 |url=http://archinte.ama-assn.org/cgi/pmidlookup?view=long&pmid=18443257}}</ref><ref name="FractureInterventionTrial">{{cite journal |author=Cummings SR, Schwartz AV, Black DM |title=Alendronate and atrial fibrillation |journal=N. Engl. J. Med. |volume=356 |issue=18 |pages=1895–6 |year=2007 |month=May |pmid=17476024 |doi=10.1056/NEJMc076132 |url=}}</ref> The inflammatory response to bisphosphonates or fluctuations in [[calcium]] blood levels have been suggested as possible mechanisms.<ref name="ArchIntMed2008"/> One study estimated that 3% of atrial fibrillation cases might have been due to alendronate use.<ref name="ArchIntMed2008"/> 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]]).<ref name="ArchIntMed2008"/> ==Footnotes== {{reflist|2}} [[Category:Bisphosphonates| ]] ==External links== *[http://www.myeloma.org/main.jsp?source=link&source_link_id=945&type=article&tab_id=13&menu_id=94&id=1165 International Myeloma Foundation article on bisphosphonates] {{Bisphosphonates}} [[de:Bisphosphonate]] [[fr:Biphosphonate]] [[it:Bifosfonati]] [[pl:Bisfosfoniany]] [[sv:Bisfosfonater]]