Alendronic acid

{{Short description|Chemical compound}} {{Use dmy dates|date=February 2024}} {{cs1 config |name-list-style=vanc |display-authors=6}} {{Infobox drug | Verifiedfields = changed | Watchedfields = changed | verifiedrevid = 477314835 | image = Alendronic acid.svg | image_class = skin-invert-image | width = | alt = | image2 = Alendronate-3D-balls.png | image_class2 = bg-transparent | width2 = | alt2 = | caption = | USAN = alendronate sodium

<!-- Clinical data --> | pronounce = | tradename = Fosamax, Binosto, others | Drugs.com = {{drugs.com|monograph|alendronate-sodium}} | MedlinePlus = a601011 | DailyMedID = Alendronate sodium | pregnancy_AU = B3 | pregnancy_AU_comment = <ref name="Drugs.com pregnancy">{{cite web | title=Alendronate Use During Pregnancy | website=Drugs.com | date=22 August 2019 | url=https://www.drugs.com/pregnancy/alendronate.html | access-date=17 May 2020}}</ref> | pregnancy_category= | routes_of_administration = By mouth | class = | ATC_prefix = M05 | ATC_suffix = BA04 | ATC_supplemental =

<!-- Legal status --> | legal_AU = <!-- S2, S3, S4, S5, S6, S7, S8, S9 or Unscheduled --> | legal_AU_comment = | legal_BR = <!-- OTC, A1, A2, A3, B1, B2, C1, C2, C3, C4, C5, D1, D2, E, F --> | legal_BR_comment = | legal_CA = Rx-only | legal_CA_comment = <ref>{{cite web | title=Product monograph brand safety updates | website=Health Canada | date=7 July 2016 | url=https://www.canada.ca/en/health-canada/services/drugs-health-products/drug-products/drug-product-database/label-safety-assessment-update/product-monograph-brand-safety-updates.html | access-date=3 April 2024}}</ref> | legal_DE = <!-- Anlage I, II, III or Unscheduled --> | legal_DE_comment = | legal_NZ = <!-- Class A, B, C --> | legal_NZ_comment = | legal_UK = POM | legal_UK_comment = | legal_US = Rx-only | legal_US_comment = <ref name="Fosamax FDA label">{{cite web | title=Fosamax- alendronate sodium tablet | website=DailyMed | date=16 April 2024 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=14e931fd-2c5f-4d90-b7db-5980706f4a56 | access-date=30 September 2024}}</ref> | legal_UN = <!-- N I, II, III, IV / P I, II, III, IV --> | legal_UN_comment = | legal_status = <!-- For countries not listed above -->

<!-- Pharmacokinetic data --> | bioavailability = 0.6% | protein_bound = | metabolism = excreted unchanged | metabolites = | onset = | elimination_half-life = 126 months | duration_of_action = | excretion = Kidney

<!-- Identifiers --> | index2_label = Sodium salt | CAS_number2_Ref = {{cascite|correct|CAS}} | CAS_number2 = 121268-17-5 | UNII2_Ref = {{fdacite|correct|FDA}} | UNII2 = 2UY4M2U3RA | CAS_number_Ref = {{cascite|correct|CAS}} | CAS_number = 66376-36-1 | CAS_supplemental = | PubChem = 2088 | IUPHAR_ligand = 3141 | DrugBank_Ref = {{drugbankcite|correct|drugbank}} | DrugBank = DB00630 | ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}} | ChemSpiderID = 2004 | UNII_Ref = {{fdacite|changed|FDA}} | UNII = X1J18R4W8P | KEGG_Ref = {{keggcite|changed|kegg}} | KEGG = D07119 | KEGG2_Ref = {{keggcite|changed|kegg}} | KEGG2 = D00939 | ChEBI_Ref = {{ebicite|correct|EBI}} | ChEBI = 2567 | ChEMBL_Ref = {{ebicite|correct|EBI}} | ChEMBL = 870 | NIAID_ChemDB = | PDB_ligand = | synonyms = Alendronate

<!-- Chemical and physical data --> | IUPAC_name = sodium [4-amino-1-hydroxy-1-(hydroxy-oxido-phosphoryl)- butyl]phosphonic acid trihydrate | C=4 | H=13 | N=1 | O=7 | P=2 | SMILES = O=P(O)(O)C(O)(CCCN)P(=O)(O)O | StdInChI_Ref = {{stdinchicite|correct|chemspider}} | StdInChI = 1S/C4H13NO7P2/c5-3-1-2-4(6,13(7,8)9)14(10,11)12/h6H,1-3,5H2,(H2,7,8,9)(H2,10,11,12) | StdInChI_comment = | StdInChIKey_Ref = {{stdinchicite|correct|chemspider}} | StdInChIKey = OGSPWJRAVKPPFI-UHFFFAOYSA-N | density = | density_notes = | melting_point = | melting_high = | melting_notes = | boiling_point = | boiling_notes = | solubility = | sol_units = | specific_rotation = }}

<!-- Definition and medical uses --> '''Alendronic acid''' or Alendronate, sold under the brand name '''Fosamax''' among others, is a bisphosphonate medication used to treat osteoporosis and Paget's disease of bone, which works by decreasing the activity of osteoclasts, the cells that break down bone.<ref name=AHFS2019/> It is taken by mouth as the neutral sodium salt, alendronate sodium, but is absorbed as the active free drug alendronic acid.<ref name=AHFS2019/> Use is often recommended together with vitamin D, calcium supplementation, and lifestyle changes.<ref name=AHFS2019>{{cite web |title=Fosamax Monograph for Professionals |url=https://www.drugs.com/monograph/fosamax.html |website=Drugs.com |publisher=American Society of Health-System Pharmacists |access-date=2 February 2019 |language=en}}</ref>

<!-- Side effects and mechanism --> Common side effects (1 to 10% of patients) include constipation, abdominal pain, nausea, and acid reflux;<ref name="AHFS2019" /> though the rate of all side effects were found by the Fracture Intervention Trial, which followed 2,027 women with osteoporosis for three years, to be nearly identical to that of the placebo. The study further found that the risk of a serious upper gastrointestinal adverse event was 60% lower (p<0.01) for the drug versus the placebo.<ref name="BlackEAlancet">{{cite journal | author = Black, DM; Cummings, SR; Karpf, DB; Cauley, JA; Thompson, DE; Nevitt, MC; Bauer, DC; Genant, HK; Haskell, WL; Marcus, R; Ott, SM; Torner, JC; Quandt, SA; Reiss, TF & Ensrud, KE for the Fracture Intervention Trial Research Group | date = 1996 | title = Randomised Trial of Effect of Alendronate on Risk of Fracture in Women with Existing Vertebral Fractures | journal = Lancet | volume = 348 | pages = 1535-1541 | url = | access-date = | doi = | pmid = }}{{full|date=December 2025}}</ref>{{full|date=December 2025}} Use is not recommended during pregnancy or in those with poor kidney function.<ref name=BNF76>{{cite book |title=British National Formulary : BNF 76 |date=2018 |publisher=Pharmaceutical Press|isbn=978-0-85711-338-2 |pages=710–711 |edition=76}}</ref>

<!-- History and culture --> Alendronic acid was first described in 1978 and approved for medical use in the United States in 1995 as alendronate sodium (Fosamax).<ref name=AHFS2019/><ref name=Fis2006>{{cite book | vauthors = Fischer J, Ganellin CR |title=Analogue-based Drug Discovery |date=2006 |publisher=John Wiley & Sons |isbn=978-3-527-60749-5 |page=523 |url=https://books.google.com/books?id=FjKfqkaKkAAC&pg=PA523 }}</ref> It is available as a <span lang="en" dir="ltr">generic medication</span>. In 2023, it was the 113th most commonly prescribed medication in the United States, with more than 5{{nbsp}}million prescriptions.<ref name="Top300Drugs">{{cite web | title=Top 300 of 2023 | url=https://clincalc.com/DrugStats/Top300Drugs.aspx | website=ClinCalc | access-date=12 August 2025 | archive-date=12 August 2025 | archive-url=https://web.archive.org/web/20250812130026/https://clincalc.com/DrugStats/Top300Drugs.aspx | url-status=live }}</ref><ref>{{cite web | title = Alendronate Drug Usage Statistics, United States, 2014 - 2023 | website = ClinCalc | url = https://clincalc.com/DrugStats/Drugs/Alendronate | access-date = 18 August 2025 }}</ref>

==Medical uses== Alendronatec sodium is indicated for the treatment and prevention of osteoporosis in postmenopausal women;<ref name="Fosamax FDA label" /> the treatment to increase bone mass in men with osteoporosis;<ref name="Fosamax FDA label" /> the treatment of glucocorticoid-induced osteoporosis;<ref name="Fosamax FDA label" /> and the treatment of Paget's disease of bone.<ref name="Fosamax FDA label" /><ref name=AHFS2019 />

==Side effects== * Gastrointestinal tract: **Ulceration and possible rupture of the esophagus; this may require hospitalization and intensive treatment. Gastric and duodenal ulceration may also occur. ** Esophageal cancer, a meta-analysis concluded that bisphosphonate treatment is ''not'' associated with excess risk of esophageal cancer.<ref name="pmid23052941">{{cite journal | vauthors = Sun K, Liu JM, Sun HX, Lu N, Ning G | title = Bisphosphonate treatment and risk of esophageal cancer: a meta-analysis of observational studies | journal = Osteoporosis International | volume = 24 | issue = 1 | pages = 279–286 | date = January 2013 | pmid = 23052941 | doi = 10.1007/s00198-012-2158-8 | s2cid = 12625687 }}</ref><ref name="pmid22333262">{{cite journal | vauthors = Haber SL, McNatty D | title = An evaluation of the use of oral bisphosphonates and risk of esophageal cancer | journal = The Annals of Pharmacotherapy | volume = 46 | issue = 3 | pages = 419–423 | date = March 2012 | pmid = 22333262 | doi = 10.1345/aph.1Q482 | s2cid = 38417272 }}</ref> * General: infrequent cases of skin rash, rarely manifesting as Stevens–Johnson syndrome and toxic epidermal necrolysis, eye problems (uveitis, scleritis) and generalized muscle, joint, and bone pain<ref>{{cite web | url = http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/psn/transcript.cfm?show=73#3 | archive-url = https://web.archive.org/web/20140415204120/http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/psn/transcript.cfm?show=73 | archive-date = 15 April 2014 | title = Severe Pain with Osteoporosis Drugs | work = FDA Patient Safety News | date = March 2008 }}</ref> (rarely severe) have been reported. * Osteonecrosis of the jaw (ONJ) may occur while on this drug, if dental work of any kind is carried out. The risk is considerably higher for extractions in the mandible (lower jaw) than other areas of the mouth, and the risk increases if you have been taking it for four or more years <ref>{{cite web | url = http://www.merck.com/product/usa/pi_circulars/f/fosamax/fosamax_pi.pdf | title = Fosamax product description | work = Merck & Co }}</ref> Although this side effect is uncommon (0.4-1.6% for oral alendronic acid), it occurs primarily in patients being administered intravenous bisphosphonates, with most cases being reported in cancer patients.<ref>{{cite journal | vauthors = Pazianas M, Miller P, Blumentals WA, Bernal M, Kothawala P | title = A review of the literature on osteonecrosis of the jaw in patients with osteoporosis treated with oral bisphosphonates: prevalence, risk factors, and clinical characteristics | journal = Clinical Therapeutics | volume = 29 | issue = 8 | pages = 1548–1558 | date = August 2007 | pmid = 17919538 | doi = 10.1016/j.clinthera.2007.08.008 }}</ref><ref>{{cite journal | vauthors = Carini F, Barbano L, Saggese V, Monai D, Porcaro G | title = Multiple systemic diseases complicated by bisphosphonate osteonecrosis: a case report | journal = Annali di Stomatologia | volume = 3 | issue = 2 Suppl | pages = 32–36 | date = April 2012 | pmid = 23285320 | pmc = 3512552 }}</ref> In fact, while ONJ was demonstrated in the RCTs of the two IV bisphosphonates dosed at higher dose and more frequently in patients with cancer, ONJ was not seen in meta-analysis of all of the osteoporosis RCTs that comprised the Fosamax clinical development program, or in an FDA analysis of all of the RCTs of 2–10 years in duration comprising almost 100,00 patient-years of RCT data from the clinical development programs for alendronate sodium (Fosamax), risedronate sodium (Actonel) ibandronate sodium (oral Boniva), ibandronic acid (IV Boniva), and zoledronic acid (Reclast). * Bone: alendronate has been linked in long-term users to the development of low-impact femoral fractures.<ref name="pmid18354114">{{cite journal | vauthors = Lenart BA, Lorich DG, Lane JM | title = Atypical fractures of the femoral diaphysis in postmenopausal women taking alendronate | journal = The New England Journal of Medicine | volume = 358 | issue = 12 | pages = 1304–1306 | date = March 2008 | pmid = 18354114 | doi = 10.1056/NEJMc0707493 | s2cid = 26968573 | doi-access = free }} *{{lay source |template=cite magazine | vauthors = Gordon S |date=19 March 2008 |title=Fosamax Linked to Unusual Femur Fractures |url=http://health.usnews.com/usnews/health/healthday/080319/fosamax-linked-to-unusual-femur-fractures.htm |archive-url=https://web.archive.org/web/20100416024059/http://health.usnews.com/usnews/health/healthday/080319/fosamax-linked-to-unusual-femur-fractures.htm |archive-date=16 April 2010 |magazine=U.S. News & World Report}}</ref> Further, studies suggest that users of alendronate have an increase in the numbers of osteoclasts and develop giant, more multinucleated osteoclasts; the significance of this development is unclear.<ref name="pmid19118304">{{cite journal | vauthors = Weinstein RS, Roberson PK, Manolagas SC | title = Giant osteoclast formation and long-term oral bisphosphonate therapy | journal = The New England Journal of Medicine | volume = 360 | issue = 1 | pages = 53–62 | date = January 2009 | pmid = 19118304 | pmc = 2866022 | doi = 10.1056/NEJMoa0802633 }} *{{lay source | vauthors = Gardner A |date=31 December 2008 |title=Osteoporosis Drug Prompts Increase in Certain Bone Cells |url=https://www.washingtonpost.com/wp-dyn/content/article/2008/12/31/AR2008123102537.html |newspaper=Washington Post}}</ref> Fosamax has been linked to a rare type of leg fracture that cuts straight across the upper thigh bone after little or no trauma (subtrochanteric fractures).<ref name="pmid18222447">{{cite journal | vauthors = Kwek EB, Goh SK, Koh JS, Png MA, Howe TS | title = An emerging pattern of subtrochanteric stress fractures: a long-term complication of alendronate therapy? | journal = Injury | volume = 39 | issue = 2 | pages = 224–231 | date = February 2008 | pmid = 18222447 | doi = 10.1016/j.injury.2007.08.036 }}</ref>

==Pharmacology== ===Mechanism of action=== Nitrogen containing bisphosphonates, which include ibandronate, pamidronate and alendronate exert their effects on osteoclasts mainly by inhibiting the synthesis of isoprenoid lipids such as isopentenyl diphosphate (IPP), farnesyl diphosphate (FPP), and geranylgeranyl diphosphate (GGPP) via the mevalonate pathway. These isoprenoids are used in posttranslational modification(prenylation) of small GTPases such as Ras, Rho, and Rac. These prenylated GTPases are necessary for various cellular processes including osteoclast morphology, endosome trafficking, and apoptosis. Alendronate has also been shown to impair the function of osteclast lysosomes.<ref>{{cite journal | vauthors = Rogers MJ, Gordon S, Benford HL, Coxon FP, Luckman SP, Monkkonen J, Frith JC | title = Cellular and molecular mechanisms of action of bisphosphonates | journal = Cancer | volume = 88 | issue = 12 Suppl | pages = 2961–2978 | date = June 2000 | pmid = 10898340 | doi = 10.1002/1097-0142(20000615)88:12+<2961::aid-cncr12>3.3.co;2-c }}</ref> {| class="wikitable" style = "float: right; margin-left:15px; text-align:center" |+Relative potency<ref>{{Cite book|title=Essentials of medical pharmacology| vauthors = Tripathi DK |isbn=978-9-350-25937-5 |edition= Seventh|location=New Delhi|oclc=868299888|date = 30 September 2013}}</ref> !Bisphosphonate !Relative potency |- |Etidronate ||1 |- |Tiludronate ||10 |- |Pamidronate ||100 |- |Alendronate ||100-500 |- |Ibandronate ||500-1000 |- |Risedronate ||1000 |- |Zoledronate ||5000 |}

===Pharmacokinetics=== The fraction of the drug that reaches the circulatory system intact (systemic bioavailability) after oral dosing is low, averaging only 0.6–0.7% in women and in men under fasting conditions. Intake together with meals and beverages other than water further reduces the bioavailability. The absorbed drug rapidly partitions, with approximately 50% binding to the exposed bone surface; the remainder is excreted unchanged by the kidneys. Unlike with most drugs, the strong negative charge on the two phosphonate moieties limits oral bioavailability, and, in turn, the exposure to tissues other than bone is very low. After absorption in the bone, alendronate has an estimated terminal elimination half-life of 10 years.<ref name="pmid8689235">{{cite journal | vauthors = Shinkai I, Ohta Y | title = New drugs--reports of new drugs recently approved by the FDA. Alendronate | journal = Bioorganic & Medicinal Chemistry | volume = 4 | issue = 1 | pages = 3–4 | date = January 1996 | pmid = 8689235 | doi = 10.1016/0968-0896(96)00042-9 }}</ref> {{Clear}}

== References == {{Reflist}}

{{Bisphosphonates}} {{Merck&Co}} {{Portal bar | Medicine}} {{Authority control}}

Category:Bisphosphonates Category:Farnesyl pyrophosphate synthase inhibitors Category:Drugs developed by Merck & Co. Category:Wikipedia medicine articles ready to translate