Wikipedia:WikiProject Chemicals/Chembox validation/VerifiedDataSandbox and Alendronic acid: Difference between pages

{{Short description|Chemical compound}}

{{Use dmy dates|date=February 2024}}

{{Infobox drug

| Watchedfields = changed

| verifiedrevid = 477314835

| image = Alendronic acid.svg

| width =

| alt =

| image2 = Alendronate-3D-balls.png

| width2 =

| alt2 =

| caption =

| USAN = alendronate sodium

<!-- Clinical data -->

| pronounce =

| tradename = Fosamax, Binosto, others

| Drugs.com = {{drugs.com|monograph|alendronate-sodium}}

| 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 = [[Oral 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 =

| legal_UN = <!-- N I, II, III, IV / P I, II, III, IV -->

| legal_UN_comment =

| legal_status = <!-- For countries not listed above -->

<!-- Pharmacokinetic data -->

| protein_bound =

| metabolites =

| onset =

| 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 =

| IUPHAR_ligand = 3141

| DrugBank_Ref = {{drugbankcite|correct|drugbank}}

| UNII = X1J18R4W8P

| KEGG = D07119

| KEGG2_Ref = {{keggcite|changed|kegg}}

| KEGG2 = D00939

| 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_comment =

| density =

| density_notes =

| melting_point =

| melting_high =

| melting_notes =

| boiling_point =

| boiling_notes =

| solubility =

| sol_units =

| specific_rotation =

<!-- Definition and medical uses -->

'''Alendronic acid''', sold under the brand name '''Fosamax''' among others, is a [[bisphosphonate]] [[medication]] used to treat [[osteoporosis]] and [[Paget's disease of bone]].<ref name=AHFS2019/> It is taken by mouth.<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 [[gastroesophageal reflux disease|acid reflux]].<ref name=AHFS2019/> Use is not recommended during [[pregnancy]] or in those with [[chronic kidney disease|poor kidney function]].<ref name=BNF76>{{cite book |title=British National Formulary : BNF 76 |date=2018 |publisher=Pharmaceutical Pres s|isbn=978-0-85711-338-2 |pages=710–711 |edition=76}}</ref> Alendronic acid works by decreasing the activity of cells that break down bone.<ref name=AHFS2019/>

<!-- History and culture -->

Alendronic acid was first described in 1978 and approved for medical use in the United States in 1995.<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 [[generic medication]]. In 2021, it was the 94th most commonly prescribed medication in the United States, with more than 7{{nbsp}}million prescriptions.<ref>{{cite web | title=The Top 300 of 2021 | url=https://clincalc.com/DrugStats/Top300Drugs.aspx | website=ClinCalc | access-date=14 January 2024 | archive-date=15 January 2024 | archive-url=https://web.archive.org/web/20240115223848/https://clincalc.com/DrugStats/Top300Drugs.aspx | url-status=live }}</ref><ref>{{cite web | title = Alendronate - Drug Usage Statistics | website = ClinCalc | url = https://clincalc.com/DrugStats/Drugs/Alendronate | access-date = 14 January 2024}}</ref>

==Medical uses==

[[File:003783568lg Alendronic acid 35 MG (as alendronate sodium 45.7 MG) Oral Tablet.jpg|thumb|Alendronic acid 35&nbsp;mg (as alendronate sodium 45.7&nbsp;mg) oral tablet|alt=]]

* Prevention and treatment of female [[osteoporosis]]<ref name=AHFS2019/>

* Treatment of male osteoporosis

* Prevention and treatment of corticosteroid-associated osteoporosis together with supplements of calcium and vitamin D<ref name=AHFS2019/>

* [[Paget's disease of bone|Paget's disease]]<ref name=AHFS2019/>

==Contraindications==

Alendronate should not be used in:

* Acute inflammations of the gastrointestinal tract (esophagitis, gastritis, ulcerations)

* Clinically manifested [[osteomalacia]]

* Certain malformations and malfunctions of the esophagus (strictures, achalasia)<ref name=AHFS2019/>

* Inability to stand, walk, or sit for 30 minutes after oral administration

* Renal impairment or chronic kidney disease as evidenced by a creatinine clearance below 30ml/min

* Hypersensitivity to alendronate or another ingredient in the product

* Hypocalcemia<ref name=AHFS2019/>

* Pregnancy and breastfeeding

* Patients below 18 yrs. of age, as no clinical data exists for this population

==Side effects==

* Gastrointestinal tract:

**[[Peptic ulcer|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. In laboratory tests, decreased calcium and phosphate values may be seen but reflect expected action of the drug and are almost always not clinically relevant.

* [[Osteonecrosis of the jaw]] 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>

* 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 [[osteoclast]]s 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>

== Interactions ==

* Food and drugs containing large amounts of calcium, magnesium or aluminium (antacids) decrease the absorption of alendronate. At least half an hour should pass after intake of alendronate before eating dairy products or taking the supplement or drug.

* Highly active vitamin D analogues or fluorides:{{clarify|date=October 2021}} no data is available. Concomitant treatment should be avoided.{{cn|date=October 2021}}

* The additional beneficial effect of [[Hormone replacement therapy (menopause)|HRT]] (hormone replacement therapy) with [[estrogens]]/[[progestins]] or [[raloxifene]] in postmenopausal women with osteoporosis remains to be elucidated, but no interactions have been seen. The combination is therefore possible, but controversial.

* Intravenous [[ranitidine]] increases the oral bioavailability of alendronate. No clinical consequences are known.

* The combination of [[Non-steroidal anti-inflammatory drug|NSAID]]s and alendronate may increase the risk of gastric ulcers. Both these drugs have the potential to irritate the upper gastro-intestinal mucosa.

==Pharmacology==

===Mechanism of action===

{| 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

|-

|[[Etidronic acid|Etidronate]] ||1

|-

|[[Tiludronic acid|Tiludronate]] ||10

|-

|[[Pamidronic acid|Pamidronate]] ||100

|-

|Alendronate ||100-500

|-

|[[Ibandronic acid|Ibandronate]] ||500-1000

|-

|[[Risedronic acid|Risedronate]] ||1000

|-

|[[Zoledronic acid|Zoledronate]] ||5000

|}

Alendronate inhibits [[osteoclast]]-mediated bone-resorption. Like all [[bisphosphonate]]s, it is chemically related to inorganic [[pyrophosphate]], the endogenous regulator of bone turnover. But while pyrophosphate inhibits both osteoclastic [[bone resorption]] and the mineralization of the bone newly formed by [[osteoblast]]s, alendronate specifically inhibits bone resorption without any effect on mineralization at pharmacologically achievable doses. Its inhibition of bone-resorption is dose-dependent and approximately 1,000 times stronger than the equimolar effect of the first bisphosphonate drug, [[etidronate]]. Under therapy, normal bone tissue develops, and alendronate is deposited in the bone-matrix in a pharmacologically inactive form. For optimal action, enough calcium and vitamin D are needed in the body in order to promote normal bone development. [[Hypocalcemia]] should, therefore, be corrected before starting therapy.

Etidronate has the same disadvantage as pyrophosphate in inhibiting mineralization, but all of the potent ''[[nitrogen|N]]''-containing bisphosphonates, including alendronate, [[risedronate]], [[ibandronate]], and [[zoledronate]], do not.

===Pharmacokinetics===

As with all potent bisphosphonates, 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 [[ Partition (chemistry) |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 [[ Moiety (chemistry)#Active moiety |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>

{{-}}

== References ==

{{Reflist}}

{{Bisphosphonates}}

{{Merck&Co}}

{{Portal bar | Medicine}}

[[Category:Bisphosphonates]]

[[Category:Farnesyl pyrophosphate synthase inhibitors]]

[[Category:Drugs developed by Merck & Co.]]

[[Category:Wikipedia medicine articles ready to translate]]