Alendronic acid

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Alendronic acid
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Clinical data
Trade namesFosamax, Binosto, others
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AHFS/Drugs.comMonograph
MedlinePlusa601011
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Pregnancy
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Routes of
administration		By mouth
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Legal status
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Pharmacokinetic data
Bioavailability0.6%
Metabolismexcreted unchanged
Elimination half-life126 months
ExcretionKidney
Identifiers
  • sodium [4-amino-1-hydroxy-1-(hydroxy-oxido-phosphoryl)- butyl]phosphonic acid trihydrate
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Chemical and physical data
FormulaC4H13NO7P2
Molar mass249.096 g·mol−1
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  • Key:OGSPWJRAVKPPFI-UHFFFAOYSA-N checkY
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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.[4] It is taken by mouth as the neutral sodium salt, alendronate sodium, but is absorbed as the active free drug alendronic acid.[4] Use is often recommended together with vitamin D, calcium supplementation, and lifestyle changes.[4]

Common side effects (1 to 10% of patients) include constipation, abdominal pain, nausea, and acid reflux;[4] 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.[5][full citation needed] Use is not recommended during pregnancy or in those with poor kidney function.[6]

Alendronic acid was first described in 1978 and approved for medical use in the United States in 1995 as alendronate sodium (Fosamax).[4][7] It is available as a generic medication. In 2023, it was the 113th most commonly prescribed medication in the United States, with more than 5 million prescriptions.[8][9]

Medical uses

Alendronatec sodium is indicated for the treatment and prevention of osteoporosis in postmenopausal women;[3] the treatment to increase bone mass in men with osteoporosis;[3] the treatment of glucocorticoid-induced osteoporosis;[3] and the treatment of Paget's disease of bone.[3][4]

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.[10][11]
  • 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[12] (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 [13] 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.[14][15] 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.[16] 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.[17] 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).[18]

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.[19]

Relative potency[20]
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.[21]

References

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  1. ^ Page Module:Citation/CS1/styles.css has no content."Alendronate Use During Pregnancy". Drugs.com. 22 August 2019. Retrieved 17 May 2020.
  2. ^ Page Module:Citation/CS1/styles.css has no content."Product monograph brand safety updates". Health Canada. 7 July 2016. Retrieved 3 April 2024.
  3. ^ a b c d e Page Module:Citation/CS1/styles.css has no content."Fosamax- alendronate sodium tablet". DailyMed. 16 April 2024. Retrieved 30 September 2024.
  4. ^ a b c d e f Page Module:Citation/CS1/styles.css has no content."Fosamax Monograph for Professionals". Drugs.com. American Society of Health-System Pharmacists. Retrieved 2 February 2019.
  5. ^ Page Module:Citation/CS1/styles.css has no content.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 (1996). "Randomised Trial of Effect of Alendronate on Risk of Fracture in Women with Existing Vertebral Fractures". Lancet. 348: 1535–1541.{{cite journal}}: CS1 maint: multiple names: authors list (link)[full citation needed]
  6. ^ Page Module:Citation/CS1/styles.css has no content.British National Formulary : BNF 76 (76 ed.). Pharmaceutical Press. 2018. pp. 710–711. ISBN 978-0-85711-338-2.
  7. ^ Page Module:Citation/CS1/styles.css has no content.Fischer J, Ganellin CR (2006). Analogue-based Drug Discovery. John Wiley & Sons. p. 523. ISBN 978-3-527-60749-5.
  8. ^ Page Module:Citation/CS1/styles.css has no content."Top 300 of 2023". ClinCalc. Archived from the original on 12 August 2025. Retrieved 12 August 2025.
  9. ^ Page Module:Citation/CS1/styles.css has no content."Alendronate Drug Usage Statistics, United States, 2014 - 2023". ClinCalc. Retrieved 18 August 2025.
  10. ^ Page Module:Citation/CS1/styles.css has no content.Sun K, Liu JM, Sun HX, Lu N, Ning G (January 2013). "Bisphosphonate treatment and risk of esophageal cancer: a meta-analysis of observational studies". Osteoporosis International. 24 (1): 279–286. doi:10.1007/s00198-012-2158-8. PMID 23052941. S2CID 12625687.
  11. ^ Page Module:Citation/CS1/styles.css has no content.Haber SL, McNatty D (March 2012). "An evaluation of the use of oral bisphosphonates and risk of esophageal cancer". The Annals of Pharmacotherapy. 46 (3): 419–423. doi:10.1345/aph.1Q482. PMID 22333262. S2CID 38417272.
  12. ^ Page Module:Citation/CS1/styles.css has no content."Severe Pain with Osteoporosis Drugs". FDA Patient Safety News. March 2008. Archived from the original on 15 April 2014.
  13. ^ Page Module:Citation/CS1/styles.css has no content."Fosamax product description" (PDF). Merck & Co.
  14. ^ Page Module:Citation/CS1/styles.css has no content.Pazianas M, Miller P, Blumentals WA, Bernal M, Kothawala P (August 2007). "A review of the literature on osteonecrosis of the jaw in patients with osteoporosis treated with oral bisphosphonates: prevalence, risk factors, and clinical characteristics". Clinical Therapeutics. 29 (8): 1548–1558. doi:10.1016/j.clinthera.2007.08.008. PMID 17919538.
  15. ^ Page Module:Citation/CS1/styles.css has no content.Carini F, Barbano L, Saggese V, Monai D, Porcaro G (April 2012). "Multiple systemic diseases complicated by bisphosphonate osteonecrosis: a case report". Annali di Stomatologia. 3 (2 Suppl): 32–36. PMC 3512552. PMID 23285320.
  16. ^ Page Module:Citation/CS1/styles.css has no content.Lenart BA, Lorich DG, Lane JM (March 2008). "Atypical fractures of the femoral diaphysis in postmenopausal women taking alendronate". The New England Journal of Medicine. 358 (12): 1304–1306. doi:10.1056/NEJMc0707493. PMID 18354114. S2CID 26968573.
  17. ^ Page Module:Citation/CS1/styles.css has no content.Weinstein RS, Roberson PK, Manolagas SC (January 2009). "Giant osteoclast formation and long-term oral bisphosphonate therapy". The New England Journal of Medicine. 360 (1): 53–62. doi:10.1056/NEJMoa0802633. PMC 2866022. PMID 19118304.
  18. ^ Page Module:Citation/CS1/styles.css has no content.Kwek EB, Goh SK, Koh JS, Png MA, Howe TS (February 2008). "An emerging pattern of subtrochanteric stress fractures: a long-term complication of alendronate therapy?". Injury. 39 (2): 224–231. doi:10.1016/j.injury.2007.08.036. PMID 18222447.
  19. ^ Page Module:Citation/CS1/styles.css has no content.Rogers MJ, Gordon S, Benford HL, Coxon FP, Luckman SP, Monkkonen J, et al. (June 2000). "Cellular and molecular mechanisms of action of bisphosphonates". Cancer. 88 (12 Suppl): 2961–2978. doi:10.1002/1097-0142(20000615)88:12+<2961::aid-cncr12>3.3.co;2-c. PMID 10898340.
  20. ^ Page Module:Citation/CS1/styles.css has no content.Tripathi DK (30 September 2013). Essentials of medical pharmacology (Seventh ed.). New Delhi. ISBN 978-9-350-25937-5. OCLC 868299888.{{cite book}}: CS1 maint: location missing publisher (link)
  21. ^ Page Module:Citation/CS1/styles.css has no content.Shinkai I, Ohta Y (January 1996). "New drugs--reports of new drugs recently approved by the FDA. Alendronate". Bioorganic & Medicinal Chemistry. 4 (1): 3–4. doi:10.1016/0968-0896(96)00042-9. PMID 8689235.

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