Alendronic acid

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Alendronic acid
Systematic (IUPAC) name
sodium [4-amino-1-hydroxy-1-(hydroxy-oxido-phosphoryl)- butyl]phosphonic acid trihydrate
Clinical data
Trade namesFosamax
AHFS/Drugs.commonograph
MedlinePlusa601011
Pregnancy cat.C
Legal status ?
RoutesOral
Pharmacokinetic data
Bioavailability0.6%
Metabolismexcreted unchanged
Half-life126 months
Excretionrenal
Identifiers
CAS number121268-17-5 N
ATC codeM05BA04
PubChemCID 2088
DrugBankDB00630
ChemSpider2004 YesY
UNIIX1J18R4W8P N
KEGGD07119 N
ChEBICHEBI:2567 YesY
ChEMBLCHEMBL870 YesY
Chemical data
FormulaC4H18NNaO10P2 
Mol. mass325.124
 N (what is this?)  (verify)
 
  (Redirected from Fosamax)
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Alendronic acid
Systematic (IUPAC) name
sodium [4-amino-1-hydroxy-1-(hydroxy-oxido-phosphoryl)- butyl]phosphonic acid trihydrate
Clinical data
Trade namesFosamax
AHFS/Drugs.commonograph
MedlinePlusa601011
Pregnancy cat.C
Legal status ?
RoutesOral
Pharmacokinetic data
Bioavailability0.6%
Metabolismexcreted unchanged
Half-life126 months
Excretionrenal
Identifiers
CAS number121268-17-5 N
ATC codeM05BA04
PubChemCID 2088
DrugBankDB00630
ChemSpider2004 YesY
UNIIX1J18R4W8P N
KEGGD07119 N
ChEBICHEBI:2567 YesY
ChEMBLCHEMBL870 YesY
Chemical data
FormulaC4H18NNaO10P2 
Mol. mass325.124
 N (what is this?)  (verify)

Alendronic acid (INN) or alendronate sodium (USAN) — sold as Fosamax by Merck — is a bisphosphonate drug used for osteoporosis and several other bone diseases. It is marketed alone as well as in combination with vitamin D (2,800 IU and 5600 IU, under the name Fosamax+D). Merck's U.S. patent on alendronate expired in 2008 and Merck lost a series of appeals to block a generic version of the drug from being certified by the U.S. Food and Drug Administration (FDA).

On February 6, 2008, the US FDA approved the first generic versions of alendronate, which were marketed by Barr Pharmaceuticals and Teva Pharmaceuticals USA. Teva Pharmaceuticals manufactures generic alendronate in 5-milligram, 10-milligram, and 40-milligram daily doses, and in 35-milligram and 70-milligram weekly doses, while Barr made generic alendronate in 70-milligram tablets, which were taken once weekly.[1] Barr pharmaceuticals were subsequently acquired by Teva in July 2008.

Contents

Pharmacokinetics

As with all potent bisphosphonates, the 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 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 half-life of 10 years.[2]

Pharmacology

Alendronate inhibits osteoclast-mediated bone-resorption. Like all bisphosphonates, 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 osteoblasts, 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 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 N-containing bisphosphonates including Alendronate and also risedronate, ibandronate, and zoledronate, do not.

Clinical data

Treatment of post-menopausal women with Fosamax has demonstrated normalization of the rate of bone turnover, significant increase in BMD (bone mineral density) of the spine, hip, wrist and total body, and significant reductions in the risk of vertebral (spine) fractures, wrist fractures, hip fractures, and all non-vertebral fractures. In the women with the highest risk of fracture (by virtue of pre-existing vertebral fractures) in the Fracture Intervention Trial, treatment with Fosamax 5 mg/day for two years followed by 10 mg/day for the third year (plus calcium and vitamin D) resulted in approximately 50% reductions in fractures of the spine, hip, and wrist compared with the control group taking placebos plus calcium and vitamin D.[3]

Uses

Contraindications and precautions

Side-effects

Interactions

Dosage

The risk of esophageal irritation places special requirements on how one takes this oral drug. The patient should take the drug only upon rising for the day with three swallows of water, not to exceed 6-8 oz., and stand, walk, or sit, and remain fasting for 30–45 minutes afterwards, then eat breakfast. Lying down or reclining after taking the drug and prior to eating breakfast may cause gastroesophageal reflux and esophageal irritation.

Alendronic acid 35 MG (as alendronate sodium 45.7 MG) Oral Tablet

Dosage forms

Bis-phossy jaw

The term given by scientists to the link between bisphosphonates and jaw necrosis is 'bis-phossy jaw.' This is derived from the 19th-century term phossy jaw, given its name after workers in match factories working with white phosphorus developed osteonecrosis of the jaw.

References

  1. ^ "First Generic Fosamax OK'd by FDA". Archived from the original on 10 February 2008. http://www.rxlist.com/script/main/art.asp?articlekey=87025. Retrieved 2008-02-21.
  2. ^ Shinkai I, Ohta Y (January 1996). "New drugs--reports of new drugs recently approved by the FDA. Alendronate". Bioorg. Med. Chem. 4 (1): 3–4. doi:10.1016/0968-0896(96)00042-9. PMID 8689235.
  3. ^ 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 (December 1996). "Randomised trial of effect of alendronate on risk of fracture in women with existing vertebral fractures. Fracture Intervention Trial Research Group". Lancet 348 (9041): 1535–41. doi:10.1016/S0140-6736(96)07088-2. PMID 8950879.
  4. ^ Sun K, Liu JM, Sun HX, Lu N, Ning G (October 2012). "Bisphosphonate treatment and risk of esophageal cancer: a meta-analysis of observational studies". Osteoporos Int 24 (1): 279–86. doi:10.1007/s00198-012-2158-8. PMID 23052941.
  5. ^ Haber SL, McNatty D (March 2012). "An evaluation of the use of oral bisphosphonates and risk of esophageal cancer". Ann Pharmacother 46 (3): 419–23. doi:10.1345/aph.1Q482. PMID 22333262.
  6. ^ FDA Patient Safety News, March 2008
  7. ^ Fosamax product description, Merck & Co
  8. ^ Pazianas, M.; Miller P, Blumentals WA, Bernal M, Kothawala P (August 29, 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 Therapy 8: 1548-58. PMID 17919538. http://www.ncbi.nlm.nih.gov/pubmed/17919538. Retrieved 2013-03-06.
  9. ^ Carini, F.; Barbano L, Saggese V, Monai D, Porcaro G. (2012 April 3). Multiple systemic diseases complicated by bisphosphonate osteonecrosis: a case report.. PMID 23285320. http://www.ncbi.nlm.nih.gov/pubmed/23285320. Retrieved 6 March 2013.
  10. ^ Craig I. Coleman, Kristen A. Perkerson, Anne Lewis (July 2, 2004). "Alendronate-Induced Auditory Hallucinations and Visual Disturbances". http://www.medscape.com/viewarticle/481375_1. Retrieved March 9, 2010.
  11. ^ Lenart BA, Lorich DG, Lane JM (March 2008). "Atypical fractures of the femoral diaphysis in postmenopausal women taking alendronate". N. Engl. J. Med. 358 (12): 1304–6. doi:10.1056/NEJMc0707493. PMID 18354114. Lay summary – US News & World Report.
  12. ^ Weinstein RS, Roberson PK, Manolagas SC (January 2009). "Giant osteoclast formation and long-term oral bisphosphonate therapy". N. Engl. J. Med. 360 (1): 53–62. doi:10.1056/NEJMoa0802633. PMC 2866022. PMID 19118304. //www.ncbi.nlm.nih.gov/pmc/articles/PMC2866022/. Lay summary – Washington Post.
  13. ^ 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): 224–31. doi:10.1016/j.injury.2007.08.036. PMID 18222447.
  14. ^ Jennifer P. Schneider (2006). "Should Bisphosphonates be Continued Indefinitely? An Unusual Fracture in a Healthy Woman on Long-Term Alendronate". Geriatrics 61 (1): 31–33. PMID 16405362.
  15. ^ "Possible increased risk of thigh bone fracture with bisphosphonates" (Press release). Food and Drug Administration. Oct. 13, 2010. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm229171.htm.

External links