Alendronic acid

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Alendronic acid
Alendronsäure.png
Alendronate sf.png
Systematic (IUPAC) name
sodium [4-amino-1-hydroxy-1-(hydroxy-oxido-phosphoryl)- butyl]phosphonic acid trihydrate
Clinical data
Trade names Fosamax
AHFS/Drugs.com monograph
MedlinePlus a601011
Pregnancy cat. C
Legal status ?
Routes Oral
Pharmacokinetic data
Bioavailability 0.6%
Metabolism excreted unchanged
Half-life 126 months
Excretion renal
Identifiers
CAS number 121268-17-5 N
ATC code M05BA04
PubChem CID 2088
DrugBank DB00630
ChemSpider 2004 YesY
UNII X1J18R4W8P N
KEGG D07119 N
ChEBI CHEBI:2567 YesY
ChEMBL CHEMBL870 YesY
Chemical data
Formula C4H13NO7P2 
Mol. mass 249.097
 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.

Pharmacokinetics[edit]

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 elimination half-life of 10 years.[2]

Pharmacology[edit]

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[edit]

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[edit]

  • Prophylaxis and treatment of female osteoporosis
  • Treatment of male osteoporosis
  • Prevention and treatment of corticosteroid-associated osteoporosis together with supplements of calcium and vitamin D
  • Paget's disease
  • Experimental treatment for Osteogenesis imperfecta

Contraindications and precautions[edit]

  • Acute inflammations of the gastrointestinal tract (esophagitis, gastritis, ulcerations)
  • Clinically manifest osteomalacia
  • Certain malformations and malfunctions of the esophagus (strictures, achalasia)
  • Inability to stand, walk, or sit for 30 minutes after oral administration
  • Renal impairment with a creatinine clearance below 30ml/min
  • Hypersensitivity to alendronate or another ingredient
  • Hypocalcemia
  • Pregnancy and breastfeeding
  • Patients below 18 yrs. of age, as no clinical data exists

Side-effects[edit]

  • Gastrointestinal tract:
    • ulceration 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 significantly associated with excess risk of esophageal cancer.[4][5]
  • 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 [6] (rarely severe) have been seen. In laboratory tests decreased calcium and phosphate values may be obtained but reflect action of the drug and are harmless.
  • Osteonecrosis of the Jaw - Deterioration of the Temporomandibular Joint (TMJ) may occur while on this drug, if dental work of any kind is carried out.[7] Although this side effect is uncommon, it occurs primarily in patients being administered intravenous biphosphonates, with most cases being reported in cancer patients.[8][9]
  • Neurological: Rare instances of auditory hallucinations and visual disturbances have been associated with alendronate and other bisphosphonates.[10]
  • Bone: Alendronate has been linked in long-term users to the development of low-impact femoral fractures.[11] 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.[12] 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).[13] This is because Fosamax makes the thigh bone more brittle and stops the cells in the body that remodel the bone. Studies are showing that people who have taken Fosamax for more than five years are at risk for developing fractures of this kind. In some cases, patients have reported that, after weeks or months of unexplained aching, their thigh bones simply snapped while they were walking or standing. One doctor reports that a 59-year old previously healthy woman visiting New York City was riding a subway train one morning when the train jolted. She shifted all her weight to one leg, felt a bone snap, and fell to the floor of the train. An x-ray in a local emergency room revealed a comminuted spiral fracture involving the upper half of the right femur. She had been taking Fosamax for 7 years.[14] On Oct. 13, 2010 the Food and Drug Administration issued a warning about these fractures.[15]

Interactions[edit]

  • Milk, diet, and drugs containing high amounts of calcium, magnesium or aluminium (antacids): the absorption of alendronate is decreased. At least half an hour should pass after intake of alendronate before taking the supplement or drug.
  • Highly active vitamin D analogues or fluorides: no data is available. Concomitant treatment should be avoided.
  • The additional beneficial effect of HRT (hormone replacement therapy) with estrogens/progestins or raloxifene in postmenopausal women remains to be elucidated, but no interactions have been seen. The combination is therefore possible.
  • Intravenous ranitidine increases the oral bioavailability of alendronate. No clinical consequences are known.
  • The combination of NSAIDs and alendronate may increase the risk of gastric ulcers. Both these drugs have the potential to irritate the upper gastro-intestinal mucosa.

Dosage[edit]

  • Prophylaxis of osteoporosis in women: 5–10 mg daily or 35–70 mg weekly.
  • Therapy of osteoporosis in women and men : 10 mg daily or 70 mg weekly.
  • Osteoporosis under corticosteroids: 5–10 mg daily or 35–70 mg weekly in men and premenopausal women or those receiving concomitant HRT. In postmenopausal women not receiving HRT, the recommended dose is 10 mg daily or 70 mg weekly.
  • Paget's Disease: 40 mg daily for 6 months.

The risk of esophageal irritation places special requirements on how this oral drug is taken. The patient should take the drug only upon rising for the day with 8 oz. of water, and stand, walk, or sit, and remain fasting for 30–45 minutes afterwards (preferably 1–2 hours), then eat breakfast. No other medications should be taken for this time. 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[edit]

  • Fosamax solution 70 mg/75ml
  • Fosamax tablets 5 mg, 10 mg, 35 mg, 40 mg, and 70 mg

Bis-phossy jaw[edit]

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[edit]

  1. ^ "First Generic Fosamax OK'd by FDA". Archived from the original on 10 February 2008. 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". Osteoporosis International 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 (8): 1548–58. doi:10.1016/j.clinthera.2007.08.008. PMID 17919538. Retrieved 2013-03-06. 
  9. ^ Carini, F.; Barbano L; Saggese V; Monai D; Porcaro G. (2012-04-03). "Multiple systemic diseases complicated by bisphosphonate osteonecrosis: a case report.". Ann Stomatol (Roma) 3 (2 Suppl): 32–6. PMID 23285320. Retrieved 6 March 2013. 
  10. ^ Craig I. Coleman, Kristen A. Perkerson, Anne Lewis (July 2, 2004). "Alendronate-Induced Auditory Hallucinations and Visual Disturbances". 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 summaryUS 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. Lay summaryWashington 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. 

External links[edit]