Alendronate

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Alendronate
Systematic (IUPAC) name
sodium [4-amino-1-hydroxy-1-(hydroxy-oxido-phosphoryl)- butyl]phosphonic acid trihydrate
Identifiers
CAS number 121268-17-5
ATC code M05BA04
PubChem 2088
DrugBank APRD00561
Chemical data
Formula C4H18NNaO10P2 
Mol. mass 325.124
Pharmacokinetic data
Bioavailability 0.6%
Metabolism excreted unchanged
Half life 126 months
Excretion renal
Therapeutic considerations
Pregnancy cat.

?
Legal status

POM (UK)
Routes oral tablets

Alendronate (Fosamax®, 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 U, under the name Fosavance).

Contents

[edit] 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. But to the strong negative charge on the two phosphate moieties, which limit oral bioavailability, unlike most drugs the exposure of tissues other than bone is very low. After absorption in the bone, alendronate has an estimated terminal half-life of 10 years.

[edit] Pharmacology

Alendronate inhibits osteoclast-mediated bone-resorption. Like all bisphosphonates It is chemically related to inorganic pyrophosphate, the endogenous regulator of bone turnover. Whereas pyrophosphate and the first bisphosphonate, etidronate, are capable of inhibiting both osteoclastic bone resorption as well as the mineralization of the bone newly formed by osteoblasts, alendronate and the other potent N-containing bisphosphonates such as ibandronate and zoledronate specifically inhibit bone resorption without any effect on mineralization at pharmacalogically achievable doses. Its inhibition of bone-resorption is dose-dependent and approximately 1,000 times stronger than the equimolar effect of 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.

[edit] Uses

  • 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

[edit] Contraindications and precautions

  • 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, because no clinical data exists

[edit] Side-effects

  • GI tract: most prominent are harmless side effects such as mild nausea, dyspepsia, abdominal cramps, flatulence, diarrhea, or obstipation. A severe side effect is an ulceration of the esophagus caused by alendronate, which may require hospitalization and intensive treatment. Gastric and duodenal ulceration.
  • 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 (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.
  • Cases of osteonecrosis of the jaw have been reported in the scientific literature..
  • Osteonecrosis of the Jaw- Deterioration of the TM Joint can also result while on this drug if dental work of any kind 'needs' to be done. Although not common, this may result when patients of on the intravenous alendronate and most cases have been reported in cancer patients.
  • Rare instances of auditory hallucinations and visual disturbances have been associated with alendronate and other bisphosphonates.[1]

[edit] Interactions

  • Milk, diet and drugs containing high amounts of calcium, magnesium or aluminium (antacids): the resorption 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 alendroate increases the risk of gastric ulcers. Both these drugs have the potential to irritate the upper gastro-intestinal mucosa.

[edit] Dosage

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

The drug is to be taken only upon rising for the day with plenty of water. Stand, walk or sit 30 minutes afterwards to avoid esophageal damage. At least 30 minutes should be waited before meals or other beverages than water are taken in.

[edit] Dosage forms

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

[edit] Patent Remarks (USA)

Its patent is set to expire in 2008 and Merck has lost a series of appeals to block a generic version of the drug from being certified by the US FDA.

[edit] Litigation

On September 24, 2004 the Journal of Oral and Maxillofacial Surgeons issued a report prompting the US Food and Drug Administration (FDA) and Merck to issue a warning to health care professionals concerning Alendronate and its brand name equivalent, Fosamax. As indicated in the side-effects, Alendronate was connected to osteonecrosis of the jaw (ONJ). Product liability attorneys maintain this condition is far more widespread than initially indicated. Moreover, pending lawsuits maintain claimants' ONJ is a direct result of the use of Alendronate, while Merck has stated the "underlying cause" of osteonecrosis of the jaw is "uncertain," though it might be triggered by a traumatic event like tooth extraction or oral surgery. Plaintiffs claim that the tooth extraction and oral surgery wouldn't be a problem if their jaws hadn't been damaged by the drug.

[edit] 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.

[edit] External links

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v • d • e
Bisphosphonates (M05A)

Nitrogenous: Pamidronic acid, Alendronic acid, Ibandronic acid, Risedronic acid, Zoledronic acid

Non-nitrogenous: Etidronic acid, Clodronic acid, Tiludronic acid

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