Alendronate

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).

Pharmacokinetics

The systemic bioavailability after oral dosing is only 0.6 % as well in women and in men (fasting state). Intake together with meals and certain drinks (coffee, orange juice) further reduces the bioavailability. Soft tissues and bones are fastly reached by about 50%. After resorption in the bone alendronate has an estimated terminal halflife of 10 years; the remainder is excreted unchanged by the kidneys.

Pharmacology

Alendronate blocks osteoclast-mediated bone-resorption. It is chemically related to etidronate and the N-containing bisphosphonates such as pamidronate, which with it shares the same mode of action. Its inhibition of bone-resorption is dose-dependent and 100 to 1,000 times stronger than the equimolar effect of etidronate. Theoretically, alendronate may also inhibit bone-mineralization but this effect is 6,000 times weaker than the inhibition of bone-resorption. 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. Hypocalcemia should therefore be corrected before starting therapy.

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

    • Contraindications and precautions

  • Acute inflammations of the gastrointestinal tract (esophagitis, gastritis, ulcerations)
  • Clinically manifest osteomalacia
  • Certain malformations and malfunctions of the oesophagus (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

    • Side-effects

  • GI tract: most prominent are harmless side effects such as mild nausea, dyspepsia, abdominal cramps, flatulence, diarrhoea, or obstipation. A severe side effect is an ulceration of the oesophagus 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..
  • Deterioration of the TM Joint can also result while on this drug if dental work of any kind 'needs' to be done.

    • 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 oestrogens/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.

    • 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 oesophageal damage. At least 30 minutes should be waited before meals or other beverages than water are taken in.

    Dosage forms

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

    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.

    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. As of May 2006, results of litigation have been mixed, with Merck winning 2 cases, losing 2 and receiving a split verdict on a fifth case. Difficulties facing those seeking damages center around the disputed connection between the drug and osteonecrosis of the jaw.

    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 phosphorous developed osteonecrosis of the jaw.

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