alendronate

Alendronic acid
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
ChemSpider	2004
Chemical data
Formula	C4H18NNaO10P2
Mol. mass	325.124
SMILES	eMolecules & PubChem
Pharmacokinetic data
Bioavailability	0.6%
Metabolism	excreted unchanged
Half life	126 months
Excretion	renal
Therapeutic considerations
Pregnancy cat.	C
Legal status	POM (UK), Rx-only (US)
Routes	Oral

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 U and 5600 U, 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 are being marketed by Barr Pharmaceuticals and Teva Pharmaceuticals USA. Teva Pharmaceuticals will make generic alendronate in 5-milligram, 10-milligram, and 40-milligram daily doses, and in 35-milligram and 70-milligram weekly doses, while Barr will make generic alendronate in 70-milligram tablets, which are taken once a week. Teva and Barr have already begun shipping their generic versions of alendronate to stores.^[1]

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 phosphate 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. 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 risedronate and 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.

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.

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 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

Side-effects

• Gastrointestinal tract: ulceration of the esophagus; this may require hospitalization and intensive treatment. Gastric and duodenal ulceration may also occur. December 31, 2008, FDA reported alendronate and related drugs, may carry an increased risk for esophageal cancer.[1]
• 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 [2] (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. Although osteonecrosis is uncommon, it occurs primarily in patients being administered intravenous biphosphonates, with most cases being reported in cancer patients.^{[citation needed]}
• Neurological: Rare instances of auditory hallucinations and visual disturbances have been associated with alendronate and other bisphosphonates.[3]
• Bone: reported increases in osteoclast numbers, cellular morphology and nuclear morphology. At this point, it's unclear what these findings mean in the "real world". Right now, we're just learning these nuances. said Dr. James Liu, chairman of the department of obstetrics and gynecology at MacDonald Women's Hospital at Case Medical Center. Whether these findings will signal future problems is an open question said study lead author Dr. Robert S. Weinstein, at Central Arkansas Veterans Healthcare System and a professor of medicine at University of Arkansas for Medical Sciences. [4]

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 may increase the risk of gastric ulcers. Both these drugs have the potential to irritate the upper gastro-intestinal mucosa.

Dosage

• Prophylaxis of osteoporosis in women: 5-10 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 drug is to be taken only upon rising for the day with three swallows of water, not to exceed 6-8 oz. Stand, walk or sit and remain fasting for 30-45 minutes afterwards, then eat breakfast. Lying down or reclining prior to eating breakfast may cause gastroesophageal reflux and esophageal irritation. At least 30 minutes should be allowed to pass before meals or other beverages than water are taken in.

On December 31, 2008, a letter in the New England Journal of Medicine, cited a finding by the U.S. Food and Drug Administration that 23 cases of esophageal cancer, possibly linked to the use of the drug, have been seen since Fosamax's 1995 market debut.^[3]

Dosage forms

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

Litigation

By 2000 the FDA had received 139 spontaneous reports through the MedWatch system of osteonecrosis of the jaw (ONJ) in cancer patients treated with intravenous (IV) bisphopshonates, either IV pamidronate (Aredia) or IV zolendronate (Zometa).

At the 2004 ODAC meeting the number of spontaneous reports had increased since 2000, and although almost all of the reports remained in cancer patients treated with one of the IV bisphosphonates 13 of the reports were in patients taking oral alendronate or risedronate, most of which were reported on September 24, 2004, in the Journal of Oral and Maxillofacial Surgery. Although this small number of reports does not remotely indicate causality, given the millions of patients who have been treated with alendronate and risedronate, in order to be cautious the FDA asked the manufacturers of the oral bisphosphonates to issue a warning to health care professionals of the potential that bisphosphonates might increase the risk of ONJ.

Despite the fact that no data links the oral bisphosphonates causally to ONJ, product liability attorneys immediately filed suit maintaining that their claimants' ONJ is a direct result of the use of alendronate. 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. As of May 13, 2007, hundreds of cases had been filed against Merck alleging Fosamax-induced ONJ. The first case is set to be tried in late 2008.

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

External links

• Fosamax information from Merck
• RxList page
• MedlinePlus listing
• Pharmacotherapy 24(6):799-802, 2004
• Fosamax Overview @ FDA