Alendronic acid

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

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.

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

The requested citation for the line "...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." is: 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 for the Fracture Intervention Trial Research Group. Randomised trial of effect of alendronate on risk of fracture in women with existing vertebral fractures. Lancet 348:1535-1541, 1996

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, as 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. 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][4]
• 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 ^[5] (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.^[6] Although osteonecrosis is uncommon, it occurs primarily in patients being administered intravenous biphosphonates, with most cases being reported in cancer patients.
• Neurological: Rare instances of auditory hallucinations and visual disturbances have been associated with alendronate and other bisphosphonates.^[7]
• Bone: Alendronate has been linked in long-term users to the development of low-impact femoral fractures.^[8] 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.^[9] 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) ^[10] 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 these kind of fractures. 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.^[11] On Oct. 13, 2010 the Food and Drug Administration issued a warning about these fractures.^[12]

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 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.

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 zoledronate (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 healthcare 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