Alendronic acid (
INNAn International Nonproprietary Name is the official non-proprietary or generic name given to a pharmaceutical substance, as designated by the World Health Organization...
) or
alendronate sodium (
USANUnited States Adopted Names are unique nonproprietary names assigned to pharmaceuticals marketed in the United States. Each name is assigned by the USAN Council, which is co-sponsored by the American Medical Association , the United States Pharmacopeial Convention , and the American Pharmacists...
, sold as
Fosamax by
MerckMerck & Co., Inc. , also known as Merck Sharp & Dohme or MSD outside the USA and Canada, is one of the largest pharmaceutical companies in the world. The headquarters of the company is located in Whitehouse Station, New Jersey, an unincorporated area in Readington Township...
) is a
bisphosphonateIn pharmacology, bisphosphonates are a class of drugs that prevent the loss of bone mass, used to treat osteoporosis and similar diseases....
drugA pharmaceutical drug, also referred to as medicine, medication or medicament, can be loosely defined as any chemical substance intended for use in the medical diagnosis, cure, treatment, or prevention of disease.- Classification :...
used for
osteoporosisOsteoporosis is a disease of bone that leads to an increased risk of fracture. In osteoporosis the bone mineral density is reduced, bone microarchitecture is disrupted, and the amount and variety of non-collagenous proteins in bone is altered...
and several other bone diseases. It is marketed alone as well as in combination with
vitamin DVitamin D is a group of fat-soluble prohormones, the two major forms of which are vitamin D2 and vitamin D3 . Vitamin D obtained from sun exposure, food, and supplements, is biologically inert and must undergo two hydroxylation reactions to be activated in the body...
(2,800 U and 5600 U, under the name
Fosamax+D). Merck's
U.S.The United States of America is a federal constitutional republic comprising fifty states and a federal district...
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.
Alendronic acid (
INNAn International Nonproprietary Name is the official non-proprietary or generic name given to a pharmaceutical substance, as designated by the World Health Organization...
) or
alendronate sodium (
USANUnited States Adopted Names are unique nonproprietary names assigned to pharmaceuticals marketed in the United States. Each name is assigned by the USAN Council, which is co-sponsored by the American Medical Association , the United States Pharmacopeial Convention , and the American Pharmacists...
, sold as
Fosamax by
MerckMerck & Co., Inc. , also known as Merck Sharp & Dohme or MSD outside the USA and Canada, is one of the largest pharmaceutical companies in the world. The headquarters of the company is located in Whitehouse Station, New Jersey, an unincorporated area in Readington Township...
) is a
bisphosphonateIn pharmacology, bisphosphonates are a class of drugs that prevent the loss of bone mass, used to treat osteoporosis and similar diseases....
drugA pharmaceutical drug, also referred to as medicine, medication or medicament, can be loosely defined as any chemical substance intended for use in the medical diagnosis, cure, treatment, or prevention of disease.- Classification :...
used for
osteoporosisOsteoporosis is a disease of bone that leads to an increased risk of fracture. In osteoporosis the bone mineral density is reduced, bone microarchitecture is disrupted, and the amount and variety of non-collagenous proteins in bone is altered...
and several other bone diseases. It is marketed alone as well as in combination with
vitamin DVitamin D is a group of fat-soluble prohormones, the two major forms of which are vitamin D2 and vitamin D3 . Vitamin D obtained from sun exposure, food, and supplements, is biologically inert and must undergo two hydroxylation reactions to be activated in the body...
(2,800 U and 5600 U, under the name
Fosamax+D). Merck's
U.S.The United States of America is a federal constitutional republic comprising fifty states and a federal district...
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.
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.
Pharmacology
Alendronate inhibits osteoclast-mediated bone-resorption. Like all bisphosphonates it is chemically related to inorganic
pyrophosphateIn chemistry, the anion, the salts, and the esters of pyrophosphoric acid are called pyrophosphates. Pyrophosphates were originally prepared by heating phosphates: the prefix pyro- derived from Greek, means "fire" in this context. Pyrophosphates are good complexing agents and have many uses in...
, 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
NNitrogen is a chemical element that has the symbol N and atomic number 7 and atomic mass 14.00674 u. Elemental nitrogen is a colorless, odorless, tasteless and mostly inert diatomic gas at standard conditions, constituting 78% by volume of Earth's atmosphere.Many industrially important...
-containing bisphosphonates such as
risedronateRisedronic acid or risedronate sodium is a bisphosphonate used to strengthen bone, treat or prevent osteoporosis, and treat Paget's disease of bone. It is produced and marketed by Procter & Gamble and Sanofi-Aventis....
and ibandronate and
zoledronateZoledronic acid or zoledronate is a bisphosphonate. Zometa is used to prevent skeletal fractures in patients with cancers such as multiple myeloma and prostate cancer...
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
Osteoporosis is a disease of bone that leads to an increased risk of fracture. In osteoporosis the bone mineral density is reduced, bone microarchitecture is disrupted, and the amount and variety of non-collagenous proteins in bone is altered...
- Treatment of male osteoporosis
- Prevention and treatment of corticosteroid-associated osteoporosis together with supplements of calcium and vitamin D
- Paget's disease
Sir James Paget, a prolific surgeon and pathologist, described several diseases, including:* Paget's disease of bone * Paget's disease of the breast* Paget-Schroetter disease* Extramammary Paget's disease...
Contraindications and precautions
- Acute inflammations of the gastrointestinal tract (esophagitis, gastritis, ulcerations)
- Clinically manifest osteomalacia
Osteomalacia term for the softening of the bones due to defective bone mineralization. Osteomalacia in children is known as rickets, and because of this, use of the term osteomalacia is often restricted to the milder, adult form of the disease. It may show signs as diffuse body pains, muscle...
- 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
A peptic ulcer, also known as ulcus pepticum, PUD or peptic ulcer disease, is an ulcer of an area of the gastrointestinal tract that is usually acidic and thus extremely painful...
of the esophagusThe esophagus or oesophagus , sometimes known as the gullet, is an organ in vertebrates which consists of a muscular tube through which food passes from the pharynx to the stomach. The word esophagus is derived from the Latin œsophagus, which derives from the Greek word oisophagos , lit...
; 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.http://uk.reuters.com/article/healthNewsMolt/idUKTRE4BU4TX20081231
- General: infrequent cases of skin rash, rarely manifesting as Stevens-Johnson syndrome
Stevens–Johnson syndrome is a life-threatening condition affecting the skin in which cell death causes the epidermis to separate from the dermis. The syndrome is thought to be a hypersensitivity complex affecting the skin and the mucous membranes...
and toxic epidermal necrolysisToxic epidermal necrolysis , also known as Lyell's syndrome, is a life-threatening dermatological condition that is frequently induced by a reaction to medications...
, eye problems (uveitisUveitis specifically refers to inflammation of the middle layer of the eye, termed the "uvea" but in common usage may refer to any inflammatory process involving the interior of the eye....
, scleritisScleritis is a serious inflammatory disease that affects the white outer coating of the eye, known as the sclera. The disease is often contracted through association with other diseases of the body, such as Wegener's granulomatosis or rheumatoid arthritis; it can also be attained through disorders...
) and generalized muscle, joint, and bone pain http://www.fda.gov/cder/drug/infopage/bisphosphonates/default.htm (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
Osteonecrosis of the jaws is a severe bone disease that affects the jaws, including the maxilla and the mandible. Jaw bone damage and death occurs as a result of reduced local blood supply...
- Deterioration of the Temporomandibular JointThe temporomandibular joint is the joint of the jaw and is frequently referred to as TMJ. There are two TMJs, one on either side, working in unison. The name is derived from the two bones which form the joint: the upper temporal bone which is part of the cranium , and the lower jaw bone called the...
(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 cancerCancer is a class of diseases in which a group of cells display uncontrolled growth , invasion , and sometimes metastasis...
patients.
- Neurological: Rare instances of auditory hallucinations and visual disturbances have been associated with alendronate and other bisphosphonates.http://www.medscape.com/viewarticle/481375_1
- Bone: reported increases in osteoclast
An osteoclast is a type of bone cell that removes bone tissue by removing its mineralized matrix and breaking up the organic bone . This process is known as bone resorption...
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 SciencesThe University of Arkansas for Medical Sciences is part of the University of Arkansas System, a state-run university in the U.S. state of Arkansas. The main campus is located in Little Rock.-Organization:UAMS has six academic units:...
. http://www.washingtonpost.com/wp-dyn/content/article/2008/12/31/AR2008123102537.html
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 may refer to:*Hormone replacement therapy *Hormone replacement therapy *Hormone replacement therapy *Androgen replacement therapy -See also:...
(hormone replacement therapy) with estrogens/progestins or raloxifeneRaloxifene is an oral selective estrogen receptor modulator that has estrogenic actions on bone and anti-estrogenic actions on the uterus and breast. It is used in the prevention of osteoporosis in postmenopausal women...
in postmenopausal women remains to be elucidated, but no interactions have been seen. The combination is therefore possible.
- Intravenous ranitidine
Ranitidine hydrochloride is a histamine H2-receptor antagonist that inhibits stomach acid production. It is commonly used in treatment of peptic ulcer disease and gastroesophageal reflux disease . Ranitidine is also used alongside fexofenadine and other antihistamines for the...
increases the oral bioavailability of alendronate. No clinical consequences are known.
- The combination of NSAID
Non-steroidal anti-inflammatory drugs, usually abbreviated to NSAIDs or NAIDs, are drugs with analgesic, antipyretic and, in higher doses, with anti-inflammatory effects...
s 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.
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 jawOsteonecrosis of the jaws is a severe bone disease that affects the jaws, including the maxilla and the mandible. Jaw bone damage and death occurs as a result of reduced local blood supply...
(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 jawPhossy jaw, formally phosphorus necrosis of the jaw is an occupational disease of those who work with white phosphorus, also known as yellow phosphorus, without proper safeguards. It was most commonly seen in workers in the match industry in the 19th and early 20th century...
, given its name after workers in match factories working with white phosphorus developed osteonecrosis of the jaw.
External links