Fosamax side effects
December 2008
A study showed that women who took the osteoporosis drug
Fosamax for up to three years saw an increase in their number of osteoclasts,
or cells that remove old, brittle bone. A FDA letter said the agency has
received reports of 23 patients taking Fosamax who have been diagnosed with
cancer of the esophagus (eight died) since the drug was first approved in
1995. Thirty-one patients from Japan and Europe also were diagnosed with
this cancer after taking Fosamax. [1]

FDA ALERT [1/7/2008] -  FDA is highlighting the possibility of severe and
sometimes incapacitating bone, joint, and/or muscle (musculoskeletal) pain in
patients taking bisphosphonates. Although severe musculoskeletal pain is
included in the prescribing information for all bisphosphonates, the association
between bisphosphonates and severe musculoskeletal pain may be
overlooked by healthcare professionals, delaying diagnosis, prolonging pain
and/or impairment, and necessitating the use of analgesics.

The severe musculoskeletal pain may occur within days, months, or years after
starting a bisphosphonate. Some patients have reported complete relief of
symptoms after discontinuing the bisphosphonate, whereas others have
reported slow or incomplete resolution. The risk factors for and incidence of
severe musculoskeletal pain associated with bisphosphonates are unknown.

This severe musculoskeletal pain is in contrast to the acute phase response
characterized by fever, chills, bone pain, myalgias, and arthralgias that
sometimes accompanies initial administration of intravenous bisphosphonates
and may occur with initial exposure to once-weekly or once-monthly doses of
oral bisphosphonates. The symptoms related to the acute phase response
tend to resolve within several days with continued drug use.

What is Fosamax?
FOSAMAX* (alendronate sodium) is a bisphosphonate that acts as a specific
inhibitor of osteoclastmediated bone resorption. Bisphosphonates are
synthetic analogs of pyrophosphate that bind to the hydroxyapatite found in
bone. Alendronate sodium is chemically described as (4-amino-1-
hydroxybutylidene) bisphosphonic acid monosodium salt trihydrate.
The empirical formula of alendronate sodium is C4H12NNaO7P2•3H2O.

Alendronate sodium is a white, crystalline, nonhygroscopic powder. It is soluble
in water, very slightly soluble in alcohol, and practically insoluble in chloroform.

How it works - Mechanism of Action
Animal studies have indicated the following mode of action. At the cellular
level, alendronate shows preferential localization to sites of bone resorption,
specifically under osteoclasts. The osteoclasts adhere normally to the bone
surface but lack the ruffled border that is indicative of active resorption.
Alendronate does not interfere with osteoclast recruitment or attachment, but it
does inhibit osteoclast activity. Studies in mice on the localization of radioactive
[3H]alendronate in bone showed about 10-fold higher uptake on
osteoclast surfaces than on osteoblast surfaces. Bones examined 6 and 49
days after [3H]alendronate administration in rats and mice, respectively,
showed that normal bone was formed on top of the alendronate, which was
incorporated inside the matrix. While incorporated in bone matrix, alendronate
is not pharmacologically active. Thus, alendronate must be continuously
administered to suppress osteoclasts on newly formed resorption surfaces.
Histomorphometry in baboons and rats showed that
alendronate treatment reduces bone turnover (i.e., the number of sites at
which bone is remodeled). In addition, bone formation exceeds bone
resorption at these remodeling sites, leading to progressive gains
in bone mass.

Pharmacokinetics - Absorption
Relative to an intravenous (IV) reference dose, the mean oral bioavailability of
alendronate in women was 0.64% for doses ranging from 5 to 70 mg when
administered after an overnight fast and two hours before a standardized
breakfast. Oral bioavailability of the 10 mg tablet in men (0.59%) was similar to
that in women when administered after an overnight fast and 2 hours before

FOSAMAX 70 mg oral solution and FOSAMAX 70 mg tablet are equally
bioavailable. A study examining the effect of timing of a meal on the
bioavailability of alendronate was performed in 49 postmenopausal women.
Bioavailability was decreased (by approximately 40%) when 10 mg
alendronate was administered either 0.5 or 1 hour before a standardized
breakfast, when compared to dosing 2 hours before eating. In studies of
treatment and prevention of osteoporosis, alendronate was effective when
administered at least 30 minutes before breakfast. Bioavailability was
negligible whether alendronate was administered with or up to two hours after
a standardized breakfast. Concomitant administration of alendronate with
coffee or orange juice reduced bioavailability by approximately 60%.

• Abnormalities of the esophagus which delay esophageal emptying such as
stricture or achalasia
• Inability to stand or sit upright for at least 30 minutes
• Patients at increased risk of aspiration should not receive FOSAMAX oral
• Hypersensitivity to any component of this product
• Hypocalcemia (see PRECAUTIONS, General)

Side effects in patients taking FOSAMAX usually have been mild. They
generally have not caused patients to stop taking FOSAMAX.
The most common side effect is abdominal (stomach area) pain. Less common
side effects are nausea, vomiting, a full or bloated feeling in the stomach,
constipation, diarrhea, black or bloody stools (bowel movements), gas,
headache, a changed sense of taste, and bone, muscle, and/or joint pain.
Severe bone, joint, and/or muscle pain has been reported in patients taking,
by mouth, bisphosphonates drugs that are used to treat osteoporosis (thin
bones). However, such reports have been rare. This group of drugs includes
FOSAMAX. Most of the patients were postmenopausal women (women who
had stopped having periods). Patients developed pain within one day to
several months after starting the drug. Most patients experienced relief after
stopping the drug. Patients who develop severe bone, joint,
and/or muscle pain after starting FOSAMAX should contact their physician.
Transient flu-like symptoms (rarely with fever), typically at the start of
treatment, have occurred.

In rare cases, patients taking FOSAMAX may get itching or eye pain, or a rash
that may be made worse by sunlight. Rarely, severe skin reactions may occur.
Patients may get allergic reactions, such as hives or, in rare cases, swelling
that can be of their face, lips, tongue, or throat, which may cause trouble in
breathing or swallowing. Mouth ulcers (sores) may occur if FOSAMAX is
chewed or dissolved in the mouth.

Rarely, patients have had jaw problems associated with delayed healing and
infection, often following tooth extraction.

SOURCE [1] Osteoporosis Drug Prompts Increase in Certain Bone Cells HealthyDay News
gov/medwatch/safety/1996/fosamax.htm [3] Insert
FOSAMAX is an aminobisphosphonate, a selective inhibitor of bone
resorption that is the first nonhormonal therapy indicated for the
treatment of osteoporosis in postmenopausal women (the daily oral
dosage is 10 mg). FOSAMAX is also indicated for the treatment of Paget's
disease of bone (the daily oral dosage is 40 mg for six months). In
controlled clinical trials of three years' duration in postmenopausal women
with osteoporosis, FOSAMAX was generally well tolerated. Like other
bisphosphonates, however, FOSAMAX was recognized to have the
potential to cause local irritation of the upper gastrointestinal mucosa. In
ongoing, carefully-monitored studies of over 12,000 patients, esophageal
irritation has been no different in incidence or severity than observed in
the completed three-year trials. (As you know, esophageal ulcers,
considered to be drug related, were reported in 1.5% of the patients
taking FOSAMAX 10 mg in three-year trials.) [2]