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New FDA-Approved Indications for Risedronate
by Marcia Wyman, Pharm.D. Candidate
Introduction:
Osteoporosis is a systemic skeletal disorder characterized by a reduction
in bone mass. Osteoporosis is defined by the World Health Organization
(WHO) as a bone mineral density (BMD) of more than 2.5 standard deviations
(SD) below the average young adult peak bone mass. Osteoporosis-induced
hip fractures are extremely painful and have a negative impact on quality
of life. Additionally, considerable morbidity and mortality are associated
with osteoporosis. The mortality rate within one year following a hip
fracture has been estimated to be as high as 50%.
Epidemiology:
The incidence of osteoporosis increases with age and occurs with greatest
frequency in post-menopausal women. Based on the WHO definition, the percent
of women with osteoporosis is 15% for ages 50 to 59, 22% for ages 70 to
80, and 70% for those 80 years of age and older. Osteoporosis is the major
cause of over 1.5 million fractures per year. The approximate cost of
fractures associated with osteoporosis is estimated to be greater
than $13 billion per year.
Pathophysiology:
Bone is composed of both a protein matrix and hydroxyapatite, a crystalline
structure which primarily consists of calcium and phosphorus. The protein
matrix serves as a foundation for the mineralization of hydroxyapatite.
The human skeleton is composed of cortical (80%) and trabecular (20%)
bone. Cortical or compact bone is found in the midshafts and surfaces
of long and flat bones. Trabecular or spongy bone is located in the inner
portions of the long bones and between the cortical surfaces of the vertebrae,
ribs, and pelvic bones.
Bone remodeling
is a dynamic process involving a continual production and breakdown of
bone tissue. There are two types of bone cells involved: osteoblasts and
osteoclasts. Osteoblasts are responsible for the formation of the protein
matrix and hydroxyapatite, while osteoclasts break down the protein matrix
and demineralize the hydroxyapatite. Estrogen and certain growth factors
promote osteoblast activity resulting in increased bone formation. Various
cytokines (e.g., interleukin-1, TNF-alpha), parathyroid hormone, and calcitriol
stimulate osteoclastic activity causing increased bone resorption. Because
of a larger surface area and more abundant cell population, trabecular
bone is more susceptible to resorption than cortical bone.
Osteoporosis
occurs when there is an imbalance between bone formation and bone resorption.
BMD is decreased. Peak BMD occurs in women and men during the second to
fourth decade of life, followed by a plateau, and then an eventual decline.
Consequently, increasing age is an important risk factor for the development
of osteoporosis. Estrogen deficiency contributes to bone resorption in
postmenopausal women. In addition, certain disease states (e.g., primary
hyperparathyroidism, Cushing's syndrome) and medications (e.g., glucocorticoids,
phenytoin) can promote bone loss.
Classifications:
Osteoporosis can be classified into three types: post- menopausal, age-related,
and secondary. Postmenopausal osteoporosis affects women within the first
5 to 15 years after menopause and is characterized primarily by trabecular
bone loss. Fractures of the vertebrae and distal forearm are common. Age-related
osteoporosis affects twice as many women as men over the age of 70. A
primary feature of this type of osteoporosis is loss of trabecular and
cortical bone resulting in fractures of femoral neck, proximal humerus,
proximal tibia and pelvis. Secondary osteoporosis is caused by other diseases
or medications and can occur in either sex at any age. Secondary osteoporosis
also causes a loss of both trabecular and cortical bone. All types of
fractures are possible with this form.
Diagnosis:
Extreme loss of BMD and osteoporotic fractures may be revealed via a radiograph.
The gold standard for measuring BMD is dual energy X-ray absorptiometry
(DEXA). DEXA results are reported as the number of standard deviations
above or below the mean average adult peak bone mass. Table 1 provides a summary of the WHO's diagnostic criteria for osteoporosis.
Risk
Factors: Table 2 lists the various
factors that can influence the risk of developing osteoporosis and subsequent
fractures.
Prevention
and Treatment: Non-pharmacologic measures which help prevent the
onset of osteoporosis include exercise, smoking cessa- tion, and limiting
alcohol and caffeine consumption. The National Institutes of Health (NIH)
recommend an elemental calcium intake of 1000 mg for females < 65 years
of age on hormone replacement therapy and 1500 mg for females < 65 years
of age not on hormone replacement therapy and for females > 65 years of
age to prevent osteoporosis. Table 3 summarizes
the elemental calcium content of select calcium supplements. Vitamin D
facilitates calcium absorption and should be supplemented in those patients
with nutritional deficiencies. Table 4 provides
a brief synopsis of prescription medications available for the prevention
and treatment of osteoporosis.
Risedronate:
The FDA recently approved a new 5 mg dose of rise- dronate (Actonel ®)
for the treatment and prevention of both post- menopausal and glucocorticoid-
induced osteoporosis. Risedronate is also available as a 30 mg tablet
for the treatment of Paget's disease. Previously, alendronate (Fosamax®)
was the only bisphosphonate approved for the treatmeat and prevention
of postmenopausal osteoporosis; however, it is not FDA-approved for use
in glucocorticoid- induced osteoporosis.
Pharmacokinetics:
The mean oral bioavailability of risedronate is only 0.63%. Bioavailability
is impaired by food and coadministration with medications containing divalent
cations (e.g., calcium supplements). After absorption, peak drug levels
are achieved in approximately 1 hour. Steady-state conditions are reached
within 57 days. Its mean steady state volume of distribution is 6.3 L/kg
and it is approximately 24% protein bound. It undergoes no systemic metabolism.
Approximately 50% of the absorbed dose is excreted in the urine within
24 hours. Unabsorbed drug is eliminated unchanged in the feces.
Contraindications/Precautions
Warnings: Risedronate is contrain- dicated in patients who have
hypocalcemia, a known hypersensitivity to any of its components, or an
inability to stand or sit upright for at least 30 minutes. Bisphosphonates
may cause upper gastrointestinal disorders such as dysphagia, esophagitis,
and esophageal or gastric ulcers. Patients are advised to take risedronate
with a sufficient amount of water (6 to 8 oz) on an empty stomach at least
30 minutes before breakfast and other medications and avoid lying down
for at least 30 minutes after administration. Patients should not chew
or suck on the tablet due to the potential of oropharyngeal irritation.
If symptoms of esophageal disease occur (e.g., difficulty or pain upon
swallowing, retrosternal pain or severe or worsening heartburn), a physician
should be consulted. Risedronate is not recommended in patients with severe
renal impairment (creatinine clearance < 30 ml/min). Adequate intake of
calcium and vitamin D is important in all patients, especially those with
Paget's disease. Weight-bearing exercises, smoking cessation, and reduction
of alcohol consumption may complement the effects of risedronate therapy.
Pregnancy
/ Lactation: Risedronate is rated a pregnancy-risk cate- gory
C. There are no adequate or well-controlled studies performed in pregnant
women. The drug should only be used during pregnancy if the benefits of
therapy outweigh the potential risks. Since it is not known whether the
drug is excreted in human breast milk, it is not recom- mended for use
during lactation.
Adverse
Effects: Common adverse effects include gastrointestinal dis-
turbances such as nausea (10.9%), diarrhea (10.6%), gastritis (2.5%),
and gastrointestinal disorders (2.3%). Additionally, back pain, abdominal
pain, asthenia, and arthralgias have been associated with risedronate
use. Most adverse effects were either mild or moderate and did not lead
to discontinuation of therapy in studies. Some potential side effects
comparable to alendronate include esophagitis, esophageal erosions, and
oropharyngeal ulcerations.
Drug
Interactions: To date, no specific drug-drug interaction studies
have been conducted. Risedronate does not induce or inhibit the cyto-
chrome P450 system. Calcium supplements, antacids, and other oral medications
containing divalent cations can interfere with the absorption of risedronate
and should be administered at different times. Hormone replacement therapy
may be used concurrently with risedronate.
Dosage
and Administration: The recommended dose of risedronate for the
treatment and prevention of postmenopausal osteoporosis and glucocorticoid-induced
osteoporosis is 5 mg administered orally once daily. The recommended dose
for Paget's disease is 30 mg administered orally once daily for 2 months.
Risedronate should be taken at least 30 minutes prior to the first food
or drink of the day other than water. The patient should not lie down
for 30 minutes after administration. Risedronate is not recommended for
use in patients with severe renal impairment (creatinine clearance <30
ml/min). No dosage adjustment is necessary for patients with creatinine
clearance >30 ml/min, hepatic impairment, or the elderly.
Discussion:
Based on clinical data, risedronate appears to be safe and efficacious
in the treatment and prevention of both postmenopausal and glucocorticoid-induced
osteoporosis. Risedronate and alendronate have similar pharmacokinetic,
pharmacodynamic, and adverse effect profiles. There are currently no comparative
studies of risedronate and alendronate. Studies focusing on the efficiency
of each individual agent for the prevention and treatment of postmenopausal
and glucocorticoid-induced osteoporosis demonstrate similar BMD increases
in selected skeletal sites for each agent. Both agents are similar in
reducing the risk of hip fractures. Additionally, both agents have the
same administration precautions to prevent serious gastrointestinal side
effects. There is, however, a difference between these two medications.
A 5 mg dose of risedronate is $1.83 (average wholesale price or AWP).
A 5- and 10-mg dose of alendronate is $2.03 (AWP). Risedronate 30 mg for
Paget's disease is $12.88 (AWP) and the cost of alendronate 40 mg for
Paget's disease is $5.30 (AWP).
References Available Upon Request
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