New FDA-Approved Indications for
Risedronate

Volume III, Number 3 | July/August 2000
Marcia Wyman, Pharm.D. Candidate

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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.

Table 1:  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.

Table 2:  Risk factors for Osteoporosis

Prevention and Treatment

Non-pharmacologic measures which help prevent the onset of osteoporosis include exercise, smoking cessation, 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.

Table 3:  Selected Oral Calcium Supplements

Table 4:  Pharmacotherapy for the Prevention and Treatment of Osteoporosis

Risedronate

The FDA recently approved a new 5 mg dose of risedronate (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 contraindicated 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 category 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 recommended for use during lactation.

Adverse Effects

Common adverse effects include gastrointestinal disturbances 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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