Pharmacotherapy of Osteoporosis
Osteoporosis is a systemic skeletal disease characterized by low bone mass and microarchitectural deterioration of bone tissue, leading to increased bone fragility and fracture. Bone remodeling occurs throughout an individual's lifetime. In normal adults, the activity of osteoclasts (bone resorption) balances that of osteoblasts (bone formation), with peak bone mass occurring in the early-to-mid 30s. Several prescription medications are currently approved for the prevention and/or treatment of osteoporosis (Table). What follows is a discussion of these agents.
Bisphosphonates are synthetic analogs of naturally occurring hydroxyapatites (bone resorption inhibitors). They are considered first-line therapy for the prevention and treatment of osteoporosis. Two agents, alendronate sodium and risedronate sodium, have been approved by the FDA for both prevention and treatment of osteoporosis. These agents have been shown to increase bone mineral density (BMD) as well as to decrease the incidence of first and future fractures.
Bisphosphonates have poor oral bioavailability and can be corrosive to the upper gastrointestinal (GI) tract. Strict administration guidelines must be followed in order to improve absorption and avoid significant upper GI problems, such as nausea, stomach upset, and esophagitis. Bisphosphonates must be taken on an empty stomach with a full glass of water after getting up for the day. Patients also must be instructed to wait at least 30 minutes before having their first food, beverage, or other medication for the day and to remain upright for at least 30 minutes after taking a bisphosphonate dose.
The safety of bisphosphonates over the long term has been a subject of interest, and a recently released study of alendronate (New England Journal of Medicine, March 2004) found that this agent was safe over a 10-year period. The issue of long-term use is important because osteoporosis is a chronic condition requiring long-term therapy. The optimum length of therapy has yet to be definitively determined, however.
It is believed that 30% to 50% of bone loss in older women is due to estrogen deficiency. If started soon after menopause, estrogen prevents the accelerated phase of bone loss that occurs in the first 5 years after the onset of menopause. To maintain this benefit, however, estrogen must be continued on a long-term basis, and recent studies (the Women's Health Initiative) have shown long-term estrogen therapy to be potentially unsafe. Although still approved for the prevention of osteoporosis, the FDA recommends that, when used solely for the purpose of osteoporosis prevention, nonestrogen treatments should be considered first.
Selective Estrogen Receptor Modulators (SERMs)
Raloxifene hydrochloride is the only SERM currently approved for the prevention and treatment of osteoporosis. SERMs demonstrate estrogen agonist activity at the bone and liver and antagonist activity at the breast and uterus. These properties result in increased BMD and reduced fracture risk without promoting breast or endometrial cancer. Breast tenderness and vaginal bleeding also are decreased, compared with estrogens. SERMs can, however, worsen hot flashes. They are contraindicated for pregnant women and for patients with a history of thromboembolic disorders.
Calcitonin-salmon is a hormone that inhibits bone resorption. It is available as a nasal spray or as an injection, the nasal spray being the most commonly used formulation. It is approved for the treatment of osteoporosis, and study results indicate increased spinal bone density and possible relief of pain associated with spinal fractures. Therapy with calcitonin-salmon should be reserved for postmenopausal women or women who cannot tolerate other therapy. Side effects are generally local reactions to the nasal spray.
Teriparatide is the newest agent approved for the treatment of osteoporosis, and it is the first drug to stimulate new bone growth. It is available as an injection that contains recombinant human parathyroid hormone. Teriparatide increases BMD and reduces the risk of vertebral and nonvertebral fractures; it is possibly more effective than the other currently available therapies. Its use is currently limited by high cost and complex administration and storage requirements.
Patients should be cautioned about the first dose effect?to sit or lie down if dizziness or increased heart rate occurs after injection. Long-term safety also is questionable due to the increased risk of bone cancer in animal studies; therefore, teriparatide is currently not recommended for use for >2 years.
Calcium should be considered an important antiresorptive agent that can significantly enhance the action of other treatment modalities. The National Institutes of Health recommends 1000 mg of calcium daily for adult women 19 to 50 years old and 1500 mg daily for those >50 years old. For men, the recommendation is 1000 mg of calcium daily for those under 65 years old and 1500 mg daily for those over 65 years old.
The best source of calcium is dietary calcium, although a variety of calcium supplements are available to assist patients in achieving their daily intake. The 2 most common forms of calcium salts are calcium carbonate and calcium citrate. Calcium carbonate has the most elemental calcium (40%), but it should be taken with food to enhance absorption. Calcium citrate is absorbed in a nonacidic environment, so it can be taken without regard to food and should be recommended for patients on acid suppression therapy or patients with achlorhydria. Calcium citrate is only 20% elemental calcium, however, so an increased number of tablets may be needed to meet daily requirements. Regardless of the salt form, calcium is best absorbed when taken in amounts of 500 mg at a time.
Adverse effects of calcium include constipation and drug interactions with iron, tetracycline, quinolone antibiotics, bisphosphonates, and phenytoin. It should be used cautiously in patients with a history of kidney stones.
Calcium is absorbed from the small intestine and is utilized only in the presence of vitamin D. Vitamin D also regulates serum calcium concentrations by mobilizing calcium from bone. Vitamin D requirements vary with age, with 400 international units daily recommended for patients aged 51 to 70 years. Vitamin D can be obtained through fortified milk and exposure to sunlight. It also may be found as a dietary supplement, and it often is included in a combination product with calcium or in a multivitamin preparation.
Dr. Singla is an assistant professor of pharmacy practice at Midwestern University College of Pharmacy?Glendale, Glendale, Ariz.
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