THERAPEUTICS LETTER

OSTEOPOROSIS: A SUMMARY OF PREVENTION

Osteoporosis currently affects more than 26 million Americans, of whom more than 20 million are women. It is a major contributor to bone fracture of many kinds, including vertebral and hip fractures. By the age of 65 years, one third of women will have a vertebral fracture. Unfortunately, fewer than 10% of women and 1% of men with osteoporosis have an appropriate diagnosis and treatment. Primary care physicians see four or more patients with this condition each day. Diagnosis, prevention, and treatment of osteoporosis are now possible with the use of bone mineral density (BMD) testing and several effective therapeutic agents.

Peak bone mass is reached between the ages of 25 and 30 years, with the rate of bone acquisition being greatest during puberty. Over a lifetime, women lose about 50% of bone density at the spine and 30% at the hip, while men lose about two thirds of these amounts. Thin bones, or a low BMD, can occur because of either poor acquisition of peak bone density or increased bone loss and/or decreased bone formation later in life. Most adult women should be made aware of the dangers of osteoporosis as well as the early and late markers. Here are a few ideas on important factors in prevention and treatment of this widespread and debilitating disease.

Diet and Exercise: Adults should aim to acquire 1,000 to 1,200 mg of calcium from the diet or supplementation each day. Postmenopausal women who are not taking estrogen should receive 1,500 to 2,000 mg of calcium. Patients at risk for osteoporosis should also receive 400 to 800 units of vitamin D daily to optimize calcium absorption. Calcium absorption is optimal when no more than 600 mg of calcium is taken at once; therefore, the most effective regimen involves taking two or three calcium supplements with vitamin D, spread throughout the day. Twenty to 30 minutes of weight-bearing exercise can improve strength and balance of muscle and bone. Exercise may also reduce the chances of fall and fracture. Whether BMD can substantially increase with a continuous exercise regimen alone remains uncertain, but it is a necessary factor

Drug Therapy: There are a few medical therapies that have been approved by the FDA for the prevention of osteoporosis and reduction of bone resorption. Estrogen replacement therapy (ERT) remains the treatment of choice for both prevention and treatment of osteoporosis in women. Estrogen is available in many varieties, including Premarin, Ogen, Estrace, Estratab, Estratest, Estraderm, and Climara. Formulations that include a progestin are Prempro, Premphase, and CombiPatch. Additional benefits of estrogen include cardiovascular protection; improvement in lipid profiles; reduced risk of Alzheimer's disease, memory deficits, colon carcinoma, and improvement in menopausal symptoms.

Several non-hormonal agents, a biphosphonate called Alendronate (Fosamax), and two Selective Estrogen Receptor Modulators (SERMs) called Raloxifene (Evista) and Tamoxifen. Alendronate is taken 5 mg PO every morning, increasing spine BMD by 3.8% and hip BMD by 2.9% over a 4 year period. This drug has also been shown to increase BMD in steroid-induced osteoporosis in both men and women, and FDA approval is pending for this indication. Raloxifene is less potent than estrogen or Fosamax in increasing BMD, demonstrating a 1% increase in both spine and hip BMD after 2 years.Two years of Evista treatment results in a 40% reduction in vertebral fractures but no reduction in hip fractures. Evista also improves lipid profile, though this aspect remains under study. Tamoxifen can be used for up to 5 years for skeletal protection in patients with breast cancer but is not FDA-approved for the prevention of osteoporosis.

The population is growing older, bringing with it an increasing prevalence of bone related diseases. As we enter a new millennium, osteoporosis is on the forefront of prevalent yet preventable disease. Though treatment options for osteoporosis are improving, the best defense against this disease is prevention and early detection. Identifying and treating patients at risk for osteoporosis means ordering appropriate evaluations, encouraging everyone to take calcium and exercise, and beginning treatment as soon as it is indicated.

NUTRITION TO BATTLE OLD AGE

The elderly population is increasing rapidly, bringing with it a public health responsibility to reduce the morbidity associated with aging. It is estimated that 80% of older adults have chronic diseases that may be caused or improved by diet. Optimizing nutrition may be an important factor in achieving this goal. The nutritional needs of most fit elderly people can be met by eating a diet incorporating the general recommendations of five portions of fruit and vegetables a day, oily fish twice a week, breakfast cereals daily and starchy foods with every meal. Extra care should be taken with those elderly individuals living in an institutional environment (e.g. nursing home) to ensure that their nutritional requirements are fulfilled.

Vitamin supplementation in large dosages is increasingly common in the older population. There have been claims that this practice can help to prevent and cure disease. For example, supplements containing antioxidants can reduce the oxidative damage caused by free radicals that are implicated in a number of diseases including atherosclerosis and ischaemic heart disease, various cancers, Parkinson's disease, Alzheimer's disease, and rheumatoid arthritis. Some have thus sought to supplement a diet that is low in fruit and vegetables with antioxidant vitamins, especially retinol (vitamin A), ascorbic acid and tocopherol (vitamin E).

Supplementation is not entirely supported by evidence from controlled trials. At least part of the reason for this is thought to be that fruit and vegetables contain many thousands of antioxidant substances that may be more powerful than the vitamins, and which may be essential as adjuncts to the vitamins. Although many may benefit from supplementation with antioxidant vitamins, supplementation is probably not necessary or helpful in individuals who have a diet rich in fresh fruit and vegetables.

Folate deficiency in the elderly is not as uncommon as once thought. Deficiency in folate has been implicated in coronary heart disease, cancer and schizophrenia. There is no evidence to support the use of folate supplementation in cancer patients or advanced cardiovascular disorders. In these patients, supplementation may come too late to be of benefit. However, supplementation can be considered in patients with elevated plasma homocysteine levels and diagnosed CVD, in elderly patients treated with drugs known to induce a folate deficiency, and in those who experience neuropsychiatric disorders such as schizophrenia. The FDA is already implementing compulsory fortification of several foods with folate, primarily to reduce the risk of neural tube birth defects.

Therapeutic Uses of Vitamins

MEDICATIONS IN CHILDREN WITH ASTHMA

Pediatric asthma remains a prevalent but manageable problem in the United States. For the past decade, mast cell stabilizers have been the treatment of choice for such patients. These agents are most often used as part of a triple drug regimen that includes corticosteroids and beta-adrenergic agonists to control asthma symptoms. Mast cell stabilizers may also be used as single-agent therapy in exercise-induced asthma. Cromolyn sodium and nedocromil are inhaled anti-inflammatory agents that have received much attention in pediatric asthma treatment.

Cromolyn and nedocromil have been documented in their efficacy in inhibiting the degranulation of mast cells. Stabilizing mast cells prevents the release of inflammatory mediators, including histamine and a leukotriene believed to play an important role in provoking asthma. Recent research with cromolyn has suggested that it indirectly inhibits calcium ions from entering the mast cell and triggering release of cellular contents. In clinical trials, both compounds have been shown to be effective in blunting the response induced by cold air, exercise, sulfur dioxide, environmental air pollutants, and other specific antigenic challenges. Neither agent has bronchodilator, anticholinergic, antihistaminic, or glucocorticoid activity.

Both cromolyn and nedocromil have been approved by the FDA for the prophylactic management of bronchial asthma. Cromolyn is also approved for the prevention of exercise-induced bronchospasm and for allergic rhinitis. It is approved for children ages 2 years and older, while nedocromil is currently only approved for children 12 and older. Cromolyn is available in a 10 mg/ml solution for nebulization and an aerosol for inhalation that delivers 800 mcg per spray. Patients with exercise-induced asthma should inhale 20 mg (nebulized) or 2 sprays (by aerosol) within 1 hr prior to exercise. Children younger than 6 years of age may respond to lower doses.

Nedocromil is available in an aerosol form that provides 1.75 mg per spray. The recommended dose is 2 inhalations 4 times daily at regular intervals for prophylaxis. Some patients can achieve satisfactory effects when using nedocromil only 2 to 3 times daily. Patients receiving either of these agents should be instructed that these agents are not effective for acute asthma exacerbations. In order to gain the most benefit from mast cell stabilizers in managing asthma, these agents must be taken on a regular basis, even when the patient is asymptomatic. Younger children may require the assistance and encouragement of their parents.

Mast cell stabilizers are useful adjuncts to therapy with corticosteroids and beta-adrenergic agonists in children with asthma. Cromolyn and nedocromil have little systemic absorption after inhalation and are well tolerated. These agents may provide better control of asthma symptoms in children and allow a reduction in the doses of therapies with more significant adverse effects.

FDA APPROVES RELENZA

The FDA recently approved Relenza (zanamivir), an inhaled anti-viral drug, for adults and adolescents 12 years and older for the treatment of uncomplicated influenza virus. The drug product is approved to treat type A and B influenza. Relenza is the first approved drug for the treatment of influenza since the approval of rimantadine (Flumadine) in 1993. Clinical studies determined that patients with influenza receiving Relenza had shorter times to improvement in influenza symptoms. Efficacy treatment studies enrolled more than 1500 patients with influenza-like illness, for example, fever, headache, muscle aches, cough and sore throat.

This product has not been shown to be effective, and may carry risk, in patients with severe or decompensated asthma or chronic obstructive pulmonary disease. Relenza is taken twice daily for five days using a breath- activated plastic inhaler device. Patients should be instructed by a health care provider in the proper use of the inhaler, including a demonstration whenever possible.Relenza will be marketed by Glaxo Wellcome, headquartered in Research Triangle Park, N.C.

Food and Drug Administration Press Release, 1999 http://www.fda.gov/bbs/topics/ANSWERS/ANS00966.html

WYETH LEDERLE WITHDRAWS ROTASHIELD FROM MARKET

Wyeth Lederle Vaccines, a division of American Home Products Corporation announced last week that it has withdrawn its RotaShield rotavirus vaccine from the market and has requested the immediate return of all doses of the vaccine. The company temporarily suspended further distribution and administration of RotaShield until more safety data on vaccine administration became available. The Food and Drug Administration consulted Wyeth Lederle following a recommendation from the CDC to postpone administration because of reports to the Vaccine Adverse Events Reporting System (VAERS) of a possible association between the use of RotaShield and the development of intussusception.

To ascertain more information on this withdrawal, physicians may call 877-ROTA-KID (877-768-2543). Consumers may call the CDC's National Information Hotline at 800-232-2522.

The information and opinions expressed in the Therapeutics Letter do not necessarily reflect the official policy of the sponsoring organizations