Preventing and Managing Corticosteroid-Induced Osteoporosis in Asthma


Preventing and Managing Corticosteroid-Induced Osteoporosis in Asthma

Page 49

Pharmaceutical Forum

Preventing and Managing Corticosteroid-Induced Osteoporosis in Asthma

Osteoporosis

The wheezing and breathlessness of asthma cause millions of people to seek treatment. Corticosteroids are the most effective anti-inflammatory asthma medication, however, systemic therapy is associated with some significant adverse effects, including the promotion of osteoporosis.

The effects of inhaled corticosteroids on bone metabolism are less certain, but a small increase in the relative risk of osteoporosis has important public health considerations, especially because physicians widely prescribe inhaled corticosteroids for asthma.

Measures & Risks
Osteoporosis is characterized by low bone mineral density (BMD) and microarchitectural deterioration of bone tissue, leading to enhanced bone fragility and a consequent increase in fracture risk. It’s defined as a reduction of BMD of 2.5 standard deviations below the maximum BMD of young adults, also known as a T-score of ­2.5. The World Health Organization defines osteopenia as a T-score reduction of 1 to 2.5 standard deviations. A Z-score is the statistical comparisons of BMD with an age-matched population. BMD is most accurately measured by dual photon X-ray absorptiometry (DEXA).

Possible mechanisms by which severe asthma may increase osteoporosis include decreased physical activity and weight bearing, decreased outdoor activity and sun exposure, reduced calcium in the diet related to milk avoidance, reduced adrenal sex hormones and systemic effects of chronic inflammation. Other diseases associated with osteoporosis include Addison’s disease, chronic obstructive lung disease, Cushing’s disease, gonadal insufficiency, insulin-dependent diabetes mellitus, malabsorption syndromes, nutritional disorders and rheumatoid arthritis.

In addition to cortico-steroid therapy and adreno-corticotropin, drug therapies associated with osteoporosis include anticonvulsants, cytotoxic drugs, excessive thyroid supplements, gonadotropin-releasing hormone agonists, heparin, lithium and tamoxifen (premenopausal). Cigarette smoking and excessive alcohol ingestion also are linked to increased osteoporosis risk.

Effects on Bone
Between 30 percent and 50 percent of subjects chronically treated with systemic corticosteroids develop osteoporosis. Dosages of prednisone less than 10 mg per day result in 10 percent to 12 percent annual reduction in lumbar spine BMD. Bone loss occurs with low-dosage, alternate-day oral corticosteroid therapy as low as 10 mg. Prednisone 6 mg per day administered for six months results in significant osteopenia. The most rapid bone loss occurs during the first six to 12 months of corticosteroids, but bone loss continues at a lower rate with prolonged therapy. The National Osteoporosis Foundation recommends screening if prednisone >= 7.5 mg per day is administered for more than one month.

Convincing, consistent data shows oral corticosteroid asthma therapy has a greater effect on bone metabolism than therapeutically equivalent dosages of inhaled corticosteroids. Most literature deals with the effects of beclomethsone dipropionate (BDP), budesonide (BUD) and fluticasone (FLU).

A cross-sectional study1 shows a decline in BMD Z-score of 0.5 standard deviations for each 1,000 micrograms per day (µg/day) of inhaled corticosteroids, primarily BDP, delivered with a pressurized metered dose inhaler using a spacer.

Suggested threshold doses for potential adverse effects on BMD based on available data are 800 to 1,200 µg/day for BDP, 800 to 1,000 µg/day for BUD and 750 to 1,000 µg/day for FLU. Most data is derived from using metered dose inhalers, hydroflurocarbon-propelled delivery systems with spacers. These thresholds may not apply to dry powder inhalers or metered dose inhalers with differing propellants (e.g., hydrofluroalkane).

Treatment
Effective therapies for osteoporosis are available, although optimal duration of treatment is not clear. (See Table, page 51.) Approved pharmacologic agents affect bone resorption but not formation. Once osteoporosis develops, it’s unlikely normal BMD can be achieved, but fracture threshold may be improved even without significant BMD improvement.

The following may be effective osteoporosis treatment methods, but all are not currently approved for this indication:

  • Vitamin D and Calcium Supplements. While the National Osteoporosis Foundation recommends all adults receive >= 1,200 mg/day of elemental calcium, the average American diet contains less than 600 mg/day. Estimate calcium content by adding up the number of dairy servings (source of 75 percent to 80 percent of calcium in the U.S. diet), multiply by the calcium concentration per serving (8 oz milk=300 mg, 8 oz yogurt=400 mg, 1 oz cheese=200 mg) and add 250 mg from nondairy sources.

    Vitamin D and oral calcium attenuate bone loss and reduce the general risk of fracture of the spine, hip and other sites. Calcium supplements do not increase bone mass in those with established osteoporosis. Optimizing daily calcium and vitamin D intake are recommended for all subjects with severe asthma.

  • Female Hormone Replacement. Hormone replacement therapy (HRT) can effectively prevent and treat postmenopausal osteoporosis. However, side effects include thromboembolism, increased risk of breast cancer, vaginal bleeding and potential for uterine cancer in women who never had a hysterectomy.
  • Raloxifene. Raloxifene, a selective estrogen receptor modulator, prevents and treats BMD loss in postmenopausal osteoporosis, yet it hasn’t been studied in corticosteroid-induced bone loss. It doesn’t treat postmenopausal, systemic symptoms, and is associated with two- to three-fold increase in the risk of thromboembolism.
  • Bisphosphonates. Bisphosphonates inhibit osteoclast-mediated bone resorption. Studies show etidronate is of some benefit for corticosteroid-induced osteoporosis. It shouldn’t be used continuously, as osteomalacia may occur, and instead used cyclically, for two weeks every three months. Alendronate and risedronate are approved for postmenopausal and corticosteroid-induced bone loss. All bisphosphonates tend to irritate the gastrointestinal tract, particularly the esophagus, and are poorly absorbed with food.
  • Calcitonin. Calcitonin is a polypeptide hormone that suppresses osteoclast activity and bone resorption. Vertebral fracture rate decreases with calcitonin therapy of postmenopausal osteoporosis.
  • Thiazide Diuretics. Systemic corticosteroids may reduce calcium absorption, which results in possible secondary hyperparathyroidism. Thiazide diuretics and sodium restriction improve gastrointestinal calcium absorption and reduce its urinary excretion, which may restore a positive calcium balance.
  • Testosterone. A one-year, unblinded study of monthly testosterone injections of 250 mg shows an increase in lumbar BMD and a decrease in serum bone resorption markers in asthmatic males treated with corticosteroids.

    The ideal approach to asthma management is to discontinue systemic corticosteroid therapy, use the lowest dose of inhaled corticosteroids possible and optimize metered dose delivery of inhaled corticosteroids with a spacer. Patients also should utilize measures to maximize bone density, which include sufficient calcium and vitamin D ingestion, regular weight-bearing exercise, avoidance of both cigarette smoking and regular alcohol ingestion, verification of euthyroid status, and hormone supplementation in subjects deficient in sex hormone.

    Reference

    1. Toogood JH, Baskerville JC, Markov AE, Hodsman AB, Fraher LJ, Jennings B, et al. Bone mineral density and the risk of fracture in patients receiving long-term inhaled steroid therapy for asthma. J Allergy Clin Immunol. 1995;96(2):157-66.

    Dr. Ledford is professor of medicine and director of training program in clinical and laboratory immunology at Joy McCann Culverhouse Airway Disease Research Center, University of South Florida College of Medicine and the James A. Haley VA Hospital in Tampa, Fla.

    Targeting Seniors for Smoking Cessation

    Seniors living in Alabama, Florida, Missouri and Ohio will be among participants in a HCFA-sponsored test seeking strategies to help people quit smoking. HCFA officials said the agency spent $14.2 billion in 1992–nearly 10 percent of the Medicare budget–treating smoking-related illnesses. They expect the tests to last three years, which will involve counseling, nicotine replacement therapy and prescription drugs. HCFA will select test subjects ages 65 and up from other states later.

    Program Helps Patients Access Rare Drug
    Researchers conducted a survey on behalf of the Alpha1 Association, an international, nonprofit organization dedicated to improving lives affected by alpha1-antitrypsin deficiency, to determine if their members benefit from increased access to medicine and more control over their therapy.

    The survey focused on the Bayer Direct program, established in October 1999 by Bayer Corp. to help patients access the limited supply of Prolastin®, the replacement therapy for alpha1, that Bayer manufactures and distributes. The program uses Express Scripts, an independent full-service pharmacy benefit manager, to ensure that the product is delivered to patients at a location of their choice.

    Roper Starch Worldwide interviewed by telephone a random cross-section of 272 patient members of the association during the period of June 8 to June 12. Surveyors determined that 93 percent of patients enrolled in Bayer Direct say they’re satisfied with the program.

    Study Looks At Sputum Color in COPD Patients
    Classifying patients with acute exacerbations of lung disease by sputum color may help physicians avoid over-prescription of antibiotics, according to a study appearing in the June issue of Chest. Researchers at Queen Elizabeth Hospital in Birmingham, England, enrolled 121 patients, 89 of whom presented a satisfactory sputum sample for analysis.

    They took expectoration of green (purulent) sputum as the primary indication for antibiotic therapy, whereas white or clear sputum was not considered representative of a bacterial episode and the need for antibiotic therapy. Researchers allocated sputum samples a number by reference to a standard color chart, based on the principle that the green-colored neutrophil myeloperoxidase enzyme concentrations reflect the number of neutrophils present and that this would relate to the degree of yellow-green coloration of the sample. Patients with mucoid samples did not receive antibiotic therapy and those with purulent sputum did receive antibiotic therapy.

    Thirty-two of the 34 patients with mucoid exacerbation showed resolution of symptoms without antibiotic therapy. Seventy-seven patients with purulent exacerbation had resolution of their symptoms after antibiotic treatment. The researchers noted that sputum purulence is clinically detectable and indicative of a new or significant bacterial stimulus. In the presence of breathlessness and sputum volume, it would suggest benefit from antibiotics. Researchers said that classification of exacerbations by sputum color might enable antibiotic therapy to be withheld in some patients.

    Edited by Jennifer Gillespie, assistant editor of ADVANCE.

    Allergy Tablets for Ages 6 to 11

    Aventis Pharmaceuticals announced that Allegra® (fexofenadine HCl) 30 mg tablets, twice daily, are available by prescription for the relief of seasonal allergic rhinitis and chronic idiopathic urticaria (hives or welts) in children ages 6 to 11 years.

    In a clinical study of 411 pediatric patients, the small nonchewable tablets significantly reduced total symptom scores compared to placebo and were well tolerated among this age group. Allergy symptoms, including sneezing; itchy, runny nose; itchy, watery, red eyes; and itchy throat, can hinder the enjoyment of outdoor activities that children like to pursue.

    This dose adds to the Allegra family of products currently available for patients 12 and older, including Allegra 60-mg capsules, Allegra-D® (fexofenadine HCL 60 mg/pseudoephedrine HCl 120 mg) Extended-Release Tablets and Allegra 180-mg tablets.

    New Antibiotic Treats CAP
    The Food and Drug Administration has added an indication for Levaquin (levofloxacin) by Ortho-McNeil Phar-maceutical Inc. It’s approved for adult patients with community-acquired pneumonia (CAP) caused by penicillin-resistant strains of Streptococcus pneumoniae. The supplemental approval is based on eight clinical studies involving more than 3,900 patients with CAP.

    The fluoroquinolone, which is available in tablets or by injection, was previously approved to treat a wide range of gram-negative and gram-positive microorganisms in adults, including pathogens in bacterial CAP, acute maxillary sinusitis and acute bacterial exacerbation of chronic bronchitis. Levaquin was also approved for indications for treatment of uncomplicated urinary tract infection, mild to moderate uncomplicated skin and skin structure infections and acute pyelonephritis.

    Table: Summary of Risk Assessment and Treatment Recommendations

    Risk * Recommendations

    Low
    Adult ¾ 800 µg/day BDP** Adequate calcium, Vitamin D; Weight

    Child ¾ 400 µg/day BDP bearing exercise; No tobacco, limited alcohol; Check TSH in patient with history of thyroid abnormality

    Medium
    Adult > 800 µg/day BDP; As above plus measure height annually;

    Child > 400 µg/day BDP consider estrogen in postmenopausal women without contraindications;

    Consider DEXA if inhaled corticosteroid dose > 1200 µg/day for adults or > 600 µg/day for children; Alternative to DEXA in adults is alendronate or risedronate 5 µg/day if no contraindication

    High
    Chronic systemic corticosteroid As above plus DEXA; Consider 24-hour

    Or systemic corticosteroid > 4 urine for those receiving chronic Continuous weeks or more than 4 systemic corticosteroid; Measure to 7 “bursts”/yearfree testosterone in men and consider replacement if low

    *Daily dose of inhaled corticosteroid includes topical nasal therapy.

    **BDP refers to beclomethasone diproprionate or equivalent.

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