Public Release: 

Glucocorticoid use increases risk of spinal fractures

Among postmenopausal women, glucocorticoid users six times more likely to fracture

Hill and Knowlton

New Orleans, La., October 25, 2002 - Daily dosing with oral glucocorticoids (corticosteroids) for chronic diseases was found to be a strong predictor of spinal fracture at one year, according to new data presented at the annual scientific meeting of the American College of Rheumatology (ACR). The risk of fracture was found to increase incrementally with every 1 mg increase above 7.5 mg in the daily dose of the glucocorticoid.

Physicians frequently prescribe glucocorticoids to treat a variety of allergic and inflammatory diseases. Long-term (=3 months) use for chronic diseases is associated with a serious complication called glucocorticoid-induced osteoporosis (GIO).

"Osteoporotic fractures are typically associated with postmenopausal osteoporosis, but up to one half of patients on chronic glucocorticoid therapy may experience an osteoporotic fracture," said Tjeerd van Staa, MD, PhD, Department of Pharmacoepidemiology and Pharmacotherapy, University of Utrecht, the Netherlands and Drug Safety & Epidemiology, Procter & Gamble Pharmaceuticals - the presenting author of this study. "At one year, postmenopausal women using glucocorticoids were almost six times more likely to experience spinal fractures when compared to a group of postmenopausal women with low bone mineral density (BMD) who did not use glucocorticoids. This increased fracture risk is notable since the glucocorticoid patients were younger, had higher baseline BMD scores, and fewer pre-existing spinal fractures.

About GIO

In as little as three months, chronic use of steroids can cause significant bone loss, which could eventually lead to fracture.

The ACR guidelines recommend a class of drugs called bisphosphonates as first-line treatment for GIO in men and postmenopausal women initiating chronic glucocorticoid therapy (> 3 months duration), along with calcium, vitamin D and modification of lifestyle risk factors.

Actonel 5 mg daily is the only therapy approved by the U. S. Food and Drug Administration (FDA) for both the prevention and treatment of GIO in men and women who are initiating or continuing oral gluocorticoid treatment (? 7.5 mg/day prednisone or equivalent) for chronic diseases. In a combined analysis of two 1-year clinical studies in 518 patients initiating or continuing glucocorticoid therapy (>7.5 mg/d prednisone or equivalent) Actonel demonstrated a 70 percent reduction in vertebral fractures in just one year.

About the Study

The objective of this analysis was to evaluate the predictors and the BMD threshold for spinal fracture in oral glucocorticoid users. Data were obtained from two randomized clinical trials studying Actonel for the prevention and treatment of GIO (as described above).

The population analyzed consisted of 306 patients (both men and women) with a one-year spinal fracture assessment (111 placebo and 195 Actonel patients) and included 30 patients who experienced a new fracture in one year. In the placebo group, the statistically significant predictors for fracture were number of existing fractures and daily glucocorticoid dose. Subsequently, the effect of Actonel was analyzed in patients stratified by these risk factors. There was a trend shown with Actonel to reduce the risk of fracture versus placebo similarly regardless of whether patients did or did not have an existing fracture or whether the daily dose of corticosteroid was 7.5 to 15 mg or >15 mg.

In the BMD threshold analysis, the one-year fracture risk in postmenopausal placebo glucocorticoid users was compared to that of 2,570 postmenopausal women with low BMD not using glucocorticoids from four other Actonel trials. Although the glucocorticoid users were younger with higher baseline BMD and fewer pre-existing fractures compared to non-users, their risk of fracture was nearly six-fold higher.

This study was sponsored by The Alliance for Better Bone Health.

About Actonel ® (risedronate sodium tablets)

Actonel is co-developed and co-marketed by Procter & Gamble Pharmaceuticals and Aventis. Actonel 35 mg Once-a-Week and Actonel 5 mg daily are indicated for the prevention and treatment of osteoporosis in postmenopausal women. Actonel 5 mg daily is also indicated for the prevention and treatment of glucocorticoid-induced osteoporosis (GIO) in men and women either initiating or continuing systemic glucocorticoid treatment (? 7.5 mg/d prednisone or equivalent) for chronic diseases.

In clinical trials, Actonel was generally well tolerated. Actonel is contraindicated in patients with hypocalcemia, known hypersensitivity to any component of this product, or inability to stand or sit upright for at least 30 minutes. Hypocalcemia and other disturbances of bone and mineral metabolism should be effectively treated before starting Actonel therapy. Actonel is not recommended for use in patients with severe renal impairment (creatinine clearance < 30 mL/min).

Bisphosphonates may cause upper gastrointestinal disorders such as dysphagia, esophagitis and esophageal or gastric ulcer. Patients should pay particular attention to the dosing instructions, as failure to take the drug according to instructions may compromise clinical benefits and may increase the risk of adverse events.

In clinical trials, the overall incidence of adverse events with Actonel 5 mg daily was comparable to placebo. The most commonly reported adverse events regardless of causality were infection (primarily upper respiratory, placebo 29.7 percent vs. Actonel 5 mg 29.9 percent), back pain (23.6 percent vs. 26.1 percent), and arthralgia (21.1 percent vs. 23.7 percent).

In a one-year clinical trial comparing Actonel 35 mg Once-a-Week and Actonel 5 mg daily, the overall incidence of adverse events with the two dosing regimens was similar. The most commonly reported adverse events regardless of causality were infection (Actonel 35 mg 20.6 percent vs. Actonel 5 mg 19.0 percent), arthralgia (14.2 percent vs. 11.5 percent) and constipation (12.2 percent vs. 12.5 percent).

About The Alliance for Better Bone Health

The Alliance for Better Bone Health was formed by Procter & Gamble and Aventis in May 1997 to develop and market Actonel collaboratively in Europe, the United States and Canada. The Alliance promotes bone health and disease awareness through numerous activities to support physicians and patients around the globe.

About Procter & Gamble

Procter & Gamble (P&G) is celebrating 165 years of providing trusted quality brands that make every day better for the world's consumers. P&G markets nearly 300 brands in more than 160 countries around the world. The P&G community consists of nearly 102,000 employees working in almost 80 countries worldwide. P&G Pharmaceuticals is part of P&G's Health Care global business unit. P&G Pharmaceuticals is focusing in the areas of endocrinology, cardiovascular and musculoskeletal diseases. Some of P&G's leading prescription products include Actonel® (risedronate sodium tablets), Didronel® (etidronate disodium), Asacol® (mesalamine) and Macrobid® (nitrofurantoin monohydrate macrocrystals). Please visit www.pg.com for the latest news and in-depth information about P&G and its brands.

About Aventis

Aventis (NYSE: AVE) is dedicated to improving life by treating and preventing human disease through the discovery and development of innovative pharmaceutical products. Aventis focuses on prescription drugs for important therapeutic areas such as oncology, cardiology, diabetes, respiratory/allergy, anti-infectives as well as on human vaccines. In 2001, Aventis generated sales of € 17.7 billion ($15.8 billion), invested approx. € 3 billion ($2.7 billion) in research and development and employed approximately 75,000 people in its core business. Aventis corporate headquarters is in Strasbourg, France. The company's prescription drugs business is conducted in the U.S. by Aventis Pharmaceuticals Inc., which is headquartered in Bridgewater, New Jersey. Aventis Pharmaceuticals was recently named one of the top companies to work for by Working Mother magazine. For more information about Aventis in the U.S., please visit: www.aventis-us.com.

Please see full prescribing information for Actonel by visiting www.actonel.com. Copies of this release are available on the Procter & Gamble Pharmaceuticals Web site at http://www.pgpharma.com, the Aventis Pharmaceuticals U.S. Web site at http://www.aventispharmaus.com, or by calling 800/207-8049.

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Statements in this news release other than historical information are forward-looking statements subject to risks and uncertainties. Actual results could differ materially depending on factors such as the availability of resources, the timing and effects of regulatory actions, the strength of competition, the outcome of litigation, and the effectiveness of patent protection. Additional information regarding risks and uncertainties is set forth in the current Annual Report on Form 20-F of Aventis on file with the Securities and Exchange Commission.

Oral Presentation at ACR Meeting: Monday, October 29, 4:00 - 5:30 pm CST

"Clinical Osteoporosis" Session, Moriel Convention Center, Rm. 275-277

ACR PRESS CONFERENCE: Monday, October 28, 1:30 pm, Moriel Convention Center, Room 237

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