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University of Cincinnati Academic Health Center
Publish Date: 06/21/02
Media Contact: AHC Public Relations, (513) 558-4553
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UC Researcher Utilizes Historical Control Group for New Osteoporotic Fracture Analysis

Cincinnati--In a new analysis of a study funded by Procter & Gamble Pharmaceuticals, Nelson Watts, MD, professor of medicine at the University of Cincinnati (UC) and director of the UC Bone Health and Osteoporosis Center, has applied an innovative new method for analyzing fracture efficacy for an osteoporosis therapy in a study that was conducted without a placebo control group. The original study was intended to compare two different dose forms of Actonel (risedronate sodium tablets), a new 35 mg once a week dose to the 5 mg daily dose, for the treatment and prevention of osteoporosis in postmenopausal women, and thus did not have a placebo control group. Dr. Watts constructed a historical placebo control group from patients in previous Actonel trials to evaluate fracture reduction efficacy of Actonel 35 mg once-a-week. The use of a historical placebo control helps address ethical concerns associated with giving a placebo to clinical trial participants when proven treatments are available in a therapeutic area.

The data, which was presented at the 84th Annual Meeting of the Endocrine Society in San Francisco, represents the first published analysis of fracture reduction using historical placebo control with an osteoporosis therapy. The novel analysis suggests that once a week treatment with Actonel reduced the risk of new vertebral fractures at one year by 77 percent in postmenopausal women. As previously reported, once-a-week treatment with Actonel 35 mg has been found to increase bone mineral density similarly to Actonel 5 mg at one year. Actonel 35 mg once a week was recently approved by the FDA for the treatment and prevention of osteoporosis in postmenopausal women.

"Historical controls have been used in therapeutic areas such as oncology and surgery; however, we are only beginning to make use of this approach in osteoporosis studies," said Dr. Watts. Using statistical methodology, Dr. Watts and his colleagues matched placebo patients from previous Actonel clinical studies with patients from the once-a-week study, based on key baseline characteristics that contribute to fracture risk. Dr. Watts is an advocate for historical controls, because they eliminate some of the ethical dilemmas of using a placebo in clinical trials.

This analysis compared historical placebo control patients (n = 114) from the risedronate Phase III vertebral fracture studies with patients (n = 402) receiving once-a-week Actonel 35 mg. At one year, the relative risk of new vertebral fractures with Actonel 35 mg once-a-week treatment was 0.23 (95 percent confidence interval, 0.05 to 0.910; p-value = 0.018) compared to the historical placebo control.

According to the World Health Organization (WHO), osteoporosis is a significant and growing public health problem. The National Osteoporosis Foundation estimates that, in the United States, approximately 40 percent of women over 50 will experience a fracture due to osteoporosis in their lifetimes. Postmenopausal osteoporosis, caused by estrogen deficiency that typically occurs at menopause, is the most common form of osteoporosis.

"Fracture prevention is the primary goal of osteoporosis treatment and these data offer more support of the rapid and consistent fracture benefits demonstrated by treatment with Actonel," said Dr. Watts. "It is especially important to reduce the risk of fracture quickly, because one in five women who have experienced a vertebral fracture will fracture again within one year, potentially resulting in a cascade of spinal fractures."

About Actonel

Actonel is co-developed and co-marketed by Procter & Gamble Pharmaceuticals and Aventis Pharmaceuticals. 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).



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